CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser. No. 63/300,592, filed Jan. 18, 2022, U.S. Provisional Application Ser. No. 63/311,668, filed Feb. 18, 2022, U.S. Provisional Application Ser. No. 63/332,553, filed Apr. 19, 2022, U.S. Provisional Application Ser. No. 63/400,359, filed Aug. 23, 2022, and U.S. Provisional Application Ser. No. 63/422,341, filed Nov. 3, 2022, each of which is hereby incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Apolipoprotein L1 (APOL1) is a pore forming innate immunity factor, protecting individuals from trypanosome parasites (Vanhamme, L. et al. Nature (2003) 422, 83-87). The secreted form of APOL1 circulates in blood as part of distinct high-density lipoprotein (HDL) complexes, known as trypanosome lytic factors (TLFs) (Rifkin, M. R. Proc. Natl. Acad. Sci. USA. (1978) 75, 3450-3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910-1916). TLFs are internalized by the parasites through endocytosis (Hager, K. M. et al. J. Cell Biol. (1994) 126, 155-167). Within trypanosomes, APOL1 forms cation pores, causing ion flux, swelling, and eventual lysis (Rifkin, M. R. Exp. Parasitol. (1984) 58, 81-93; Molina-Portela, M. P. et al. Mol. Biochem. Parasitol. (2005) 144, 218-226; Pérez-Morga, D. et al. Science. (2005) 309, 469-472; Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA. (2015) 112, 2894-2899).

Several Trypanosoma brucei subspecies (T.b. rhodesiense and T.b. gambiense) developed resistance mechanisms to APOL1-dependent killing (Pays, E. et al. Nat. Rev. Microbiol. (2014) 12, 575-584). Positive selection resulted in APOL1 variants, G1 (S342G, 1384M) and G2 (N388Δ, Y389Δ), capable of interfering with these resistance mechanisms (Genovese, G. et al. Science. (2010) 329, 841-845). However, individuals with any binary combination of these variants (G1/G1, G2/G2, or G1/G2), have a greater risk of developing a variety of chronic kidney diseases, including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN) (Genovese, G. et al. Science. (2010) 329, 841-845; Tzur, S. et al. Hum. Genet. (2010) 128, 345-350; Kopp, J. B. et al. J. Am. Soc. Nephrol. (2011) 22, 2129-2137), sickle cell nephropathy (Ashley-Koch, A. E. et al. Br. J. Haematol. (2011) 155, 386-394), lupus nephritis (Freedman, B. I. et al. Arthritis Rheumatol. (2014) 66, 390-396), and an increased rate of Glomerular Filtration Rate (GFR) decline in diabetic kidney disease (Parsa, A. et al. N. Engl. J. Med. (2013) 369, 2183-2196). The APOL1 high-risk genotype has also been associated with COVID-19 associated nephropathy and other viral nephropathies (Shetty, A. et al. J. Am. Soc. Nephrol. (2021) 32, 33-40; Chang, J. H. et al. Am. J. Kidney Dis. (2019) 73, 134-139). Moreover, decreased renal allograft survival has been observed after deceased-donor kidney transplantations from APOL1 high-risk genotype donors (Freedman, B. I. et al. Transplantation. (2016) 100, 194-202). In addition, having two APOL1 risk alleles increases risk for preeclampsia (Reidy, K. J. et al. Am. J. Hum. Genet. (2018) 103, 367-376) and sepsis (Chaudhary, N. S. et al. Clin. J. Am. Soc. Nephrol. (2019) 14, 1733-1740). There are no approved therapies for APOL1-associated nephropathy, and patients are treated based on the standard of care for their underlying form of chronic kidney disease. This presents a clear unmet need for therapies targeted to people with the APOL1 high-risk genotype.

Numerous studies have shown that APOL1 risk variants are toxic when overexpressed in human cells (Wan, G. et al. J. Biol. Chem. (2008) 283, 21540-21549; Lan, X. et al. Am. J. Physiol. Renal Physiol. (2014) 307, F326-F336; Olabisi, O. A. et al. Proc. Natl. Acad. Sci. USA. (2016) 113, 830-837; Ma, L. et al. J. Am. Soc. Nephrol. (2017) 28, 1093-1105; Lannon, H. et al. Kidney Int. (2019) 96, 1303-1307). Recent findings suggest that this toxicity is associated with APOL1 pore function (Giovinazzo, J. A. et al. eLife. (2020) 9, e51185). Thus, there is a need to develop compounds suitable for inhibiting APOL1 activity and methods for inhibiting the activity of APOL1 using such compounds.

BRIEF SUMMARY OF THE INVENTION

This disclosure describes compounds and compositions that may be useful for the treatment of APOL1-mediated diseases, including a variety of chronic kidney diseases such as FSGS, hypertension-attributed kidney disease, HIVAN, sickle cell nephropathy, lupus nephritis, diabetic kidney disease, viral nephropathy, COVID-19 associated nephropathy, and APOL1-associated nephropathy. The compounds and compositions may treat other APOL1-mediated disorders such as preeclampsia and sepsis. Additionally, for individuals with the APOL1 high-risk genotype, the disclosed compounds and may prevent the onset of non-diabetic renal disease and/or delaying the progression of any form of chronic kidney disease. The disclosed chemical matter may also prevent and/or delay progressive renal allograft loss in patients who have received a kidney transplant from a high-risk APOL1 genotype donor.

In one aspect, provided is a compound of formula (II):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 10;

R¹, if present is, independently at each occurrence selected from the group consisting of halo, —CN, C_1-6alkoxy, and C_1-6alkyl, wherein

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more deuterium, halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein
- the C_1-6alkylene of L¹is optionally substituted with one or more deuterium or C_1-6alkyl, and
- wherein
  - the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
    
    L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and
    
    either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH or C_1-6alkyl,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH or C_1-6alkyl, wherein
  - the C_1-6alkyl is optionally substituted with one or more —OH, and
- the 3-10 membered heterocyclyl of L³is optionally substituted with one or more —OH or C_1-6alkyl;
  
  X¹and X²are each independently N or C(R⁵); and

R⁴is:

(i) —S(O)₂—R^a;

(ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;

(iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,

(iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl is optionally substituted with one or more —OH,

(v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein
- the 3-10 membered heterocycle of R^eis optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein
  - the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,

(vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a,

(vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),

(viii) —CN,

(ix) —(CH₂)_qOH, wherein q is an integer from 0-6,

(x) —C(O)—C_1-6alkyl, or

(xi) —P(O)(C_1-6alkyl)₂;

or

(2) L³is absent; and

one of X¹and X²is N or C(R⁵); and

the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
- the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein
  - R^bis, independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, and wherein
      - the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, and wherein
      - the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, deuterium, or halo, and
- the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein
  - R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl, and
    - the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl, and wherein
      - the C_1-6alkyl of the 3-10 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:

(i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,

(ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein
- the C_1-6alkyl is optionally substituted with one or more —OH,

(iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, or

(iv) NH(C_1-6alkyl);

R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein
- the C_1-6alkyl of R⁵is optionally substituted with one or more halo or —OH, and
- the C_1-6alkoxy of R⁵is optionally substituted with one or more halo;
  
  X³is N or C(R⁶)
  
  X⁴is N or C(R⁷);
  
  and
  
  R⁶and R⁷are each independently H or halo.

In one aspect, provided is a compound of formula (I′):

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
  
  L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-10cycloalkyl is optionally substituted with one or more —OH or C_1-6alkyl,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH or C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl is optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or
- 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo, or —S(O)₂R^a,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN,
  - (ix) —(CH₂)_qOH, wherein q is an integer from 0-6,
  - (x) —C(O)—C_1-6alkyl, or
  - (xi) —P(O)(C_1-6alkyl)₂;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴and the atoms to which they are attached to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, and
      - wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein
- R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
  - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
  - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl,
  - and the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl, and
    - wherein the C_1-6alkyl of the 3-10 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
      
      R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or

(iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;

R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo; and

R⁶and R⁷are each independently H or halo.

In one aspect, provided is a compound of formula (I):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 10;

R¹if present is, independently at each occurrence, selected from the group consisting of halo, —CN, C_1-6alkoxy or —C_1-6alkyl, wherein

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
  
  L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a,
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl,
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl or oxo,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl), or
  - (viii) —CN;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein
- R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
  - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and
  - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH;
    
    R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl, or
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo or —OH, and wherein the C_1-6alkoxy is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo.

Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

Any embodiments provided herein of a compound of formula (I) or (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-A):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is 1 or 2; and wherein m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷are as defined elsewhere herein. In another variation, m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷of formula (I-A) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-B):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, p, R¹, R², R³, L¹, L³, R⁴, R⁵, R⁶, and R⁷are as defined elsewhere herein. In another variation, m, p, R¹, R², R³, L¹, L³, R⁴, R⁵, R⁶, and R⁷of formula (I-B) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-C):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R¹, R², R³, L¹, L³, R⁴, and R⁵are as defined elsewhere herein. In another variation, m, p, R¹, R², R³, L¹, L³, R⁴, and R⁵of formula (I-C) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-D):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R¹, R², R³, L¹, L³, and R⁴are as defined elsewhere herein. In another variation, m, p, R¹, R², R³, L¹, L³, and R⁴of formula (I-D) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-E):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R¹, R², R³, L¹, X², R⁶, R⁷, and ring A are as defined elsewhere herein. In another variation, m, p, R¹, R², R³, L¹, X², R⁶, R⁷, and ring A of formula (I-E) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-F):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R¹, R², R³, L¹, R⁵, and ring A are as defined elsewhere herein. In another variation, m, p, R¹, R², R³, L¹, R⁵, and ring A of formula (I-F) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-G):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R¹, R², R³, L¹, and ring A are as defined elsewhere herein. In another variation, m, p, R¹, R², R³, L¹, and ring A of formula (I-G) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (II-A):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R¹, R², R³, L¹, X², X³, X⁴, and ring A are as defined elsewhere herein.

In one aspect, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (II), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising (i) a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a kit, comprising (i) a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. In another variation, provided herein is a kit, comprising (i) a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. In another variation, provided herein is a kit, comprising (i) a compound of formula (II), or any embodiment or variation thereof, such as a compound of (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

In some aspect, provided herein are methods of preparing a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In another variation, provided herein are methods of preparing a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In another variation, provided herein are methods of preparing a compound of formula (I′), or any embodiment or variation thereof, such as a compound of formula of (I), (I′), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

DETAILED DESCRIPTION OF THE INVENTION

Unless clearly indicated otherwise, the terms “a,” “an,” and the like, refer to one or more.

As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

“Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, some primates and humans. In some embodiments, individual refers to a human.

As used herein, an “at risk” individual is an individual who is at risk of developing a disease or condition. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).

“Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).

As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.

As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.

As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

The term “alkyl”, as used herein, refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C_1-20alkyl), 1-16 carbons (i.e., C_1-16alkyl), 1-12 carbons (i.e., C_1-12alkyl), 1-10 carbons (i.e., C_1-10alkyl), 1-8 carbons (i.e., C_1-8alkyl), 1-6 carbons (i.e., C_1-6alkyl), 1-4 carbons (i.e., C_1-4alkyl), or 1-3 carbons (i.e., C_1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso-propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”.

The term “alkoxy”, as used herein, refers to an —O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C_6-20aryl), 6 to 16 annular carbon atoms (i.e., C_6-12aryl), 6 to 12 annular carbon atoms (i.e., C_6-12aryl), or 6 to 10 annular carbon atoms (i.e., C_6-10aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C_3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C_3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C_3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C_3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C_3-6cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C_3-6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C_3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

The term “halo”, as used herein, refers to atoms occupying group VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzindolyl, benzofuranyl, benzonaphthofuranyl, benzoxazolyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, furanyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses —CH₃, —CH₂Cl, —CHCl₂, and —CCl₃moieties.

It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.

The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Such compositions are well known in the pharmaceutical art. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl), amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O ³¹P ³²P ³⁵S ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. In some embodiments, a compound of formula (I), or formula (I′) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.

Also provided herein are prodrugs of the compounds depicted herein, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vivo to release the parent drug compound. The development of prodrug compounds is well known in the pharmaceutical art. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat. Rev. Drug. Discov. 7, 255-270 (2008), which is incorporated herein by reference.

The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-(or as (D)- or (L)-for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,

[Image Omitted]

Where enantiomeric forms exist of a given structure, flat bonds and the presence of a “*” symbol indicate that the composition is made up of at least 90%, by weight, of a single isomer with unknown absolute stereochemistry, e.g.,

[Image Omitted]

Where enantiomeric and/or diastereomeric forms exist of a given structure with two or more stereocenters, flat bonds and the presence of two or more “*” symbols indicate the composition is made up of at least 90%, by weight, of a single enantiomer or diastereomer with unknown absolute stereochemistry, e.g.,

[Image Omitted]

Where enantiomeric and/or diastereomeric forms exist of a given structure, the composition is made up of at least 90%, by weight, dashes or wedges indicate a single enantiomer or diastereomer with known relative or absolute stereochemistry, e.g

[Image Omitted]

Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^thEd, hereby incorporated herein by reference in its entirety. The following examples are intended to be illustrative only and not limiting in any way.

° C.
degrees Celsius

μL
microliter

μW
microwave

[M + XX]⁺
observed mass

AC₅₀
half-maximal activity

concentration

Ac₂O
acetic anhydride

AIBN
azobisisobutyronitrile

app
apparent (NMR)

br
broad (NMR)

BH₃•THF
borane-tetrahydrofuran complex

BBr₃
boron tribromide

BnCl
benzyl chloride

B(Pin)₂
bis(pinacolato)diboron

Calc’d
calculated

Cbz-Cl
benzyl chloroformate

CCl₄
carbontetrachloride

CDI
carbonyldiimidazole

CHCl₃
chloroform

CO₂
carbon dioxide

CS₂CO₃
cesium carbonate

CuI
copper iodide

d
deuterated (NMR solvents)

d
doublet (NMR)

dd
doublet of doublets (NMR)

DAST
diethylaminosulfur trifluoride

DMA
N,N-dimethylacetamide

DCE
1,2-dichloroethane

DCM
dichloromethane

DIAD
diisopropyl azodicarboxylate

DIEA
N,N-diisopropylethylamine

DME
dimethoxyethane

DMEDA
N,N-dimethylethylenediamine

DMA
dimethylacetamide

DMF
N,N-dimethylformamide

DPPF
1,1′-

bis(diphenylphosphino)ferrocene

EC₅₀
half-maximal effective

concentration

EDCI
1-ethyl-3-(3-

dimethylamino-

propyl)carbodiimide

Et₃N
triethyl amine

EtOAc
ethyl acetate

EtOH
ethanol

g
grams

h
hours

H
hydrogen

H₂
hydrogen gas

H₂O
water

H₂O₂
hydrogen peroxide

HATU
N-[(Dimethylamino)-1H-1,2,3 -

triazolo-[4,5-b]pyridin-1-

ylmethylene]-N-

methylmethanaminium

hexafluorophosphate N-oxide

HCl
hydrochloric acid

HOBt
hydroxybenzotriazole

HPLC
high-performance liquid

chromatography

In vacuo
in a vacuum

(Ir[dF(CF₃)ppy]₂(dtbpy))PF₆
[4,4′-Bis(1,1-dimethylethyl)-

2,2′-bipyridine-N1,N1′]bis[3,5-

difluoro-2-[5-(trifluoromethyl)-

2-pyridinyl-N]phenyl-C]

Iridium(III)

hexafluorophosphate

IUPAC
International Union of Pure and

Applied Chemistry

J
J-coupling value (NMR)

K₂CO₃
potassium carbonate

KI
potassium iodide

KOAc
potassium acetate

KOH
potassium hydroxide

LiAlH₄
lithium aluminum hydride

LiHMDS
lithium bis(trimethylsilyl)amide

LiOH
lithium hydroxide

MeOH
methanol

MeCN
acetonitrile

MHz
megahertz

m
multiplet (NMR)

mg
milligrams

min
minutes

mL
milliliter

mmol
millimole

mM
millimolar

M
molarity or molar

m-CPBA
meta-chloroperoxybenzoic acid

MeCN
acetonitrile

MeSO₂Na
sodium methanesulfinate

MS
mass spectrometry

MsCl
methanesulfonyl chloride

Ms₂O
methanesulfonic anhydride

MTBE
methyl tert-butyl ether

n/a
not applicable

NaBH(OAc)₃
sodium triacetoxyborohydride

NaH
sodium hydride

NBS
N-bromosuccinimide

NH₄
ammonium

NH₄OH
ammonium hydroxide

NH₄HCO₃
ammonium bicarbonate

Na₂SO₄
sodium sulfate

NaBH₃CN
sodium cyanoborohydride

NMP
1-methyl-2-pyrrolidinone

NMR
nuclear magnetic resonance

NaIO₄
sodium periodate

NaOH
sodium hydroxide

OsO₄
osmium tetraoxide

Pd/C
palladium on carbon

PCy₃
tricyclohexylphosphine

Pd₂(dba)3
tris(dibenzylideneacetone)di-

palladium(0)

Pd(PPh₃)₂
bis(triphenylphosphine)pal-

ladium(II) chloride

Pd(dba)3
tris(dibenzylideneacetone)di-

palladium(0)

pH
potential of hydrogen

PPh₃
triphenyl phosphine

PSI
pounds per square inch

s
singlet (NMR)

SEMCl
(2-chloromethoxyethyl)tri-

methylsilane

SFC
super fluid chromatography

SOCl₂
thionyl chloride

t
triplet (NMR)

T3P
propanephosphonic acid

anhydride

TBAB
tetrabutylammonium bromide

TBAI
tetrabutylammonium iodide

TEA
triethylamine

TFA
trifluoroacetic acid

THF
tetrahydrofuran

TMSCl
trimethylsilyl chloride

Xantphos
4,5-bis(diphenylphosphino)-9,9-

dimethylxanthene

Zn(CN)₂
zinc cyanide

Compounds

Provided herein is a compound of formula (II):

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more deuterium, halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein
- the C_1-6alkylene of L¹is optionally substituted with one or more deuterium or C_1-6alkyl, and
- wherein
  - the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
    
    L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and
    
    either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH or C_1-6alkyl,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH or C_1-6alkyl, wherein
  - the C_1-6alkyl is optionally substituted with one or more —OH, and
- the 3-10 membered heterocyclyl of L³is optionally substituted with one or more —OH or C_1-6alkyl;
  
  X¹and X²are each independently N or C(R⁵); and

R⁴is:

(i) —S(O)₂—R^a;

(ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;

(iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,

(iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl is optionally substituted with one or more —OH,

(v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein
- the 3-10 membered heterocycle of R^eis optionally substituted with one or more oxo, or both
- R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein
  - the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,

(vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a,

(vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),

(viii) —CN,

(ix) —(CH₂)_qOH, wherein q is an integer from 0-6,

(x) —C(O)—C_1-6alkyl, or

(xi) —P(O)(C_1-6alkyl)₂;

or

(2) L³is absent; and

one of X¹and X²is N or C(R⁵); and

the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
- the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein
  - R^bis, independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, and wherein
      - the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, and wherein
      - the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, deuterium, or halo, and
- the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein
  - R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl, and
    - the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl, and wherein
      - the C_1-6alkyl of the 3-10 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:

(i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,

(ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH,

(iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, or

(iv) NH(C_1-6alkyl);

R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein
- the C_1-6alkyl of R⁵is optionally substituted with one or more halo or —OH, and
- the C_1-6alkoxy of R⁵is optionally substituted with one or more halo;
  
  X³is N or C(R⁶)
  
  X⁴is N or C(R⁷);
  
  and
  
  R⁶and R⁷are each independently H or halo.

Provided herein is a compound of formula (I′):

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
  
  L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and
  
  either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-10cycloalkyl is optionally substituted with one or more —OH or C_1-6alkyl,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH or C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl is optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN,
  - (ix) —(CH₂)_qOH, wherein q is an integer from 0-6,
  - (x) —C(O)—C_1-6alkyl, or
  - (xi) —P(O)(C_1-6alkyl)₂;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴and the atoms to which they are attached to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, and
      - wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl,
    - and the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the 3-10 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:

(i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,

(ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or

(iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;

R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo; and

R⁶and R⁷are each independently H or halo.

Provided herein is a compound of formula (I):

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
  
  L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and
  
  either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a,
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl,
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl or oxo,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl), or
  - (viii) —CN;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴and the atoms to which they are attached to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH;
      
      R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl, or
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo.

Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also embodiments of a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is an integer from 0 to 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH. In some embodiments, R²is H, C_1-3alkyl, C_3-6cycloalkyl, or 3-6 membered heterocyclyl, wherein the C_1-3alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-3alkoxy, and the C_3-6cycloalkyl of R²is optionally substituted with one or more —OH. In some embodiments, R²is selected from the group consisting of H,

[Image Omitted]

In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more deuterieum, halo, —OH, —NH₂, or C_1-6alkoxy, and the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH. In some embodiments, R²is H, C_1-3alkyl, C_3-6cycloalkyl, or 3-6 membered heterocyclyl, wherein the C_1-3alkyl of R²is optionally substituted with one or more deuterieum, halo, —OH, —NH₂, or C_1-3alkoxy, and the C_3-6cycloalkyl of R²is optionally substituted with one or more —OH. In some embodiments, R²is selected from the group consisting of H,

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl. In some embodiments, R²is C_1-3alkyl. In some embodiments R²is methyl or ethyl. In some embodiments, R²is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy. In some embodiments, R²is C_1-3alkyl optionally substituted with one or more halo, —OH, —NH₂, or C_1-3alkoxy. In some embodiments, R²is methyl. In some embodiments, R²is ethyl optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy. In some embodiments, R²is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl optionally substituted with one or more deuterium, halo, —OH, —NH₂, or C_1-6alkoxy. In some embodiments, R²is C_1-3alkyl optionally substituted with one or more deuterium, halo, —OH, —NH₂, or C_1-3alkoxy. In some embodiments, R²is methyl. In some embodiments, R²is ethyl optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy. In some embodiments, R²is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH. In some embodiments, R²is C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R²is optionally substituted with one or more —OH.

In some embodiments, R²is

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is 3-15 membered heterocyclyl. In some embodiments, R²is 3-6 membered heterocyclyl. In some embodiments, R²is

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0. In some embodiments m is 1. In some embodiments, m is 2. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo, —CN, C_1-6alkoxy or —C_1-6alkyl, wherein the C_1-6alkoxy or R¹is optionally substituted with one or more halo, and wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is halo, —CN, C_1-3alkoxy, or —C_1-3alkyl, wherein the C_1-3alkoxy of R¹is optionally substituted with one or more halo, and wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is selected from the group consisting of Cl, Br, —CN, methyl,

[Image Omitted]

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo, —CN, C_1-6alkoxy or —C_1-6alkyl, wherein the C_1-6alkoxy or R¹is optionally substituted with one or more halo, and wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is halo, —CN, C_1-3alkoxy, or —C_1-3alkyl, wherein the C_1-3alkoxy of R¹is optionally substituted with one or more halo, and wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is selected from the group consisting of Cl, Br, F, I, —CN, methyl,

[Image Omitted]

In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some embodiments, R¹is Br. In some embodiments, R¹is F. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some embodiments, R¹is Br. In some embodiments, R¹is F. In some embodiments R¹is I. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkyl, wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is methyl, wherein the methyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is methyl. In some embodiments, R¹is

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkoxy, wherein the C_1-6alkoxy of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-alkoxy, wherein the C_1-3alkoxy of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkoxy, wherein the C_1-3alkoxy of R¹is optionally substituted with one or more F. In some embodiments, R¹is methoxy, wherein the methoxy of R¹is optionally substituted with one or more F. In some embodiments, R¹is

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is an integer from 0 to 10. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R³is C_1-6alkyl. In some embodiments, R³is C_1-3alkyl. In some embodiments, R³is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring bearing (R¹)_mand R²is a 2-indolinone optionally substituted at one or more of positions 1, 5, and 7. In some embodiments, the 2-indolinone ring is unsubstituted. In some embodiments, the 2-indolinone ring is substituted at position 1. In some embodiments, the 2-indolinone ring is substituted at position 5. In some embodiments, the 2-indolinone ring is substituted at position 7. In some embodiments, the 2-indolinone ring is substituted at positions 1, and 5. In some embodiments, the 2-indolinone ring is substituted at positions 5 and 7. In some embodiments, the 2-indolinone ring is substituted at positions 1, 5, and 7. In some embodiments positions 1, 5 and 7 are defined as indicated in the structure,

[Image Omitted]

wherein position 1 is a N atom, each of positions 5 and 7 is a C atom, and ## represent the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

wherein ## represents the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring bearing (R¹)_mand R²is selected from the group consisting of

[Image Omitted]

wherein ## represents the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring bearing (R′)_mand R²is selected from the group consisting of

[Image Omitted]

wherein ## represents the point of attachment to the remainder of the molecule.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring bearing (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring bearing (R′)_m, R², and (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring bearing (R′)_m, R², and (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments, the ring bearing (R′)_m, R², and (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments, the ring bearing (R′)_m, R², and (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments, the ring bearing (R′)_m, R², and (R³)_pis

[Image Omitted]

In some embodiments, the ring bearing (R¹)_m, R², and (R³)_pis

[Image Omitted]

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the ring bearing (R′)_m, R², and (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments, the ring bearing (R¹)_m, R², and (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments, the ring bearing (R¹)_m, R², and (R³)_pis selected from the group consisting of

[Image Omitted]

In some embodiments, the ring bearing (R¹)_m, R², and (R³)_pis

[Image Omitted]

In some embodiments, the ring bearing (R¹)_m, R², and (R³)_pis

[Image Omitted]

In some embodiments, the ring bearing (R¹)_m, R², and (R)_pis

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene optionally substituted with one or more C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with —OH or C_1-6alkoxy. In some embodiments, L¹is C_1-3alkylene optionally substituted with one or more C_1-alkyl, wherein the C_1-3alkyl is optionally substituted with —OH or C_1-3alkoxy. In some embodiments, L¹is methylene. In some embodiments, L¹is ethylene. In some embodiments, L¹is ethylene optionally substituted with one or more C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH or C_1-3alkoxy. In some embodiments, L¹is selected from the group consisting of

[Image Omitted]

wherein, for each L¹, # denotes the point of attachment to L²and ## denotes the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene optionally substituted with one or more deuterieum, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with —OH or C_1-6alkoxy. In some embodiments, L¹is C_1-3alkylene optionally substituted with one or more deuterium, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with —OH or C_1-3alkoxy. In some embodiments, L¹is methylene. In some embodiments, L¹is ethylene. In some embodiments, L¹is ethylene optionally substituted with one or more deuterium, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH or C_1-3alkoxy. In some embodiments, L¹is selected from the group consisting of

[Image Omitted]

wherein, for each L¹, # denotes the point of attachment to L²and ## denotes the point of attachment to the remainder of the molecule.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L²is O or N(R^x), wherein R^xis H or C_1-6alkyl. In some embodiments, L²is O or N(R^x), wherein R^xis H or C_1-3alkyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L²is O. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH, and the 3-10 membered heterocyclyl of L³is optionally substituted with one or more —OH. In some embodiments, L³absent or is selected from the group consisting of O,

[Image Omitted]

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein the C_3-10cycloalkyl is optionally substituted with one or more —OH, or C_1-6alkyl, the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl, and the 3-10 membered heterocyclyl is optionally substituted with one or more —OH. In some embodiments, L³absent or is selected from the group consisting of O,

[Image Omitted]

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH, or C_1-6alkyl; the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl wherein the C_1-6alkyl is optionally substituted with one or more —OH; and the 3-10 membered heterocyclyl is optionally substituted with one or more —OH or C_1-6alkyl. In some embodiments, L³absent or is selected from the group consisting of O,

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is O. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_1-6alkylene. In some embodiments, L³is C_1-3alkylene. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_1-6alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, L³is C_1-3alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_1-6alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, L³is C_1-3alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is C_3-8cycloalkyl, wherein the C_3-8cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I′), (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is C_3-8cycloalkyl, wherein the C_3-8cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is 3-10 membered heterocyclyl. In some embodiments, L³is 3-6 membered heterocyclyl. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L3 is 3-10 membered heterocyclyl. In some embodiments, L³is 3-6 membered heterocyclyl. In some embodiments, L3 is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L3 is 3-10 membered heterocyclyl. In some embodiments, L³is 3-6 membered heterocyclyl. In some embodiments, L3 is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing R⁴is —S(O)₂—R^a, 5-20 membered heteroaryl, —N(R^d)₂, —NS(O)—(C_1-6alkyl)₂, —C(O)—N(R^e)₂, 3-10 membered heterocyclyl, —S(O)(N—C_1-6alkyl)-(C_1-6alkyl), or —CN. In some embodiments, R⁴is S(O)₂—R^a, 5-10 membered heteroaryl, —N(R^d)₂, —NS(O)—(C_1-3alkyl)₂, —C(O)—N(R^e)₂, 3-6 membered heterocyclyl, —S(O)(N-C_1-3alkyl)-(C_1-3alkyl), or —CN. In some embodiments, R⁴is selected from the group consisting of —NH₂, —CN, —C(O)—N(CH₃)₂,

[Image Omitted]

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing R⁴is —S(O)₂—R^a, 5-20 membered heteroaryl, —N(R^d)₂, —NS(O)—(C_1-6alkyl)₂, —C(O)—N(R^e)₂, 3-10 membered heterocyclyl, —S(O)—N(C_1-6alkyl)-(C_1-6alkyl), —CN, —(CH₂)_qOH, —C(O)—C_1-6alkyl, or —P(O)(C_1-6alkyl)₂. In some embodiments, R⁴is S(O)₂—R^a, 5-10 membered heteroaryl, —N(R^d)₂, —NS(O)—(C_1-3alkyl)₂, —C(O)—N(R^e)₂, 3-6 membered heterocyclyl, —S(O)(N—C_1-3alkyl)-(C_1-3alkyl), —CN, —OH, —CH₂OH, —C(O)—C_1-alkyl, or —P(O)(C_1-3alkyl)₂. In some embodiments, R⁴is selected from the group consisting of —NH₂, —CN, —OH, —CH₂H, —C(O)—N(CH₃)₂,

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In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-3alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-3alkyl, or —N(C_1-3alkyl)-C(O)—C_1-3alkyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_3-10cycloalkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_3-10cycloalkyl optionally substituted with one or more —OH, C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —C(O)—C_3-10heterocyclyl or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_3-6cycloalkyl optionally substituted with one or more —OH, C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_3-6cycloalkyl optionally substituted with one or more —OH, C(O)₂—C_1-3alkyl, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —C(O)—C_3-6heterocyclyl, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 5-20 membered heteroaryl. In some embodiments, R⁴is 5-20 membered heteroaryl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 5-6 membered heteroaryl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 5-6 membered heteroaryl optionally substituted with one or more C_1-3alkyl. In some embodiments, R⁴is 5-6 membered heteroaryl optionally substituted with one or more methyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH, and wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-3alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH, and wherein R^ais C_1-3alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH, and wherein R^ais methyl. In some embodiments, R⁴is selected from the group consisting of —NH₂,

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In some embodiments of a compound of formula (I), formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH, and wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-3alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH, and wherein R^ais C_1-3alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH, and wherein R^ais methyl. In some embodiments, R⁴is selected from the group consisting of —NH₂,

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-6alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-3alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or methyl. In some embodiments, R⁴is —C(O)—NH₂. In some embodiments, R⁴is —C(O)—NH(CH₃). In some embodiments, R⁴is —C(O)—N(CH₃)₂. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, —NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, —NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais methyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 3-10 membered heterocyclyl optionally substituted with one or more oxo or C_1-6alkyl. In some embodiments, R⁴is 3-7 membered heterocyclyl optionally substituted with one or more oxo or C_1-6alkyl. In some embodiments, R⁴is 3-7 membered heterocyclyl optionally substituted with one or more oxo or C_1-3alkyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a. In some embodiments, R⁴is 3-7 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a. In some embodiments, R⁴is 3-7 membered heterocyclyl optionally substituted with one or more C_1-3alkyl, —OH, oxo or —S(O)₂R^a. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a. In some embodiments, R⁴is 3-7 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a. In some embodiments, R⁴is 3-7 membered heterocyclyl optionally substituted with one or more C_1-3alkyl, —OH, oxo or —S(O)₂R^a. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —NS(O)—(C_1-6alkyl)₂. In some embodiments, R⁴is —NS(O)—(C_1-3alkyl)₂. In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)(N—C_1-6alkyl)-(C_1-6alkyl). In some embodiments, R⁴is —S(O)(N—C_1-3alkyl)-(C_1-3alkyl). In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —(CH₂)_qOH, wherein q is an integer from 0-6. R⁴is —(CH₂)_qOH, wherein q is an integer from 0-2. In some embodiments, R⁴is —OH. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—C_1-6alkyl. In some embodiments, R⁴is —C(O)—C_1-3alkyl. In some embodiments, R⁴is —C(O)CH₃. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —P(O)(C_1-6alkyl)₂. In some embodiments, R⁴is —P(O)(C_1-3alkyl)₂. In some embodiments, R⁴is —P(O)(CH₃)₂. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each of X¹and X²is independently N or C(R⁵). In some embodiments, each of X¹and X²is N. In some embodiments, each of X¹and X²is C(R⁵). In some embodiments, one of X¹and X²is CR⁵, and the other of X¹and X²is N. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl optionally substituted with one or more of R^b. In some embodiments, one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-8 membered heterocyclyl optionally substituted with one or more of R^b. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH. In some embodiments, R^bis halo, oxo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C_1-3alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-3alkyl, and the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH. In some embodiments, R^bis selected from the group consisting of oxo, —S(O)₂CH₃,

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH, and the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH. In some embodiments, R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C_1-3alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH, and the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, wherein the C_1-3alkyl of the C_3-6cycloalkyl of R^bis further optionally substituted with one or more —OH. In some embodiments, R^bis selected from the group consisting of oxo, —S(O)₂CH₃,

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In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis, independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH, and the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, deuterium, or halo. In some embodiments, R^bis, independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C_1-3alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH, and the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-alkyl, wherein the C_1-3alkyl of the C_3-6cycloalkyl of R^bis further optionally substituted with one or more —OH, deuterium or halo. In some embodiments, R^bis selected from the group consisting of —OH, oxo, —S(O)₂CH₃,

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis oxo. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_1-6alkyl. In some embodiments, R^bis C_1-6alkyl optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl. In some embodiments, R^bis C_1-3alkyl optionally substituted with one or more halo, OH, or —S(O)₂—C_1-3alkyl. In some embodiments, R^bis selected from the group consisting of

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_1-6alkyl. In some embodiments, the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH. In some embodiments, R^bis C_1-3alkyl optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH.

In some embodiments, R^bis selected from the group consisting of

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In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_1-6alkyl. In some embodiments, the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH. In some embodiments, R^bis C_1-3alkyl optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH. In some embodiments, R^bis selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis —C(O)—NH(C_1-6alkyl). In some embodiments, R^bis —C(O)—NH(C_1-3alkyl). In some embodiments, R^bis

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis —C(O)—C_1-6alkyl. In some embodiments, R^bis —C(O)—C_1-3alkyl. In some embodiments, R^bis

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing R^bis —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R^bis —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R^bis —S(O)₂—R^a, R^ais methyl. In some embodiments, R^bis —S(O)₂CH₃. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_3-10cycloalkyl optionally substituted with one or more —OH. In some embodiments, R^bis C_3-6cycloalkyl optionally substituted with one or more —OH. In some embodiments, R^bis

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_3-10cycloalkyl optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl is further optionally substituted with one or more —OH. In some embodiments, R^bis C_3-6cycloalkyl optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, wherein the C_1-3alkyl is further optionally substituted with one or more —OH. In some embodiments, R^bis selected from the group consisting of

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In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_3-10cycloalkyl optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl is further optionally substituted with one or more —OH, deuterium, or halo. In some embodiments, R^bis C_3-6cycloalkyl optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, wherein the C_1-3alkyl is further optionally substituted with one or more —OH, deuterium, or halo. In some embodiments, R^bis selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis 3-10 membered heterocyclyl. In some embodiments, R^bis 3-6 membered heterocyclyl. In some embodiments, R^bis

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heteroaryl. In some embodiments, one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-6 membered heteroaryl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heteroaryl optionally substituted with one or more R^c. In some embodiments one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-6 membered heteroaryl optionally substituted with one or more R^c. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH. In some embodiments, R^cis halo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-3alkyl, and the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH. In some embodiments, R^cis selected from the group consisting of methyl, isopropyl, —S(O)₂CH₃, and

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl, and the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl, wherein the C_1-6alkyl is further optionally substituted with one or more —OH. In some embodiments, R^cis independently at each occurrence, selected from the group consisting of halo, C_1-3alkyl, —C(O)—C_1-alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein the C_1-3alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-3alkyl, the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-alkyl, and the 3-6 membered heterocyclyl of R^cis optionally substituted with one or more —OH, or C_1-3alkyl, wherein the C_1-3alkyl is further optionally substituted with one or more —OH. In some embodiments, R^cis selected from the group consisting of methyl, isopropyl, —S(O)₂CH₃, and

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis C_1-6alkyl, —S(O)₂—R^a. In some embodiments, R^cis C_1-3alkyl. In some embodiments, R^cis methyl. In some embodiments, R^cis isopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis C_1-6alkyl optionally substituted with one or more —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R^cis C_1-alkyl optionally substituted with one or more —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R^cis C_1-3alkyl optionally substituted with one or more —S(O)₂—R^a, wherein R^ais methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis C_3-10cycloalkyl optionally substituted with one or more —OH. In some embodiments, R^cis C_3-6cycloalkyl optionally substituted with one or more —OH. In some embodiments, R^cis

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis C_3-10cycloalkyl optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, R^cis C_3-6cycloalkyl optionally substituted with one or more —OH, or C_1-3alkyl. In some embodiments, R^cis selected from the group consisting of

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis 3-10 membered heterocyclyl optionally substituted with one or more —OH, or C_1-6alkyl, wherein the C_1-6alkyl is further optionally substituted with one or more —OH. In some embodiments, R^cis 3-6 membered heterocyclyl optionally substituted with one or more —OH, or C_1-3alkyl, wherein the C_1-3alkyl is further optionally substituted with one or more —OH. In some embodiments, R^cis selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo. In some embodiments, R⁵is independently at each occurrence, H, halo, —CN, 3-6 membered heterocyclyl, C_1-3alkyl, or C_1-3alkoxy, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-3alkoxy is optionally substituted with one or more halo. In some embodiments, R⁵is selected from the group consisting of H, Cl, F, —CN,

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is halo. In some embodiments, R⁵is Cl, or F. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is C_1-6alkyl. In some embodiments, R⁵is C_1-3alkyl. In some embodiments, R⁵is methyl. In some embodiments, R⁵is C_1-6alkyl, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more halo, or —OH. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more fluoro, or —OH. In some embodiments, R⁵is independently selected from the group consisting of methyl,

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is 3-10 membered heterocyclyl. In some embodiments, R⁵is 3-6 membered heterocyclyl. In some embodiments, R⁵is

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is C_1-6alkoxy optionally substituted with one or more halo. In some embodiments, R⁵is C_1-3alkoxy optionally substituted with one or more halo. In some embodiments, R⁵is C_1-3alkoxy optionally substituted with one or more fluoro. In some embodiments, R⁵is

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁶and R⁷are each independently H or halo. In some embodiments, R⁶and R⁷are each independently H or fluoro. In some embodiments, each of R⁶and R⁷is H. In some embodiments, each of R⁶and R⁷is fluoro. In some embodiments, one of R⁶and R⁷is H and the other of R⁶and R⁷is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted phenyl with one group bound at the para position relative to the phenyl's attachment to L². In some embodiments, the bi-substituted phenyl is selected from the group consisting of

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted phenyl with one group bound at the para position relative to the phenyl's attachment to L². In some embodiments, the bi-substituted phenyl is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted phenyl with one group bound at the para position relative to the phenyl's attachment to L². In some embodiments, the bi-substituted phenyl is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a tri-substituted phenyl with two groups bound at a meta, and the para positions relative to the phenyl's attachment to L². In some embodiments, the tri-substituted phenyl is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a tri-substituted phenyl with two groups bound at a meta, and the para positions relative to the phenyl's attachment to L². In some embodiments, the tri-substituted phenyl is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a tetra-substituted phenyl with three groups bound at the meta, and para positions relative to the phenyl's attachment to L². In some embodiments, the tetra-substituted phenyl is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted pyridine with one group bound at the para position relative to the pyridine's attachment to L². In some embodiments, the bi-substituted pyridine is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a tri-substituted pyridine with two groups bound at the meta, and para positions relative to the pyridine's attachment to L². In some embodiments, the tri-substituted pyridine is

[Image Omitted]

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a tri-substituted pyridine with two groups bound at the meta, and para positions relative to the pyridine's attachment to L². In some embodiments, the tri-substituted pyridine is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a tri-substituted pyridine with two groups bound at the meta, and para positions relative to the pyridine's attachment to L². In some embodiments, the tri-substituted pyridine is selected from the group consisting of

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted pyrimidine with two groups bound at the para position relative to the pyrimidine's attachment to L². In some embodiments, the bi-substituted pyrimidine is selected from the group consisting of

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In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted pyrimidine with two groups bound at the para position relative to the pyrimidine's attachment to L². In some embodiments, the bi-substituted pyrimidine is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted pyrimidine with two groups bound at the para position relative to the pyrimidine's attachment to L². In some embodiments, the bi-substituted pyrimidine is selected from the group consisting of

[Image Omitted]

In some embodiments, the bi-substituted pyrimidine is selected from the group consisting of

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In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a bi-substituted pyrimidine with two groups bound at the para position relative to the pyrimidine's attachment to L². In some embodiments, the bi-substituted pyrimidine is selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L2, and the ring bearing L³, R⁴, R⁶, and R⁷together form a heteroaryl selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heteroaryl selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heteroaryl selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form

[Image Omitted]

In some variations, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heterocycle selected from the group consisting of

[Image Omitted]

In certain variations, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form

[Image Omitted]

In certain variations, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form

[Image Omitted]

In certain variations, L¹, L², and the ring bearing L³, and R⁴together form

[Image Omitted]

In certain variations, L¹, L², and the ring bearing L³, and R⁴together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and R⁷together form a heteroaryl selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing L³, R⁴, R⁶, and together form a heteroaryl selected from the group consisting of

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing R⁶, and R⁷together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing R⁶, and R⁷together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing R⁶, and R⁷together form

[Image Omitted]

In some embodiments, L¹, L², and the ring bearing R⁶, and R⁷together

[Image Omitted]

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is 1 or 2, and L²is —O—. In some embodiments, n is 2, and L²is —O—. In some embodiments, n is 1, and L²is 0. In some embodiments, n is 1 or 2, L²is —O— and R⁴is —S(O)₂—R^a. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is 1, p is 0, L²is 0 and each of X¹and X²is C(R⁵), wherein each R⁵is independently H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH, and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo. In some embodiments, n is 1, p is 0, L²is 0 and each of X¹and X²is C(R⁵), wherein each R⁵is independently H. In some embodiments, n is 1, p is 0, L²is 0 and each of X¹and X²is C(R⁵), wherein one of R⁵is H and the other of R⁵is halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH, and wherein the C_1-6alkoxy is optionally substituted with one or more halo. In some embodiments, n is 1, p is 0, L²is 0 and each of X¹and X²is C(R⁵), wherein each R⁵is independently halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH, and wherein the C_1-6alkoxy is optionally substituted with one or more halo. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is 1, p is 0, L²is 0, one of X¹and X²is N, and the other of X¹and X²is C(R⁵), wherein R⁵is H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH, and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo. In some embodiments, n is 1, p is 0, L²is 0, one of X¹and X²is N, and the other of X¹and X²is C(R⁵), wherein R⁵is H. In some embodiments, n is 1, p is 0, L²is 0, one of X¹and X²is N, and the other of X¹and X²is C(R⁵), wherein R⁵is halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH, and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is 1, L²is O, and each of X¹and X²is N. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is 1, p is 0, L²is 0, one of X¹and X²is C(R⁵), wherein R⁵is H, the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, and each of R⁶and R⁷is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is 1, L²is 0, one of X¹and X²is C(R⁵), wherein R⁵is H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH, and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo, the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, and each of R⁶and R⁷is H. In some embodiments, n is 1, L²is 0, one of X¹and X²is C(R⁵), wherein R⁵is H, the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, and each of R⁶and R⁷is H. In some embodiments, n is 1, L²is 0, one of X¹and X²is C(R⁵), wherein R⁵is halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH, and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo, the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, and each of R⁶and R⁷is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, n is 1, p is 0, L²is 0, one of X¹and X²is N, the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form (i) a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, or (ii) a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, and each of R⁶and R⁷is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing:

m is an integer from 0 to 2;

n is an integer from 1 to 2;

p is an integer from 0 to 2;

R¹, if present is, independently at each occurrence selected from the group consisting of halo, —CN, C_1-3alkoxy, or C_1-3alkyl, wherein

- the C_1-3alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-3alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-3alkyl, C_3-6cycloalkyl, or 3-10 membered heterocyclyl, wherein
- the C_1-3alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-3alkoxy, and
- the C_3-6cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-3alkyl;
  
  L¹is C_1-3alkylene, wherein the C_1-3alkylene of L¹is optionally substituted with one or more C_1-alkyl, and wherein the C_1-3alkyl is further optionally substituted with one or more —OH or C_1-alkoxy;
  
  L²is O or N(R^x), wherein R^xis H or C_1-3alkyl; and either

(1) L³is absent or is O, C_3-6cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-6cycloalkyl is optionally substituted with one or more —OH, or C_1-3alkyl,
- the C_1-3alkylene of L³is optionally substituted with one or more —OH or C_1-3alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or —C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R⁴is optionally substituted with one or more C_1-3alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-3alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-3alkyl)₂, wherein the C_1-3alkyl is optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-3alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-alkyl, —OH, oxo or —S(O)₂R^a,
  - (vii) —S(O)—N(C_1-3alkyl)-(C_1-3alkyl),
  - (viii) —CN, (ix) —(CH₂)_qOH, wherein q is an integer from 0-4,
  - (x) —C(O)—C_1-3alkyl, or
  - (xi) —P(O)(C_1-3alkyl)₂;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴and the atoms to which they are attached to form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein
    - the C_1-3alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, and
      - wherein the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH and
    - the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, and
      - wherein the C_1-3alkyl of the C_3-6cycloalkyl of R^bis further optionally substituted with one or more —OH, and
  - the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein
    - the C_1-3alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
    - the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-6alkyl,
    - and the 3-6 membered heterocyclyl of R^cis optionally substituted with one or more —OH or C_1-3alkyl, and
      - wherein the C_1-3alkyl of the 3-6 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:
- (i) C_1-3alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-3alkyl, or —N(C_1-3alkyl)-C(O)—C_1-3alkyl,
- (ii) C_3-6cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-3alkyl, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, or —C(O)—C_3-6heterocyclyl, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH, or
- (iii) 3-6 membered heterocyclyl optionally substituted with one or more C_1-3alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-6 membered heterocyclyl, C_1-3alkyl, or C_1-alkoxy, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more halo or —OH, and wherein the C_1-3alkoxy of R⁵is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing:

m is an integer from 0 to 2;

n is an integer from 1 to 2;

p is an integer from 0 to 1;

R¹, if present is, independently at each occurrence selected from the group consisting of Cl, Br, F, I, —CN, C_1-3alkoxy, or C_1-3alkyl, wherein

- the C_1-3alkoxy of R¹is optionally substituted with one or more F, and
- the C_1-3alkyl of R¹is optionally substituted with one or more F;
  
  R²is H, C_1-3alkyl, C_3-4cycloalkyl, or 3-4 membered heterocyclyl, wherein
- the C_1-3alkyl of R²is optionally substituted with one or more F, —OH, —NH₂, or —OCH₃, and
- the C_3-4cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-3alkyl;
  
  L¹is C_1-3alkylene, wherein the C₁₃alkylene of L¹is optionally substituted with one or more methyl, and wherein the methyl is further optionally substituted with one or more —OH or —OCH₃;

L²is O; and

either

(1) L³is absent or is O, C_3-4cycloalkyl, 3-7 membered heterocyclyl, or C_1-4alkylene, wherein
- the C_3-4cycloalkyl is optionally substituted with one or more —OH, or —CH₃,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH, —CH₃, and
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of R⁴is optionally substituted with one or more —CH₃;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-3alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(CH₃)₂
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, CH₃, or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more F, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-7 membered heterocyclyl optionally substituted with one or more C_1-3alkyl, —OH, oxo or —S(O)₂R^a,
  - (vii) —S(O)—N(CH₃)—(CH₃),
  - (viii) —CN,
  - (ix) —(CH₂)_qOH, wherein q is an integer from 0-2, or
  - (x) —C(O)—CH₃, or
  - (xi) —P(O)(CH₃)₂;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴and the atoms to which they are attached to form a 5-8 membered heterocyclyl or a 5-6 membered heteroaryl, wherein
  - the 5-8 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of oxo, C_1-3alkyl, —C(O)—CH₃, —C(O)—NH₂, —C(O)—NH(CH₃), —C(O)—N(CH₃)₂, —S(O)₂—R^a, C_3-4cycloalkyl, and 3-4 membered heterocyclyl, wherein
    - the C_1-3alkyl of R^bis optionally substituted with one or more F, OH, —S(O)₂—CH₃, or C_3-4cycloalkyl, and
      - wherein the C_3-4cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more CH₃or —OH and
    - the C_3-4cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-4cycloalkyl, or C_1-3alkyl, and
      - wherein the C_1-3alkyl of the C_3-4cycloalkyl of R^bis further optionally substituted with one or more —OH, and
  - the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of C_1-3alkyl, —S(O)₂—R^a, C_3-4cycloalkyl, and 3-4 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—CH₃
    - the C_3-4cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-alkyl,
    - and the 3-4 membered heterocyclyl of R^cis optionally substituted with one or more —OH or methyl, and
      - wherein the methyl of the 3-4 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:
- (i) C_1-3alkyl optionally substituted with one or more F, —OH, —S(O)₂—CH₃, or —N(CH₃)—C(O)—CH₃,
- (ii) C_3-4cycloalkyl optionally substituted with one or more —OH, —C(O)₂—CH₃, —C(O)—NH(CH₃), —C(O)—N(CH₃)₂, or —C(O)—C_3-4heterocyclyl, or methyl, wherein the methyl is optionally substituted with one or more —OH, or
- (iii) 3-4 membered heterocyclyl optionally substituted with one or more methyl;
  
  R⁵is, independently at each occurrence, H, Cl, F, —CN, 3-4 membered heterocyclyl, C_1-3alkyl, or C_1-alkoxy, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more F or —OH and wherein the C_1-3alkoxy of R⁵is optionally substituted with one or more F; and
  
  R⁶and R⁷are each independently H or F. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

m is an integer from 0 to 2;

n is an integer from 1 to 2;

p is an integer from 0 to 1;

R¹, if present is, independently at each occurrence selected from the group consisting of halo, —CN, C_1-3alkoxy, and C_1-3alkyl, wherein

- the C_1-3alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-3alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-3alkyl, C_3-6cycloalkyl, or 3-6 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more deuterium, halo, —OH, —NH₂, or C_1-3alkoxy, and
- the C_3-6cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-3alkyl;
  
  L¹is C_1-3alkylene, wherein
- the C_1-6alkylene of L¹is optionally substituted with one or more deuterium or C_1-3alkyl, and wherein
  - the C_1-3alkyl is further optionally substituted with one or more —OH or C_1-3alkoxy;

L²is O; and

either

(1) L³is absent or is O, C_3-6cycloalkyl, 3-6 membered heterocyclyl, or C_1-3alkylene, wherein
- the C_3-6cycloalkyl of L³is optionally substituted with one or more —OH or C_1-3alkyl,
- the C_1-3alkylene of L³is optionally substituted with one or more —OH or C_1-3alkyl, wherein
  - the C_1-3alkyl is optionally substituted with one or more —OH, and the 3-6 membered heterocyclyl of L³is optionally substituted with one or more —OH or C_1-alkyl;
    
    X¹and X²are each independently N or C(R⁵); and

R⁴is:

(i) —S(O)₂—R^a;

(ii) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R⁴is optionally substituted with one or more C_1-3alkyl;

(iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-3alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH,

(iv) —NS(O)—(C_1-3alkyl)₂, wherein the C_1-3alkyl is optionally substituted with one or more —OH,

(v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-3alkyl, or 3-6 membered heterocycle, wherein
- the 3-6 membered heterocycle of R^eis optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-6 membered heterocyclyl, wherein
  - the 3-6 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,

(vi) 3-6 membered heterocyclyl optionally substituted with one or more C_1-3alkyl, —OH, oxo or —S(O)₂R^a,

(vii) —S(O)—N(C_1-3alkyl)-(C_1-3alkyl),

(viii) —CN, (ix) —(CH₂)_qOH, wherein q is an integer from 0-3,

(x) —C(O)—C_1-3alkyl, or

(xi) —P(O)(C_1-3alkyl)₂;

or

(2) L³is absent; and

one of X¹and X²is N or C(R⁵); and

the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-8 membered heterocyclyl or a 5-10 membered heteroaryl, wherein
- the 5-8 membered heterocyclyl is optionally substituted with one or more R^b, wherein
  - R^bis, independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein
    - the C_1-3alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, and wherein
      - the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH and
    - the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, and wherein
      - the C_1-3alkyl of the C_3-6cycloalkyl of R^bis further optionally substituted with one or more —OH, deuterium, or halo, and
- the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein
  - R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein
    - the C_1-3alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-3alkyl,
    - the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-alkyl, and
    - the 3-6 membered heterocyclyl of R^cis optionally substituted with one or more —OH or C_1-3alkyl, and wherein
      - the C_1-3alkyl of the 3-6 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:

(i) C_1-3alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-3alkyl, or —N(C_1-3alkyl)-C(O)—C_1-3alkyl,

(ii) C_3-6cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-3alkyl, —C(O)—NH(C_1-alkyl), —C(O)—N(C_1-3alkyl)₂, or —C(O)—C_3-6heterocyclyl, or C_1-3alkyl, wherein
- the C_1-3alkyl is optionally substituted with one or more —OH,

(iii) 3-6 membered heterocyclyl optionally substituted with one or more C_1-3alkyl, or

(iv) NH(C_1-3alkyl);

R⁵is, independently at each occurrence, H, halo, —CN, 3-6 membered heterocyclyl, C_1-3alkyl, or C_1-alkoxy, wherein
- the C_1-3alkyl of R⁵is optionally substituted with one or more halo or —OH, and
- the C_1-3alkoxy of R⁵is optionally substituted with one or more halo;
  
  X³is N or C(R⁶)
  
  X⁴is N or C(R⁷);
  
  and
  
  R⁶and R⁷are each independently H or halo.

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

m is an integer from 0 to 2;

n is 1;

p is an integer from 0;

R¹, if present is, independently at each occurrence selected from the group consisting of halo, —CN, C_1-3alkoxy, and C_1-3alkyl, wherein

- the C_1-3alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-3alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-3alkyl, C_3-6cycloalkyl, or 3-6 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more deuterium, halo, —OH, —NH₂, or C_1-3alkoxy, and
- the C_3-6cycloalkyl of R²is optionally substituted with one or more —OH;
  
  L¹is C_1-3alkylene, wherein
- the C_1-6alkylene of L¹is optionally substituted with one or more deuterium;

L²is O; and

either

(1) L³is absent or is O, C_3-6cycloalkyl, 3-6 membered heterocyclyl, or C_1-3alkylene, wherein
- the C_3-6cycloalkyl of L³is optionally substituted with one or more —OH or C_1-3alkyl,
- the C_1-3alkylene of L³is optionally substituted with one or more —OH or C_1-3alkyl, wherein
  - the C_1-3alkyl is optionally substituted with one or more —OH, and
- the 3-6 membered heterocyclyl of L³is optionally substituted with one or more —OH or C_1-alkyl;
  
  X¹and X²are each independently N or C(R⁵); and

R⁴is:

(i) —S(O)₂—R^a;

(ii) 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R⁴is optionally substituted with one or more C_1-3alkyl;

(iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-3alkyl, or —S(O)₂—R^a, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH,

(iv) —NS(O)—(C_1-3alkyl)₂, wherein the C_1-3alkyl is optionally substituted with one or more —OH,

(v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-3alkyl, or 3-6 membered heterocycle, wherein
- the 3-6 membered heterocycle of R^eis optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-6 membered heterocyclyl, wherein
  - the 3-6 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,

(vi) 3-6 membered heterocyclyl optionally substituted with one or more C_1-3alkyl, —OH, oxo or —S(O)₂R^a,

(ix) —(CH₂)_qOH, wherein q is an integer from 0-3;

or

(2) L³is absent; and

one of X¹and X²is N or C(R⁵); and

the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-8 membered heterocyclyl or a 5-10 membered heteroaryl, wherein
- the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein
  - R^bis, independently at each occurrence, selected from the group consisting of —OH, halo, oxo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein
    - the C_1-3alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, and wherein
      - the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH and
    - the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, and wherein
      - the C_1-3alkyl of the C_3-6cycloalkyl of R^bis further optionally substituted with one or more —OH, deuterium, or halo, and
- the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein
  - R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-3alkyl, —C(O)—C_1-3alkyl, —C(O)—NH₂, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —S(O)₂—R^a, C_3-6cycloalkyl, and 3-6 membered heterocyclyl, wherein
    - the C_1-3alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-3alkyl,
    - the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-alkyl, and
    - the 3-6 membered heterocyclyl of R^cis optionally substituted with one or more —OH or C_1-3alkyl, and wherein
      - the C_1-3alkyl of the 3-6 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:

(i) C_1-3alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-3alkyl, or —N(C_1-3alkyl)-C(O)—C_1-3alkyl,

(ii) C_3-6cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-3alkyl, —C(O)—NH(C_1-alkyl), —C(O)—N(C_1-3alkyl)₂, or —C(O)—C_3-6heterocyclyl, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH,

(iii) 3-6 membered heterocyclyl optionally substituted with one or more C_1-3alkyl, or

(iv) NH(C_1-3alkyl);

R⁵is, independently at each occurrence, H, halo, —CN, 3-6 membered heterocyclyl, C_1-3alkyl, or C_1-alkoxy, wherein
- the C_1-3alkyl of R⁵is optionally substituted with one or more halo or —OH, and
- the C_1-3alkoxy of R⁵is optionally substituted with one or more halo;
  
  X³is N or C(R⁶)
  
  X⁴is N or C(R⁷);
  
  and
  
  R⁶and R⁷are each independently H or halo.

In some embodiments of a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

- the C_1-3alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-3alkyl of R¹is optionally substituted with one or more halo;

R²is H;

L¹is C_1-3alkylene, wherein

- the C_1-6alkylene of L¹is optionally substituted with one or more deuterium;

L²is O; and

either

(1) L³is absent or is C_1-3alkylene, wherein
- the C_1-3alkylene of L³is optionally substituted with one or more —OH or C_1-3alkyl;
  
  X¹and X²are each independently N or C(R⁵); and

R⁴is:

(i) —S(O)₂—R^a;

(ii) —(CH₂)_qOH, wherein q is an integer from 0-3;

or

(2) L³is absent; and

one of X¹and X²is N or C(R⁵); and

the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-8 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
- the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein
  - R^bis, independently at each occurrence oxo, or C_3-6cycloalkyl, wherein the C_3-6cycloalkyl is optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-alkyl, and
- the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein
  - R^cis, independently at each occurrence, selected from the group consisting of C_1-3alkyl, C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH or C_1-3alkyl;
    
    R^ais, independently at each occurrence:

(i) C_1-3alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-3alkyl, or —N(C_1-3alkyl)-C(O)—C_1-3alkyl;

R⁵is, independently at each occurrence, H, halo, C_1-3alkyl, or C_1-3alkoxy, wherein
- the C_1-3alkyl of R⁵is optionally substituted with one or more halo or —OH, and
- the C_1-3alkoxy of R⁵is optionally substituted with one or more halo;
  
  X³is N or C(R⁶)
  
  X⁴is N or C(R⁷);
  
  and
  
  R⁶and R⁷are each independently H or halo.

In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A):

[Image Omitted]

- or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is 1 or 2; and m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷are as defined for formula (I). In some variations m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷of formula (I-A) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided herein is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A1):

[Image Omitted]

- or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷are as defined for formula (I). In some variations m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷of formula (I-A1) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is an integer from 0 to 10. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene. In some embodiments, L¹is C_1-3alkylene. In some embodiments, L¹is ethylene. In some embodiments, L¹is

[Image Omitted]

wherein, # denotes the point of attachment to —O— and ## denotes the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais methyl. In some embodiments, R⁴

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each of X¹and X²is C(R⁵). In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each of R⁶and R⁷is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷are as defined for formula (I). In some variations, m, p, R¹, R², R³, L¹, L³, R⁴, X¹, X², R⁶, and R⁷of formula (I-A2) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: n is 1 or 2; and wherein m, n, p, R¹, R², R³, L¹, X¹, X², R⁶, R⁷, and R^aare as defined for formula (I). In some variations, m, n, p, R¹, R², R³, L¹, X¹, X², R⁶, R⁷, and R^aof formula (I-A3) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided herein is a compound of formula (I), (I-A), or (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-B):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, p, R¹, R², R³, L¹, L³, R⁴, R⁵, R⁶, and R⁷are as defined for formula (I). In some variations, m, p, R¹, R², R³, L¹, L³, R⁴, R⁵, R⁶, and R⁷of formula (I-B) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided herein is a compound of formula (I), (I-A), (I-A2), or (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-B1):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, R¹, R², L¹, L³, R⁴, R⁶, and R⁷are as defined for formula (I). In some variations, m, R¹, R², L¹, L³, R⁴, R⁶, and R⁷of formula (I-B1) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl. In some embodiments, R²is C_1-3alkyl. In some embodiments, R²is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl optionally substituted with one or more halo, —OH, or C_1-6alkoxy. In some embodiments, R²is C_1-3alkyl optionally substituted with one or more halo, —OH, or C_1-3alkoxy. In some embodiments, R²is ethyl optionally substituted with one or more halo, —OH, NH₂, or C_1-3alkoxy. In some embodiments, R²is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), such as a compound of formula (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl optionally substituted with one or more deuterium, halo, —OH, or C_1-6alkoxy. In some embodiments, R²is C_1-3alkyl optionally substituted with one or more deuterium, halo, —OH, or C_1-3alkoxy. In some embodiments, R²is methyl optionally substituted with one or more deuterium halo, —OH, NH₂, or C_1-3alkoxy. In some embodiments, R²is ethyl optionally substituted with one or more deuterium halo, —OH, NH₂, or C_1-3alkoxy. In some embodiments, R²is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_3-10cycloalkyl optionally substituted with one or more —OH. In some embodiments, R²is C_3-6cycloalkyl optionally substituted with one or more —OH. In some embodiments, R²is

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0. In some embodiments m is 1. In some embodiments, m is 2. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some embodiments, R¹is Br. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkyl. In some embodiments, R¹is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkyl, wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is methyl, wherein the methyl of R¹is optionally substituted with one or more F. In some embodiments. R¹is

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is an integer from 0 to 10. In some embodiments, p is 0. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl. In some embodiments, L¹is C_1-3alkylene optionally substituted with one or more C_1-3alkyl. In some embodiments, L¹is ethylene optionally substituted with one or more C_1-6alkyl. In some embodiments, L¹is selected from the group consisting of

[Image Omitted]

wherein, for each L¹, # denotes the point of attachment to —O— and ## denotes the point of attachment to the remainder of the molecule. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is C_3-8cycloalkyl, wherein the C_3-6cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some variations, the embodiments provided herein also apply to a compound of formula (I′) or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is 3-10 membered heterocyclyl. In some embodiments, L³is 3-6 membered heterocyclyl. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), such as a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is 3-10 membered heterocyclyl. In some embodiments, L³is 3-6 membered heterocyclyl. In some embodiments, L³is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl, wherein the C_1-6alkyl of R^ais optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-3alkyl, wherein the C_1-3alkyl of R^ais optionally substituted with one or more halo, —OH, —S(O)₂—C_1-3alkyl, or —N(C_1-3alkyl)-C(O)—C_1-3alkyl. In some embodiments, R⁴is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), such as a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B 1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_3-10cycloalkyl. R⁴is —S(O)₂—R^a, wherein R^ais C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R^ais optionally substituted with one or more —OH, C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —C(O)—C_3-10heterocyclyl or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^ais optionally substituted with one or more —OH, C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^ais optionally substituted with one or more —OH, C(O)₂—C_1-3alkyl, —C(O)—NH(C_1-3alkyl), —C(O)—N(C_1-3alkyl)₂, —C(O)—C_3-6heterocyclyl, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais 3-10 membered heterocyclyl. In some embodiments R⁴is —S(O)₂—R^a, wherein R^ais 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of R^ais optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R^ais optionally substituted with one or more C_1-6alkyl. In some embodiments, wherein R⁴is —S(O)₂—R^a, wherein R^ais 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R^ais optionally substituted with one or more C_1-3alkyl. In some embodiments, R⁴is

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 5-20 membered heteroaryl. In some embodiments, R⁴is 5-20 membered heteroaryl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 5-6 membered heteroaryl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 5-6 membered heteroaryl optionally substituted with one or more C_1-3alkyl. In some embodiments, R⁴is 5-6 membered heteroaryl optionally substituted with one or more methyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —N(R^d)₂, wherein each of R^dis independently H, or C_1-6alkyl, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH or —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, or C_1-3alkyl, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH, or —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, or C_1-3alkyl, wherein the C_1-3alkyl of R^dis optionally substituted with one or more —OH or —S(O)₂—R^a, wherein R^ais methyl. In some embodiments, R⁴is selected from the group consisting of —NH₂,

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-6alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-3alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or methyl. In some embodiments, R⁴is —C(O)—NH₂. In some embodiments, R⁴is —C(O)—NH(CH₃). In some embodiments, R⁴is —C(O)—N(CH₃)₂. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais C_1-alkyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais methyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 3-10 membered heterocyclyl optionally substituted with one or more oxo. In some embodiments, R⁴is 3-7 membered heterocyclyl optionally substituted with one or more oxo. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —P(O)(C_1-6alkyl)₂. In some embodiments, R⁴is —P(O)(C_1-3alkyl)₂. In some embodiments, R⁴is —P(O)(CH₃)₂. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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- or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R⁵is halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; and m, R¹, R², L¹, L³, R⁴, R⁶, and R⁷are as defined for formula (I). In some variations, m, R¹, R², L¹, L³, R⁴, R⁶, and R⁷of formula (I-B2) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH. In some embodiments, R²is C_1-3alkyl, wherein the C_1-3alkyl of R²is optionally substituted with one or more halo, —OH. In some embodiments, R²is methyl. In some embodiments, R²is ethyl, wherein the ethyl of R²is optionally substituted with one or more halo, —OH. In some embodiments, R²is

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In some embodiments of a compound of formula (II), such as a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more deuterium. In some embodiments, R²is C_1-3alkyl, wherein the C_1-3alkyl of R²is optionally substituted with one or more deuterium. In some embodiments, R²is methyl, wherein the methyl of R²is optionally substituted with one of more deuterium. In some embodiments, R²is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene optionally substituted with one or more C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with —OH or C_1-6alkoxy. In some embodiments, L¹is methylene. In some embodiments, L¹is ethylene optionally substituted with one or more C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH or C_1-6alkoxy. In some embodiments, L¹is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R⁴is

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In some embodiments of a compound of formula (II) such as a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —NS(O)—(C_1-6alkyl)₂. In some embodiments, R⁴is —NS(O)—(C_1-6alkyl)₂. In some embodiments, R⁴is —NS(O)—(C_1-3alkyl)₂. In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-6alkyl, or —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-3alkyl, or —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently H, C_1-6alkyl, or —S(O)₂—R^a, wherein R^ais methyl. In some embodiments, R⁴is selected from the group consisting of —NH₂, and

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-6alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-3alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or methyl. In some embodiments, R⁴is —C(O)—NH₂. In some embodiments, R⁴is —C(O)—NH(CH₃). In some embodiments, R⁴is —C(O)—N(CH₃)₂. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or 3-6 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more oxo, —OH, NH₂, or —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais methyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is halo. In some embodiments, R⁵is Cl, or F. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is C_1-6alkyl, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more halo, or —OH. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more fluoro, or —OH. In some embodiments, R⁵is selected from the group consisting of methyl,

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is C_1-6alkoxy, wherein the C_1-6alkoxy is optionally substituted with one or more halo. In some embodiments R⁵is C_1-3alkoxy, wherein the C_1-3alkoxy is optionally substituted with one or more halo. In some embodiments, R⁵is C_1-3alkoxy, wherein the C_1-3alkoxy is optionally substituted with one or more fluoro. In some embodiments, R⁵is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁶and R⁷are each independently H or halo. In some embodiments, R⁶and R⁷are each independently H or fluoro. In some embodiments, each of R⁶and R⁷is H. In some embodiments, one of R⁶and R⁷is H and the other of R⁶and R⁷is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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- or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: each R⁵is, independently at each occurrence, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; and m, R¹, R², L¹, L³, R⁴, R⁶, and R⁷are as defined for formula (I). In some variations, m, R¹, R², L¹, L³, R⁴, R⁶, and R⁷of formula (I-B3) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl. In some embodiments, R²is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene optionally substituted with one or more C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with —OH or C_1-6alkoxy. In some embodiments, L¹is methylene. In some embodiments, L¹is ethylene optionally substituted with one or more C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH or C_1-6alkoxy. In some embodiments, L¹is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —N(R^d)₂, wherein each of R^dis independently C_1-6alkyl, or —S(O)₂—R^a, and wherein R^ais C_1-6alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis independently C_1-3alkyl, or —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, R⁴is —N(R^d)₂, wherein each of R^dis methyl, or —S(O)₂—R^a, wherein R^ais methyl. In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more oxo. In some embodiments R⁴is —C(O)—N(R^e)₂, wherein both R^etogether with the N to which they are attached are taken together to form a 3-7 membered heterocyclyl, wherein the 3-7 membered heterocyclyl is optionally substituted with one or more oxo.

In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-B), or (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is, independently at each occurrence selected from the group consisting of, halo and C_1-6alkyl. In some embodiments, R⁵is, independently at each occurrence selected from the group consisting of halo and C_1-3alkyl. In some embodiments, R⁵is, independently at each occurrence, selected from the group consisting of F and methyl. In some embodiments, each R⁵is F. In some embodiments, each R⁵is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, p, R¹, R², R³, L¹, L³, R⁴, and R⁵are as defined for formula (I). In some variations m, p, R¹, R², R³, L¹, L³, R⁴, and R⁵of formula (I-C) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided herein is a compound of formula (I), (I-A), (I-A2), or (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-C1):

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, R¹, R², R³, L¹, L³, and R⁴, are as defined for formula (I). In some variations m, R¹, R², R³, L¹, L³, and R⁴of formula (I-C) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais C_3-10cycloalkyl. R⁴is —S(O)₂—R^a, wherein R^ais C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R^ais optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^ais optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^ais optionally substituted with one or more C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH. In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —S(O)₂—R^a, wherein R^ais 3-10 membered heterocyclyl. In some embodiments R⁴is —S(O)₂—R^a, wherein R^ais 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl of R^ais optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is —S(O)₂—R^a, wherein R^ais 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R^ais optionally substituted with one or more C_1-6alkyl. In some embodiments, wherein R⁴is —S(O)₂—R^a, wherein R^ais 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl of R^ais optionally substituted with one or more C_1-3alkyl. In some embodiments, R⁴is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-6alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or C_1-3alkyl. In some embodiments, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis independently H or methyl. In some embodiments, R⁴is —C(O)—NH₂. In some embodiments, R⁴is —C(O)—N(CH₃)₂. In some embodiments, R⁴is —C(O)—NH₂. In some embodiments, R⁴is —C(O)—NH(CH₃). In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R⁵is, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; m, p, R¹, R², R³, L¹, L³, and R⁴, are as defined for formula (I). In some variations, R⁵is halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo; m, p, R¹, R², R³, L¹, L³, and R⁴of formula (I-C2) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′). or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkyl, wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is methyl, wherein the methyl of R¹is optionally substituted with one or more F. In some embodiments. R¹is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound formula (I′), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_1-6alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, L³is C_1-3alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, L³is selected from the group consisting of

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In some embodiments of a compound formula (II), such as a compound of formula (I′), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_1-6alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH. In some embodiments, L³is C_1-3alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more —OH. In some embodiments, L³is selected from the group consisting of

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In some embodiments, R⁴

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In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —(CH₂)_qOH, wherein q is an integer from 0-6. R⁴is —(CH₂)_qOH, wherein q is an integer from 0-2. In some embodiments, R⁴is —OH. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I′), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—C_1-6alkyl. In some embodiments, R⁴is —C(O)—C_1-3alkyl. In some embodiments, R⁴is —C(O)CH₃. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is C_1-6alkyl. In some embodiments, R⁵is C_1-3alkyl. In some embodiments, R⁵is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A), (I-A2), (I-C), or (I-C2) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is C_1-6alkyl, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more halo. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more fluoro. In some embodiments, R⁵is

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In some embodiments, R⁵is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A), (I-A2), (I-C), or (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is halo. In some embodiments, R⁵is Cl, or F. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m, p, R¹, R², R³, L¹, L³, and R⁴, are as defined for formula (I). In some variations, m, p, R¹, R², R³, L¹, L³, and R⁴of formula (I-D) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), such as a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl optionally substituted with one or more deuterium. In some embodiments, R²is C_1-3alkyl optionally substituted with one or more deuterium. In some embodiments, R²is methyl optionally substituted with one or more deuterium. In some embodiments, R²is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkyl, wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is methyl, wherein the methyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is

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In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene optionally substituted with one or more C_1-6alkyl. In some embodiments, L¹is ethylene optionally substituted with one or more C_1-6alkyl. In some embodiments, L¹is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is absent. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is —O—. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_1-6alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, L³is C_1-3alkylene, wherein the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, L³is selected from the group consisting of

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In some embodiments of a compound of formula (I′), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is C_3-8cycloalkyl, wherein the C_3-8cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is selected from the group consisting of

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In some embodiments of a compound of formula (II), such as a compound of formula (I′), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is C_3-8cycloalkyl, wherein the C_3-8-cycloalkyl of L³is optionally substituted with one or more —OH. In some embodiments, L³is selected from the group consisting of

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In some embodiments of a compound of formula (I′), (I-A), (I-A2), or (I-D) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is 3-10 membered heterocyclyl. In some embodiments, L³is 3-6 membered heterocyclyl. In some embodiments, L³is selected from the group consisting of

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In some embodiments of a compound of formula (II), such as a compound of (I′), (I-A), (I-A2), or (I-D) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L³is 3-10 membered heterocyclyl. In some embodiments, L³is 3-6 membered heterocyclyl. In some embodiments, L³is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —C(O)—N(R^e)₂, wherein each of R^eis H. In some embodiments, R⁴is —C(O)—NH₂. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 3-6 membered heterocyclyl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 3-6 membered heterocyclyl optionally substituted with one or more C_1-3alkyl. In some embodiments, R⁴is 3-6 membered heterocyclyl optionally substituted with one or more methyl. In some embodiments, R⁴is

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In some embodiments of a compound of formula (I′), (I-A), (I-A2), or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 3-6 membered heterocyclyl optionally substituted with one or more C_1-6alkyl. In some embodiments, R⁴is 3-6 membered heterocyclyl optionally substituted with one or more C_1-3alkyl. In some embodiments, R⁴is 3-6 membered heterocyclyl optionally substituted with one or more methyl. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I′), (I-A), (I-A2), or (I-D) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —(CH₂)_qOH, wherein q is an integer from 0-6. R⁴is —(CH₂)_qOH, wherein q is an integer from 0-2. In some embodiments, R⁴is —OH. In some embodiments, R⁴is selected from the group consisting of

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In some embodiments of a compound of formula (I′), (I-A), (I-A2), or (I-D) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —N(R^d)₂, wherein each of R^dis independently H. In some embodiments, R⁴is —NH₂. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A), (I-A2), or (I-D) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁴is —P(O)(C_1-6alkyl)₂. In some embodiments, R⁴is —P(O)(C_1-3alkyl)₂. In some embodiments, R⁴is —P(O)(CH₃)₂. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided herein is a compound of formula (I), (I-A) or (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-E):

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, p, R¹, R², R³L¹, X², R^b, R^c, R⁶, and R⁷are as defined for formula (I). In some variations, ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, p, R¹, R², R³L¹, X², R^b, R^c, R⁶, and R⁷of formula (I-E) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, p, R¹, R², R³, L¹, X¹, R^b, R^c, R⁶, and R⁷are as defined for formula (I). In some variations, ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, p, R¹, R², R³, L¹, X¹, R^b, R^c, R⁶, and R⁷of formula (I-E1) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided herein is a compound of formula (I′), (I-A), (I-A2), or (I-E) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-E2):

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: r is an integer from 0-1; Y¹and Y²are each independently C or N, optionally substituted by one or more H or R^b; and m, R¹, R², L¹, X², and R^bare as defined for formula (I′), or (II); and wherein the dashed line represents a single or double bond.

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: r is an integer from 0-1; Y¹and Y²are each independently C or N, optionally substituted by one or more H or R^b; R^b1is OH; R^b2is H, C_1-6alkyl, or C_3-10cycloalkyl, wherein the C_1-6alkyl of R^b2is optionally substituted with one or more OH; and m, R¹, R², L¹, X², and R^bare as defined for formula (I′), or (II); and wherein the dashed line represents a single or double bond.

In some embodiments of a compound of formula (I′), (I-A) (I-A2), or (I-E3) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

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has a stereochemical configuration represented by

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has a stereochemical configuration represented by

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: r is an integer from 0-1; Y², Y³and Y⁴are each independently C or N, optionally substituted by one or more H or R^c; and m, R¹, R², L¹, X², and R^care as defined for formula (I′), or (II); and wherein the dashed line represents a single or double bond.

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: r is an integer from 0-1; Y³, Y⁴and Y⁵are each independently C or N, optionally substituted by one or more H or R^c; R^c1is OH; R^c2is H, C_1-6alkyl, or C_3-10cycloalkyl, wherein the C_1-6alkyl of R^c2is optionally substituted with one or more OH; and m, R¹, R², L¹, X², and R^care as defined for formula (I′), or (II); and wherein the dashed line represents a single or double bond.

In some embodiments of a compound of formula (I′), (I-A) (I-A2), or (I-E5) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

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has a stereochemical configuration represented by

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In some embodiments of a compound of formula (I′), (I-A) (I-A2), or (I-E) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

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has a stereochemical configuration represented by

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In some embodiments, provided herein is a compound of formula (I), (I-A) or (I-A2), (I-E), or (I-E1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-F):

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, p, R¹, R², R³, L¹, R⁵, R^b, and R^c, are as defined for formula (I). In some variations, ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, p, R¹, R², R³, L¹, R⁵, R^b, and R^cof formula (I-F) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided herein is a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-F1):

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, R¹, R², L¹, R^b, and R^c, are as defined for formula (I). In some variations, ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, R¹, R², L¹, R^b, and R^cof formula (I-F1) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more —OH, —NH₂, or C_1-6alkoxy. In some embodiments, R²is methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), such as a compound of formula (I′), (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more deuterium, —OH, —NH₂, or C_1-6alkoxy. In some embodiments, R²is methyl optionally substituted with one or more deuterium. In some embodiments, R²is

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In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH. In some embodiments, R²is C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R²is optionally substituted with one or more —OH. In some embodiments, R²is

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl. In some embodiments, L¹is ethylene, wherein the ethylene of L¹is optionally substituted with one or more C_1-6alkyl. In some embodiments, L¹is selected from the group consisting of

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In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, wherein R^bis oxo. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, wherein R^bis oxo. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E1), (I-E2), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-3alkyl, wherein the C_1-3alkyl of R^bis optionally substituted with one or more halo, —OH, or —S(O)₂—C_1-3alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently selected from the group consisting of oxo,

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E1), (I-E2), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein one or more of R^bis —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein one or more of R^bis —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein one or more of R^bis —S(O)₂—R^a, wherein R^ais methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I′), (I-A) or (I-A2), (I-E1), (I-E2), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH or C_1-3alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein one or more of R^bis selected from the group consisting of

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E1), (I-E2), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heteroaryl. In some embodiments, ring A is a 5-6 membered heteroaryl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_1-6alkyl. In some embodiments ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_1-3alkyl. In some embodiments, ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis methyl. In some embodiments, ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis isopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E1), (I-E2), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_1-6alkyl, wherein the C_1-6alkyl of R is optionally substituted with one or more —S(O)₂—R^a, wherein R^ais C_1-6alkyl. In some embodiments, ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_1-3alkyl, wherein the C_1-3alkyl of R^cis optionally substituted with one or more —S(O)₂—R^a, wherein R^ais C_1-3alkyl. In some embodiments, ring A is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_1-3alkyl, wherein the C_1-alkyl of R^cis optionally substituted with one or more —S(O)₂—R^a, wherein R^ais methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I′), (I-A) or (I-A2), (I-E1), (I-E2), (I-F), or (I-F1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-3alkyl. In some embodiments, ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis selected from the group consisting of

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R⁵is halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, R¹, R², L¹, R^b, and R^c, are as defined for formula (I). In some variations, R⁵is halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo; ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, R¹, R², L¹, R^b, and R^c, of formula (I-F2) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

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In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), such as a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkyl, wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is methyl, wherein the methyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is

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In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene. In some embodiments, L¹is ethylene. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments, L¹is

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In some embodiments of a compound of formula (II), such as a compound of formula (I′), (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L¹is C_1-6alkylene, optionally substituted with one or more deuterium. In some embodiments, L¹is ethylene optionally substituted with one or more deuterium. In some embodiments, L¹is

[Image Omitted]

wherein, for each L¹, # denotes the point of attachment to L²and ## denotes the point of attachment to the remainder of the molecule.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, wherein one or more R^bis oxo. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more of R^b, wherein one or more R^bis oxo. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-3alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently selected from the group consisting of oxo, and

[Image Omitted]

In some embodiments of a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH or C_1-3alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein one or more of R^bis selected from the group consisting of

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), such as a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_1-6alkyl and wherein, the C_1-6alkyl of R^bis optionally substituted with one or more —OH. In some embodiments, ring A is 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_1-3alkyl and wherein, the C_1-3alkyl of R^bis optionally substituted with one or more —OH. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is optionally substituted with one or more R^b, wherein one or more of R^bis —CH₂OH.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.

In some embodiments of a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-3alkyl. In some embodiments, ring A is a 5-10 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with one or more R^c, wherein one or more R^cis selected from the group consisting of

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is halo. In some embodiments, R⁵is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), (I-F), or (I-F2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁵is C_1-6alkyl. In some embodiments, R⁵is C_1-3alkyl. In some embodiments, R⁵is methyl. In some embodiments, R⁵is C_1-6alkyl, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more halo. In some embodiments, R⁵is C_1-3alkyl, wherein the C_1-3alkyl of R⁵is optionally substituted with one or more fluoro. In some embodiments, R⁵is

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In some embodiments, provided herein is a compound of formula (I), (I-A) or (I-A2), (I-E1), or (I-E2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-G):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, R¹, R², L¹, R^b, and R^c, are as defined for formula (I). In some variations, ring A is 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocyclyl of ring A is optionally substituted with one or more R^b, and wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more R^c; and m, R¹, R², L¹, R^b, and R^cof formula (I-G) are as defined for a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (II), such as a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is C_1-6alkyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more deuterium. In some embodiments, R²is methyl optionally substituted with one or more deuterium. In some embodiments, R²is

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 0 to 4. In some embodiments, m is an integer from 0 to 2. In some embodiments, m is 0 or 1. In some embodiments m is 1. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is halo. In some embodiments R¹is Cl. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is —CN. In some variations, the embodiments provided herein also apply to a compound of formula (I′), or (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R¹is C_1-6alkyl, wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more halo. In some embodiments, R¹is C_1-3alkyl, wherein the C_1-3alkyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is methyl, wherein the methyl of R¹is optionally substituted with one or more F. In some embodiments, R¹is methyl. In some embodiments, R¹is

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more —OH. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-alkyl, wherein the C_1-3alkyl of R^bis optionally substituted with one or more —OH. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently selected from the group consisting of oxo,

[Image Omitted]

In some embodiments of a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently oxo, or C_1-6alkyl. In some embodiments, the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH. In some embodiments, each R^bis independently oxo, or C_1-3alkyl. In some embodiments the C_1-3alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-3alkyl, or C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of the C_1-3alkyl of R^bis further optionally substituted with one or more C_1-3alkyl or —OH. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently selected from the group consisting of oxo,

[Image Omitted]

In some embodiments of a compound of formula (II), such as a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein each R^bis independently selected from the group consisting of oxo,

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.

[Image Omitted]

In some embodiments of a compound of formula (I), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_3-10cycloalkyl, wherein the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis C_3-6cycloalkyl, wherein the C_3-6cycloalkyl of R^bis optionally substituted with one or more —OH. In some embodiments, ring A is a 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein one or more of R^bis

[Image Omitted]

In some embodiments of a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_3-10cycloalkyl optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl is further optionally substituted with one or more —OH. In some embodiments, R^bis C_3-6cycloalkyl optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, wherein the C_1-3alkyl is further optionally substituted with one or more —OH. In some embodiments, R^bis selected from the group consisting of

[Image Omitted]

In some embodiments of a compound of formula (II), such as a compound of formula (I′), (I-A) or (I-A2), (I-E), (I-E1), or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^bis C_3-10cycloalkyl optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl is further optionally substituted with one or more —OH or deuterium. In some embodiments, R^bis C_3-6cycloalkyl optionally substituted with one or more —OH, C_3-6cycloalkyl, or C_1-3alkyl, wherein the C_1-3alkyl is further optionally substituted with one or more —OH or deuterium. In some embodiments, R^bis selected from the group consisting of

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some embodiments, ring A is selected from the group consisting of

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond. In some variations, the embodiments provided herein also apply to a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.

In some embodiments, provided herein is a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A):

[Image Omitted]

In some embodiments, provided herein is a compound of formula (II), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A1):

[Image Omitted]

In some embodiments of a compound of formula (II), (II-A), (II-A1), or (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R²is H.

[Image Omitted]

wherein, for each L¹, # denotes the point of attachment to —O- and ## denotes the point of attachment to the remainder of the molecule.

In some embodiments of a compound of formula (II), (II-A), (II-A1), or (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R^cis independently at each occurrence C_3-10cycloalkyl optionally substituted with one or more —OH, or C_1-6alkyl. In some embodiments, R^cis independently at each occurrence, C_3-6cycloalkyl optionally substituted with one or more —OH, or C_1-3alkyl. In some embodiments, R^cis

[Image Omitted]

In some embodiments of a compound of formula (II), (II-A), (II-A1), or (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is

[Image Omitted]

wherein ## represent a point of attachment to the remainder of the molecule and the dashed line represents a single or double bond.

In some embodiments of a compound of formula (II), (II-A), or (II-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁶is H.

In some embodiments of a compound of formula (II), (II-A), or (II-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R⁷is H.

It is to be understood that any variation or embodiment of m, n, p, R¹, R², R³, L¹, L²L3, X¹, X², X³, X⁴, R⁴, R⁵, R⁶, R⁷, R^a, R^b, R^c, Y¹, Y², and Y³provided herein can be combined with every other variation or embodiment of m, n, p, R¹, R², R³, L¹, L²L3, X¹, X², X³, X⁴, R⁴, R⁵, R⁶, R⁷, R^a, R^b, R^c, Y¹, Y², and Y³, the same as if each and every combination had been individually and specifically described. For example, embodiments where m is 1, n is 1, p is 0, R¹is Cl, R²is H, L¹is ethylene, L²is 0, L³is C_1-6alkyl, R⁴is SO₂R^awherein R^ais C_1-6alkyl, X is N, X²is N, R⁶is H, and R⁷is H, can be combined to give

[Image Omitted]

In some embodiments, provided herein is a compound of formula (I), or any variation of embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

TABLE 1

Compound

Number
Structure
Name

1

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5-chloro-1′-(2-{[2-(1- methanesulfonylethyl)pyrimidin- 5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

2

[Image Omitted]

5-chloro-1′-[2-({2-[(1S) or (1R)-1- methanesulfonylethyl]pyrimidin- 5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

3

[Image Omitted]

5-chloro-1′-[2-({2-[(1R) or (1S)-1- methanesulfonylethyl]pyrimidin- 5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

4

[Image Omitted]

5-chloro-1′-(2-{[2-(1- methanesulfonylcyclopropyl) pyrimidin-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

5

[Image Omitted]

5-(difluoromethyl)-1′-(2-{[2-(1- methanesulfonylcyclopropyl) pyrimidin-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

6

[Image Omitted]

5-(difluoromethoxy)-1′-(2-{[2-(1- methanesulfonylcyclopropyl) pyrimidin-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

7

[Image Omitted]

5,7-dichloro-1′-[2-(4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

8

[Image Omitted]

7-chloro-1′-[2-(4- methanesulfonylphenoxy)ethyl]-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

9

[Image Omitted]

5-chloro-1′-[2-(4- methanesulfonylphenoxy)ethyl]-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-7-carbonitrile

10

[Image Omitted]

5-chloro-1′-[(2S)-1-(4- methanesulfonylphenoxy)propan- 2-yl]-1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

11

[Image Omitted]

5-chloro-1′-[(2S)-2-(4- methanesulfonylphenoxy)propyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

12

[Image Omitted]

1′-[(2S)-1-(4- methanesulfonylphenoxy)propan- 2-yl]-1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

13

[Image Omitted]

1′-[(2S)-2-(4- methanesulfonylphenoxy)propyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

14

[Image Omitted]

5-chloro-1′-(2-{[1-(3- methanesulfonylpropyl)-1H- indazol-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

15

[Image Omitted]

5-chloro-1′-(2-{[1-(oxetan-3-yl)- 1H-indazol-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

16

[Image Omitted]

5-chloro-1′-(2-{[1-(propan-2-yl)- 1H-indazol-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

17

[Image Omitted]

5-chloro-1′-[2-(4-{[(cis)-3- hydroxycyclobutyl]sulfonyl} phenoxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

18

[Image Omitted]

5-chloro-1-(2-hydroxyethyl)-1′-[2- (4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

19

[Image Omitted]

1′-2-(4- methanesulfonylphenoxy)ethyl]-1- [(cis)-3-hydroxycyclobutyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

20

[Image Omitted]

5-chloro-1′-[2-(4- methanesulfonylphenoxy)ethyl]-1- (2-methoxyethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

21

[Image Omitted]

1′-[2-(4- methanesulfonylphenoxy)ethyl]-1- (2-methoxyethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

22

[Image Omitted]

5-chloro-1′-[2-(4- methanesulfonylphenoxy)ethyl]-1- (oxetan-3-yl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

23

[Image Omitted]

5-chloro-1′-{2-[4-(3- methanesulfonylpropanesulfonyl) phenoxy]ethyl}-1-methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

24

[Image Omitted]

5-bromo-1-(2-hydroxyethyl)-1′-[2- (4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

25

[Image Omitted]

1′-[2-(4- methanesulfonylphenoxy)ethyl]-1- (2-methoxyethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

26

[Image Omitted]

l-[2-(4- methanesulfonylphenoxy)ethyl]- 1′,2′-dihydrospiro[azepane-4,3′- indol]-2′-one

27

[Image Omitted]

5-chloro-1′-{2-[(1-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

28

[Image Omitted]

1′-[1-(4- methanesulfonylphenoxy)propan- 2-yl]-1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

29

[Image Omitted]

1-methyl-1′-{2-[(3-methyl-4-oxo- 3,4-dihydroquinazolin-6- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

30

[Image Omitted]

1-methyl-1′-{2-[(2-methyl-1-oxo- 2,3-dihydro-1H-isoindol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

31

[Image Omitted]

1-methyl-1′-{2-[4-(1-methyl-1H- pyrazol-4-yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

32

[Image Omitted]

5-(2-{1-methyl-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2,3- dihydro-1λ⁶-benzothiophene-1,1- dione

33

[Image Omitted]

1-methyl-1′-{2-[(1-methyl-2-oxo- 2,3-dihydro-1H-indol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

34

[Image Omitted]

1-methyl-1′-[2-(quinoxalin-6- yloxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

35

[Image Omitted]

1-methyl-1′-{2-[4-(5-methyl- 1,2,4-oxadiazol-3- yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

36

[Image Omitted]

1′-{2-[(1-acetyl-1,2,3,4- tetrahydroquinolin-6- yl)oxy]ethyl}-1-methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

37

[Image Omitted]

l-methyl-1′-{2-[4-(2- oxopyrrolidin-1- yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

38

[Image Omitted]

5-chloro-1′-{2-[4-(1- methanesulfonylethyl)phenoxy] ethyl}-1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

39

[Image Omitted]

5-chloro-1′-(2-{4-[(1S or 1R)-1- methanesulfonylethyl]phenoxy} ethyl)-1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

40

[Image Omitted]

5-chloro-1′-(2-{4-[(1R or 1S)-1- methanesulfonylethyl]phenoxy} ethyl)-1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

41

[Image Omitted]

5-chloro-1′-{2-[4-(3- methanesulfonylpropanesulfonyl) phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

42

[Image Omitted]

1′-[2-(3,5-difluoro-4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

43

[Image Omitted]

5-chloro-1′-{2-[4- (cyclopropanesulfonyl)phenoxy] ethyl}-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

44

[Image Omitted]

1′-[2-(4- difluoromethanesulfonylphenoxy) ethyl]-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

45

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)benzamide

46

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- fluorobenzamide

47

[Image Omitted]

5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)pyridine- 2-carboxamide

48

[Image Omitted]

5-chloro-1′-[2-(2-fluoro-4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

49

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- methylbenzamide

50

[Image Omitted]

5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- methanesulfonylbenzonitrile

51

[Image Omitted]

5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N,N- dimethylpyridine-2-carboxamide

52

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N- methylbenzamide

53

[Image Omitted]

5-chloro-1′-{2-[(1- methanesulfonyl-1,2,3,4- tetrahydroquinolin-6- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

54

[Image Omitted]

5-chloro-1′-{2-[(2- methanesulfonyl-2,3-dihydro-1H- isoindol-5-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

55

[Image Omitted]

1′-{2-[(2-methanesulfonyl-1,2,3,4- tetrahydroisoquinolin-6- yl)oxy]ethyl}-1-methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

56

[Image Omitted]

1′-{2-[(1-acetyl-1,2,3,4- tetrahydroquinolin-6- yl)oxy]ethyl}-5-chloro-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

57

[Image Omitted]

1′-{2-[(2-acetyl-2,3-dihydro-1H- isoindol-5-yl)oxy]ethyl}-5-chloro- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

58

[Image Omitted]

1′-(2-[(2-acetyl-1,2,3,4- tetrahydroisoquinolin-6- yl)oxy]ethyl}-1-methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

59

[Image Omitted]

1′-{2-[(1-acetyl-1,2,3,4- tetrahydroquinolin-6- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

60

[Image Omitted]

6-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N- methyl-1,2,3,4- tetrahydroquinoline-1- carboxamide

61

[Image Omitted]

5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N- methyl-2,3-dihydro-1H-isoindole- 2-carboxamide

62

[Image Omitted]

5-chloro-1′-[2-(quinoxalin-6- yloxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

63

[Image Omitted]

5-chloro-1′-[2-(3-fluoro-4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

64

[Image Omitted]

5-chloro-1′-{2-[(6- methanesulfonylpyridin-3- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

65

[Image Omitted]

5-chloro-1′-{2-[(1-methyl-2-oxo- 2,3-dihydro-1H-indol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

66

[Image Omitted]

1′-[2-(4- methanesulfonylphenoxy)ethyl]-5- methyl-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

67

[Image Omitted]

1-2-(4- methanesulfonylphenoxy)ethyl]-1- methyl-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

68

[Image Omitted]

5-chloro-1′-{2-[(1-methyl-1H- indazol-5-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

69

[Image Omitted]

5-chloro-1′-[2-(4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

70

[Image Omitted]

1′-{2-[(1-methyl-1H-indazol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

71

[Image Omitted]

1′-[2-(4- methanesulfonylphenoxy)ethyl]-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

72

[Image Omitted]

5-bromo-1′-[2-(4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2- ″one

73

[Image Omitted]

1′-[2-(4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

74

[Image Omitted]

1′-[2-(3-fluoro-4- methanesulfonylphenoxy)ethyl]-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

75

[Image Omitted]

N-[4-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- N-methylmethanesulfonamide

76

[Image Omitted]

N-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- N-methylmethanesulfonamide

77

[Image Omitted]

1′-[2-(4-{[dimethyl(oxo)-λ⁶- sulfanylidene]amino}phenoxy) ethyl]-2-oxo-1,2-dihydrospiro [indole-3,4′-piperidine]- 5-carbonitrile

78

[Image Omitted]

5-chloro-1′-{2-[(8-methyl-7-oxo- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

79

[Image Omitted]

1′-{2-[(8-methyl-7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

80

[Image Omitted]

1′-{2-[(8-acetyl-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-5-chloro-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

81

[Image Omitted]

1′-(2-[(8-acetyl-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

82

[Image Omitted]

5-chloro-1′-[2-([2-oxo-1,2,3,4- tetrahydroquinolin-6- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

83

[Image Omitted]

2-oxo-1′-{2-[(1,3,3-trimethyl-2- oxo-2,3-dihydro-1H-indol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

84

[Image Omitted]

1′-{2-(3,5-difluoro-4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

85

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxycyclobutyl]-1H-indazol-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

86

[Image Omitted]

5-chloro-1′-[2-({1-[(trans)-3- hydroxycyclobutyl]-1H-indazol-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

87

[Image Omitted]

5-chloro-1′-[2-(1H-indazol-5- yloxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

88

[Image Omitted]

5-chloro-1′-{2-[(1-methyl-2-oxo- 2,3-dihydro-1H-1,3-benzodiazol- 5-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

89

[Image Omitted]

5-chloro-1′-[2-(3,5-difluoro-4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

90

[Image Omitted]

1′-[2-(3,5-difluoro-4- methanesulfonylphenoxy)ethyl]-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

91

[Image Omitted]

methyl 1-[4-(2-{5-chloro-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidin]-1′- yl}ethoxy)benzenesulfonyl] cyclopropane-1-carboxylate

92

[Image Omitted]

5-chloro-1′-(2-{4-[(3- methyloxetan-3- yl)sulfonyl]phenoxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

93

[Image Omitted]

1′-(2-{4-[(3-methyloxetan-3- yl)sulfonyl]phenoxy}ethyl)-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

94

[Image Omitted]

5-chloro-1′-{2-[(2- methanesulfonyl-1,2,3,4- tetrahydroisoquinolin-6- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

95

[Image Omitted]

1′-{2-[(1-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

96

[Image Omitted]

2-oxo-1′-(2-{[2-oxo-1-(propan-2- yl)-1,2,3,4-tetrahydroquinolin-6- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

97

[Image Omitted]

5-chloro-1′-(2-{[2-oxo-1-(propan- 2-yl)-1,2,3,4-tetrahydroquinolin-6- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

98

[Image Omitted]

N-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- N-(2- hydroxyethyl)methanesulfonamide

99

[Image Omitted]

5-chloro-1′-(2-{[1-(oxetan-3-yl)-2- oxo-1,2,3,4-tetrahydroquinolin-6- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

100

[Image Omitted]

1′-{2-[3-(difluoromethyl)-4- methanesulfonylphenoxy]ethyl}- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

101

[Image Omitted]

1′-{2-[4-(1- methanesulfonylcyclopropyl) phenoxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

102

[Image Omitted]

5-chloro-1′-{2-[4-(1- methanesulfonylcyclopropyl) phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

103

[Image Omitted]

6-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-1-methyl- 3,4-dihydro-1H-2λ6,1- benzothiazine-2,2-dione

104

[Image Omitted]

1′-{2-[(1-methyl-2,2-dioxo-3,4- dihydro-1H-2λ6,1-benzothiazin-6- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

105

[Image Omitted]

1′-(2-{[1-(2,2-difluoroethyl)-2- oxo-1,2,3,4-tetrahydroquinolin-6- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

106

[Image Omitted]

5-chloro-1′-(2-{[1-(2,2- difluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-6- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

107

[Image Omitted]

1′-{2-[4-methanesulfonyl-3- (trifluoromethyl)phenoxy]ethyl}- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

108

[Image Omitted]

5-chloro-1′-{2-[4- methanesulfonyl-3- (trifluoromethyl)phenoxy]ethyl}- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

109

[Image Omitted]

1′-{2-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

110

[Image Omitted]

5-chloro-1′-[2-(4- methanesulfonyl-3- methylphenoxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

111

[Image Omitted]

1′-[2-(4-methanesulfonyl-3- methylphenoxy)ethyl]-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

112

[Image Omitted]

5-chloro-1′-[2-(4- difluoromethanesulfonylphenoxy) ethyl]-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

113

[Image Omitted]

1′-[2-(4- difluoromethanesulfonylphenoxy) ethyl]-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

114

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(cis)-3- hydroxycyclobutyl]-1,2,3,4- tetrahydroquinolin-6- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

115

[Image Omitted]

5-chloro-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- imidazo[4,3-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

116

[Image Omitted]

(S) or (R)-5-chloro-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- imidazo[4,3-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

117

[Image Omitted]

(R) or (S)-5-chloro-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- imidazo[4,3-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

118

[Image Omitted]

2-oxo-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- imidazo[4,3-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

119

[Image Omitted]

(S) or (R)-2-oxo-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- imidazo[4,3-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

120

[Image Omitted]

(R) or (S)-2-oxo-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- imidazo[4,3-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

121

[Image Omitted]

5-chloro-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- pyrrolo[2,1-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

122

[Image Omitted]

(S) or (R)-5-chloro-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- pyrrolo[2,1-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

123

[Image Omitted]

(R) or (S)-5-chloro-1′-[2-({3-oxo- 1H,2H,3H,5H,6H,10bH- pyrrolo[2,1-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

124

[Image Omitted]

2-oxo-1′-(2-({3-oxo- 1H,2H,3H,5H,6H,10bH- pyrrolo[2,1-a]isoquinolin-8- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

125

[Image Omitted]

(S) or (R)-2-oxo-1′-(2-((3-oxo- 1,2,3,5,6,10b- hexahydropyrrolo[2,1- a]isoquinolin-8- yl)oxy)ethyl)spiro[indoline-3,4′- piperidine]-5-carbonitrile

126

[Image Omitted]

(R) or (S)-2-oxo-1′-(2-((3-oxo- 1,2,3,5,6,10b- hexahydropyrrolo[2,1- a]isoquinolin-8- yl)oxy)ethyl)spiro[indoline-3,4′- piperidine]-5-carbonitrile

127

[Image Omitted]

N-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2,6- difluorophenyl]-N- methylmethanesulfonamide

128

[Image Omitted]

N-[4-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2,6- difluorophenyl]-N- methylmethanesulfonamide

129

[Image Omitted]

5-chloro-1′-[2-(4- methanesulfonyl-3,5- dimethylphenoxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

130

[Image Omitted]

1′-[2-(4-methanesulfonyl-3,5- dimethylphenoxy)ethyl]-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

131

[Image Omitted]

5-chloro-1′-{2-[(3-methyl-2-oxo- 2,3-dihydro-1,3-benzoxazol-6- yl)oxy]ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

132

[Image Omitted]

1′-{2-[(3-methyl-2-oxo-2,3- dihydro-1,3-benzoxazol-6- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

133

[Image Omitted]

1′-(2-[4-(1- methanesulfonylethyl)phenoxy] ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

134

[Image Omitted]

(S) or (R)-1′-{2-[4-(1- methanesulfonylethyl)phenoxy] ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

135

[Image Omitted]

(R) or (S)-1′-{2-[4-(1- methanesulfonylethyl)phenoxy] ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

136

[Image Omitted]

5-chloro-1′-{2-[3,5-difluoro-4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

137

[Image Omitted]

1′-(2-[3,5-difluoro-4-(1- methanesulfonylethyl)phenoxy] ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

138

[Image Omitted]

(S) or (R)-1′-{2-[3,5-difluoro-4-(1- methanesulfonylethyl)phenoxy] ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

139

[Image Omitted]

(R) or (S)-1′-{2-[3,5-difluoro-4-(1- methanesulfonylethyl)phenoxy] ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

140

[Image Omitted]

1′-{2-[(6-methanesulfony1-5- methylpyridin-3-yl)oxy]ethyl}-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

141

[Image Omitted]

5-chloro-1′-{2-[3,5-difluoro-4-(1- methanesulfonylethyl)phenoxy] ethyl}-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

142

[Image Omitted]

(S) or (R)-5-chloro-1′-{2-[3,5- difluoro-4-(1- methanesulfonylethyl)phenoxy] ethyl}-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

143

[Image Omitted]

(R) or (S)-5-chloro-1′-{2-[3,5- difluoro-4-(1- methanesulfonylethyl)phenoxy] ethyl}-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

144

[Image Omitted]

2-oxo-1′-(2-{[2-oxo-1-(propan-2- yl)-2,3-dihydro-1H-indol-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

145

[Image Omitted]

5-chloro-1′-(2-{[2-oxo-1-(propan- 2-yl)-2,3-dihydro-1H-indol-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

146

[Image Omitted]

5-chloro-1′-{2-[(2-methyl-1-oxo- 2,3-dihydro-1H-isoindol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

147

[Image Omitted]

5-chloro-1′-(2-{4- [methyl(methylimino)oxo-λ⁶- sulfanyl]phenoxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

148

[Image Omitted]

(S) or (R)-5-chloro-1′-(2-{4- [methyl(methylimino)oxo- sulfanyl]phenoxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

149

[Image Omitted]

(R) or (S)-5-chloro-1′-(2-{4- [methyl(methylimino)oxo-λ⁶- sulfanyl]phenoxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

150

[Image Omitted]

1′-(2-{4- [methyl(methylimino)oxo-λ⁶- sulfanyl]phenoxy}ethyl)-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

151

[Image Omitted]

(S) or (R)-1′-(2-{4- [methyl(methylimino)oxo-λ⁶- sulfanyl]phenoxy}ethyl)-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

152

[Image Omitted]

(R) or (S)-1′-(2-{4- [methyl(methylimino)oxo-λ⁶- sulfanyl]phenoxy}ethyl)-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

153

[Image Omitted]

6-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2-methyl- 3,4-dihydro-2H-1λ⁶,2- benzothiazine-1,1-dione

154

[Image Omitted]

1′-{2-[(2-methyl-1,l-dioxo-3,4- dihydro-2H-1λ⁶,2-benzothiazin-6- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

155

[Image Omitted]

5-chloro-1′-[2-(3-chloro-4- methanesulfonylphenoxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

156

[Image Omitted]

1′-[2-(3-chloro-4- methanesulfonylphenoxy)ethyl]-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

157

[Image Omitted]

1′-{2-[4-(1-cyano-1- methylethyl)phenoxy]ethyl}-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

158

[Image Omitted]

5-chloro-1′-[2-({6-[(3- methyloxetan-3- yl)sulfonyl]pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

159

[Image Omitted]

1-(2-hydroxyethyl)-1′-{2-[4- methanesulfonyl-3- (trifluoromethyl)phenoxy]ethyl}- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

160

[Image Omitted]

5-chloro-1-(2-hydroxyethyl)-1′- {2-[4-(3-methanesulfonyloxetan- 3-yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

161

[Image Omitted]

5-chloro-1′-{2-[(6- methanesulfonyl-5-methylpyridin- 3-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

162

[Image Omitted]

5-chloro-1′-(2-{[1-(2- hydroxyethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-6- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

163

[Image Omitted]

5-chloro-1′-{2-[3- (difluoromethoxy)-4- methanesulfonylphenoxy]ethyl}- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

164

[Image Omitted]

1′-{2-[3-(difluoromethoxy)-4- methanesulfonylphenoxy]ethyl}- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

165

[Image Omitted]

5-chloro-1′-{2-[4-(3- methanesulfonyloxetan-3-yl)-3- (trifluoromethyl)phenoxy]ethyl}- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

166

[Image Omitted]

1′-(2-[4-(3- methanesulfonyloxetan-3-yl)-3- (trifluoromethyl)phenoxy]ethyl}- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

167

[Image Omitted]

6-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-3,4- dihydro-2H-1λ⁶,2-benzothiazine- 1,1-dione

168

[Image Omitted]

1′-{2-[(1,1-dioxo-3,4-dihydro-2H- 1λ⁶,2-benzothiazin-6- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

169

[Image Omitted]

1′-{2-[(7-fluoro-1-methyl-2-oxo- 2,3-dihydro-1H-indol-5- yl)oxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

170

[Image Omitted]

2-oxo-1′-{2-[(1-oxo-2,3-dihydro- 1H-isoindol-5-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

171

[Image Omitted]

5-chloro-1′-{2-[(1-oxo-2,3- dihydro-1H-isoindol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

172

[Image Omitted]

5-chloro-1′-[2-({2-[(3- methyloxetan-3-yl)oxy]pyrimidin- 5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

173

[Image Omitted]

1′-[2-({2-[(3-methyloxetan-3- yl)oxy]pyrimidin-5-yl}oxy)ethyl]- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

174

[Image Omitted]

1′-(2-(4-[3- (ethanesulfonyl)oxetan-3- yl]phenoxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

175

[Image Omitted]

2-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- 1λ⁶-thiolane-1,1-dione

176

[Image Omitted]

(S) or (R)-2-[4-(2-{5-chloro-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- 1λ⁶-thiolane-1,1-dione

177

[Image Omitted]

(R) or (S)-2-[4-(2-{5-chloro-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- 1λ⁶-thiolane-1,1-dione

178

[Image Omitted]

1′-{2-[4-(1,1-dioxo-1λ⁶-thiolan-2- yl)phenoxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

179

[Image Omitted]

5-chloro-1′-(2-{3-oxo-3H-spiro[2- benzofuran-1,3′-oxetan]-5- yloxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

180

[Image Omitted]

5-chloro-1′-{2-[4-(1- methanesulfonylcyclobutyl) phenoxy]ethyl}-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

181

[Image Omitted]

1′-{2-[4-(1- methanesulfonylcyclobutyl) phenoxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

182

[Image Omitted]

5-chloro-1′-[2-(4-{6- methanesulfonyl-2- oxaspiro[3.3]heptan-6- yl}phenoxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

183

[Image Omitted]

1′-[2-(4-{6-methanesulfonyl-2- oxaspiro[3.3]heptan-6- yl}phenoxy)ethyl]-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

184

[Image Omitted]

1′-{2-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-2-oxo-1-(2,2,2- trifluoroethyl)-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

185

[Image Omitted]

5-chloro-1′-{2-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-1-(2,2,2- trifluoroethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

186

[Image Omitted]

N-(4-{2-[5-chloro-1-(2- hydroxyethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl]ethoxy}-2- (trifluoromethyl)phenyl) methanesulfonamide

187

[Image Omitted]

1′-{2-[4-(4-methanesulfonyloxan- 4-yl)phenoxy]ethyl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

188

[Image Omitted]

5-chloro-1′-{2-[4-(4- methanesulfonyloxan-4- yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

189

[Image Omitted]

1′-{2-[3,5-difluoro-4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-1-methyl-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

190

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- hydroxycyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

191

[Image Omitted]

1′-(2-{[(6-(2- methanesulfonylpropan-2- yl)pyridin-3-yl]oxy}ethyl)-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

192

[Image Omitted]

5-chloro-1′-(2-{[8-(2- hydroxyethyl)-7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

193

[Image Omitted]

N-{2-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′- yl}ethoxy)benzenesulfonyl]ethyl}- N-methylacetamide

194

[Image Omitted]

1′-(2-[(2-acetyl-1,2,3,4- tetrahydroisoquinolin-6- yl)oxy]ethyl}-5-chloro-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

195

[Image Omitted]

5-chloro-1′-{2-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

196

[Image Omitted]

5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2,3- dihydro-1λ⁶-benzothiophene-1,1- dione

197

[Image Omitted]

5-chloro-1′-{2-[3- (difluoromethyl)-4- methanesulfonylphenoxy]ethyl}- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

198

[Image Omitted]

5-chloro-1′-{2-[4-(2- hydroxyethanesulfonyl)phenoxy] ethyl}-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

199

[Image Omitted]

5-chloro-1′-{1-[(1-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6- yl)oxy]propan-2-yl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

200

[Image Omitted]

chloro-1′-[(2S) or (2R)-1-[(1- methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6- yl)oxy]propan-2-yl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

201

[Image Omitted]

chloro-1′-[(2R) or (2S)-1-[(1- methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6- yl)oxy]propan-2-yl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

202

[Image Omitted]

1′-{1-[(1-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6- yl)oxy]propan-2-yl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

203

[Image Omitted]

(S) or (R)-1′-{1-[(1-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6- yl)oxy]propan-2-yl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

204

[Image Omitted]

(R) or (S)-1′-{1-[(1-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6- yl)oxy]propan-2-yl}-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

205

[Image Omitted]

5-chloro-1′-[1-(4- methanesulfonylphenoxy)propan- 2-yl]-1-[3-hydroxycyclobutyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

206

[Image Omitted]

5-chloro-1′-[(2S) or (2R)-1-(4- methanesulfonylphenoxy)propan- 2-yl]-1-[(cis) or (trans)-3- hydroxycyclobutyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

207

[Image Omitted]

5-chloro-1′-[(2S) or (2R)-1-(4- methanesulfonylphenoxy)propan- 2-yl]-1-[(trans) or (cis)-3- hydroxycyclobutyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

208

[Image Omitted]

5-chloro-1′-[(2R) or (2S)-1-(4- methanesulfonylphenoxy)propan- 2-yl]-1-[(cis) or (trans)-3- hydroxycyclobutyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

209

[Image Omitted]

5-chloro-1′-[(2R) or (2S)-1-(4- methanesulfonylphenoxy)propan- 2-yl]-1-[(trans) or (cis)-3- hydroxycyclobutyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

210

[Image Omitted]

5-chloro-1′-[(2S)-1-[3- (difluoromethyl)-4- methanesulfonylphenoxy]propan- 2-yl]-1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

211

[Image Omitted]

5-chloro-1′-[(2S)-1-[(1-methyl- 1H-indazol-5-yl)oxy]propan-2-yl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

212

[Image Omitted]

1′-[(2S)-1-[3-(difluoromethyl)-4- methanesulfonylphenoxy]propan- 2-yl]-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

213

[Image Omitted]

1′-[(2S)-1-(3,5-difluoro-4- methanesulfonylphenoxy)propan- 2-yl]-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

214

[Image Omitted]

N-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′- yl}ethoxy)phenyl] methanesulfonamide

215

[Image Omitted]

5-chloro-1′-[2-(4-{[(trans)-3- hydroxycyclobutyl]sulfonyl} phenoxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

216

[Image Omitted]

5-chloro-1′-(2-[3-(1,2- dihydroxyethyl)-4- methanesulfonylphenoxy]ethyl}- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

217

[Image Omitted]

5-chloro-1′-{2-[3-(1,2- difluoroethyl)-4- methanesulfonylphenoxy]ethyl}- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

218

[Image Omitted]

5-chloro-1′-(2-{3-[(1S or 1R)-1,2- difluoroethyl]-4- methanesulfonylphenoxy}ethyl)- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

219

[Image Omitted]

5-chloro-1′-(2-{3-[(1R or 1S)-1,2- difluoroethyl]-4- methanesulfonylphenoxy}ethyl)- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

220

[Image Omitted]

1′-{2-[3-(1,2-difluoroethyl)-4- methanesulfonylphenoxy]ethyl}- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

221

[Image Omitted]

1′-(2-(3-[(1S or 1R)-1,2- difluoroethyl]-4- methanesulfonylphenoxy}ethyl)- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

222

[Image Omitted]

1′-(2-(3-[(1R or 1S)-1,2- difluoroethyl]-4- methanesulfonylphenoxy}ethyl)- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

223

[Image Omitted]

5-chloro-1′-{2-[4- methanesulfony1-3-(oxetan-3- yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

224

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(trans)- 3-hydroxycyclobutyl]-1,2,3,4- tetrahydroquinolin-6- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

225

[Image Omitted]

5-chloro-1′-[2-(4-{[1- (hydroxymethyl)cyclopropyl] sulfonyl}phenoxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

226

[Image Omitted]

l-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′- yl}ethoxy)benzenesulfonyl]-N- methylcyclopropane-1- carboxamide

227

[Image Omitted]

l-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′- yl}ethoxy)benzenesulfonyl]-N,N- dimethylcyclopropane-1- carboxamide

228

[Image Omitted]

1′-[2-(4-{[1-(azetidine-1- carbonyl)cyclopropyl]sulfonyl} phenoxy)ethyl]-5-chloro-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

229

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2-fluoro- N-methylbenzamide

230

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2-fluoro- N,N-dimethyibenzamide

231

[Image Omitted]

5-chloro-1′-{2-[3-fluoro-4- (morpholine-4- carbonyl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

232

[Image Omitted]

4-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- fluorobenzoyl]-1λ⁶- thiomorpholine-1,1-dione

233

[Image Omitted]

5-chloro-1′-(2-[3-fluoro-4-(3- methanesulfonylazetidine-1- carbonyl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

234

[Image Omitted]

1′-{2-[4-(azetidine-1-carbonyl)-3- fluorophenoxy]ethyl}-5-chloro- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

235

[Image Omitted]

5-chloro-1′-{2-[3-fluoro-4-(3- hydroxyazetidine-1- carbonyl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

236

[Image Omitted]

1′-{2-[4-(3-aminoazetidine-1- carbonyl)-3-fluorophenoxy]ethyl}- 5-chloro-1,2-dihydrospiro[indole- 3,4′-piperidin]-2-one

237

[Image Omitted]

N-{l-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- fluorobenzoyl]azetidin-3- yl}methanesulfonamide

238

[Image Omitted]

4-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- fluorobenzamide

239

[Image Omitted]

6-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- fluorobenzoyl]-2λ⁶-thia-6- azaspiro[3.3]heptane-2,2-dione

240

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N-(1,1- dioxo-1λ⁶-thian-4-yl)-2- fluorobenzamide

241

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N-(,1- dioxo-1λ⁶-thiolan-3-yl)-2- fluorobenzamide

242

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N-[(3S) or (3R)-1,1-dioxo-1λ⁶-thiolan-3- yl]-2-fluorobenzamide

243

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N-[(3R) or (3S)-1,1-dioxo-1λ⁶-thiolan-3- yl]-2-fluorobenzamide

244

[Image Omitted]

5-chloro-1′-{2-[4-(3-methyl-1H- pyrazol-4-yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

245

[Image Omitted]

6-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N- methyl-1,2,3,4- tetrahydroisoquinoline-2- carboxamide

246

[Image Omitted]

6-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-N- methyl-1,2,3,4- tetrahydroisoquinoline-2- carboxamide

247

[Image Omitted]

5-chloro-1′-[2-({3-methyl-2-oxo- 1H,2H,3H-imidazo[4,5-b]pyridin- 6-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

248

[Image Omitted]

5-chloro-1′-(2-[(6-{[1- (hydroxymethyl)cyclopropyl] sulfonyl}pyridin-3-yl)oxy]ethyl}- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

249

[Image Omitted]

4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- (difluoromethyl)benzamide

250

[Image Omitted]

4-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- (difluoromethyl)benzamide

251

[Image Omitted]

1′-{2-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]ethyl}-1-methyl-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

252

[Image Omitted]

1′-(2-{4-[3-(3-fluoroazetidine-1- carbonyl)oxetan-3- yl]phenoxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

253

[Image Omitted]

1′-(2-{4-[3-(azetidine-1- carbonyl)oxetan-3- yl]phenoxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

254

[Image Omitted]

3-[4-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- N,N-dimethyloxetane-3- carboxamide

255

[Image Omitted]

3-[4-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]- N-methyloxetane-3-carboxamide

256

[Image Omitted]

5-chloro-1′-{2-[(7-fluoro-2-oxo- 2,3-dihydro-1H-indol-5- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

257

[Image Omitted]

2-[4-(2-{5-cyano-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)phenyl]-2- methylpropanamide

258

[Image Omitted]

5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′- yl}ethoxy)pyrimidine-2- carboxamide

259

[Image Omitted]

4-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2,6- difluorobenzoyl]-1λ⁶- thiomorpholine-1,1-dione

260

[Image Omitted]

1′-{2-[4-(1,1-dioxo-1λ⁶- thiomorpholine-4-carbonyl)-3,5- difluorophenoxy]ethyl}-1-methyl- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

261

[Image Omitted]

1′-{2-[4-(1,1-dioxo-1λ⁶- thiomorpholine-4-carbonyl)-3- (trifluoromethyl)phenoxy]ethyl}- 1-methyl-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

262

[Image Omitted]

1′-{1-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]propan-2-yl}-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

263

[Image Omitted]

(S) or (R)-1′-{l-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]propan-2-yl}-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

264

[Image Omitted]

(R) or (S)-1′-(1-[4-(3- methanesulfonyloxetan-3- yl)phenoxy]propan-2-yl}-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

265

[Image Omitted]

5-chloro-1′-(2-[3- (difluoromethyl)-4- methanesulfonylphenoxy]ethyl}- l-(2-hydroxyethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

266

[Image Omitted]

1′-{2-[3-(difluoromethyl)-4- methanesulfonylphenoxy]ethyl}- l-(2-hydroxyethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

267

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(trans)- 3-hydroxycyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

268

[Image Omitted]

5-chloro-1′-{2-[4-(3-hydroxy-1- methanesulfonylcyclobutyl) phenoxy]ethyl}-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

269

[Image Omitted]

5-chloro-1′-(2-{4-[(cis) or (trans)- 3-hydroxy-1- methanesulfonylcyclobutyl] phenoxy}ethyl)-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

270

[Image Omitted]

5-chloro-1′-(2-{4-[(trans) or (cis)- 3-hydroxy-1- methanesulfonylcyclobutyl] phenoxy}ethyl)-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

271

[Image Omitted]

4-(4-(2-[5-chloro-1-(2- hydroxyethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl]ethoxy}-2- (trifluoromethyl)benzoyl)-1λ⁶- thiomorpholine-1,1-dione

272

[Image Omitted]

4-[4-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-2- (trifluoromethyl)benzoyl]-1λ⁶- thiomorpholine-1,1-dione

273

[Image Omitted]

5-chloro-1′-[2-(3-fluoro-4-{6- methanesulfonyl-2,6- diazaspiro[3.3]heptane-2- carbonyl}phenoxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

274

[Image Omitted]

5-(difluoromethyl)-1′-[2-({7-oxo- 8-[(cis)-3-hydroxy-3- methylcyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

275

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

276

[Image Omitted]

5-chloro-1′-(2-{[2-(3- methanesulfonyloxetan-3- yl)pyrimidin-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

277

[Image Omitted]

5-(difluoromethyl)-1′-{2-[4-(3- hydroxy-1- methanesulfonylcyclobutyl) phenoxy]ethyl}-1-methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

278

[Image Omitted]

5-(difluoromethyl)-1-methyl-1′-(2- {4-[(cis) or (trans)-3-hydroxy-1- methanesulfonylcyclobutyl] phenoxy}ethyl)-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

279

[Image Omitted]

5-(difluoromethyl)-1-methyl-1′-(2- {4-[(trans) or (cis)-3-hydroxy-1- methanesulfonylcyclobutyl] phenoxy}ethyl)-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

280

[Image Omitted]

5-(difluoromethyl)-1′-{2-[4-(3- hydroxy-1- methanesulfonylcyclobutyl) phenoxy]ethyl}-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

281

[Image Omitted]

5-(difluoromethyl)-1′-(2-{4-[(cis) or(trans)-3-hydroxy-1- methanesulfonylcyclobutyl] phenoxy}ethyl)-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

282

[Image Omitted]

5-(difluoromethyl)-1′-(2-{4- [(trans) or (cis)-3-hydroxy-1- methanesulfonylcyclobutyl] phenoxy}ethyl)-1,2-dihydrospiro [indole-3,4′-piperidin]-2-one

283

[Image Omitted]

1′-(2-{[5-fluoro-6-(1- methanesulfonylcyclopropyl) pyridin-3-yl]oxy}ethyl)-2-oxo- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

284

[Image Omitted]

5-chloro-1′-(2-{[2-(1- hydroxyethyl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

285

[Image Omitted]

5-chloro-1′-[2-({2-[(1S) or (1R)-1- hydroxyethyl]pyrimidin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

286

[Image Omitted]

5-chloro-1′-[2-((2-[(1R) or (1S)-1- hydroxyethyl]pyrimidin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

287

[Image Omitted]

5-(difluoromethy1)-1′-[2-({6-[(1S) or (1R)-1-hydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

288

[Image Omitted]

5-(difluoromethyl)-1′-[2-({6-[(1R) or (1S)-1-hydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

289

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]- 1H,2H,4H-pyrido[2,3- d][1,3]oxazin-6-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

290

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(trans)- 3-ethyl-3-hydroxycyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

291

[Image Omitted]

5-chloro-1′-[2-({6-[(1S) or (1R)-1- hydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

292

[Image Omitted]

5-chloro-1′-[2-({6-[(1R) or (1S)-1- hydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

293

[Image Omitted]

5-chloro-1′-{2-[(7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

294

[Image Omitted]

1′-(2-{[6-acetyl-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-5-chloro-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

295

[Image Omitted]

1′-(2-{[6-acetyl-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-5-(difluoromethyl)- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

296

[Image Omitted]

5-(difluoromethyl)-1′-(2-{[6-(1- hydroxyethyl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

297

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(trans)- 3-cyclopropyl-3- hydroxycyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

298

[Image Omitted]

1′-(2-{[6-acetyl-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

299

[Image Omitted]

5-chloro-1′-(2-{[8-(3-cyclopropyl- 3-hydroxycyclobutyl)-7-oxo- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

300

[Image Omitted]

5-chloro-1′-(2-{[2-(3-hydroxy-3- methylazetidin-1-yl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

301

[Image Omitted]

5-chloro-1′-(2-{[2-(3- hydroxyazetidin-1-yl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

302

[Image Omitted]

5-chloro-1′-(2-{[2-(3- methanesulfonylazetidin-1- yl)pyrimidin-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

303

[Image Omitted]

5-chloro-1′-(2-{[2- (dimethylamino)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

304

[Image Omitted]

6-[5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)pyrimidin- 2-yl]-2λ⁶-thia-6- azaspiro[3.3]heptane-2,2-dione

305

[Image Omitted]

5-chloro-1′-(2-{[2-(2- hydroxypropan-2-yl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

306

[Image Omitted]

5-chloro-1′-(2-{[8-(3-hydroxy-3- methylazetidin-1-yl)-1,7- naphthyridin-3-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

307

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(trans)- 3-hydroxy-3-methylcyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

308

[Image Omitted]

5-chloro-1′-(2-{[2-(1- hydroxycyclopropyl)pyrimidin-5- yl]oxy]ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

309

[Image Omitted]

5-(difluoromethyl)-1′-[2-({7-oxo- 8-[(cis) or (trans)-3- (hydroxymethyl)cyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

310

[Image Omitted]

5-(difluoromethyl)-1′-[2-({7-oxo- 8-[(trans) or (cis)-3- (hydroxymethyl)cyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

311

[Image Omitted]

5-(difluoromethyl)-1′-{2-[(7-oxo- 8-{[(cis) or (trans)-3-hydroxy-3- methylcyclobutyl]methyl}-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

312

[Image Omitted]

5-(difluoromethyl)-1′-{2-[(7-oxo- 8-{[(trans) or (cis)-3-hydroxy-3- methylcyclobutyl]methyl}-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

313

[Image Omitted]

5-chloro-1′-{2-[(7-oxo-8-{[(cis) or (trans)-3-hydroxy-3- methyleyclobutyl]methyl}-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

314

[Image Omitted]

5-chloro-1′-(2-{[8-(3- hydroxyazetidin-1-yl)-1,7- naphthyridin-3-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

315

[Image Omitted]

5-chloro-1′-(2-{[8-(3-hydroxy-3- methylcyclobutyl)-7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

316

[Image Omitted]

5-(difluoromethyl)-1′-[2-({8-[3- (hydroxymethyl)cyclobutyl]-7- oxo-5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

317

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-/(cis)-3- hydroxy-3-(propan-2- yl)cyclobuty1]-5,6,7,8-tetrahydro- 1,8-naphthyridin-3-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

318

[Image Omitted]

5-chloro-1′-(2-{[8-(3-ethyl-3- hydroxycyclobutyl)-7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

319

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- (hydroxymethyl)cyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

320

[Image Omitted]

5-(difluoromethyl)-1′-[2-({8-[(3- hydroxy-3- methylcyclobutyl)methyl]-7-oxo- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

321

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- ethyl-3-hydroxycyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

322

[Image Omitted]

5-chloro-1′-{2-[(7-oxo-8-{[(trans) or(cis)-3-hydroxy-3- methylcyclobutyl]methyl}-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

323

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]-7,8- dihydro-1,8-naphthyridin-3- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

324

[Image Omitted]

5-(difluoromethyl)-1′-[2-({7-oxo- 8-[(cis)-3-hydroxy-3- methylcyclobutyl]-7,8-dihydro- 1,8-naphthyridin-3-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

325

[Image Omitted]

5-(difluoromethoxy)-1′-[2-({7- oxo-8-[(cis)-3-hydroxy-3- methylcyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

326

[Image Omitted]

5-chloro-1′-[2-((8-[3- (hydroxymethyl)cyclobutyl]-7- oxo-5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

327

[Image Omitted]

5-chloro-1′-[2-({8-[(3-hydroxy-3- methylcyclobutyl)methyl]-7-oxo- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

328

[Image Omitted]

5-(difluoromethoxy)-1′-[2-({7- oxo-8-[(cis)-3-hydroxy-3- methylcyclobutyl]-7,8-dihydro- 1,8-naphthyridin-3-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

329

[Image Omitted]

5-chloro-7-iodo-1′-[2-({7-oxo-8- [(cis)-3-hydroxy-3- methylcyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

330

[Image Omitted]

5-chloro-1′-(2-{[2-(1,2- dihydroxyethyl)pyrimidin-5- yl]oxy]ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

331

[Image Omitted]

5-chloro-1′-(2-{[2-(2- hydroxyethyl)pyrimidin-5- yl]oxy]ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

332

[Image Omitted]

1′-(2-{[2-(2- hydroxyethyl)pyrimidin-5- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

333

[Image Omitted]

5-chloro-1′-[2-((2-[1- (hydroxymethyl)cyclopropyl] pyrimidin-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

334

[Image Omitted]

5-chloro-1′-(2-{[2-(1-hydroxy-2- methylpropan-2-yl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

335

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(trans)- 3-hydroxy-3-(propan-2- yl)cyclobuty1]-5,6,7,8-tetrahydro- 1,8-naphthyridin-3-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

336

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(trans)- 3-(hydroxymethyl)cyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

338

[Image Omitted]

1′-(2-{[6-(1-hydroxyethyl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

339

[Image Omitted]

5-chloro-1′-(2-{[5- (difluoromethyl)-7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]-7,8- dihydro-1,8-naphthyridin-3- yl]oxy]ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

340

[Image Omitted]

5-(difluoromethyl)-1′-(2-{[5- (difluoromethyl)-7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]-7,8- dihydro-1,8-naphthyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

341

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]-5- (trifluoromethyl)-7,8-dihydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

342

[Image Omitted]

5-(difluoromethyl)-1′-[2-({7-oxo- 8-[(cis)-3-hydroxy-3- methylcyclobutyl]-5- (trifluoromethyl)-7,8-dihydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

343

[Image Omitted]

5-chloro-1′-(2-{4-[1- (dimethylphosphoryl)cyclopropyl] phenoxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

344

[Image Omitted]

5-chloro-1′-[2-({2-[l- (dimethylphosphoryl)cyclopropyl] pyrimidin-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

345

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]- 1H,2H,3H-pyrrolo[2,3-b]pyridin- 5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

346

[Image Omitted]

5-(difluoromethyl)-1′-[2-({2-oxo- 1-[(cis)-3-hydroxy-3- methylcyclobutyl]-1H,2H,3H- pyrrolo[2,3-b]pyridin-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

347

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(trans)- 3-hydroxy-3-methylcyclobutyl]- 1H,2H,3H-pyrrolo[2,3-b]pyridin- 5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

348

[Image Omitted]

5-(difluoromethyl)-1′-[2-({2-oxo- l-[(trans)-3-hydroxy-3- methylcyclobutyl]-1H,2H,3H- pyrrolo[2,3-b]pyridin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

349

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-1H- pyrrolo[2,3-b]pyridin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

350

[Image Omitted]

5-(difluoromethyl)-1′-[2-({1- [(cis)-3-hydroxy-3- methylcyclobutyl]-1H- pyrrolo[2,3-b]pyridin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

351

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-1H- 1,3-benzodiazol-5-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

352

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

353

[Image Omitted]

5-chloro-1[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-8- (trifluoromethyl)-1,2,3,4- tetrahydroquinolin-6- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

354

[Image Omitted]

2-oxo-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-8- (trifluoromethyl)-1,2,3,4- tetrahydroquinolin-6- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

355

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]- 1H,2H-pyrido[2,3-d]pyrimidin-6- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

356

[Image Omitted]

5-chloro-1[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]- 1H,2H,3H,4H-pyrido[2,3- d]pyrimidin-6-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

357

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-1H- pyrazolo[3,4-b]pyridin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

358

[Image Omitted]

5-chloro-1′-[2-({3-oxo-4-[(cis)-3- hydroxy-3-methylcyclobutyl]- 3H,4H-pyrido[2,3-b]pyrazin-7- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

359

[Image Omitted]

5-chloro-1[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-1,2- dihydroquinoxalin-6- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

360

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-8- (trifluoromethyl)-1,2- dihydroquinoxalin-6- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

361

[Image Omitted]

5-chloro-1′-(2-{[4-(3-hydroxy-3- methylcyclobutyl)pyrido[3,2- d]pyrimidin-7-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

362

[Image Omitted]

5-chloro-1′-(2-{[8-(3-hydroxy-3- methylcyclobutyl)-1,7- naphthyridin-3-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

363

[Image Omitted]

5-chloro-1′-(2-{[8-(3-hydroxy-3- methylazetidin-1-yl)pyrido[2,3- d]pyridazin-3-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

364

[Image Omitted]

5-chloro-1′-(2-{[4-(3-hydroxy-3- methylazetidin-1-yl)pyrido[3,2- d]pyrimidin-7-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

365

[Image Omitted]

5-chloro-1′-(2-{[8-(3- hydroxyazetidin-1-yl)pyrido[2,3- d]pyridazin-3-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

366

[Image Omitted]

5-chloro-1′-(2-{[4-(3- hydroxyazetidin-1-yl)pyrido[3,2- d]pyrimidin-7-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

367

[Image Omitted]

5-chloro-1′-[2-((3-[(cis)-3- hydroxy-3-methylcyclobutyl]-3H- imidazo[4,5-b]pyridin-6- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

368

[Image Omitted]

5-chloro-1′-(2-{[2-(1,2- dihydroxypropan-2-yl)pyrimidin- 5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

369

[Image Omitted]

5-chloro-1′-(2-((6-(1,2- dihydroxyethyl)-5- (trifluoromethyl)pyridin-3- yl)oxy)ethyl)spiro[indoline-3,4′- piperidin]-2-one

370

[Image Omitted]

5-chloro-1′-(2-{[6-(1,2- dihydroxypropan-2-yl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

371

[Image Omitted]

5-chloro-1′-(2-{[6-(2- hydroxypropan-2-yl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

372

[Image Omitted]

5-chloro-1′-(2-{[6-(1- hydroxycyclopropyl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

373

[Image Omitted]

5-chloro-1′-(2-{[2-(3-hydroxy-3- methylcyclobutyl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

374

[Image Omitted]

5-chloro-1′-[2-({2-oxo-3-[(cis)-3- hydroxy-3-methylcyclobutyl]- 1H,2H,3H-imidazo[4,5-b]pyridin- 6-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

375

[Image Omitted]

5-chloro-1′-[2-((8-[3- (hydroxymethyl)azetidin-1-y1]- 1,7-naphthyridin-3-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

376

[Image Omitted]

1′-[2-({6-[(1S) or (1R)-1- hydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

377

[Image Omitted]

1′-[2-({6-[(1R) or (1S)-1- hydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

378

[Image Omitted]

5-chloro-1′-[2-({2-[(1S) or (1R)- 1,2-dihydroxyethyl]pyrimidin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

379

[Image Omitted]

5-chloro-1′-[2-((2-[(1R) or (1S)- 1,2-dihydroxyethyl]pyrimidin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

380

[Image Omitted]

5-chloro-1′-[2-({2-[(2S) or (2R)- 1,2-dihydroxypropan-2- yl]pyrimidin-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

381

[Image Omitted]

5-chloro-1′-[2-({2-[(2R) or (2S)- 1,2-dihydroxypropan-2- yl]pyrimidin-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

382

[Image Omitted]

5-chloro-1′-[2-({6-[(1S) or (1R)- 1,2-dihydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

383

[Image Omitted]

5-chloro-1′-[2-({6-[(1R) or (1S)- 1,2-dihydroxyethyl]-5- (trifluoromethyl)pyridin-3- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

384

[Image Omitted]

5-chloro-1′-[2-({6-[(2S) or (2R)- 1,2-dihydroxypropan-2-yl]-5- (trifluoromethyl)pyridin-3- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

385

[Image Omitted]

5-chloro-1′-[2-({6-[(2R) or (2S)- 1,2-dihydroxypropan-2-yl]-5- (trifluoromethyl)pyridin-3- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

386

[Image Omitted]

5-chloro-1′-[2-((8-[(cis) or (trans)-3-hydroxy-3- methylcyclobutyl]-1,7- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

387

[Image Omitted]

5-chloro-1′-[2-({8-[(trans) or (cis)-3-hydroxy-3- methylcyclobutyl]-1,7- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

388

[Image Omitted]

5-chloro-1′-[2-({4-[(cis) or (trans)-3-hydroxy-3- methylcyclobutyl]pyrido[3,2- d]pyrimidin-7-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

389

[Image Omitted]

5-chloro-1′-[2-({4-[(trans) or (cis)-3-hydroxy-3- methylcyclobutyl]pyrido[3,2- d]pyrimidin-7-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

390

[Image Omitted]

5-chloro-1′-[2-((8-L(cis) or (trans)-3-hydroxy-3- methylcyclobutyl]pyrido[2,3- d]pyridazin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

391

[Image Omitted]

5-chloro-1′-[2-({8-[(trans) or (cis)-3-hydroxy-3- methylcyclobutyl]pyrido[2,3- d]pyridazin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

392

[Image Omitted]

5-chloro-1′-[2-({2-[(cis) or (trans)-3-hydroxy-3- methylcyclobutyl]pyrimidin-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

393

[Image Omitted]

5-chloro-1′-[2-({2-[(trans) or (cis)-3-hydroxy-3- methylcyclobutyl]pyrimidin-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

394

[Image Omitted]

5-chloro-1′-[2-({2-oxo-3-[(cis)-3- hydroxy-3-methylcyclobutyl]- 2H,3H-[1,3]oxazolo[4,5- b]pyridin-6-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

395

[Image Omitted]

5-(difluoromethyl)-1′-(2-{[2-(3- hydroxy-3-methylazetidin-1- yl)pyrimidin-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

396

[Image Omitted]

5-chloro-1′-{2-[(2-{6-hydroxy-2- azaspiro[3.3]heptan-2- yl}pyrimidin-5-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

397

[Image Omitted]

5-chloro-1′-(2-{[2-(3-ethyl-3- hydroxyazetidin-1-yl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

398

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- cyclopropyl-3- hydroxycyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

399

[Image Omitted]

5-chloro-1′-(2-{[6-(1- hydroxyethyl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

400

[Image Omitted]

5,7-dichloro-1′-(2-{[2-(1- methanesulfonylcyclopropyl) pyrimidin-5-yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

401

[Image Omitted]

5-chloro-1′-(2-{[6-(1-hydroxy-2- methanesulfonylpropan-2-yl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

402

[Image Omitted]

5-chloro-1′-[2-({6-[(2S or 2R)-1- hydroxy-2- methanesulfonylpropan-2-yl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

403

[Image Omitted]

5-chloro-1′-[2-({6-[(2R or 2S)-1- hydroxy-2- methanesulfonylpropan-2-yl]-5- (trifluoromethyl)pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

404

[Image Omitted]

2-oxo-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

405

[Image Omitted]

5-chloro-1′-(2-{[6-(3-hydroxy-3- methylazetidin-1-yl)-5- (trifluoromethyl)pyridin-3- yl]oxy]ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

406

[Image Omitted]

2-oxo-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]-7,8- dihydro-1,8-naphthyridin-3- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

407

[Image Omitted]

5-chloro-1′-(2-{[l-(3-hydroxy-3- methylcyclobutyl)-1H- pyrazolo[3,4-b]pyridin-5- yl]oxy]ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

408

[Image Omitted]

5-chloro-1′-[2-({1-[(trans)-3- hydroxy-3-methylcyclobutyl]-1H- pyrazolo[3,4-b]pyridin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

409

[Image Omitted]

5,7-dichloro-1′-[2-({7-oxo-8- [(cis)-3-hydroxy-3- methylcyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

410

[Image Omitted]

2-oxo-1′-[2-({1-[(cis)-3-hydroxy- 3-methylcyclobutyl]-1H- pyrrolo[2,3-b]pyridin-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

411

[Image Omitted]

1′-(2-{[6-(2-hydroxypropan-2-yl)- 5-(trifluoromethyl)pyridin-3- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

412

[Image Omitted]

5-chloro-1′-{2-[4-(1- methanesulfonylpiperidin-4- yl)phenoxy]ethyl}-1-(²H₃)methyl- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

413

[Image Omitted]

5-chloro-1-(²H₃)methyl-1′-(2-{4- [methyl(methylimino)oxo-λ⁶- sulfanyl]-3- (trifluoromethyl)phenoxy}ethyl)- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

414

[Image Omitted]

5-chloro-1-(²H₃)methyl-1′-(2-{4- [3-(propane-2-sulfonyl)oxetan-3- yl]phenoxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

415

[Image Omitted]

5-chloro-1′-{2-[4-(1- methanesulfonylcyclobutyl) phenoxy]ethyl}-1-(²H₃)methyl- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

416

[Image Omitted]

5-chloro-1-(²H₃)methyl-1′-{2-[(2- methyl-1-oxo-2,3-dihydro-1H- isoindol-5-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

417

[Image Omitted]

5-chloro-1′-(2-{[8-(2-hydroxy-2- methylpropyl)-7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl]oxy}ethyl)-1-(²H₃)methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

418

[Image Omitted]

5-chloro-1′-[2-(4- methanesulfonylphenoxy)ethyl]-1- (²H₃)methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

419

[Image Omitted]

5-chloro-1-(²H₃)methyl-1′-[2-({7- oxo-8-[(cis)-3-hydroxy-3- methylcyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

420

[Image Omitted]

5-chloro-1′-[2-({2-[l- (hydroxymethyl)cyclopropyl] pyrimidin-5-yl}oxy)ethyl]-1- (²H₃)methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

421

[Image Omitted]

6-{2-[5-chloro-1-(²H₃)methyl-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl]ethoxy}-8-fluoro- 3,4-dihydro-2H-1λ6,2- benzothiazine-1,1-dione

422

[Image Omitted]

5-chloro-1′-(2-{[2-(3- methanesulfonyloxetan-3- yl)pyrimidin-5-yl]oxy}ethyl)-1- (²H₃)methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

423

[Image Omitted]

5-chloro-1-(²H₃)methyl-1′-[2-({7- oxo-8-[(cis)-3- hydroxycyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

424

[Image Omitted]

5-chloro-1′-(2-{[2-(1- methanesulfonylcyclopropyl) pyrimidin-5-yl]oxy}ethyl)-1- (²H₃)methyl-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

425

[Image Omitted]

5-chloro-1′-(2-{[2-(1- methanesulfonylethyl)pyrimidin- 5-yl]oxy}ethyl)-1-(²H₃)methyl- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

426

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3-methylcyclobutyl]- 5,6,7,8-tetrahydro-1,8- naphthyridin-3-yl}oxy)(1,1,2,2- ²H₄)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

427

[Image Omitted]

5-chloro-1′-[2-({2-(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-2H-indazol-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

428

[Image Omitted]

2-oxo-1′-[2-({2-[(cis)-3-hydroxy- 3-methylcyclobutyl]-7- (trifluoromethyl)-2H-indazol-5- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

429

[Image Omitted]

5-chloro-1′-(2-{[2-(3- hydroxyoxetan-3-yl)pyrimidin-5- yl]oxy]ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

430

[Image Omitted]

5-chloro-1′-(2-{[2-(1- hydroxycyclobutyl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

431

[Image Omitted]

1′-(2-{[6-(3-hydroxy-3- methylazetidin-1-yl)-5- (trifluoromethyl)pyridin-3- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

432

[Image Omitted]

1′-(2-{[2-(1-hydroxy-2- methylpropan-2-yl)pyrimidin-5- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

433

[Image Omitted]

2-oxo-1′-[2-({1-[(cis)-3-hydroxy- 3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

434

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,2,3- benzotriazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

435

[Image Omitted]

2-oxo-1′-[2-({1-[(cis)-3-hydroxy- 3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,2,3- benzotriazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

436

[Image Omitted]

1′-(2-{[1-(3-hydroxy-3- methylcyclobutyl)-1H- pyrazolo[3,4-b]pyridin-5- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

437

[Image Omitted]

2-oxo-1′-[2-({1-[(cis)-3-hydroxy- 3-methylcyclobutyl]-1H- pyrazolo[3,4-b]pyridin-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

438

[Image Omitted]

1′-(2-{[1-(3-hydroxy-3- methylcyclobutyl)-1H- pyrazolo[3,4-b]pyridin-5- yl]oxy}ethyl)-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

439

[Image Omitted]

5-(2-{5-chloro-2-oxo-1,2- dihydrospiro[indole-3,4′- piperidin]-1′-yl}ethoxy)-1-[(cis)- 3-hydroxy-3-methylcyclobutyl]- 1H-1,3-benzodiazole-7- carbonitrile

440

[Image Omitted]

5-chloro-1′-[2-({3-[(cis)-3- hydroxy-3-methylcyclobutyl]-3H- [1,2,3]triazolo[4,5-b]pyridin-6- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

441

[Image Omitted]

5-chloro-1′-(2-{[2-(2,2-dimethyl- 1,3-dioxolan-4-yl)pyrimidin-5- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

442

[Image Omitted]

5-chloro-1′-[2-({2-methyl-1-[(cis)- 3-hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

443

[Image Omitted]

1′-[2-({2-methyl-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)ethyl]-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

444

[Image Omitted]

5-chloro-1′-{2-[4-(1- methanesulfonylpiperidin-4- yl)phenoxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

445

[Image Omitted]

5-chloro-1′-(2-{[7- (difluoromethyl)-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-1H- 1,3-benzodiazol-5-yl]oxy}ethyl)- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

446

[Image Omitted]

1′-(2-{[7-(difluoromethyl)-1- [(cis)-3-hydroxy-3- methylcyclobutyl]-1H-1,3- benzodiazol-5-yl]oxy}ethyl)-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

447

[Image Omitted]

5-chloro-1′-(2-{[7- (difluoromethoxy)-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-1H- 1,3-benzodiazol-5-yl]oxy}ethyl)- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

448

[Image Omitted]

1′-(2-{[7-(difluoromethoxy)-1- [(cis)-3-hydroxy-3- methylcyclobutyl]-1H-1,3- benzodiazol-5-yl]oxy}ethyl)-2- oxo-1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

449

[Image Omitted]

5-chloro-1′-(2-{[2-(2- hydroxypropan-2-yl)pyrimidin-5- yl]oxy}ethyl)-7-iodo-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

450

[Image Omitted]

5-(difluoromethyl)-1′-[2-({1- [(cis)-3-hydroxy-3- methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

451

[Image Omitted]

5-chloro-1′-[2-({2-methyl-3-[(cis)- 3-hydroxy-3-methylcyclobutyl]- 3H-imidazo[4,5-b]pyridin-6- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

452

[Image Omitted]

5-chloro-1′-(2-{[8-(2-hydroxy-2- methylpropyl)-7-oxo-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl]oxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

453

[Image Omitted]

5-chloro-7-iodo-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

454

[Image Omitted]

5-chloro-1′-[2-({7-fluoro-1-[(cis)- 3-hydroxy-3-methylcyclobutyl]- 1H-1,3-benzodiazol-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

455

[Image Omitted]

1′-[2-({7-fluoro-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-1H- 1,3-benzodiazol-5-yl}oxy)ethyl]- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

456

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-8- (trifluoromethyl)-1,2,3,4- tetrahydroquinazolin-6- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

457

[Image Omitted]

2-oxo-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-8- (trifluoromethyl)-1,2,3,4- tetrahydroquinazolin-6- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

458

[Image Omitted]

5-chloro-1′-[2-({7,7-dimethyl-5- oxo-5H,7H-furo[3,4-b]pyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

459

[Image Omitted]

5-chloro-1′-{2-[(2-{6-hydroxy-6- methyl-2-azaspiro[3.3]heptan-2- yl}pyrimidin-5-yl)oxy]ethyl}-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

460

[Image Omitted]

5-chloro-1′-(2-{2′-oxo-1′-[(cis)-3- hydroxy-3-methylcyclobutyl]- 1′,2′-dihydrospiro[cyclopropane- 1,3′-pyrrolo[2,3-b]pyridin]-5′- yloxy}ethyl)-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

461

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3- (²H₃)methylcyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

462

[Image Omitted]

5-chloro-1′-[2-({7-oxo-8-[(cis)-3- hydroxy-3- (²H₃)methylcyclobutyl]-5,6,7,8- tetrahydro-1,8-naphthyridin-3- yl}oxy)(1,1,2,2-²H₄)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

463

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)(1,1,2,2- ²H₄)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

464

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-indazol-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

465

[Image Omitted]

2-oxo-1′-[2-({1-[(cis)-3-hydroxy- 3-methylcyclobutyl]-7- (trifluoromethyl)-1H-indazol-5- yl]oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

466

[Image Omitted]

5-chloro-1′-[2-({2-[(1r,3s)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-1,3- benzodiazol-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

467

[Image Omitted]

5-chloro-1′-(2-{[3- (hydroxymethyl)-2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-2,3-dihydro-1H- 1,3-benzodiazol-5-yl]oxy}ethyl)- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

468

[Image Omitted]

5-chloro-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-2,3-dihydro-1H- 1,3-benzodiazol-5-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidin]-2-one

469

[Image Omitted]

1′-(2-{[3-(hydroxymethyl)-2-oxo- 1-[(cis)-3-hydroxy-3- methylcyclobutyl]-7- (trifluoromethyl)-2,3-dihydro-1H- 1,3-benzodiazol-5-yl]oxy}ethyl)- 2-oxo-1,2-dihydrospiro[indole- 3,4′-piperidine]-5-carbonitrile

470

[Image Omitted]

2-oxo-1′-[2-({2-oxo-1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-2,3-dihydro-1H- 1,3-benzodiazol-5-yl}oxy)ethyl]- 1,2-dihydrospiro[indole-3,4′- piperidine]-5-carbonitrile

471

[Image Omitted]

5-chloro-1′-[2-({1-[(cis)-3- hydroxy-3-methylcyclobutyl]-7- (trifluoromethyl)-1H-imidazo[4,5- b]pyridin-5-yl}oxy)ethyl]-1,2- dihydrospiro[indole-3,4′- piperidin]-2-one

472

[Image Omitted]

5-chloro-1′-(2-{3-[(cis)-3- hydroxy-3-methylcyclobutyl]-4- (trifluoromethy1)-3H-1,3,5- triazainden-6- yloxy}ethyl)spiro[indoline-3,4′- piperidin]-2-one

In some embodiments, a compound of formula (I) is selected from the group consisting of:

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(2-methoxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-bromo-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(1-methyl-1H-indazol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-bromo-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(2-methoxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(2-methoxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one; 1-[2-(4-methanesulfonylphenoxy)ethyl]-1′,2′-dihydrospiro[azepane-4,3′-indol]-2′-one;

1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)propyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methyl-1H-indazol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-difluoromethanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3,5-difluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one; 1-(3-hydroxycyclobutyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-methanesulfonylpropanesulfonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(cyclopropanesulfonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5,7-dichloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[4-(2-oxopyrrolidin-1-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-[2-(quinoxalin-6-yloxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(2-{1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,3-dihydro-1lambda6-benzothiophene-1,1-dione;

5-chloro-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(oxetan-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

7-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(propan-2-yl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-methanesulfonylpropyl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(6-methanesulfonylpyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)propyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-methanesulfonylpropanesulfonyl)phenoxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[4-(1-methyl-1H-pyrazol-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(3-fluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-7-carbonitrile;

5-chloro-1′-(2-{4-[(3-hydroxycyclobutyl)sulfonyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(oxetan-3-yl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(2-hydroxyethanesulfonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{1-[(1-methyl-1H-indazol-5-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-5-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(quinoxalin-6-yloxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3,5-difluoro-4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(3-methyl-1H-pyrazol-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(3,5-difluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methanesulfonyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(1H-indazol-5-yloxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one; 6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-1,2,3,4-tetrahydroquinoline-1-carboxamide;

1′-{2-[(2-acetyl-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonyl-3-methylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-difluoromethanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-difluoromethanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

N-{2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]ethyl}-N-methylacetamide;

5-chloro-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonyl-3-methylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[(3-methyloxetan-3-yl)sulfonyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxamide;

5-chloro-1′-(2-{[1-(3-hydroxycyclobutyl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,3-dihydro-1lambda6-benzothiophene-1,1-dione;

1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[(3-hydroxycyclobutyl)sulfonyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxycyclobutyl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-2,3-dihydro-1H-isoindole-2-carboxamide;

1′-(2-{4-[(3-methyloxetan-3-yl)sulfonyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-(2-fluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-(2-{[2-oxo-1-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(1-methanesulfonylcyclopropyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-oxo-1-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{1-[3-(difluoromethyl)-4-methanesulfonylphenoxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(1-methanesulfonylcyclopropyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{1-[3-(difluoromethyl)-4-methanesulfonylphenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1-(3-hydroxycyclobutyl)-1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-methylmethanesulfonamide;

N-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-methylmethanesulfonamide;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-methanesulfonylbenzonitrile;

5-chloro-1′-(2-{[1-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-methanesulfonyl-3-(trifluoromethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-methanesulfonyl-3-(trifluoromethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

methyl 1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]cyclopropane-1-carboxylate;

1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-1-(2-hydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-1-(2-hydroxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[1-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1-(3-hydroxycyclobutyl)-1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-{2-[(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzamide;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)pyridine-2-carboxamide;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-1-methyl-3,4-dihydro-1H-2lambda6,1-benzothiazine-2,2-dione;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]methanesulfonamide;

1′-{2-[(1-methyl-2,2-dioxo-3,4-dihydro-1H-2lambda6,1-benzothiazin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(oxetan-3-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(3-hydroxycyclobutyl)-1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1-(3-hydroxycyclobutyl)-1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(3-hydroxycyclobutyl)-1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-{[1-(hydroxymethyl)cyclopropyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3-fluoro-4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(8-methyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(8-methyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-[2-(4-methanesulfonyl-3,5-dimethylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

6-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxamide;

5-chloro-1′-(2-{[1-(3-hydroxycyclobutyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonyl-3,5-dimethylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(1-cyano-1-methylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-(2-{[2-oxo-1-(propan-2-yl)-2,3-dihydro-1H-indol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(6-methanesulfonyl-5-methylpyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(6-methanesulfonyl-5-methylpyridin-3-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(8-acetyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(8-acetyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-methanesulfonyl-3-(oxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-(3-chloro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3-chloro-4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-oxo-1-(propan-2-yl)-2,3-dihydro-1H-indol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-[1-(3,5-difluoro-4-methanesulfonylphenoxy)propan-2-yl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-methylbenzamide;

5-chloro-1′-{2-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluoro-N,N-dimethylbenzamide;

5-chloro-1′-{2-[3-fluoro-4-(morpholine-4-carbonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one; 4-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzoyl]-1lambda6-thiomorpholine-1,1-dione;

1′-[2-(4-{[1-(azetidine-1-carbonyl)cyclopropyl]sulfonyl}phenoxy)ethyl]-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-fluoro-4-(3-methanesulfonylazetidine-1-carbonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-methyl-3,4-dihydro-2H-1lambda6,2-benzothiazine-1,1-dione;

1′-{2-[(2-methyl-1,1-dioxo-3,4-dihydro-2H-1lambda6,2-benzothiazin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(azetidine-1-carbonyl)-3-fluorophenoxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-fluoro-4-(3-hydroxyazetidine-1-carbonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,6-difluorophenyl]-N-methylmethanesulfonamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluoro-N-methylbenzamide;

1-(2-hydroxyethyl)-1′-{2-[4-methanesulfonyl-3-(trifluoromethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

N-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,6-difluorophenyl]-N-methylmethanesulfonamide;

1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]-N-methylcyclopropane-1-carboxamide;

5-chloro-1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]-N,N-dimethylcyclopropane-1-carboxamide;

1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[3-(1,2-dihydroxyethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N,N-dimethylpyridine-2-carboxamide;

4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzamide;

1′-{2-[4-(3-aminoazetidine-1-carbonyl)-3-fluorophenoxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({6-[(3-methyloxetan-3-yl)sulfonyl]pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxycyclobutyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N-{1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzoyl]azetidin-3-yl}methanesulfonamide;

1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methylbenzamide;

1′-(2-{4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(2-hydroxyethyl)-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{4-[methyl(methylimino)oxo-lambda6-sulfanyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-[2-(4-{[dimethyl(oxo)-lambda6-sulfanylidene]amino}phenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(1-methanesulfonylcyclobutyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[3-(difluoromethoxy)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[3-(difluoromethoxy)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(6-{[1-(hydroxymethyl)cyclopropyl]sulfonyl}pyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(7-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(4-methanesulfonyloxan-4-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(4-methanesulfonyloxan-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{3-oxo-3H-spiro[2-benzofuran-1,3′-oxetan]-5-yloxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)-3-(trifluoromethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N-(4-{2-[5-chloro-1-(2-hydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl]ethoxy}-2-(trifluoromethyl)phenyl)methanesulfonamide;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)-3-(trifluoromethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-3,4-dihydro-2H-1lambda6,2-benzothiazine-1,1-dione;

2-oxo-1′-{2-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1,1-dioxo-3,4-dihydro-2H-1lambda6,2-benzothiazin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

3-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-methyloxetane-3-carboxamide;

3-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N,N-dimethyloxetane-3-carboxamide;

2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-1lambda6-thiolane-1,1-dione;

2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-1lambda6-thiolane-1,1-dione;

1′-[2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{4-[3-(azetidine-1-carbonyl)oxetan-3-yl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)pyrimidine-2-carboxamide;

2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-1lambda6-thiolane-1,1-dione;

1′-(2-{4-[3-(ethanesulfonyl)oxetan-3-yl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-2-methylpropanamide;

1′-{2-[4-(1,1-dioxo-1lambda6-thiolan-2-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide;

1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-[2-({2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-yl}oxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{4-[3-(3-fluoroazetidine-1-carbonyl)oxetan-3-yl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide;

5-chloro-1′-[2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-(2-hydroxyethyl)methanesulfonamide;

6-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzoyl]-2lambda6-thia-6-azaspiro[3.3]heptane-2,2-dione;

5-chloro-1′-[2-(3-fluoro-4-{6-methanesulfonyl-2,6-diazaspiro[3.3]heptane-2-carbonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,6-difluorobenzoyl]-1lambda6-thiomorpholine-1,1-dione;

5-chloro-1′-(2-{[8-(2-hydroxyethyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(1,1-dioxo-1lambda6-thiomorpholine-4-carbonyl)-3,5-difluorophenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

4-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(trifluoromethyl)benzoyl]-1lambda6-thiomorpholine-1,1-dione;

1′-{2-[4-(1,1-dioxo-1lambda6-thiomorpholine-4-carbonyl)-3-(trifluoromethyl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxycyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(4-{2-[5-chloro-1-(2-hydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl]ethoxy}-2-(trifluoromethyl)benzoyl)-1lambda6-thiomorpholine-1,1-dione;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-(1,1-dioxo-1lambda6-thiolan-3-yl)-2-fluorobenzamide;

5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-(1,1-dioxo-1lambda6-thian-4-yl)-2-fluorobenzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-(1,1-dioxo-1lambda6-thiolan-3-yl)-2-fluorobenzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-(1,1-dioxo-1lambda6-thiolan-3-yl)-2-fluorobenzamide;

5-chloro-1′-(2-{[8-(3-hydroxycyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethoxy)-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[3-hydroxy-3-methylcyclobutyl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-cyclopropyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-cyclopropyl-3-hydroxycyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[3-(hydroxymethyl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-{2-[(7-oxo-8-{[3-hydroxy-3-methylcyclobutyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(7-oxo-8-{[3-hydroxy-3-methylcyclobutyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({8-[3-(hydroxymethyl)cyclobutyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-hydroxy-3-(propan-2-yl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-ethyl-3-hydroxycyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-(hydroxymethyl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({8-[(3-hydroxy-3-methylcyclobutyl)methyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethoxy)-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[3-(hydroxymethyl)cyclobutyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[(3-hydroxy-3-methylcyclobutyl)methyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethoxy)-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-7-iodo-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-hydroxy-3-(propan-2-yl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-(hydroxymethyl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[6-(1-hydroxyethyl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[6-(1-hydroxyethyl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[5-(difluoromethyl)-7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[5-(difluoromethyl)-7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-7, 8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({2-oxo-1-[3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({2-oxo-1-[3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[3-hydroxy-3-methylcyclobutyl]-1H,2H-pyrido[2,3-d]pyrimidin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[3-hydroxy-3-methylcyclobutyl]-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[3-hydroxy-3-methylcyclobutyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-oxo-4-[3-hydroxy-3-methylcyclobutyl]-3H,4H-pyrido[2,3-b]pyrazin-7-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[4-(3-hydroxy-3-methylcyclobutyl)pyrido[3,2-d]pyrimidin-7-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylazetidin-1-yl)pyrido[2,3-d]pyridazin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[4-(3-hydroxy-3-methylazetidin-1-yl)pyrido[3,2-d]pyrimidin-7-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)pyrido[2,3-d]pyridazin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[4-(3-hydroxyazetidin-1-yl)pyrido[3,2-d]pyrimidin-7-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-[3-hydroxy-3-methylcyclobutyl]-3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-3-[3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[3-(hydroxymethyl)azetidin-1-yl]-1,7-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-2H,3H-[1,3]oxazolo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(3-ethyl-3-hydroxyazetidin-1-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-cyclopropyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[6-(1-hydroxyethyl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5,7-dichloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[6-(1-hydroxy-2-methanesulfonylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[6-(1-hydroxy-2-methanesulfonylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[6-(1-hydroxy-2-methanesulfonylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[6-(3-hydroxy-3-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-7-oxo-7,8-dihydro-1,8-naphthyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5,7-dichloro-1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(1-methanesulfonylpiperidin-4-yl)phenoxy]ethyl}-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(2H3)methyl-1′-(2-{4-[methyl(methylimino)oxo-lambda6-sulfanyl]-3-(trifluoromethyl)phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(2H3)methyl-1′-(2-{4-[3-(propane-2-sulfonyl)oxetan-3-yl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(2H3)methyl-1′-{2-[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(2-hydroxy-2-methylpropyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[1-(hydroxymethyl)cyclopropyl]pyrimidin-5-yl}oxy)ethyl]-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

6-{2-[5-chloro-1-(2H3)methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl]ethoxy}-8-fluoro-3,4-dihydro-2H-1lambda6,2-benzothiazine-1,1-dione;

5-chloro-1′-(2-{[2-(3-methanesulfonyloxetan-3-yl)pyrimidin-5-yl]oxy}ethyl)-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxycyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1-(2H3)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}(1,1,2,2-2H4)ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-2H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[2-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-2H-indazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-(3-hydroxyoxetan-3-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-hydroxycyclobutyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[6-(3-hydroxy-3-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,2,3-benzotriazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,2,3-benzotriazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzodiazole-7-carbonitrile;

5-chloro-1′-(2-{[3-(3-hydroxy-3-methylcyclobutyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-2-methyl-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(1-methanesulfonylpiperidin-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[7-(difluoromethyl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[7-(difluoromethyl)-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[7-(difluoromethoxy)-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[7-(difluoromethoxy)-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-7-iodo-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[3-(3-hydroxy-3-methylcyclobutyl)-2-methyl-3H-imidazo[4,5-b]pyridin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(2-hydroxy-2-methylpropyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-7-iodo-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[7-fluoro-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[7-fluoro-1-(3-hydroxy-3-methylcyclobutyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-2-oxo-8-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-2-oxo-8-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({7,7-dimethyl-5-oxo-5H,7H-furo[3,4-b]pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[1′-(3-hydroxy-3-methylcyclobutyl)-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[2,3-b]pyridin]-5′-yloxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[3-hydroxy-3-(2H3)methylcyclobutyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[3-hydroxy-3-(2H3)methylcyclobutyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)(1,1,2,2-2H4)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]oxy}(1,1,2,2-2H4)ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one; 1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-indazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-3-(hydroxymethyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-3-(hydroxymethyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one; and

5-chloro-1′-(2-{3-[(3-hydroxy-3-methylcyclobutyl]-4-(trifluoromethyl)-3H-1,3,5-triazainden-6-yloxy}ethyl)spiro[indoline-3,4′-piperidin]-2-one.

In some embodiments, a compound of formula (I) is selected from the group consisting of:

5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(1S)-1-methanesulfonylethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(1R)-1-methanesulfonylethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethoxy)-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5,7-dichloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

7-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-7-carbonitrile;

5-chloro-1′-[(2S)-1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[(2S)-2-(4-methanesulfonylphenoxy)propyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[(2S)-1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[(2S)-2-(4-methanesulfonylphenoxy)propyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(3-methanesulfonylpropyl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(oxetan-3-yl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(propan-2-yl)-1H-indazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-{[(cis)-3-hydroxycyclobutyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-[(cis)-3-hydroxycyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(2-methoxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(2-methoxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(oxetan-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-methanesulfonylpropanesulfonyl)phenoxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-bromo-1-(2-hydroxyethyl)-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(2-methoxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1-[2-(4-methanesulfonylphenoxy)ethyl]-1′,2′-dihydrospiro[azepane-4,3′-indol]-2′-one;

5-chloro-1′-{2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[4-(1-methyl-1H-pyrazol-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(2-{1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,3-dihydro-1λ⁶-benzothiophene-1,1-dione;

1-methyl-1′-{2-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-[2-(quinoxalin-6-yloxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-methyl-1′-{2-[4-(2-oxopyrrolidin-1-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[(1S)-1-methanesulfonylethyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[(1R)-1-methanesulfonylethyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-methanesulfonylpropanesulfonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3,5-difluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(cyclopropanesulfonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-difluoromethanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzamide;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)pyridine-2-carboxamide;

5-chloro-1′-[2-(2-fluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-methylbenzamide;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-methanesulfonylbenzonitrile;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N,N-dimethylpyridine-2-carboxamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methylbenzamide;

5-chloro-1′-{2-[(1-methanesulfonyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(2-acetyl-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-1,2,3,4-tetrahydroquinoline-1-carboxamide;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-2,3-dihydro-1H-isoindole-2-carboxamide;

5-chloro-1′-[2-(quinoxalin-6-yloxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(3-fluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(6-methanesulfonylpyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-5-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methyl-1H-indazol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1-methyl-1H-indazol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-bromo-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-″one;

1′-[2-(4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3-fluoro-4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

N-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-methylmethanesulfonamide;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-methylmethanesulfonamide;

1′-[2-(4-{[dimethyl(oxo)-λ⁶-sulfanylidene]amino}phenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(8-methyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(8-methyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(8-acetyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(8-acetyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-{2-[(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({1-[(cis)-3-hydroxycyclobutyl]-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(trans)-3-hydroxycyclobutyl]-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(1H-indazol-5-yloxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(3,5-difluoro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3,5-difluoro-4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

methyl 1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]cyclopropane-1-carboxylate;

5-chloro-1′-(2-{4-[(3-methyloxetan-3-yl)sulfonyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{4-[(3-methyloxetan-3-yl)sulfonyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-(2-{[2-oxo-1-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-oxo-1-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-(2-hydroxyethyl)methanesulfonamide;

5-chloro-1′-(2-{[1-(oxetan-3-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(1-methanesulfonylcyclopropyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(1-methanesulfonylcyclopropyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-1-methyl-3,4-dihydro-1H-2λ⁶,1-benzothiazine-2,2-dione;

1′-{2-[(1-methyl-2,2-dioxo-3,4-dihydro-1H-2)_6,1-benzothiazin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-methanesulfonyl-3-(trifluoromethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-methanesulfonyl-3-(trifluoromethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-(4-methanesulfonyl-3-methylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonyl-3-methylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-(4-difluoro-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-difluoromethanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(S)-5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(R)-5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(S)-2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(R)-2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-imidazo[4,3-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(S)-5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(R)-5-chloro-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({3-oxo-1H,2H,3H,5H,6H,10bH-pyrrolo[2,1-a]isoquinolin-8-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(S)-2-oxo-1′-(2-((3-oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-8-yl)oxy)ethyl)spiro[indoline-3,4′-piperidine]-5-carbonitrile;

(R)-2-oxo-1′-(2-((3-oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-8-yl)oxy)ethyl)spiro[indoline-3,4′-piperidine]-5-carbonitrile;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,6-difluorophenyl]-N-methylmethanesulfonamide;

N-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,6-difluorophenyl]-N-methylmethanesulfonamide;

5-chloro-1′-[2-(4-methanesulfonyl-3,5-dimethylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-methanesulfonyl-3,5-dimethylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(S)-1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(R)-1′-{2-[4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(S)-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(R)-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(6-methanesulfonyl-5-methylpyridin-3-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(S)-5-chloro-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(R)-5-chloro-1′-{2-[3,5-difluoro-4-(1-methanesulfonylethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-(2-{[2-oxo-1-(propan-2-yl)-2,3-dihydro-1H-indol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-oxo-1-(propan-2-yl)-2,3-dihydro-1H-indol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(S)-5-chloro-1′-(2-{4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

(R)-5-chloro-1′-(2-{4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(S)-1′-(2-{4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(R)-1′-(2-{4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-methyl-3,4-dihydro-2H-1λ^6,2-benzothiazine-1,1-dione;

1′-{2-[(2-methyl-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2-benzothiazin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-(3-chloro-4-methanesulfonylphenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(3-chloro-4-methanesulfonylphenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(1-cyano-1-methylethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({6-[(3-methyloxetan-3-yl)sulfonyl]pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-(2-hydroxyethyl)-1′-{2-[4-methanesulfonyl-3-(trifluoromethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1-(2-hydroxyethyl)-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(6-methanesulfonyl-5-methylpyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-(difluoromethoxy)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3-(difluoromethoxy)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)-3-(trifluoromethyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)-3-(trifluoromethyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione;

1′-{2-[(1,1-dioxo-3,4-dihydro-2H-1)⁶,2-benzothiazin-6-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[(7-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-{2-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-({2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-yl}oxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{4-[3-(ethanesulfonyl)oxetan-3-yl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-1λ⁶-thiolane-1,1-dione;

(S)-2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-1λ⁶-thiolane-1,1-dione;

(R)-2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-1λ⁶-thiolane-1,1-dione;

1′-{2-[4-(1,1-dioxo-1λ⁶-thiolan-2-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{3-oxo-3H-spiro[2-benzofuran-1,3′-oxetan]-5-yloxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(1-methanesulfonylcyclobutyl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N-(4-{2-[5-chloro-1-(2-hydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl]ethoxy}-2-(trifluoromethyl)phenyl)methanesulfonamide;

1′-{2-[4-(4-methanesulfonyloxan-4-yl)phenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(4-methanesulfonyloxan-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[6-(2-methanesulfonylpropan-2-yl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[8-(2-hydroxyethyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N′-{2-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]ethyl}-N-methylacetamide;

1′-{2-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,3-dihydro-1λ⁶-benzothiophene-1,1-dione;

5-chloro-1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(2-hydroxyethanesulfonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

chloro-1′-[(2S)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

chloro-1′-[(2R)-1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(S)-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(R)-1′-{1-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[1-(4-methanesulfonylphenoxy)propan-2-yl]-1-[3-hydroxycyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[(2S)-1-(4-methanesulfonylphenoxy)propan-2-yl]-1-[(cis)-3-hydroxycyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[(2S)-1-(4-methanesulfonylphenoxy)propan-2-yl]-1-[(trans)-3-hydroxycyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[(2R)-1-(4-methanesulfonylphenoxy)propan-2-yl]-1-[(cis)-3-hydroxycyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[(2R)-1-(4-methanesulfonylphenoxy)propan-2-yl]-1-[(trans)-3-hydroxycyclobutyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[(2S)-1-[3-(difluoromethyl)-4-methanesulfonylphenoxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[(2S)-1-[(1-methyl-1H-indazol-5-yl)oxy]propan-2-yl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[(2S)-1-[3-(difluoromethyl)-4-methanesulfonylphenoxy]propan-2-yl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-[(2S)-1-(3,5-difluoro-4-methanesulfonylphenoxy)propan-2-yl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

N-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]methanesulfonamide;

5-chloro-1′-[2-(4-{[(trans)-3-hydroxycyclobutyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-(1,2-dihydroxyethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{3-[(1S)-1,2-difluoroethyl]-4-methanesulfonylphenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{3-[(1R)-1,2-difluoroethyl]-4-methanesulfonylphenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3-(1,2-difluoroethyl)-4-methanesulfonylphenoxy]ethyl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{3-[(1S)-1,2-difluoroethyl]-4-methanesulfonylphenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{3-[(1R)-1,2-difluoroethyl]-4-methanesulfonylphenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-methanesulfonyl-3-(oxetan-3-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(trans)-3-hydroxycyclobutyl]-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-{[1-(hydroxymethyl)cyclopropyl]sulfonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]-N-methylcyclopropane-1-carboxamide;

1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)benzenesulfonyl]-N,N-dimethylcyclopropane-1-carboxamide;

1′-[2-(4-{[1-(azetidine-1-carbonyl)cyclopropyl]sulfonyl}phenoxy)ethyl]-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluoro-N-methylbenzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluoro-N,N-dimethylbenzamide;

5-chloro-1′-{2-[3-fluoro-4-(morpholine-4-carbonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzoyl]-1λ⁶-thiomorpholine-1,1-dione;

5-chloro-1′-{2-[3-fluoro-4-(3-methanesulfonylazetidine-1-carbonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(azetidine-1-carbonyl)-3-fluorophenoxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[3-fluoro-4-(3-hydroxyazetidine-1-carbonyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[4-(3-aminoazetidine-1-carbonyl)-3-fluorophenoxy]ethyl}-5-chloro-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

N-{1-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzoyl]azetidin-3-yl}methanesulfonamide;

4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzamide;

6-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-fluorobenzoyl]-2λ⁶-thia-6-azaspiro[3.3]heptane-2,2-dione;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-(1,1-dioxo-1)⁶-thian-4-yl)-2-fluorobenzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-(1,1-dioxo-1λ⁶-thiolan-3-yl)-2-fluorobenzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-[(3S)-1,1-dioxo-1λ⁶-thiolan-3-yl]-2-fluorobenzamide;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-[(3R)-1,1-dioxo-1λ⁶-thiolan-3-yl]-2-fluorobenzamide;

5-chloro-1′-{2-[4-(3-methyl-1H-pyrazol-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

6-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxamide;

6-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-N-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxamide;

5-chloro-1′-[2-({3-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(6-{[1-(hydroxymethyl)cyclopropyl]sulfonyl}pyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide;

4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(difluoromethyl)benzamide;

1′-{2-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{4-[3-(3-fluoroazetidine-1-carbonyl)oxetan-3-yl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{4-[3-(azetidine-1-carbonyl)oxetan-3-yl]phenoxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

3-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N,N-dimethyloxetane-3-carboxamide;

3-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-N-methyloxetane-3-carboxamide;

5-chloro-1′-{2-[(7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-[4-(2-{5-cyano-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)phenyl]-2-methylpropanamide;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)pyrimidine-2-carboxamide;

4-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2,6-difluorobenzoyl]-1λ⁶-thiomorpholine-1,1-dione;

1′-{2-[4-(1,1-dioxo-1λ⁶-thiomorpholine-4-carbonyl)-3,5-difluorophenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{2-[4-(1,1-dioxo-1λ⁶-thiomorpholine-4-carbonyl)-3-(trifluoromethyl)phenoxy]ethyl}-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(S)-1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

(R)-1′-{1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl}-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-1-(2-hydroxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-{2-[3-(difluoromethyl)-4-methanesulfonylphenoxy]ethyl}-1-(2-hydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({7-oxo-8-[(trans)-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(3-hydroxy-1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[(cis)-3-hydroxy-1-methanesulfonylcyclobutyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[(trans)-3-hydroxy-1-methanesulfonylcyclobutyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

4-(4-{2-[5-chloro-1-(2-hydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl]ethoxy}-2-(trifluoromethyl)benzoyl)-1λ⁶-thiomorpholine-1,1-dione;

4-[4-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-2-(trifluoromethyl)benzoyl]-1λ⁶-thiomorpholine-1,1-dione;

5-chloro-1′-[2-(3-fluoro-4-{6-methanesulfonyl-2,6-diazaspiro[3.3]heptane-2-carbonyl}phenoxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H,4H-pyrido[2,3-d][1,3]oxazin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(trans)-3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(trans)-3-cyclopropyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-cyclopropyl-3-hydroxycyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(trans)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-(hydroxymethyl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[(trans)-3-(hydroxymethyl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-{2-[(7-oxo-8-{[(cis)-3-hydroxy-3-methylcyclobutyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-{2-[(7-oxo-8-{[(trans)-3-hydroxy-3-methylcyclobutyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(7-oxo-8-{[(cis)-3-hydroxy-3-methylcyclobutyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({8-[3-(hydroxymethyl)cyclobutyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-(propan-2-yl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-ethyl-3-hydroxycyclobutyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-(hydroxymethyl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({8-[(3-hydroxy-3-methylcyclobutyl)methyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-ethyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(7-oxo-8-{[(trans)-3-hydroxy-3-methylcyclobutyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethoxy)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[3-(hydroxymethyl)cyclobutyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[(3-hydroxy-3-methylcyclobutyl)methyl]-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethoxy)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-7-iodo-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(trans)-3-hydroxy-3-(propan-2-yl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(trans)-3-(hydroxymethyl)cyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[6-(1-hydroxyethyl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[6-(1-hydroxyethyl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[5-(difluoromethyl)-7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[5-(difluoromethyl)-7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(trans)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({2-oxo-1-[(trans)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H-pyrido[2,3-d]pyrimidin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-oxo-4-[(cis)-3-hydroxy-3-methylcyclobutyl]-3H,4H-pyrido[2,3-b]pyrazin-7-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[4-(3-hydroxy-3-methylcyclobutyl)pyrido[3,2-d]pyrimidin-7-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylcyclobutyl)-1,7-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxy-3-methylazetidin-1-yl)pyrido[2,3-d]pyridazin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[4-(3-hydroxy-3-methylazetidin-1-yl)pyrido[3,2-d]pyrimidin-7-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(3-hydroxyazetidin-1-yl)pyrido[2,3-d]pyridazin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[4-(3-hydroxyazetidin-1-yl)pyrido[3,2-d]pyrimidin-7-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-[(cis)-3-hydroxy-3-methylcyclobutyl]-3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[3-(hydroxymethyl)azetidin-1-yl]-1,7-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-({6-[(1S)-1-hydroxyethyl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-[2-({6-[(1R)-1-hydroxyethyl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({2-[(1S)-1,2-dihydroxyethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(1R)-1,2-dihydroxyethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(2S)-1,2-dihydroxypropan-2-yl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(2R)-1,2-dihydroxypropan-2-yl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({6-[(1S)-1,2-dihydroxyethyl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({6-[(1R)-1,2-dihydroxyethyl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({6-[(2S)-1,2-dihydroxypropan-2-yl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({6-[(2R)-1,2-dihydroxypropan-2-yl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[(cis)-3-hydroxy-3-methylcyclobutyl]-1,7-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[(trans)-3-hydroxy-3-methylcyclobutyl]-1,7-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({4-[(cis)-3-hydroxy-3-methylcyclobutyl]pyrido[3,2-d]pyrimidin-7-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({4-[(trans)-3-hydroxy-3-methylcyclobutyl]pyrido[3,2-d]pyrimidin-7-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[(cis)-3-hydroxy-3-methylcyclobutyl]pyrido[2,3-d]pyridazin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({8-[(trans)-3-hydroxy-3-methylcyclobutyl]pyrido[2,3-d]pyridazin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(trans)-3-hydroxy-3-methylcyclobutyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-2H,3H-[1,3]oxazolo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-{6-hydroxy-2-azaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(3-ethyl-3-hydroxyazetidin-1-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-cyclopropyl-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[6-(1-hydroxyethyl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5,7-dichloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1,2-dihydroxyethyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[1-(hydroxymethyl)cyclopropyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[5-(difluoromethyl)-7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-(2-{[5-(difluoromethyl)-7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5-(trifluoromethyl)-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{4-[1-(dimethylphosphoryl)cyclopropyl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[1-(dimethylphosphoryl)cyclopropyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(1r,3s)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({2-oxo-1-[(1r,3s)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H,4H-pyrido[2,3-d]pyrimidin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-oxo-4-[(cis)-3-hydroxy-3-methylcyclobutyl]-3H,4H-pyrido[2,3-b]pyrazin-7-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({3-[(cis)-3-hydroxy-3-methylcyclobutyl]-3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(3-hydroxy-3-methylcyclobutyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(1R or 1S)-1,2-dihydroxyethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(1S or 1R)-1,2-dihydroxyethyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(cis) or (trans)-3-hydroxy-3-methylcyclobutyl]pyrimidin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[6-(1-hydroxy-2-methanesulfonylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({6-[(2S or 2R)-1-hydroxy-2-methanesulfonylpropan-2-yl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({6-[(2R or 2S)-1-hydroxy-2-methanesulfonylpropan-2-yl]-5-(trifluoromethyl)pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[6-(3-hydroxy-3-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(trans)-3-hydroxy-3-methylcyclobutyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5,7-dichloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(1-methanesulfonylpiperidin-4-yl)phenoxy]ethyl}-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(²H₃)methyl-1′-(2-{4-[methyl(methylimino)oxo-λ⁶-sulfanyl]-3-(trifluoromethyl)phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(²H₃)methyl-1′-(2-{4-[3-(propane-2-sulfonyl)oxetan-3-yl]phenoxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[4-(1-methanesulfonylcyclobutyl)phenoxy]ethyl}-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(²H₃)methyl-1′-{2-[(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(2-hydroxy-2-methylpropyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-(4-methanesulfonylphenoxy)ethyl]-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(²H₃)methyl-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[1-(hydroxymethyl)cyclopropyl]pyrimidin-5-yl}oxy)ethyl]-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

6-{2-[5-chloro-1-(²H₃)methyl-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl]ethoxy}-8-fluoro-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione;

5-chloro-1′-(2-{[2-(3-methanesulfonyloxetan-3-yl)pyrimidin-5-yl]oxy}ethyl)-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1-(²H₃)methyl-1′-[2-({7-oxo-8-[(cis)-3-hydroxycyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylcyclopropyl)pyrimidin-5-yl]oxy}ethyl)-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-methanesulfonylethyl)pyrimidin-5-yl]oxy}ethyl)-1-(²H₃)methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)(1,1,2,2-²H₄)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({2-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-(3-hydroxyoxetan-3-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(1-hydroxycyclobutyl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[6-(3-hydroxy-3-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,2,3-benzotriazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,2,3-benzotriazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

1′-(2-{[1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-(2-{5-chloro-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}ethoxy)-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazole-7-carbonitrile;

5-chloro-1′-[2-({3-[(cis)-3-hydroxy-3-methylcyclobutyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-({2-methyl-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-{2-[4-(1-methanesulfonylpiperidin-4-yl)phenoxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[7-(difluoromethyl)-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[7-(difluoromethyl)-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[7-(difluoromethoxy)-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[7-(difluoromethoxy)-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-(2-{[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]oxy}ethyl)-7-iodo-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-(difluoromethyl)-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-methyl-3-[(cis)-3-hydroxy-3-methylcyclobutyl]-3H-imidazo[4,5-b]pyridin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[8-(2-hydroxy-2-methylpropyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-7-iodo-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-[2-({7-fluoro-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-8-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-6-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({7,7-dimethyl-5-oxo-5H,7H-furo[3,4-b]pyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-{2-[(2-{6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl}pyrimidin-5-yl)oxy]ethyl}-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{2′-oxo-1′-[(cis)-3-hydroxy-3-methylcyclobutyl]-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[2,3-b]pyridin]-5′-yloxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-(²H₃)methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({7-oxo-8-[(cis)-3-hydroxy-3-(²H₃)methylcyclobutyl]-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl}oxy)(1,1,2,2-²H₄)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)(1,1,2,2-²H₄)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

2-oxo-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-indazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({2-[(1r,3s)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{[3-(hydroxymethyl)-2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

1′-(2-{[3-(hydroxymethyl)-2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl]oxy}ethyl)-2-oxo-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

2-oxo-1′-[2-({2-oxo-1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidine]-5-carbonitrile;

5-chloro-1′-[2-({1-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl}oxy)ethyl]-1,2-dihydrospiro[indole-3,4′-piperidin]-2-one;

5-chloro-1′-(2-{3-[(cis)-3-hydroxy-3-methylcyclobutyl]-4-(trifluoromethyl)-3H-1,3,5-triazainden-6-yloxy}ethyl)spiro[indoline-3,4′-piperidin]-2-one, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Isotopically labeled forms of any of the foregoing are also embraced, such as deuterated or tritiated forms (wherein at least one hydrogen is replaced by at least one deuterium or tritium) of any of the specific compounds detailed herein. Mixtures of any of the foregoing are also embraced and described. Prodrugs of any of the foregoing are also embraced herein.

As a non-limiting example, compounds of formula (II), formula (I′), or formula (I), or any embodiment or variation thereof, are provided, wherein any one or more H atoms are replaced with deuterium. For example, compounds of formula (II), formula (I′), or formula (I), or any embodiment or variation thereof, are provided wherein L¹is C_1-6alkylene, wherein one or more H atoms of the C_1-6alkylene are replaced with deuterium. For example, compounds of formula (II), formula (I′), or formula (I), or any embodiment or variation thereof, are provided wherein L¹is —(CD₂)_1-6-. In some embodiments of formula (II), formula (I′), or formula (I), or any embodiment or variation thereof, L¹is —(CD₂)-(CD₂)-.

In some embodiments, compounds of formula (II), formula (I′), or formula (I) contain one or more hydrogen atoms that are replaced with deuterium, wherein deuterium is present in an amount that is greater than its natural abundance. Thus, as used herein, designation of an atom as deuterium at a position indicates that the abundance of deuterium is significantly greater than the natural abundance of deuterium. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its naturally abundant isotopic composition. Also, unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is significantly greater than the natural abundance of deuterium, e.g., at least 3000 times greater than the natural abundance of deuterium, which is about 0.015% (i.e., the term “D” or “deuterium” indicates at least about 45% incorporation of deuterium).

Compound Names included in Table 1 and in the list in the paragraph above were generated ChemDraw® software version 18.1.0.458, ChemDraw® software version 18.0.0.231, or Collaborative Drug Discovery Inc. (CDD) CDD Vault update #3.

Compositions

Provided herein are pharmaceutical compositions comprising one or more compounds of formula (II), formula (I), formula (I′), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, provided herein is a pharmaceutical composition comprising (i) a compound of formula (II), formula (I), formula (I′) or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Examples of suitable excipients are well-known to those skilled in the art. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Academic Press, 23^rded. (2020), which is incorporated herein by reference.

The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, oral, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

The specific dose level of a compound as described herein will depend upon a variety of factors such as the age, body weight and sex of the individual as well as the route of administration and other factors. In some embodiments, a dosage is expressed as a number of milligrams of a compound described herein per kilogram of the individual's body weight (mg/kg). Dosages of between about 0.1 mg/kg and 100-150 mg/kg may be appropriate.

The compound may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life.

Methods of Treatment

Provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. Isotopically labeled forms of any of the foregoing are also embraced, including, but not limited to, deuterated or tritiated forms (wherein at least one hydrogen is replaced by at least one deuterium, or tritium) of any of the specific compounds detailed herein.

Provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to an effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of inhibiting APOL1 in a cell, comprising exposing the cell to a pharmaceutical composition comprising an effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

Provided herein is a method of inhibiting APOL1 in an individual, comprising administering to the individual an effective amount of a compound of formula (I), formula (I′), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of inhibiting APOL1 in an individual, comprising administering to the individual a pharmaceutical composition comprising an effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

In some embodiments, the compounds provided herein inhibit APOL1 at a concentration of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein inhibit APOL1 at a concentration of 1 to 10 PM, 0.01 to 1 μM, or 0.01 to 10 PM.

In some embodiments, the compounds provided herein reduce cell death caused by overexpression of APOL1. In some embodiments, the compounds provided herein reduce cell death caused by overexpression APOL1 at a concentration of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein reduce cell death caused by APOL1 overexpression at a concentration of 1 to 10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

In some embodiments, compounds provided herein have an EC₅₀of less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein have an EC₅₀of 1 to 10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

In some embodiments, compounds provided herein have an AC₅₀of less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein have an AC₅₀of 1 to 10 μM, 0.01 to 1 μM, or 0.01 to 10 μM. In some embodiments, the AC₅₀value reflects the compound's ability to prevent calcium influx by inhibiting APOL1.

In some embodiments, the compounds provided herein inhibit a cation channel. In some embodiments, the compounds of the present disclosure inhibit a calcium channel. In some embodiments, the compounds of the present disclosure reduce calcium transport.

Provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

Provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

In some embodiments, the individual has a chronic kidney disease. In some embodiments, the individual has hypertension-attributed kidney disease. In some embodiments, the kidney disease, disorder, or condition is an APOL1-mediated kidney disease, disorder, or condition. In some embodiments, the kidney disease, disorder, or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, viral nephropathy, COVID-19 associated nephropathy, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, and diabetic kidney disease.

Also provided herein is a method of treating an APOL1-mediated disorder, such as preeclampsia and sepsis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the individual is genetically predisposed to developing the APOL1-mediated disorder.

Also provided herein is a method of delaying development of progressive renal allograft loss in a kidney transplant recipient comprising administering to the kidney transplant recipient a therapeutically effective amount of a compound of formula (I), formula (I′), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the kidney transplant recipient receives a kidney from a high-risk APOL1 genotype donor. In some embodiments, the kidney transplant recipient is administered a therapeutically effective amount of the compound for a period of time before receiving the kidney transplant. In some embodiments, the kidney transplant recipient is administered a therapeutically effective amount of the compound subsequent to receiving the kidney transplant.

Provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the individual has an APOL1 mutation. Also provided herein is a method of treating a kidney disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, wherein the individual has an APOL1 mutation.

The compounds provided herein may also be used in a method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition. In some embodiments, the APOL1-mediated disease, disorder, or condition is preeclampsia or sepsis and the individual has two APOL1 risk alleles. In some embodiments, the APOL1-mediated disease, disorder, or condition is a chronic kidney disease and the individual has any binary combination of G1 and G2 APOL1 risk alleles. In some embodiments, the chronic kidney disease is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), hypertension-attributed kidney disease, sickle cell nephropathy, viral nephropathy, COVID-19 associated nephropathy, lupus nephritis, diabetic kidney disease, or APOL1-associated nephropathy. The compounds as provided herein may also be used in a method of delaying the development of progressive renal allograft loss in an individual who has received a kidney transplantation from a high-risk APOL1 genotype donor.

In some embodiments, the individual has a gain-of-function mutation in APOL1. In some embodiments, the individual has an APOL1 risk allele. In some embodiments, the APOL1 risk allele is a missense variant. In some embodiments, the APOL1 risk allele is a G1 variant. In some embodiments, the G1 variant is G1^G(p.S342 G) or G1^M(p.I384 M). In some embodiments, the APOL1 risk allele is the G2 variant. In some embodiments, the G2 variant is NYK388-389K. In some embodiments, the APOL1 risk variant is a mutation in the serum resistance-associated (SRA) binding domain of the APOL1 protein. In some embodiments, the individual has two APOL1 risk alleles.

Also provided herein is a method of inhibiting APOL1 in an individual comprising administering to the individual a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Also provided herein is method of preventing kidney failure in an individual comprising administering a therapeutically effective amount of a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing to the individual. In some embodiments, the compound prevents tissue necrosis. In some embodiments, the compound prevents apoptosis. In some embodiments, the compound reduces inflammation.

In some embodiments, the compounds provided herein reduce or eliminate one or more symptoms of a kidney disease. In some embodiments, the compounds reduce nausea, vomiting, loss of appetite, fatigue and weakness, sleep problems, urinary frequency issues, muscle twinges and cramps, swelling, itching, chest pain, shortness of breath, and/or high blood pressure.

In some embodiments, the compounds provided herein reduce the rate of kidney damage and/or progression of kidney damage. In some embodiments, the compounds provided herein reduce the rate of kidney failure. In some embodiments, the compounds provided herein reverse kidney damage. In some embodiments, the compounds reduce the need for dialysis. In some embodiments, the compounds provided herein delay the need for dialysis at least one month, at least two months, at least three months, or at least one year.

In some embodiments, the compounds reduce the rate of or delay the need for a kidney transplant. For example, in some embodiments, the compounds provided herein delay the need for a kidney transplant at least one month, at least two months, at least three months, at least six months, or at least one year. In some embodiments, the compounds provided herein eliminate the need for a kidney transplant.

In some embodiments, the individual has stage 1, stage 2, stage 3A, stage 3B, stage 4, or stage 5 chronic kidney disease. In some embodiments, kidney function is evaluated using an estimated glomerular filtration rate (eGFR) kidney function test.

The compounds and compositions comprising the compounds provided herein may also be used in a method of delaying or preventing proteinuria, the method comprising administering the compound, or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to an individual. In one aspect, the methods herein comprise preventing or reducing protein in the urine, e.g., proteinuria. In some embodiments, the methods provided herein prevent proteinuria. In some embodiments, the methods reduce proteinuria. In some embodiments, the methods provided herein prevent albuminuria. In some embodiments, the methods reduce albuminuria. In some embodiments, the methods reduce urine albumin. In some embodiments, urine albumin is reduced by at least about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine albumin is reduced by at least about 50%. In some embodiments, urine albumin is reduced by at least about 60%. In some embodiments, urine albumin is reduced by at least about 70%. In some embodiments, urine albumin is reduced by at least about 80%. In some embodiments, urine albumin is reduced by at least about 90%. In some embodiments, reduction of urine albumin is dose-dependent. In some embodiments, the methods provided herein reduce urine albumin/creatine ratio. In some embodiments, urine albumin/creatine ratio is reduced by at least about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine albumin/creatine ratio is reduced by at least about 50%. In some embodiments, urine albumin/creatine ratio is reduced by at least about 60%. In some embodiments, urine albumin/creatine ratio is reduced by at least about 70%. In some embodiments, urine albumin/creatine ratio is reduced by at least about 80%. In some embodiments, urine albumin/creatine ratio is reduced by at least about 90%. In some embodiments, reduction of urine albumin/creatine ratio is dose-dependent. In some embodiments, the reduction and/or ratios are measured according to assays detailed herein. In any of the aforementioned methods, the individual is an individual in need thereof, such as an individual having an APOL1-mediated disease, disorder, or condition. In some embodiments, the APOL1-mediated disease, disorder, or condition is a kidney disease. In some embodiments, the APOL1-mediated disease, disorder, or condition is a chronic kidney disease. In some embodiments, the individual has hypertension-attributed kidney disease. In some embodiments, the kidney disease, disorder, or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, viral nephropathy, COVID-19 associated nephropathy, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, and diabetic kidney disease.

In some embodiments, the administration is oral administration.

Kits

The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and/or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound.

Provided herein are kits, comprising (i) a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

Enumerated Embodiments

Embodiment 1A. A compound of formula (I):

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
  
  L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and
  
  either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or
- 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl or oxo,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein
- R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
  - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and
  - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH;
    
    R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl, or
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo.

Embodiment 2A. The compound of embodiment 1A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L²is O, such that the compound is of formula (I-A):

[Image Omitted]

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Embodiment 3A. The compound of embodiment 1A or embodiment 2A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1, or 2.

Embodiment 4A. The compound of any one of embodiments 1A-3A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH.

Embodiment 5A. The compound of any one of embodiments 1A-4A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 0, 1, or 2.

Embodiment 6A. The compound of any one of embodiments 1A-5A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R¹is halo, —CN, or —C_1-6alkyl, wherein the C_1-6alkyl of R¹is optionally substituted with one or more halo.

Embodiment 7A. The compound of any one of embodiments 1A-6A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 0 or 1.

Embodiment 8A. The compound of any one of embodiments 1A-7A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R³is C_1-6alkyl.

Embodiment 9A. The compound of any one of embodiments 1A-8A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with —OH or C_1-6alkoxy.

Embodiment 10A. The compound of any one of embodiments 1A-9A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L¹is selected from the group consisting of

[Image Omitted]

wherein, for each L¹, * denotes the point of attachment to L²and ** denotes the point of attachment to the remainder of the molecule.

Embodiment 11A. The compound of any one of embodiments 1A-10A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L²is O.

Embodiment 12A. The compound of any one of embodiments 1A-11A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L³is absent.

Embodiment 13A. The compound of any one of embodiments 1A-12A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L³is —O—, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein

- the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl,
- the C_3-10cycloalkyl membered heterocyclyl of L³is optionally substituted with one or more —OH, and
- the 3-10 membered heterocyclyl of L³is optionally substituted with one or more —OH.

Embodiment 14A. The compound of any one of embodiments 1A-11A, and 13A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L³is selected from the group consisting of —O—,

[Image Omitted]

Embodiment 15A. The compound of any one of embodiments 1A-14A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R⁴is S(O)₂—R^a, 5-10 membered heteroaryl, —N(R^d)₂, —NS(O)—(C_1-3alkyl)₂, —C(O)—N(R^e)₂, 3-6 membered heterocyclyl, —S(O)(N—C_1-3alkyl)-(C_1-3alkyl), or —CN, wherein

- the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl, and
- the 3-6 membered heterocyclyl optionally substituted with one or more oxo or C_1-6alkyl.

Embodiment 16A. The compound of embodiment 15A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R^ais C_1-6alkyl, is C_3-10cycloalkyl, or is 3-10 membered heterocyclyl, wherein

- the C_1-6alkyl of R^ais optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,
- the C_3-10cycloalkyl of R^ais optionally substituted with one or more —OH, C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —C(O)—C_3-10heterocyclyl or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, and
- the 3-10 membered heterocyclyl of R^ais optionally substituted with one or more C_1-6alkyl.

Embodiment 17A. The compound of embodiment 15A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each of R^dis independently H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH, and wherein R^ais C_1-6alkyl.

Embodiment 18A. The compound of embodiment 15A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each of R^eis independently H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-6 membered heterocycle is optionally substituted with one or more oxo.

Embodiment 19A. The compound of embodiment 15A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, —NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a, wherein R^ais C_1-6alkyl.

Embodiment 20A. The compound of any one of embodiments 1A-19A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each of X¹and X²is C(R⁵).

Embodiment 21A. The compound of any one of embodiments 1A-19A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X¹and X²is N and the other is C(R⁵).

Embodiment 22A. The compound of any one of embodiments 1A-19A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl optionally substituted with one or more of R^b.

Embodiment 23A. The compound of embodiment 22A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R^bis halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH.

Embodiment 24A. The compound of any one of embodiments 1A-19A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heteroaryl optionally substituted with one or more R^c.

Embodiment 25A. The compound of embodiment 24A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, R^cis halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH.

Embodiment 26A. The compound of any one of embodiments 1A-25A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R⁵is independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo.

Embodiment 27A. The compound of embodiment 1A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Compounds 1-273 of Table 1.

Embodiment 29A. A method for preparing a compound of embodiment 1A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising a step of reacting a compound of formula I′-A:

[Image Omitted]

wherein:

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 10;

R¹, if present is, independently at each occurrence selected from the group consisting of halo, —CN, C_1-6alkoxy or —C_1-6alkyl, wherein

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH; and
  
  R³, if present, is C_1-6alkyl;
  
  with:
  
  a compound of formula (I′-B):

[Image Omitted]

wherein:

the dashed line represents a single or double bond;

Y¹is halo, oxo, or a sulfonate ester

L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;

L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and

either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl or oxo,
    - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
    - (viii) —CN
      
      or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH;
      
      R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl, or
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo;
  
  R⁶and R⁷are each independently H or halo; to give a compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Embodiment 30A. The method of embodiment 29A, wherein the compound of embodiment 1 is prepared by a step comprising:

- a) alkylation of an amine of formula (I′-A) with an alkyl halide, or sulfonate ester compound of formula (I′-B) in the presence of an inorganic base; or
- b) reductive amination of a ketone of formula (I′-B) with an amine of formula (I′-A).

Embodiment 31A. The method of embodiment 30A, wherein the inorganic base is selected from the group consisting of potassium carbonate, and sodium bicarbonate.

Embodiment 32A. The method of embodiment 30A, wherein the reductive amination proceeds under the action of sodium triacetoxyborohydride, titanium tetraiopropoxide and acetic acid.

Embodiment 33A. A method for preparing a compound of embodiment 1A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising a step of reacting a compound of formula I′-C:

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy; and
  
  Y²is halo, —OH or NH₂;
  
  with:
  
  a compound of formula (I′-D):

[Image Omitted]

wherein:

Y³is —OH or NH(R^x), wherein R^xis H or C_1-6alkyl; and

either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl or oxo,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH;
      
      R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl, or
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo; to give a compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Embodiment 34A. The method of embodiment 33A, wherein the compound of embodiment 1 is prepared by a step comprising:

- a) coupling of an alcohol compound of formula (I′-C) with a phenol compound of formula (I′-D), or a heterocyclic variant, under Mitsunobu-type reaction conditions; or
- b) reacting an alkyl halide compound of formula (I′-C) with a phenol or amine compound of formula (I′-D), in the presence of a catalyst.

Embodiment 35A. The method of embodiment 34A, wherein the Mitsunobi-type reaction conditions comprises coupling of an alcohol compound of formula (I′-C) with a phenol compound of formula (I′-D), or a heterocyclic variant, in the presence of triphenylphosphine and diisopropyl azodicarboxylate.

Embodiment 36A. The method of embodiment 34A, wherein the catalyst is silver oxide or potassium carbonate.

Embodiment 37A. A pharmaceutical composition, comprising (i) a compound of any one of embodiments 1A-28A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

Embodiment 38A. A method of modulating APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or embodiments 1A-28A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 37A.

Embodiment 39A. A method of inhibiting APOL1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or embodiments 1A-28A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 37A.

Embodiment 40A. A method of treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of any one of embodiments 1A-28A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 37A.

Embodiment 41A. The method of embodiment 40A, wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

Embodiment 42A. The method of embodiment 40A or embodiment 41A, wherein the disease, disorder, or condition is a kidney disease.

Embodiment 43A. The method of any one of embodiments 40A-42A, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

Embodiment 44A. A method of delaying the development of an APOL1-mediated disease, disorder, or condition, comprising administering a compound of any one of embodiments 1A-28A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 37A, to an individual who is at risk of developing an APOL1-mediated disease, disorder, or condition.

Embodiment 45A. The method of embodiment 44A, wherein the APOL1-mediated disease, disorder, or condition is a kidney disease.

Embodiment 46A. The method of embodiment 44A or embodiment 45A, wherein the APOL1-mediated disease, disorder, or condition is a chronic kidney disease.

Embodiment 47A. The method of embodiment 44A, wherein the APOL1-mediated disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

Embodiment 48A. The method of any one of embodiments 40A-47A, wherein the individual has an APOL1 mutation.

Embodiment 49A. The method of embodiment 48A, wherein the APOL1 mutation is a gain-of-function mutation.

Embodiment 50A. The method of any one of embodiments 40A-49A, wherein a therapeutically effective amount of a compound of any one of embodiments 1A-28A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 37A, is administered.

Embodiment 51A. A kit, comprising (i) a compound of any one of embodiments 1A-28A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 37A, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof.

Embodiment 52A. The kit of embodiment 51A, wherein the disease, disorder, or condition is a kidney disease.

Embodiment 53A. The kit of embodiment 51A or embodiment 52A, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

Embodiment 54A. The kit of any one of embodiments 51A-53A, wherein the disease, disorder, or condition is selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.

Embodiment 55A. The kit of any one of embodiments 51A-54A, wherein the individual has an APOL1 mutation.

Embodiment 56A. The kit of embodiment 55A, wherein the APOL1 mutation is a gain-of-function mutation.

Embodiment 1B. A compound of formula (I′):

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy;
  
  L²is O or N(R^x), wherein R^xis H or C_1-6alkyl; and either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-10cycloalkyl is optionally substituted with one or more —OH, or C_1-6alkyl,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH; X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl is optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN,
  - (ix) —(CH₂)_qOH, wherein q is an integer from 0-6,
  - (x) —C(O)—C_1-6alkyl, or
  - (xi) —P(O)(C_1-6alkyl)₂;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, and
      - wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl,
    - and the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of 3-10 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo.

Embodiment 15B. The compound of embodiments 1B or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R⁴is S(O)₂—R^a, 5-10 membered heteroaryl, —N(R^d)₂, —NS(O)—(C_1-3alkyl)₂, —C(O)—N(R^e)₂, 3-6 membered heterocyclyl, —S(O)(N—C_1-3alkyl)-(C_1-3alkyl), —CN, or —OH, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl, and the 3-6 membered heterocyclyl optionally substituted with one or more oxo or C_1-6alkyl.

Embodiment 23B. The compound of embodiment 1B, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of X¹and X²is CR⁵, and the other of X¹and X²is C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl optionally substituted with one or more of R^b.

Embodiments 24B. The compound of embodiment 23B, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R^bis halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl.

Embodiments 25B. The compound of embodiment 24B, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, R^cis halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl.

Methods of Preparing

The present disclosure further provides methods for preparing the compounds of present invention. In some aspect, provided herein are methods of preparing a compound of formula (II), or any embodiment or variation thereof, such as a compound of formula (I′), (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, a method for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises a step of reacting a compound of formula I′-A:

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH; and
  
  R³, if present, is C_1-6alkyl;
  
  with:
  
  a compound of formula (I′-B):

[Image Omitted]

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a,
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl,
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl or oxo,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl), or
  - (viii) —CN;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH;
      
      R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl, or
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo;
  
  R⁶and R⁷are each independently H or halo; to give a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, a method for preparing a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises a step of reacting a compound of formula I′-A′:

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH; and
  
  R³, if present, is C_1-6alkyl;
  
  with:
  
  a compound of formula (I′-B′):

[Image Omitted]

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-10cycloalkyl is optionally substituted with one or more —OH, or C_1-6alkyl,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl is optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN,
  - (ix) —(CH₂)_qOH, wherein q is an integer from 0-6,
  - (x) —C(O)—C_1-6alkyl, or
  - (xi) —P(O)(C_1-6alkyl)₂;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, and
      - wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl,
    - and the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the 3-10 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo; to give a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound of formula (I) is prepared by a step comprising:

- a) alkylation of an amine of formula (I′-A) with an alkyl halide, or sulfonate ester compound of formula (I′-B) in the presence of an inorganic base; or
- b) reductive amination of a ketone of formula (I′-B) with an amine of formula (I′-A).

In some embodiments, the compound of formula (I′) is prepared by a step comprising:

- a) alkylation of an amine of formula (I′-A′) with an alkyl halide, or sulfonate ester compound of formula (I′-B′) in the presence of an inorganic base; or
- b) reductive amination of a ketone of formula (I′-B′) with an amine of formula (I′-A′).

In some embodiments, the compound of formula (I) is prepared by a step comprising alkylation of an amine of formula (I′-A) with an alkyl halide, or sulfonate ester compound of formula (I′-B) in the presence of an inorganic base. In some embodiments, the inorganic base is selected from the group consisting of potassium carbonate, and sodium bicarbonate.

In some embodiments, the compound of formula (I′) is prepared by a step comprising alkylation of an amine of formula (I′-A′) with an alkyl halide, or sulfonate ester compound of formula (I′-B′) in the presence of an inorganic base. In some embodiments, the inorganic base is selected from the group consisting of potassium carbonate, and sodium bicarbonate.

In some embodiments, the sulfonate ester compound of formula (I′-B) is a mesylate or a tosylate. In some embodiments, the sulfonate ester compound of formula (I′-B) is a mesylate, or CH₃SO₃—. In some embodiments, the sulfonate ester compound of formula (I′-B) is a tosylate or CH₃C₆H₄SO₃—.

In some embodiments, the sulfonate ester compound of formula (I′-B′) is a mesylate or a tosylate. In some embodiments, the sulfonate ester compound of formula (I′-B′) is a mesylate, or CH₃SO₃—. In some embodiments, the sulfonate ester compound of formula (I′-B′) is a tosylate or CH₃C₆H₄SO₃—.

In some embodiments, the compound of formula (I) is prepared by a step comprising reductive amination of a ketone of formula (I′-B) with an amine of formula (I′-A). In some embodiments, the reductive amination proceeds under the action of sodium triacetoxyborohydride, titanium tetraiopropoxide and acetic acid.

In some embodiments, the compound of formula (I′) is prepared by a step comprising reductive amination of a ketone of formula (I′-B′) with an amine of formula (I′-A′). In some embodiments, the reductive amination proceeds under the action of sodium triacetoxyborohydride, titanium tetraiopropoxide and acetic acid.

It is understood that the present disclosure also provides for methods of preparing compounds of formula (II). For example, compounds of formula (II) may be prepared by reacting a compound of formula (II′-A):

[Image Omitted]

wherein and m, n, p, R¹, and R²are as defined for a compound of formula (II), with a compound of formula (II′-B):

[Image Omitted]

wherein Y¹is halo, oxo, or a sulfonate ester; and L¹, L², L³, R⁴, X¹, X², X³, and X⁴are as defined for a compound of formula (II),

to give a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy; and
  
  Y²is halo, —OH or —NH₂;
  
  with:
  
  a compound of formula (I′-D):

[Image Omitted]

wherein:

Y³is —OH or —NH(R^x), wherein each R^xis independently H or C_1-6alkyl; and

either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_1-6alkylene of L³is optionally substituted with one or more C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl or oxo,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN;
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, or —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl, and
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH;
      
      R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl, or
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo; to give a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[Image Omitted]

- the C_1-6alkoxy of R¹is optionally substituted with one or more halo, and
- the C_1-6alkyl of R¹is optionally substituted with one or more halo;
  
  R²is H, C_1-6alkyl, C_3-10cycloalkyl, or 3-15 membered heterocyclyl, wherein
- the C_1-6alkyl of R²is optionally substituted with one or more halo, —OH, —NH₂, or C_1-6alkoxy, and
- the C_3-10cycloalkyl of R²is optionally substituted with one or more —OH;
  
  R³, if present, is C_1-6alkyl;
  
  L¹is C_1-6alkylene, wherein the C_1-6alkylene of L¹is optionally substituted with one or more C_1-6alkyl, and wherein the C_1-6alkyl is further optionally substituted with one or more —OH or C_1-6alkoxy; and
  
  Y²is halo, —OH or —NH₂;
  
  with:
  
  a compound of formula (I′-D′):

[Image Omitted]

wherein:

Y³is —OH or NH(R^x), wherein each R^xis independently H or C_1-6alkyl; and

either

(1) L³is absent or is O, C_3-10cycloalkyl, 3-10 membered heterocyclyl, or C_1-6alkylene, wherein
- the C_3-10cycloalkyl is optionally substituted with one or more —OH, or C_1-6alkyl,
- the C_1-6alkylene of L³is optionally substituted with one or more —OH, or C_1-6alkyl, and
- the 3-10 membered heterocyclyl is optionally substituted with one or more —OH;
- X¹and X²are each independently N or C(R⁵); and
- R⁴is:
  - (i) —S(O)₂—R^a;
  - (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R⁴is optionally substituted with one or more C_1-6alkyl;
  - (iii) —N(R^d)₂, wherein R^dis independently at each occurrence H, C_1-6alkyl, or —S(O)₂—R^a, wherein the C_1-6alkyl of R^dis optionally substituted with one or more —OH,
  - (iv) —NS(O)—(C_1-6alkyl)₂, wherein the C_1-6alkyl is optionally substituted with one or more —OH,
  - (v) —C(O)—N(R^e)₂wherein R^eis independently at each occurrence H, C_1-6alkyl, or 3-10 membered heterocycle, wherein the 3-10 membered heterocycle is optionally substituted with one or more oxo, or both R^etogether with the N to which they are attached are taken together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more halo, oxo, —OH, NH₂, —NH—S(O)₂—R^a, or —S(O)₂—R^a,
  - (vi) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl, —OH, oxo or —S(O)₂R^a,
  - (vii) —S(O)—N(C_1-6alkyl)-(C_1-6alkyl),
  - (viii) —CN;
  - (ix) —(CH₂)_qOH, wherein q is an integer from 0-6; or
  - (x) —C(O)—C_1-6alkyl
  - (xi) —P(O)(C_1-6alkyl)₂
    
    or

(2) L³is absent; and
- one of X¹and X²is N or C(R⁵); and
- the other of X¹and X²is N or C that is taken together with R⁴, and the atoms to which they are attached, to form a 5-10 membered heterocyclyl or a 5-20 membered heteroaryl, wherein
  - the 5-10 membered heterocyclyl is optionally substituted with one or more R^b, wherein R^bis, independently at each occurrence, selected from the group consisting of halo, oxo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^bis optionally substituted with one or more halo, OH, —S(O)₂—C_1-6alkyl, or C_3-10cycloalkyl, and
      - wherein the C_3-10cycloalkyl of the C_1-6alkyl of R^bis further optionally substituted with one or more C_1-6alkyl or —OH and
    - the C_3-10cycloalkyl of R^bis optionally substituted with one or more —OH, C_3-10cycloalkyl, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the C_3-10cycloalkyl of R^bis further optionally substituted with one or more —OH, and
  - the 5-20 membered heteroaryl is optionally substituted with one or more R^c, wherein R^cis, independently at each occurrence, selected from the group consisting of halo, C_1-6alkyl, —C(O)—C_1-6alkyl, —C(O)—NH₂, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, —S(O)₂—R^a, C_3-10cycloalkyl, and 3-10 membered heterocyclyl, wherein
    - the C_1-6alkyl of R^cis optionally substituted with one or more —S(O)₂—C_1-6alkyl,
    - the C_3-10cycloalkyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl,
    - and the 3-10 membered heterocyclyl of R^cis optionally substituted with one or more —OH, or C_1-6alkyl, and
      - wherein the C_1-6alkyl of the 3-10 membered heterocyclyl of R^cis further optionally substituted with one or more —OH;
        
        R^ais, independently at each occurrence:
- (i) C_1-6alkyl optionally substituted with one or more halo, —OH, —S(O)₂—C_1-6alkyl, or —N(C_1-6alkyl)-C(O)—C_1-6alkyl,
- (ii) C_3-10cycloalkyl optionally substituted with one or more —OH, —C(O)₂—C_1-6alkyl, —C(O)—NH(C_1-6alkyl), —C(O)—N(C_1-6alkyl)₂, or —C(O)—C_3-10heterocyclyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more —OH, or
- (iii) 3-10 membered heterocyclyl optionally substituted with one or more C_1-6alkyl;
  
  R⁵is, independently at each occurrence, H, halo, —CN, 3-10 membered heterocyclyl, C_1-6alkyl, or C_1-6alkoxy, wherein the C_1-6alkyl of R⁵is optionally substituted with one or more halo, or —OH and wherein the C_1-6alkoxy of R⁵is optionally substituted with one or more halo; and
  
  R⁶and R⁷are each independently H or halo; to give a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound of formula (I) is prepared by a step comprising:

- a) coupling of an alcohol compound of formula (I′-C) with a phenol compound of formula (I′-D), or a heterocyclic variant, under Mitsunobu-type reaction conditions; or
- b) reacting an alkyl halide compound of formula (I′-C) with a phenol or amine compound of formula (I′-D), in the presence of a catalyst.

In some embodiments, the compound of formula (I′) is prepared by a step comprising:

- a) coupling of an alcohol compound of formula (I′-C′) with a phenol compound of formula (I′-D′), or a heterocyclic variant, under Mitsunobu-type reaction conditions; or
- b) reacting an alkyl halide compound of formula (I′-C′) with a phenol or amine compound of formula (I′-D′), in the presence of a catalyst.

In some embodiments, the compound of formula (I) is prepared by a step comprising coupling of an alcohol compound of formula (I′-C) with a phenol compound of formula (I′-D), or a heterocyclic variant, under Mitsunobu-type reaction conditions. In some embodiments, the Mitsunobu-type reaction conditions comprises coupling of an alcohol compound of formula (I′-C) with a phenol compound of formula (I′-D), or a heterocyclic variant, in the presence of triphenylphosphine and diisopropyl azodicarboxylate.

In some embodiments, the compound of formula (I′) is prepared by a step comprising coupling of an alcohol compound of formula (I′-C′) with a phenol compound of formula (I′-D′), or a heterocyclic variant, under Mitsunobu-type reaction conditions. In some embodiments, the Mitsunobu-type reaction conditions comprises coupling of an alcohol compound of formula (I′-C′) with a phenol compound of formula (I′-D′), or a heterocyclic variant, in the presence of triphenylphosphine and diisopropyl azodicarboxylate.

In some embodiments, the compound of formula (I) is prepared by a step comprising reacting an alkyl halide compound of formula (I′-C) with a phenol compound of formula (I′-D), in the presence of a base. In some embodiments, the base is silver oxide or potassium carbonate.

In some embodiments, the compound of formula (I′) is prepared by a step comprising reacting an alkyl halide compound of formula (I′-C′) with a phenol compound of formula (I′-D′), in the presence of a base. In some embodiments, the base is silver oxide or potassium carbonate.

[Image Omitted]

wherein Y²is halo, —OH or —NH₂; and m, n, p, R¹, R², R³, and L¹are as defined for a compound of formula (II), with a compound of formula (II′-D):

[Image Omitted]

wherein Y³is —OH or —NH(R^x), wherein each R^xis independently H or C_1-6alkyl; L³, R⁴, X¹, X², X³, and X⁴are as defined for a compound of formula (II), to give a compound of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In further examples, the compound of formula (II), formula (I′), formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A) (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), or (II-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is prepared by methods shown in the examples below.

EXAMPLES

The following synthetic reaction schemes, which are detailed in the Schemes, General Procedures, and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art.

Synthetic Examples

As depicted in the Schemes, General Procedures, and Examples below, in certain exemplary embodiments, compounds of formula (I), formula (I′), formula (II), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein.

[Image Omitted]

Compounds of formula S1-3 may be prepared according to Scheme 1. Alkylation of amine S1-2 with an alkyl halide such as S1-1 in the presence of an inorganic base such as potassium carbonate and a polar aprotic solvent such as DMF provides compound S1-3. In cases where L3 represents a chiral atom, compound S1-3 may be further purified by chiral SFC to deliver single stereoisomers.

[Image Omitted]

Compounds of formula S2-3 may be prepared may also be prepared by coupling a phenol or heterocyclic variant such as S2-1 with an alcohol such as S2-2 in the presence of triphenylphosphine and DIAD in an aprotic solvent such as THF, as depicted in Scheme 2. Alternative Mitsunobu-type reaction conditions with polymer-bound triphenylphosphine and DIAD in toluene may also be used to generate compounds of formula S2-3.

[Image Omitted]

As outlined in Scheme 3, compounds of formula S3-3 may be prepared from alkyl chlorides such as S3-1 and amine S3-2 by heating in an aprotic solvent such as DMF in the presence of sodium iodide and an inorganic base such as potassium carbonate.

[Image Omitted]

Compounds of formula S4-3 may also be prepared from phenol S4-1 and alkyl halide S4-2 by heating in an aprotic solvent such as DMF in the presence of silver oxide, as shown in Scheme 4. Alternative reaction conditions involving potassium carbonate in DMF may also be used to generate compounds of formula S4-3.

[Image Omitted]

Oxindoles such as S5-1 may be elaborated by reaction with an alkyl halide in the presence of an inorganic base such as potassium carbonate in DMF, at elevated temperature. This provides compounds such as S5-2, as depicted in Scheme 5.

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Scheme 6 depicts an approach to compounds of formula S6-5. Alkylation of oxindole S6-1 with an alkyl halide in the presence of a base such as potassium carbonate generates S6-2. Removal of the Boc group by treatment with a protic acid such as TFA in an aprotic solvent such as DCM generates amine S6-3, which can be further elaborated by coupling with an alkyl halide such as S6-4, according to procedures shown in Scheme 1.

[Image Omitted]

An alternative approach to compounds of formula S7-3 involving reductive amination of ketone S7-2 with amine S7-2 under the action of sodium triacetoxyborohydride, titanium tetraisopropoxide and acetic acid, is depicted in Scheme 7.

[Image Omitted]

Scheme 8 depicts an alternative approach to compounds of formula S8-6. Generation of benzylic chloride S8-2 from benzylic alcohol S8-1, followed by introduction of a sulfonyl group, gives rise to compound S8-3. Deprotection of S8-3 with in situ-formed TMSI gives phenol S8-4, which can be coupled with alkyl chloride S8-5 in the presence of potassium carbonate and sodium iodide in acetone at elevated temperature. Single stereoisomers may be obtained by chiral SFC purification of S8-6.

[Image Omitted]

Scheme 9 shows an approach to compounds of formula S9-7. Alkylation of phenol S9-1 with ethylene oxide, followed by S_NAr reaction with sodium methanethiolate gives thioether S9-3. Oxidation with mCPBA gives sulfone S9-4. Treatment of S9-4 with methanesulfonyl chloride and a tertiary amine base such as DIPEA gives S9-5, which can be converted to S9-7 under conditions similar to Scheme 1.

[Image Omitted]

As shown in Scheme 10, compounds of formula S10-1 may be further elaborated via coupling with a sulfonyl chloride such as methanesulfonyl chloride in the presence of triethylamine in DCM to provide S10-2. Compound S10-1 may also be acylated with an anhydride such as acetic anhydride and triethylamine to generate S10-3.

[Image Omitted]

As shown in Scheme 11, compounds of formula S11-1 may be elaborated via coupling with a carbamoyl chloride such as N-methylcarbamoyl chloride in the presence of triethylamine to give a urea of the formula S11-2.

[Image Omitted]

An alternative approach to compounds of formula S12-3 is depicted in Scheme 12, via coupling of a mesylate such as S12-1 and amine such as S12-2 in acetonitrile using sodium bicarbonate as base.

[Image Omitted]

Scheme 13 depicts the conversion of cis isomer S13-1 to trans isomer S13-3. Mitsunobu coupling with p-nitrobenzoic acid generates ester S13-2, which can undergo hydrolysis with lithium hydroxide to generate the trans isomer S13-3.

[Image Omitted]

Elaboration of compounds of formula S14-1 (generated using methods described in Scheme 1) is depicted in Scheme 14. Cross coupling of S14-1 with potassium vinyltrifluoroborate using a palladium catalyst and an inorganic base provides olefin S14-2. Dihydroxylation with an osmium catalyst and NMO gives S14-3. Diol S14-3 may be further modified by treatment with DAST, giving rise to difluoride S14-4 as an isomeric mixture. Single isomer analogs such as S14-5 may be obtained by chiral SFC purification.

[Image Omitted]

Iodide S15-1 may be elaborated using photoredox methods outlined in Scheme 15. Coupling of S15-1 and 3-iodooxetane can be achieved with nickel(II) chloride ethylene glycol dimethyl ether complex, ligand S15-2, (Ir[dF(CF₃)ppy]₂(dtbpy))PF₆, bis(trimethylsilyl)silyl-trimethylsilane, Na₂CO₃and blue LED to generate S15-3.

[Image Omitted]

Conversion of cis-disubstituted cyclobutanol S16-1 to the trans isomer S16-4 is depicted in Scheme 16. Treatment with methanesulfonic anhydride and TEA generates mesylate S16-2. Heating with potassium acetate generates ester S16-3, which can be converted to the alcohol under the action of potassium carbonate in MeOH to give S16-4.

[Image Omitted]

Compounds of the formula S17-1 can be converted to the corresponding alcohol by treatment with a reducing agent such as LiBH₄, as depicted in Scheme 17. Alternatively, S17-1 can underdo hydrolysis with lithium hydroxide to give acid S17-3. Amide bond formation with an amine such as methylamine under the action of T3P and TEA generates amide S17-4.

[Image Omitted]

Compounds of formula S18-1 can be elaborated by Suzuki couplings of boronate esters such as S18-2, a catalyst such as bis(4-(di-tert-butylphosphanyl)-N,N-dimethylaniline) dichloropalladium, and a base such as KOAc, as depicted in Scheme 18.

[Image Omitted]

Scheme 19 begins with protection of an oxindole nitrogen using sodium hydride and SEMCl to give S19-2. Coupling with a phenol such as S19-3 gives S19-4. Removal of the SEM group is achieved by heating a mixture of S19-4, potassium carbonate, and NaI in acetone to give compound of formula S19-5.

[Image Omitted]

Heterocyclic electrophiles bearing protecting groups such as compound S20-1 may be coupled with amine nucleophiles such as S20-2 under the conditions shown in Scheme 20. Deprotection of a protecting group such as a SEM N—O acetal may be achieved by treatment of S20-3 with a protic acid such as TFA to deliver S20-4.

[Image Omitted]

An approach to compounds of formula S21-9 is shown in Scheme 21. Alkylation of thiol S21-1 followed by oxidation to the sulfone generates compound S21-3. Cyclopropane formation via double alkylation in the presence of potassium carbonate gives S21-4. S_NAr reaction with ethylene glycol and mesylation of S21-5 provides compound S21-6, which can be coupled with amine S21-7 under standard conditions (Scheme 12). Treatment of compound S21-8 with a reducing agent such as LiAlH₄gives compound S21-9.

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Compounds of formula S22-2 may be obtained by treatment of compound S22-1 with a base such as sodium hydride and an alkylating agent such as iodomethane, as depicted in Scheme 22.

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Primary amides of formula S23-7 can be generated according to Scheme 23. Palladium-catalyzed borylation of pyrimidine S23-1 followed by oxidation gives compound S23-3. Alkylation with 1,2-dibromoethane to provide S23-4 and coupling with amine S23-5 under conditions outlined above (Scheme 12) generates compound S23-6. Conversion of the nitrile to the primary amide S23-7 occurs upon treatment with potassium carbonate and aqueous H₂O₂.

[Image Omitted]

Compounds of formula S24-8 can be synthesized according to Scheme 24. Esterification and alkylation of carboxylic acid S24-1 provides alkyl bromide S24-3. Coupling with amine S24-4 under standard conditions (Scheme 12) gives S24-5. Hydrolysis followed by amide bond formation with amine S24-7, using N-methyl imidazole and TCFH, gives S24-8.

[Image Omitted]

Compounds of formula S25-3 may also be prepared by reaction of an amine such as S25-1 with a secondary mesylate such as S25-2 in the presence of NaHCO₃and potassium iodide in DMF at elevated temperature, as depicted in Scheme 25. Compounds of formula S25-3 may be further purified by chiral SFC to generate isomerically pure analogs.

[Image Omitted]

Compounds of formula S26-10 may be prepared according to Scheme 26. Lithium-halogen exchange with aryl bromide S26-1, followed by addition to a ketone such as S26-2, gives alcohol S26-3 as a mixture of cis and trans isomers. Reaction with sodium methanesulfinate and TFA gives sulfone S26-4. Removal of benzyl ethers by hydrogenation gives diol S26-5. Selective alkylation of the phenol moiety with bromoethyl acetate gives ester S26-6. Reduction with LiAlH₄gives alcohol S26-7, which can be converted to S26-8 and coupled with amine S26-9 using procedures described above (Scheme 12). Further purification of S26-10 to obtain single stereoiosmers may be achieved by methods such as reverse phase HPLC or chiral SFC.

[Image Omitted]

Compounds of formula S27-5 can be prepared according to Scheme 27. Coupling of acid S27-1 with an amine such as S27-2 under the action of EDCI and HOBt gives amide S27-3. Treatment with a protic acid such as TFA gives amine S27-4. Amine S27-4 may be further elaborated, such as by reaction with methanesulfonic anhydride and TEA, to give compounds such as S27-5.

[Image Omitted]

Compounds of formula S28-3 can be prepared according to Scheme 28, using reaction conditions similar to those described above. Coupling of amine S28-1 with azatetrahydronaphthyridinones bearing tertiary alcohol moieties such S28-2 occurs upon heating in an aprotic solvent such as acetonitrile in the presence of an inorganic base such as sodium bicarbonate to give compounds of formula S28-3.

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Compounds of formula S29-4 may can be prepared according to Scheme 29. Reaction of amine S29-1 with an alkyl bromide bearing a secondary alcohol such as S29-2 occurs upon heating in an aprotic solvent such as acetonitrile in the presence of an inorganic base such as sodium bicarbonate to give compounds of formula S29-3. Further purification using methods such as chiral SFC may be used to generate single isomer analogs such as S29-4.

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Compounds of formula S30-3 and S30-5, which bear multiple substituents on the pyrimidine moiety, are depicted in Scheme 30. Thus, coupling of the amine HCl salt S30-1 with alkyl halide S30-2 may be achieved upon heating in an aprotic solvent such as DMF, in the presence of potassium carbonate and potassium iodide, to deliver compounds of formula 30-3. Alternatively, coupling under identical reaction conditions as those described above with amine S30-1 and a chiral center bearing intermediate such as S30-4, may give rise to compounds of the formula S30-5. If desired, further purification of S30-5 may be achieved using methods such as chiral SFC.

[Image Omitted]

Compounds of formula S31-12 may be prepared according to Scheme 31. Treatment of indazole S31-1 with iodine and potassium hydroxide in a solvent such as DMF provides S31-2. Alkylation of S31-2 with an electrophile such as S31-3 occurs in the presence of an inorganic base such as potassium carbonate in warm acetone to give S31-4. Treatment with a Grignard reagent such as methylmagnesium bromide at −10° C. in a solvent such as DCM gives tertiary alcohol S31-5. Protodeiodination occurs on treatment with Zn metal and acetic acid in methanol to give S31-6. Palladium catalyzed borylation may be conducted in a solvent such as 1,4-dioxane by reaction with Bis(pinacolato)diboron, potassium acetate as base, and a palladium catalyst such as [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S31-7. Reaction with Oxone gives rise to alcohol S31-8. Phenol alkylation occurs on treatment with an electrophile such as bis-tosylate S31-9 to give S31-10. Heating a mixture of S31-10, an amine nucleophile such as S31-11, and an inorganic base such as sodium bicarbonate in a solvent such as acetonitrile gives compounds of formula S31-12.

[Image Omitted]

Compounds of formula S32-6 may be prepared according to Scheme 32. Heating a mixture of S32-1,1,2-dibromoethane, and an inorganic base such as cesium carbonate gives S32-2. Heating a mixture of S32-2, an amine nucleophile such as S32-3, an inorganic base such as potassium bicarbonate, and potassium iodide in a solvent such as DMF gives compounds of formula S32-4. Compounds of formula S32-4 may be further elaborated by S_NAr reaction with an amine such as S32-5, a tertiary amine base such as triethylamine, in DMSO at 100° C. in a microwave reactor to give compounds of formula S32-6.

[Image Omitted]

Compounds of formula S33-12 may be prepared according to Scheme 33. Reaction of diamine derivative S33-1 with a carboxylic acid such as S33-2 gives amide S33-3. Cyclization to benzimidazole S33-4 may be achieved by heating S33-3 in acetic acid. Treatment of S33-4 with an excess of 2-(Trimethylsilyl)ethoxymethyl chloride and sodium hydride in an aprotic solvent such as THF gives S33-5. Palladium catalyzed borylation may be conducted in a solvent such as 1,4-dioxane by reaction with diboron reagent S33-6, potassium acetate as base, and a palladium catalyst such as [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) to give S33-7. Treatment with Oxone in a mixed solvent such as THF and water gives S33-8. Alkylation with 1,2-dibromoethane in the presence of an inorganic base such as cesium carbonate gives S33-9. S33-9 may be coupled with amine S33-10 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give S33-11. SEM-protecting group removal is achieved by treatment with a protic acid such as TFA, to give a benzimidazole which may then be converted to the free base by treatment with aqueous ammonia to deliver compounds of formula S33-12.

[Image Omitted]

Compounds of formula S34-11 may be prepared according to Scheme 34. Reductive amination of an ortho-fluoro aldehyde such as S34-1 with an amine such as S34-2 with TFA and triethylsilane gives S34-3. S_NAr reaction with an amine such as S34-4 occurs upon heating with DIEA in DMSO to give S34-5. Removal of the Boc-protecting group by treatment with a protic acid such as HCl in an aprotic solvent such as EtOAc gives amine S34-6, which can undergo conversion to the cyclic urea on treatment with CDI to give S34-7. Heating S34-7 in ethylene glycol, copper(I) iodide, and lithium tert-butoxide gives alcohol S34-8. Conversion of the alcohol moiety to an alkyl bromide may be achieved by reaction with carbon tetrabromide and triphenyl phosphine in a solvent such as DCM to give S34-9. S34-9 may be coupled with amine S34-10 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give compounds of formula S34-11.

[Image Omitted]

Compounds of formula S35-9 may be prepared according to Scheme 35. S_NAr reaction between S35-1 and amine S35-2 occurs upon heating with a tertiary amine base such as DIEA in DMSO solvent to give S35-3. Nitro group reduction by heating with iron and ammonium chloride in a mixed solvent such as ethanol and water gives S35-4. S35-4 is then converted to benzimidazole derivative S35-5 by heating in trimethyl orthoformate in the presence of p-toluene sulfonic acid. Heating S35-5 in ethylene glycol in the presence of copper (II) chloride and potassium carbonate gives the primary alcohol S35-6. Conversion to the alkyl iodide by treatment with iodine, imidazole, and triphenyl phosphine provides S35-7. S35-7 may be coupled with amine S35-8 in hot acetonitrile in the presence of a base such as sodium bicarbonate to give compounds of formula S35-9.

[Image Omitted]

Compounds of formula S36-13 may be prepared according to Scheme 36. Conversion of aniline S36-1 to corresponding sulfonyl chloride S36-2 occurs upon treatment with sodium nitrite, thionyl chloride, copper(I) chloride, and HCl. Reaction of S36-2 with aqueous ammonia provides sulfonamide S36-3. Reaction with N,N-dimethylformamide dimethyl acetal then generates N-sulfonylformamidine S36-4. Suzuki coupling with a vinyl boronate ester such as S36-5 gives enol ether S36-6. Treatment with HCl leads to hydrolysis of the formamidine and enol ether and cyclization to give S36-7. Hydrogenation of S36-7 with Pd/C as catalyst gives S36-8. C—H oxidation of S36-8 with pinacol borane in the presence of catalyst Bis(1,5-cyclooctadiene)dimethoxydiiridium gives S36-9, which may undergo oxidation upon treatment with H₂O₂and potassium carbonate to give phenol derivative S36-10. S36-10 undergoes alkylation with 1,2-dibromoethane under conditions described above to deliver S36-11. Coupling of S36-11 with amine S36-12 under conditions described above gives compounds of formula S36-13.

General Procedure for Intermediate A-1

[Image Omitted]

Step 1: 1-(4-methanesulfonylphenoxy)propan-2-one

[Image Omitted]

A mixture of 4-methylsulfonylphenol (500 mg, 2.90 mmol), 1-chloropropan-2-one (268 mg, 2.90 mmol) and K₂CO₃(521 mg, 3.77 mmol) in DMF (10 mL) was stirred for 3 h. The reaction mixture was cooled to 0° C. and H₂O (20 mL) was added. The biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 1-(4-methylsulfonylphenoxy)propan-2-one (Intermediate A-1), which was taken to the next step without further purification. MS=229.1 [M+H]⁺.

The following intermediate in Table 2 was prepared according to procedures similar those described for Intermediate A-1 using the appropriate starting materials.

General Procedure for Intermediate A-2

TABLE 2

Exact Mass

Intermediate #
Structure
IUPAC Name
[M + H]⁺

A-2

[Image Omitted]

1-methyl-6-(2-oxopropoxy)- 1,2,3,4-tetrahydroquinolin-2- one
Calc'd 234.1 Found 234.2

General Procedure for Intermediate A-3

[Image Omitted]

Step 1: 1-(2-bromoethoxy)-4-methanesulfonylbenzene

[Image Omitted]

To a solution of 4-(methylsulfonyl)phenol (5.00 g, 29.0 mmol) in DMF (50 mL) were added Cs₂CO₃(18.9 g, 58.1 mmol) and 1,2-dibromoethane (11.0 mL, 145 mmol). The mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (250 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 40 g cartridge, 0-60% EtOAc:petroleum ether). The crude product was triturated with MTBE (10 mL) to give 1-(2-bromoethoxy)-4-methanesulfonylbenzene (Intermediate A-3). ¹H NMR (400 MHz, DMSO-d₆): δ 7.85 (d, J=7.2 Hz, 2H), 7.19 (d, J=6.8 Hz, 2H), 4.44 (t, J=4.2 Hz, 2H), 3.84 (t, J=4.2 Hz, 2H), 3.16 (s, 3H). MS=279.0/281.0 [M+H]⁺.

The following intermediates in Table 3 were prepared according to procedures similar to steps described for Intermediate A-3 using the appropriate starting materials.

General Procedure for Intermediates A-4 to A-8 & A-83

TABLE 3

Exact Mass

Intermediate #
Structure
IUPAC Name
[M + H]⁺

A-4

[Image Omitted]

5-(2-bromoethoxy)-1- methyl-2,3-dihydro-1H- indol-2-one
Calc'd 270.0 Found 270.0

A-5

[Image Omitted]

5-(2-bromoethoxy)-1- methyl-1H-indazole
Calc'd 255.0 Found 255.0

A-6

[Image Omitted]

4-(2-bromoethoxy)-2- fluoro-1- methanesulfonylbenzene
No charge in LCMS

A-7

[Image Omitted]

N-[4-(2- bromoethoxy)phenyl]-N- methylmethane- sulfonamide
Calc'd 308.0 Found 308.0

A-8

[Image Omitted]

{[4-(2- bromoethoxy)phenyl] imino}dimethyl-λ⁶- sulfanone
Calc'd 292.0 Found 292.0

A-83

[Image Omitted]

6-(2-bromoethoxy)- 1,2,3,4- tetrahydroquinolin-2- one
Calc'd 270.0/ 272.0 Found 270.0/ 271.9

General Procedure for Intermediates A-9 and A-10

[Image Omitted]

Step 1: 3-methanesulfonylpropyl methanesulfonate

[Image Omitted]

To a 0° C. solution of 3-methanesulfonylpropan-1-ol (500 mg, 3.62 mmol) in DCM (5 mL) were added TEA (1.01 mL, 7.24 mmol) and methanesulfonic anhydride (945 mg, 5.43 mmol). The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with H₂O (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 3-methanesulfonylpropyl methanesulfonate, which was used in the next step without further purification.

Step 2: 4-[(3-methanesulfonylpropyl)sulfanyl]phenol

[Image Omitted]

To a mixture of 4-sulfanylphenol (319 mg, 2.52 mmol) and 3-methanesulfonylpropyl methanesulfonate (390 mg, 1.80 mmol) in MeCN (10 mL) was added Cs₂CO₃(705 mg, 2.16 mmol). The mixture was stirred for 2 h, then was diluted with H₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (12 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-60% EtOAc:petroleum ether) to give 4-[(3-methanesulfonylpropyl)sulfanyl]phenol. MS=245.1 [M−H]⁻.

Step 3: 4-(3-methanesulfonylpropanesulfonyl)phenol

[Image Omitted]

To a solution of 4-[(3-methanesulfonylpropyl)sulfanyl]phenol (370 mg, 1.50 mmol) in THF (3 mL) and H₂O (3 mL) was added NaIO₄(250 μL, 4.51 mmol). The mixture was stirred at 70° C. for 12 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous Na₂SO₃(20 mL), then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-60% EtOAc:petroleum ether) to give 4-(3-methanesulfonylpropanesulfonyl)phenol (Intermediate A-9). MS=277.1 [M−H]⁻.

Step 4: 1-(2-bromoethoxy)-4-(3-methanesulfonylpropanesulfonyl)benzene

[Image Omitted]

To a solution of 4-(3-methanesulfonylpropanesulfonyl)phenol (Intermediate A-9) (300 mg, 1.08 mmol) in DMF (3 mL) were added K₂CO₃(223 mg, 1.62 mmol) and 1,2-dibromoethane (407 μL, 5.39 mmol). The mixture was stirred at 100° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (8 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC (SiO₂, 1:1 EtOAc:petroleum ether) to give 1-(2-bromoethoxy)-4-(3-methanesulfonylpropanesulfonyl)benzene (Intermediate A-10). ¹H NMR (400 MHz, DMSO-d₆): δ 7.84 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 4.47 (t, J=4.8 Hz, 2H), 3.86 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.22 (t, J=7.6 Hz, 2H), 2.98 (s, 3H), 2.00-1.92 (m, 2H).

General Procedure for Intermediate A-11

[Image Omitted]

Step 1: 3,5-difluoro-4-methanesulfonylphenol

[Image Omitted]

To a solution of 4-bromo-3,5-difluorophenol (1.00 g, 4.78 mmol) and MeSO₂Na (4.88 g, 47.8 mmol) in DMSO (15 mL) were added CuI (91.1 mg, 0.478 mmol), DMEDA (84 mg, 0.956 mmol) and K₃PO₄(203 mg, 0.956 mmol). The mixture was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-50% EtOAc:petroleum ether) to give the crude product. The product was further purified by reverse phase preparative HPLC (Agela C₁₈column, 5-35% Methanol: 0.04% HCl in H₂O) to give 3,5-difluoro-4-methanesulfonylphenol (Intermediate A-11). MS=207.1 [M−H]⁻.

General Procedure for Intermediates A-12 and A-13

[Image Omitted]

Step 1: 4-bromo-3-(difluoromethyl)phenol

[Image Omitted]

To a 0° C. solution of 2-bromo-5-hydroxybenzaldehyde (17.6 g, 87.5 mmol) in DCM (170 mL) was added DAST (14.1 g, 87.6 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was cooled to 0° C., quenched with saturated aqueous NaHCO₃(150 mL), and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 120 g cartridge, 8-15% EtOAc:petroleum ether) to give 4-bromo-3-(difluoromethyl)phenol.

Step 2: 3-(difluoromethyl)-4-methanesulfonylphenol

[Image Omitted]

A mixture of 4-bromo-3-(difluoromethyl)phenol (3.60 g, 16.1 mmol), sodium methanesulfinate (16.5 g, 161 mmol), NaOH (323 mg, 8.07 mmol), (2S)-pyrrolidine-2-carboxylic acid (929 mg, 8.07 mmol) and copper(I) iodide (3.07 g, 16.1 mmol) in DMSO (40 mL) was degassed and purged with N₂(3×). The mixture was stirred at 100° C. for 48 h. The reaction mixture was poured into ice water (200 mL) and then extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×300 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-30% EtOAc:petroleum ether) to give 3-(difluoromethyl)-4-methanesulfonylphenol (Intermediate A-12). ¹H NMR (400 MHz, DMSO-d₆): δ 11.04 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.67-7.40 (m, 1H), 7.20 (s, 1H), 7.11 (d, J=4.2 Hz, 1H), 3.21 (s, 3H).

Step 3: 4-(2-bromoethoxy)-2-(difluoromethyl)-1-methanesulfonylbenzene

[Image Omitted]

To a solution of 3-(difluoromethyl)-4-methanesulfonylphenol (300 mg, 1.35 mmol) in 1,2-dibromoethane (7.5 mL) was added Cs₂CO₃(1.32 g, 4.05 mmol). The mixture was stirred at 100° C. for 12 h. After cooling to room temperature, solids were removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-30% EtOAc:petroleum ether) to give 4-(2-bromoethoxy)-2-(difluoromethyl)-1-methanesulfonylbenzene (Intermediate A-13). ¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (d, J=8.8 Hz, 1H), 7.74-7.55 (m, 1H), 7.47-7.32 (m, 2H), 4.56-4.49 (m, 2H), 3.87-3.82 (m, 2H), 3.26 (s, 3H).

General Procedure for Intermediate A-14

[Image Omitted]

Step 1: 4-methoxy-N-(propan-2-yl)aniline

[Image Omitted]

To a solution of 4-methoxyaniline (500 mg, 4.06 mmol) in DCM (10 mL) was added dropwise acetone (943 mg, 16.2 mmol) and AcOH (975 mg, 16.2 mmol). The mixture was stirred at room temperature for 1 h, and then NaBH(OAc)₃(1.08 g, 5.08 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-30% EtOAc:petroleum ether) to give 4-methoxy-N-(propan-2-yl)aniline. ¹H NMR (400 MHz, DMSO-d₆): δ 6.72-6.61 (m, 2H), 6.54-6.45 (m, 2H), 4.81 (s, 1H), 3.62 (s, 3H), 3.49-3.39 (m, 1H), 1.08 (d, J=6.4 Hz, 6H). MS=166.2 [M+H]⁺.

Step 2: 2-chloro-N-(4-methoxyphenyl)-N-(propan-2-yl)acetamide

[Image Omitted]

A mixture of 4-methoxy-N-(propan-2-yl)aniline (200 mg, 1.21 mmol), TEA (253 μL, 1.82 mmol) in DCM (3 mL) was degassed and purged with N₂(3×). The mixture was cooled to 0° C. and 2-chloroacetyl chloride (273 mg, 2.42 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 12 h under N₂atmosphere. The reaction mixture was quenched with H₂O (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with saturated aqueous NaHCO₃(20 ml) followed by brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Isco 4 g cartridge, 0-40% EtOAc:petroleum ether) to give 2-chloro-N-(4-methoxyphenyl)-N-(propan-2-yl)acetamide. MS=242.1 [M+H]⁺.

Step 3: 5-hydroxy-1-(propan-2-yl)-2,3-dihydro-1H-indol-2-one

[Image Omitted]

To 2-chloro-N-(4-methoxyphenyl)-N-(propan-2-yl)acetamide (1.00 g, 4.14 mmol) was slowly added aluminum chloride (2.21 g, 16.6 mmol). The mixture was stirred at 130° C. for 3 h. After cooling to room temperature, the reaction mixture was quenched with aqueous 1.0 M NaOH (20 mL), diluted with H₂O (10 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Isco 12 g cartridge, 0-40% EtOAc:petroleum ether) to give 5-hydroxy-1-(propan-2-yl)-2,3-dihydro-1H-indol-2-one. MS=192.2 [M+H]⁺.

Step 4: 5-(2-bromoethoxy)-1-(propan-2-yl)-2,3-dihydro-1H-indol-2-one

[Image Omitted]

To a solution of 5-hydroxy-1-(propan-2-yl)-2,3-dihydro-1H-indol-2-one (500 mg, 2.61 mmol) in 1,2-dibromoethane (8 mL) was added Cs₂CO₃(2.56 g, 7.84 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, solids were removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Isco 12 g cartridge, 0-60% EtOAc:petroleum ether) to give 5-(2-bromoethoxy)-1-(propan-2-yl)-2,3-dihydro-1H-indol-2-one (Intermediate A-14). MS=298.1/300.1 [M+H]⁺.

General Procedure for Intermediates A-15 & A-16

[Image Omitted]

Step 1: 4-[(difluoromethyl)sulfanyl]phenol

[Image Omitted]

To a solution of 4-sulfanylphenol (300 mg, 2.38 mmol) in DMF (4 mL) and H₂O (1 mL) were added K₂CO₃(1.97 g, 14.3 mmol) and 2-chloro-2,2-difluoro-acetic acid (302 μL, 3.57 mmol). The mixture was stirred at 120° C. for 15 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-30% EtOAc:petroleum ether) to give 4-[(difluoromethyl)sulfanyl]phenol. MS=177.0 [M+H]⁺.

Step 2: 4-difluoromethanesulfonylphenol

[Image Omitted]

To a 0° C. solution of 4-[(difluoromethyl)sulfanyl]phenol (100 mg, 0.568 mmol) in THF (1 mL) and H₂O (1 mL) was added NaIO₄(94.4 μL, 1.70 mmol). The mixture was stirred at 70° C. for 15 h. After cooling to room temperature, the reaction mixture was quenched by the addition of saturated aqueous Na₂SO₃(20 mL), and then extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-30% EtOAc:petroleum ether) to give 4-difluoromethanesulfonylphenol (Intermediate A-15). MS=207.0 [M−H]⁺.

Step 3: 1-(2-bromoethoxy)-4-difluoromethanesulfonylbenzene

[Image Omitted]

To a mixture of 4-(difluoromethylsulfonyl)phenol (500 mg, 2.40 mmol) and 1,2-dibromoethane (906 μL, 12.0 mmol) in DMF (5 mL) was added K₂CO₃(664 mg, 4.80 mmol). The mixture was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (20 mL), and then extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-50% EtOAc:petroleum ether) to give 1-(2-bromoethoxy)-4-difluoromethanesulfonylbenzene (Intermediate A-16). ¹H NMR (400 MHz, DMSO-d₆): δ 7.80 (d, J=2.8 Hz, 2H), 7.21-7.04 (m, 3H), 4.95 (t, J=7.2 Hz, 2H), 3.85 (t, J=7.2 Hz, 2H).

General Procedure for Intermediate A-17

[Image Omitted]

Step 1: 4-methanesulfonyl-3-(trifluoromethyl)phenol

[Image Omitted]

A mixture of 4-bromo-3-(trifluoromethyl)phenol (7.00 g, 29.1 mmol), sodium methanesulfinate (29.7 g, 290 mmol), CuI (2.77 g, 14.5 mmol), NaOH (581 mg, 14.5 mmol) and L-Proline (1.67 g, 14.5 mmol) in DMSO (100 mL) was degassed and purged with N₂(3×). The mixture was stirred at 100° C. for 3 d under N₂atmosphere. After cooling to room temperature, the reaction mixture was quenched with H₂O (80 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-50% EtOAc:petroleum ether) to give 4-methanesulfonyl-3-(trifluoromethyl)phenol. MS=239.1 [M−H]⁻.

Step 2: 4-(2-bromoethoxy)-1-methanesulfonyl-2-(trifluoromethyl)benzene

[Image Omitted]

To a solution of 4-methylsulfonyl-3-(trifluoromethyl)phenol (500 mg, 2.08 mmol) in DMF (5 mL) were added 1,2-dibromoethane (2.36 mL, 31.2 mmol) and K₂CO₃(575 mg, 4.16 mmol). The mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was quenched with H₂(8 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-25% EtOAc:petroleum ether) to give 4-(2-bromoethoxy)-1-methanesulfonyl-2-(trifluoromethyl)benzene (Intermediate A-17). MS 347.0/349.0 [M+H]⁺.

The following intermediates in Table 4 were prepared according to procedures similar those described for Intermediate A-17 using the appropriate starting materials.

General Procedure for Intermediates A-18 to A-22

TABLE 4

Exact Mass

Intermediate #
Structure
Name
[M + H]⁺

A-18

[Image Omitted]

5-(2-bromoethoxy)-1,3- difluoro-2- methanesulfonylbenzene
Calc'd 332.0/ 334.0 Found 332.1/ 334.0 [M + NH₄]⁺

A-19

[Image Omitted]

4-(2-bromoethoxy)-2-chloro- 1-methanesulfonylbenzene
Calc'd 312.9/ 314.9 Found 312.9/ 315.0

A-20

[Image Omitted]

5-(2-bromoethoxy)-2- methanesulfonyl-1,3- dimethylbenzene
Calc'd 307.0/ 309.0 Found 307.1/ 309.0

A-21

[Image Omitted]

5-(2-bromoethoxy)-2- methanesulfonyl-3- methylpyridine
Calc'd 294.0/ 296.0 Found 294.0/ 296.0

A-22

[Image Omitted]

4-(2-bromoethoxy)-1- methanesulfonyl-2- methylbenzene
Calc'd 293.0/ 295.0 Found 293.0/ 295.0

General Procedure for Intermediate A-23

[Image Omitted]

Step 1: 1-bromo-2-(difluoromethoxy)-4-methoxybenzene

[Image Omitted]

To a solution of 2-bromo-5-methoxyphenol (2.50 g, 12.3 mmol) in DMF (36 mL) and H₂O (9 mL) were added K₂CO₃(10.2 g, 73.9 mmol) and sodium chlorodifluoroacetate (4.69 g, 30.8 mmol). The mixture was stirred at 120° C. for 15 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Isco 40 g cartridge, 0-7% EtOAc:petroleum ether) to give 1-bromo-2-(difluoromethoxy)-4-methoxybenzene.

Step 2: 2-(difluoromethoxy)-1-methanesulfonyl-4-methoxybenzene

[Image Omitted]

A mixture of 1-bromo-2-(difluoromethoxy)-4-methoxybenzene (3.00 g, 11.9 mmol), sodium methanesulfinate (6.05 g, 59.3 mmol), L-Proline (409 mg, 3.56 mmol), sodium hydroxide (142 mg, 3.56 mmol) and copper (I) iodide (1.13 g, 5.93 mmol) in DMSO (30 mL) was degassed and purged with N₂(3×). The mixture was stirred at 100° C. for 12 h under N₂atmosphere. After cooling to room temperature, the reaction mixture was quenched with H₂O (80 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Isco 80 g cartridge, 0-23% EtOAc:petroleum ether) to give 2-(difluoromethoxy)-1-methanesulfonyl-4-methoxybenzene. MS=253.2 [M+H]⁺.

Step 3: 3-(difluoromethoxy)-4-methanesulfonylphenol

[Image Omitted]

A mixture of 2,2,4,6,6-pentamethylheptane-4-thiol (2.70 g, 13.3 mmol) and t-BuOK (1.56 g, 13.9 mmol) in DMF (14 mL) was degassed and purged with N₂(3×). The mixture was cooled to 0° C. and a solution of 2-(difluoromethoxy)-1-methanesulfonyl-4-methoxybenzene (1.4 g, 5.55 mmol) in DMF (14 mL) was added dropwise. The resulting mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Isco 40 g cartridge, 0-33% EtOAc:petroleum ether) to give 3-(difluoromethoxy)-4-methanesulfonylphenol. MS=239.2 [M+H]⁺.

Step 4: 4-(2-bromoethoxy)-2-(difluoromethoxy)-1-methanesulfonylbenzene

[Image Omitted]

To a mixture of 3-(difluoromethoxy)-4-methanesulfonylphenol (370 mg, 1.55 mmol) and 1,2-dibromoethane (3.00 mL, 39.7 mmol) in DMF (3 mL) was added Cs₂CO₃(1.01 g, 3.11 mmol). After stirring at room temperature for 12 h, the mixture was diluted with H₂O (15 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Isco 4 g cartridge, 0-30% EtOAc:petroleum ether) to give 4-(2-bromoethoxy)-2-(difluoromethoxy)-1-methanesulfonylbenzene (Intermediate A-23). MS=362.1/364.0 [M+NH₄]⁺.

General Procedure for Intermediate A-24

[Image Omitted]

Step 1: methyl 2-[(4-fluorophenyl)sulfanyl]acetate

[Image Omitted]

To a solution of 4-fluorobenzene-1-thiol (1.25 mL, 11.7 mmol) in DMF (15 mL) were added K₂CO₃(3.23 g, 23.4 mmol) and methyl 2-bromoacetate (1.33 mL, 14.0 mmol). The mixture was stirred at room temperature for 5 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 25 g cartridge, 1-20% EtOAc:petroleum ether) to give methyl 2-[(4-fluorophenyl)sulfanyl]acetate. MS=201.0 [M+H]⁺.

Step 2: methyl 2-(4-fluorobenzenesulfonyl)acetate

[Image Omitted]

To a solution of methyl 2-[(4-fluorophenyl)sulfanyl]acetate (2.20 g, 11.0 mmol) in MeCN (30 mL) and H₂O (3 mL) was added Oxone (8.11 g, 13.2 mmol). After stirring at room temperature for 16 h, the mixture cooled to 0° C. and quenched with saturated aqueous Na₂S203 (40 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 25 g cartridge, 15-45% EtOAc:petroleum ether) to give methyl 2-(4-fluorobenzenesulfonyl)acetate. MS=233.0 [M+H]⁺.

Step 3: methyl 1-(4-fluorobenzenesulfonyl)cyclopropane-1-carboxylate

[Image Omitted]

To a solution of methyl 2-(4-fluorobenzenesulfonyl)acetate (1.10 g, 4.74 mmol) in DMF (10 mL) were added K₂CO₃(1.64 g, 11.8 mmol) and 1,2-dibromoethane (429 μL, 5.68 mmol). The mixture was stirred at 60° C. for 6 h. The reaction mixture was cooled to 0° C., quenched with H₂O (20 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 15-45% EtOAc:petroleum ether) to give methyl 1-(4-fluorobenzenesulfonyl)cyclopropane-1-carboxylate. MS=259.0 [M+H]⁺.

Step 4: methyl 1-[4-(2-hydroxyethoxy)benzenesulfonyl]cyclopropane-1-carboxylate

[Image Omitted]

To a solution of methyl 1-(4-fluorobenzenesulfonyl)cyclopropane-1-carboxylate (1.50 g, 5.81 mmol) in DMSO (15 mL) were added Cs₂CO₃(5.68 g, 17.4 mmol) and ethylene glycol (6.50 mL, 116 mmol). The mixture was stirred at 100° C. for 5 h. The hydrolysis product of the ester was detected. After cooling to room temperature, MeI (1.08 mL, 17.4 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 1 h and was then quenched with H₂O (30 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 45-80% EtOAc:petroleum ether) to give methyl 1-[4-(2-hydroxyethoxy)benzenesulfonyl]cyclopropane-1-carboxylate. MS=301.1 [M+H]⁺.

Step 5: methyl 1-{4-[2-(methanesulfonyloxy)ethoxy]benzenesulfonyl}cyclopropane-1-carboxylate

[Image Omitted]

To a 0° C. solution of methyl 1-[4-(2-hydroxyethoxy)benzenesulfonyl]cyclopropane-1-carboxylate (570 mg, 1.90 mmol) in DCM (10 mL) were added TEA (528 μL, 3.80 mmol) and methylsulfonyl methanesulfonate (397 mg, 2.28 mmol). The mixture was stirred at 0° C. for 3 h, and then quenched with H₂O (10 mL). 4 M aqueous HCl (0.1 mL) was added, and the mixture was extracted with EtOAc (8 mL×2). The combined organic layers were washed with brine (2×8 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give methyl 1-{4-[2-(methanesulfonyloxy)ethoxy]benzenesulfonyl}cyclopropane-1-carboxylate (Intermediate A-24), which was used in the subsequent step without further purification. MS=378.9 [M+H]⁺.

General Procedure for Intermediates A-25 & A-85

[Image Omitted]

Step 1: 4-[(2-hydroxyethyl)sulfanyl]phenol

[Image Omitted]

A solution of 4-bromophenol (10.0 g, 57.8 mmol), 2-sulfanylethanol (5.24 mL, 75.1 mmol), XantPhos (6.69 g, 11.6 mmol), Pd₂(dba)₃(5.29 g, 5.78 mmol) and DIEA (25.2 mL, 145 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N₂(3×). The mixture was stirred at 100° C. for 12 h under N₂atmosphere. After cooling to room temperature, the reaction mixture was quenched with H₂O (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-50% EtOAc:petroleum ether) to give 4-[(2-hydroxyethyl)sulfanyl]phenol.

Step 2: 4-(2-hydroxyethanesulfonyl)phenol

[Image Omitted]

A solution of 4-[(2-hydroxyethyl)sulfanyl]phenol (4.80 g, 28.2 mmol), NaIO₄(4.69 mL, 84.6 mmol) in THF (50 mL) and H₂O (50 mL) was degassed and purged with N₂(3×). The mixture was stirred at 70° C. for 12 h under N₂atmosphere. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous Na₂S203 (100 mL) and extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine (70 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 4-(2-hydroxyethanesulfonyl)phenol (Intermediate A-85), which was used in the subsequent step without further purification. MS=203.0 [M+H]⁺.

Step 3: 4-(2-chloroethanesulfonyl)phenol

[Image Omitted]

To a 0° C. mixture of 4-(2-hydroxyethanesulfonyl)phenol (600 mg, 2.97 mmol) and pyridine (478 μL, 5.93 mmol) in DCM (6 mL) was added SOCl₂(645 μL, 8.90 mmol). The mixture was stirred at 35° C. for 16 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-100% EtOAc:petroleum ether) to give 4-(2-chloroethanesulfonyl)phenol.

Step 4: 4-[2-(methylamino)ethanesulfonyl]phenol

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A mixture of 4-(2-chloroethanesulfonyl)phenol (250 mg, 1.13 mmol), 2.0 M methylamine in MeOH (7.93 mL, 15.9 mmol), and KI (75 mg, 0.45 mmol) in THF (2 mL) was stirred at 60° C. for 16 h under N₂atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo to give 4-[2-(methylamino)ethanesulfonyl]phenol, which was used in the subsequent step without further purification. MS=216.1 [M+H]⁺.

Step 5: N-[2-(4-hydroxybenzenesulfonyl)ethyl]-N-methylacetamide

[Image Omitted]

A mixture of 4-[2-(methylamino)ethanesulfonyl]phenol (340 mg, 1.58 mmol) and Ac2O (147 μL, 1.58 mmol) in THF (5 mL) was stirred for 16 h. The mixture was filtered and the filtered cake was concentrated under in vacuo to give N-[2-(4-hydroxybenzenesulfonyl)ethyl]-N-methylacetamide (Intermediate A-25), which was used in the subsequent step without further purification. MS=258.2 [M+H]⁺.

General Procedure for Intermediate A-26

[Image Omitted]

Step 1: 5-chloro-2-(oxetan-3-ylsulfanyl)pyridine

[Image Omitted]

To a solution of 5-chloropyridine-2-thiol (4.50 g, 30.9 mmol) in DMF (50 mL) were added K₂CO₃(8.54 g, 61.8 mmol) and 3-iodooxetane (6.82 g, 37.1 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H₂O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-15% EtOAc:petroleum ether) to give 5-chloro-2-(oxetan-3-ylsulfanyl)pyridine. MS=202.0 [M+H]⁺.

Step 2: 5-chloro-2-(oxetane-3-sulfonyl)pyridine

[Image Omitted]

To a 0° C. solution of 5-chloro-2-(oxetan-3-ylsulfanyl)pyridine (3.00 g, 14.9 mmol) in DCM (40 mL) was added m-CPBA (6.04 g, 85% purity, 29.8 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous Na₂SO₃(20 mL), diluted with H₂O (100 mL), and extracted with DCM (3×50 mL). The combined organic layers were washed with saturated aqueous Na₂SO₃(2×50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was triturated with EtOAc (5 mL) and isolated by filtration to give 5-chloro-2-(oxetane-3-sulfonyl)pyridine. MS=234.0 [M+H]⁺.

Step 3: 5-chloro-2-[(3-methyloxetan-3-yl)sulfonyl]pyridine

[Image Omitted]

To a −78° C. solution of 5-chloro-2-(oxetane-3-sulfonyl)pyridine (500 mg, 2.14 mmol) in THF (8 mL) was added 1.0 M LiHMDS in THF (4.28 mL, 4.28 mmol). After stirring for 30 min, MeI (160 μL, 2.57 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was quenched with saturated aqueous NH₄Cl (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-15% EtOAc:petroleum ether) to give 5-chloro-2-[(3-methyloxetan-3-yl)sulfonyl]pyridine. MS=248.0 [M+H]⁺.

Step 4: 2-({6-[(3-methyloxetan-3-yl)sulfonyl]pyridin-3-yl}oxy)ethan-1-ol

[Image Omitted]

To a solution of 5-chloro-2-[(3-methyloxetan-3-yl)sulfonyl]pyridine (350 mg, 1.41 mmol) in DMSO (2 mL) were added ethylene glycol (2.00 mL, 35.8 mmol) and Cs₂CO₃(921 mg, 2.83 mmol). The mixture was stirred at 100° C. for 7 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (20 mL) and extracted with EtOAc (6×10 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-70% EtOAc:petroleum ether) to give 2-({6-[(3-methyloxetan-3-yl)sulfonyl]pyridin-3-yl}oxy)ethan-1-ol. MS=274.1 [M+H]⁺.

Step 5: 2-({6-[(3-methyloxetan-3-yl)sulfonyl]pyridin-3-yl}oxy)ethyl methanesulfonate

[Image Omitted]

To a solution of 2-({6-[(3-methyloxetan-3-yl)sulfonyl]pyridin-3-yl}oxy)ethan-1-ol (130 mg, 0.476 mmol) in DCM (3 mL) was added TEA (199 μL, 1.43 mmol) and methanesulfonic anhydride (166 mg, 0.951 mmol). The mixture was stirred at room temperature for 5 h, and then diluted with H₂O (10 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to give 2-({6-[(3-methyloxetan-3-yl)sulfonyl]pyridin-3-yl}oxy)ethyl methanesulfonate (Intermediate A-26), which was used in the subsequent step without further purification. MS=352.1 [M+H]⁺.

The following intermediate in Table 5 was prepared using procedures similar to those described for Intermediate A-26, using the appropriate starting materials.

General Procedure for Intermediate A-27

TABLE 5

Exact Mass

Intermediate #
Structure
Name
[M + H]⁺

A-27

[Image Omitted]

2-{4-[(3- methyloxetan-3- yl)sulfonyl]phenoxy} ethyl methanesulfonatele
Calc'd 351.1 Found 350.9

General Procedure for Intermediate A-28

[Image Omitted]

Step 1: 1-(methanesulfonylmethyl)-4-methoxybenzene

[Image Omitted]

A mixture of 1-(chloromethyl)-4-methoxybenzene (8.70 mL, 63.9 mmol), sodium methanesulfinate (9.13 g, 89.4 mmol) and NaI (28.7 mg, 0.192 mmol) in DMF (80 mL) was stirred at 80° C. for 3 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was triturated with EtOAc (50 mL) to give 1-(methanesulfonylmethyl)-4-methoxybenzene, which was used in the subsequent step without further purification.

Step 2: 1-(1-methanesulfonylethenyl)-4-methoxybenzene

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A mixture of 1-(methanesulfonylmethyl)-4-methoxybenzene (9.00 g, 44.9 mmol), Cs₂CO₃(43.9 g, 135 mmol), TBAI (166 mg, 0.449 mmol) and HCHO (12.4 mL, 449 mmol) in toluene (150 mL) was stirred at 70° C. for 3 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 120 g cartridge, 0-30% EtOAc:petroleum ether) to give 1-(1-methanesulfonylethenyl)-4-methoxybenzene. MS=213.1 [M+H]⁺.

Step 3: 1-(1-methanesulfonylcyclopropyl)-4-methoxybenzene

[Image Omitted]

To a solution of trimethylsulfoxonium iodide (523 mg, 2.37 mmol) in DMSO (5 mL) was added NaH (84.4 mg, 60 wt % in mineral oil, 2.11 mmol). After stirring at room temperature for 1 h, 1-(1-methanesulfonylethenyl)-4-methoxybenzene (0.28 g, 1.32 mmol) was added. The mixture was stirred for 16 h, then cooled to 0° C., quenched with saturated aqueous NH₄Cl (10 mL), and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-50% EtOAc:petroleum ether) to give 1-(1-methanesulfonylcyclopropyl)-4-methoxybenzene. MS=244.2 [M+NH₄]⁺.

Step 4: 4-(1-methanesulfonylcyclopropyl)phenol

[Image Omitted]

To a 0° C. solution of 1-(1-methanesulfonylcyclopropyl)-4-methoxybenzene (1.20 g, 5.30 mmol) in DCM (20 mL) was added BBr₃(1.53 mL, 15.9 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (30 mL). The pH of the 0° C. solution was adjusted to pH=7 with the dropwise addition of saturated aqueous NaHCO₃. The biphasic mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to give 4-(1-methanesulfonylcyclopropyl)phenol, which was used in the subsequent step without further purification.

Step 5: 1-(2-bromoethoxy)-4-(1-methanesulfonylcyclopropyl)benzene

[Image Omitted]

To a solution of 4-(1-methanesulfonylcyclopropyl)phenol (200 mg, 0.942 mmol) in 1,2-dibromoethane (4.27 mL, 56.5 mmol) was added Cs₂CO₃(614 mg, 1.88 mmol). The mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (10 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-30% EtOAc:petroleum ether) to give 1-(2-bromoethoxy)-4-(1-methanesulfonylcyclopropyl)benzene (Intermediate A-28). MS=336.0/338.1 [M+NH₄]⁺.

General Procedure for Intermediates A-29 & A-30

[Image Omitted]

Step 1: 5-(benzyloxy)-2-bromo-1,3-difluorobenzene

[Image Omitted]

To a solution of 4-bromo-3,5-difluorophenol (10.0 g, 47.8 mmol) in MeCN (100 mL) were added BnBr (6.82 mL, 57.4 mmol) and K₂CO₃(19.8 g, 144 mmol). The mixture was stirred at 60° C. for 12 h. After cooling to room temperature, the mixture was poured into saturated aqueous NaHCO₃(400 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×200 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-1% EtOAc:petroleum ether) to give 5-(benzyloxy)-2-bromo-1,3-difluorobenzene (Intermediate A-29). ¹H NMR (400 MHz, CDCl₃): δ 7.42-7.35 (m, 5H), 6.64-6.60 (m, 2H), 5.04 (s, 2H).

Step 2: 1-[4-(benzyloxy)-2,6-difluorophenyl]ethan-1-ol

[Image Omitted]

To a 0° C. solution of 5-(benzyloxy)-2-bromo-1,3-difluorobenzene (12.0 g, 40.1 mmol) in THF (24 mL) was added 1.3 M i-PrMgCl·LiCl in THF (34.0 mL, 44.1 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was cooled to 0° C. and 5.0 M acetaldehyde in THF (8.82 mL, 44.1 mmol) was added into the reaction mixture. After stirring at 0° C. for 30 min, the mixture was warmed to room temperature and stirred for another 30 min. The reaction mixture was quenched with saturated aqueous NH₄Cl (300 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×300 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-35% EtOAc:petroleum ether) to give 1-[4-(benzyloxy)-2,6-difluorophenyl]ethan-1-ol. MS=247.2 [M-OH]⁺.

Step 3: 5-(benzyloxy)-2-(1-chloroethyl)-1,3-difluorobenzene

[Image Omitted]

To a 0° C. solution of 1-[4-(benzyloxy)-2,6-difluorophenyl]ethan-1-ol (5.8 g, 21.9 mmol) in DCM (60 mL) was added SOCl₂(3.18 mL, 43.9 mmol). The mixture was stirred at room temperature for 4 h, and then concentrated in vacuo to give 5-(benzyloxy)-2-(1-chloroethyl)-1,3-difluorobenzene, which was used in the subsequent step without further purification.

Step 4: 5-(benzyloxy)-1,3-difluoro-2-(1-methanesulfonylethyl)benzene

[Image Omitted]

To a solution of 5-(benzyloxy)-2-(1-chloroethyl)-1,3-difluorobenzene (6.20 g, 21.9 mmol) in DMF (60 mL) was added sodium methanesulfinate (4.48 g, 43.9 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-50% EtOAc:petroleum ether) to give 5-(benzyloxy)-1,3-difluoro-2-(1-methanesulfonylethyl)benzene.

Step 5: 3,5-difluoro-4-(1-methanesulfonylethyl)phenol

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To a solution of 5-(benzyloxy)-1,3-difluoro-2-(1-methanesulfonylethyl)benzene (3.00 g, 9.19 mmol) in MeOH (30 mL) was added Pd/C (0.50 g, 10 wt %, 0.47 mmol) and Pd(OH)₂/C (0.50 g, 20 wt %, 0.70 mmol). The mixture was stirred at 40° C. for 16 h under an atmosphere of H₂(50 psi). After cooling to room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-100% EtOAc:petroleum ether) to give 3,5-difluoro-4-(1-methanesulfonylethyl)phenol. MS=254.1 [M+NH₄]⁺.

Step 6: 5-(2-bromoethoxy)-1,3-difluoro-2-(1-methanesulfonylethyl)benzene

[Image Omitted]

To a solution of 3,5-difluoro-4-(1-methanesulfonylethyl)phenol (0.43 g, 1.82 mmol) in 1,2-dibromoethane (10 mL, 132 mmol) was added Cs₂CO₃(1.19 g, 3.64 mmol). The mixture was stirred at 100° C. for 12 h. After cooling to room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-50% EtOAc:petroleum ether) to give 5-(2-bromoethoxy)-1,3-difluoro-2-(1-methanesulfonylethyl)benzene (Intermediate A-30). MS=360.1/362.1 [M+NH₄]⁺.

The following intermediate in Table 6 was prepared using procedures similar to those described for Intermediate A-30, using the appropriate starting materials.

TABLE 6

Intermediate #
Structure
Name
Exact Mass [M + H]⁺

A-31

[Image Omitted]

1-(2-bromoethoxy)-4-(1- methanesulfonylethyl)benzene
Calc'd 227.0/229.0 Found 227.1/229.1 [M − CH₃O₂S]⁺

General Procedure for Intermediate A-31

[Image Omitted]

Step 1: 3-[4-(benzyloxy)-2,6-difluorophenyl]oxetan-3-ol

[Image Omitted]

To a 0° C. solution of 5-(benzyloxy)-2-bromo-1,3-difluorobenzene (Intermediate A-29, 14.0 g, 46.8 mmol) in THF (150 mL) was added 2.0 M i-PrMgCl in THF (25.7 mL, 51.4 mmol). After stirring at 0° C. for 30 min, oxetan-3-one (4.05 g, 56.2 mmol) was added. The mixture was stirred at 0° C. for another 30 min, and then quenched with H₂O (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 1:10 EtOAc:petroleum ether) to give 3-[4-(benzyloxy)-2,6-difluorophenyl]oxetan-3-ol. MS=315.2 [M+Na]⁺.

Step 2: 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-[(triphenylmethyl)sulfanyl]oxetane

[Image Omitted]

To a solution of 3-[4-(benzyloxy)-2,6-difluorophenyl]oxetan-3-ol (20.0 g, 68.4 mmol) and triphenylmethanethiol (75.7 g, 274 mmol) in CHCl₃(200 mL) was added [bis(trifluoromethylsulfonyl)amino]lithium (2.16 g, 7.53 mmol) and tetrabutylammonium hexafluorophosphate (1.46 g, 3.76 mmol). The mixture was stirred at 40° C. for 2 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (300 mL) and extracted with DCM (3×150 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 330 g cartridge, 0-40% EtOAc:petroleum ether) to give 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-[(triphenylmethyl)sulfanyl]oxetane.

Step 3: 3-[4-(benzyloxy)-2,6-difluorophenyl]oxetane-3-thiol

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To a solution of 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-[(triphenylmethyl)sulfanyl]oxetane (400 mg, 0.726 mmol) in DCM (2 mL) was added TFA (4 mL) and Et₃SiH (290 μL, 1.82 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H₂O (10 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-10% EtOAc:petroleum ether) to give 3-[4-(benzyloxy)-2,6-difluorophenyl]oxetane-3-thiol. MS=307.1 [M−H]⁻.

Step 4: 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-(methylsulfonyl)oxetane

[Image Omitted]

To a solution of 3-[4-(benzyloxy)-2,6-difluorophenyl]oxetane-3-thiol (2.50 g, 8.11 mmol) in DMF (25 mL) was added K₂CO₃(1.68 g, 12.2 mmol) and MeI (2.52 mL, 40.5 mmol). The mixture was stirred at room temperature for 1 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (50 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (3×30 mL) dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-15% EtOAc:petroleum ether) to give 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-(methylsulfonyl)oxetane. MS=321.0 [M−H]⁻.

Step 5: 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-methanesulfonyloxetane

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To a solution of 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-(methylsulfonyl)oxetane (2.00 g, 6.20 mmol) in DCM (30 mL) was added m-CPBA (3.78 g, 85% purity, 18.6 mmol). The reaction mixture was diluted with H₂O (50 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with saturated aqueous Na₂SO₃(2×20 mL) dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was triturated with EtOAc and then dried in vacuo to give 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-methanesulfonyloxetane, which was used in the subsequent step without further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 7.46-7.35 (m, 5H), 6.95-6.92 (m, 2H), 5.16-5.10 (m, 6H), 3.13 (s, 3H).

Step 6: 3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenol

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To a solution of 3-[4-(benzyloxy)-2,6-difluorophenyl]-3-methanesulfonyloxetane (600 mg, 1.69 mmol) in EtOAc (20 mL) under Argon atmosphere was added Pd/C (1.00 g, 10 wt %, 0.943 mmol). The mixture was stirred at room temperature for 3 h under an atmosphere of H₂(15 psi). The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give 3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenol, which was used in the subsequent step without further purification. ¹H NMR (400 MHz, DMSO-d₆, 9/10 H): δ 6.54-6.51 (m, 2H), 5.13-5.08 (m, 4H), 3.09 (s, 3H).

Step 7: 3-[4-(2-bromoethoxy)-2,6-difluorophenyl]-3-methanesulfonyloxetane

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To a solution of 3,5-difluoro-4-(3-methanesulfonyloxetan-3-yl)phenol (200 mg, 0.757 mmol) in 1,2-dibromoethane (2.00 mL, 26.5 mmol) was added Cs₂CO₃(493 mg, 1.51 mmol). The mixture was stirred at 80° C. for 3 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (10 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-40% EtOAc:petroleum ether) to give 3-[4-(2-bromoethoxy)-2,6-difluorophenyl]-3-methanesulfonyloxetane (Intermediate A-32). MS=388.0/390.0 [M+NH₄]⁺.

The following intermediates in Table 7 were prepared using procedures similar to those described for Intermediate A-32, using the appropriate starting materials.

General Procedure for Intermediates A-33 & A-34

TABLE 7

Intermediate #
Structure
Name
Exact Mass [M + H]⁺

A-33

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3-[4-(2- bromoethoxy)phenyl]-3- methanesulfonyloxetane
Calc'd 352.0/354.0 Found 352.1/354.0 [M + NH₄]⁺

A-34

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3-[4-(2-bromoethoxy)-2- (trifluoromethyl)phenyl]- 3- methanesulfonyloxetane
Calc'd 420.0/422.0 Found 420.0/422.0 [M + NH₄]⁺

General Procedure for Intermediates A-35, A-36, & A-84

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Step 1: 3-[4-(benzyloxy)phenyl]oxetane-3-ol

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To a −78° C. solution of 1-(benzyloxy)-4-bromobenzene (3.00 g, 11.4 mmol) in THF (20 mL) was added 2.5 M n-BuLi in THF (7.30 mL, 18.3 mmol). After stirring for 1 h at −78° C., oxetan-3-one (986 mg, 13.7 mmol) was added. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture cooled to 0° C., quenched with H₂O (30 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 45 g cartridge, 0-50% EtOAc:petroleum ether) to give 3-[4-(benzyloxy)phenyl]oxetan-3-ol (Intermediate A-35). MS=279.1 [M+Na]⁺.

Step 2: 3-[4-(benzyloxy)phenyl]-3-[(triphenylmethyl)sulfanyl]oxetane

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To a solution of 3-[4-(benzyloxy)phenyl]oxetan-3-ol (7.40 g, 28.9 mmol) and triphenylmethanethiol (39.9 g, 144 mmol) in CHCl₃(80 mL) were added [bis(trifluoromethylsulfonyl)amino]lithium (911 mg, 3.18 mmol) and tetrabutylammonium hexafluorophosphate (615 mg, 1.59 mmol). The mixture was stirred at 40° C. for 30 min. After cooling to room temperature, the reaction mixture was quenched with H₂O (80 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 120 g cartridge, 0-40% EtOAc:petroleum ether) to give 3-[4-(benzyloxy)phenyl]-3-[(triphenylmethyl)sulfanyl]oxetane. MS=537.3 [M+Na]⁺.

Step 3: 3-[4-(benzyloxy)phenyl]oxetane-3-thiol

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To a solution of 3-[4-(benzyloxy)phenyl]-3-[(triphenylmethyl)sulfanyl]oxetane (10.0 g, 19.4 mmol) in DCM (40 mL) was added TFA (60.0 mL, 810 mmol) and Et₃SiH (7.76 mL, 48.6 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with H₂O (80 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 3-(4-benzyloxyphenyl)oxetane-3-thiol, which was used in the subsequent step without further purification. MS=273.1 [M+H]⁺.

Step 4: 3-[4-(benzyloxy)phenyl]-3-(methylsulfanyl)oxetane

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To a solution of 3-(4-benzyloxyphenyl)oxetane-3-thiol (5.00 g, 18.4 mmol) in DMF (40 mL) was added MeI (13.0 g, 91.8 mmol) and K₂CO₃(3.81 g, 27.5 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with H₂O (80 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 80 g cartridge, 0-30% EtOAc:petroleum ether) to give 3-[4-(benzyloxy)phenyl]-3-(methylsulfanyl)oxetane. ¹H NMR (400 MHz, CDCl₃): δ 7.46-7.39 (m, 5H), 7.11 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 5.18 (d, J=6.4 Hz, 2H), 5.08 (s, 2H), 4.90 (d, J=6.4 Hz, 2H), 2.04 (s, 3H).

Step 5: 3-[4-(benzyloxy)phenyl]-3-methanesulfonyloxetane

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To a 0° C. solution of 3-[4-(benzyloxy)phenyl]-3-(methylsulfanyl)oxetane (3.25 g, 11.4 mmol) in DCM (40 mL) was added m-CPBA (6.91 g, 85% purity, 34.04 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous Na₂SO₃(20 mL), diluted with H₂O (60 mL), and extracted with DCM (3×40 mL). The combined organic layers were with saturated aqueous NaHCO₃(3×50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was triturated with EtOAc, the solids were collected via filtration, and the filter cake was dried in vacuo to give 3-[4-(benzyloxy)phenyl]-3-methanesulfonyloxetane. MS=336.2 [M+NH₄]⁺.

Step 6: 4-(3-methanesulfonyloxetan-3-yl)phenol

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To a solution of 3-[4-(benzyloxy)phenyl]-3-methanesulfonyloxetane (1.60 g, 5.03 mmol) in EtOAc (100 mL) under N₂atmosphere was added Pd/C (2.00 g, 10 wt %, 1.89 mmol). The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂(15 psi) at room temperature for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo give 4-(3-methanesulfonyloxetan-3-yl)phenol (Intermediate A-84), which was used in the subsequent step without further purification. MS=246.1 [M+NH₄]⁺.

Step 7: 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-one

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To a solution of 4-(3-methylsulfonyloxetan-3-yl)phenol (500 mg, 2.19 mmol) in DMF (5 mL) was added K₂CO₃(605 mg, 4.38 mmol) and 1-chloropropan-2-one (304 mg, 3.29 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and quenched with H₂O (15 mL), and then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-one, which was used in the subsequent step without further purification. MS=302.2 [M+NH₄]⁺.

Step 8: 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-ol

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To a solution of 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-one (600 mg, 2.11 mmol) in THF (15 mL) and EtOH (2 mL) was added NaBH₄(120 mg, 3.17 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., quenched with H₂O (15 mL), and the solution was adjusted to pH=6-7 with the dropwise addition of 4.0 M aqueous HCl. The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-ol, which was used in the subsequent step without further purification. MS=304.1 [M+NH₄]⁺.

Step 9: 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl methanesulfonate

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To a solution of 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-ol (570 mg, 1.99 mmol) in DCM (15 mL) was added TEA (0.831 mL, 5.97 mmol) and methanesulfonic anhydride (694 mg, 3.98 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with H₂O (15 mL), and the solution was adjusted to pH=6 with the dropwise addition of 4.0 M aqueous HCl. The mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give 1-[4-(3-methanesulfonyloxetan-3-yl)phenoxy]propan-2-yl methanesulfonate, which was used in the subsequent step without further purification (Intermediate A-36). MS=382.1 [M+NH₄]⁺.

General Procedure for Intermediate A-37

[Image Omitted]

Step 1: 3-[4-(benzyloxy)phenyl]-3-(ethanesulfonyl)oxetane

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To a 0° C. solution of 3-[4-(benzyloxy)phenyl]oxetan-3-ol (Intermediate A-35, 400 mg, 1.56 mmol) in DCM (5 mL) was added sodium ethanesulfinate (906 mg, 7.80 mmol) and TFA (2.31 mL, 31.2 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with H₂O (30 mL). The resulting precipitate was collected by filtration and dried in vacuo to give 3-[4-(benzyloxy)phenyl]-3-(ethanesulfonyl)oxetane. MS=350.1 [M+NH₄]⁺.

Step 2: 4-[3-(ethanesulfonyl)oxetan-3-yl]phenol

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To a solution of 3-[4-(benzyloxy)phenyl]-3-(ethanesulfonyl)oxetane (400 mg, 1.20 mmol) in EtOAc (20 mL) under N₂atmosphere was added Pd/C (1.00 g, 10 wt %, 0.943 mmol). The suspension was degassed under vacuum and purged with H₂(3×). The mixture was stirred under H₂(15 psi) at room temperature for 3 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give 4-[3-(ethanesulfonyl)oxetan-3-yl]phenol, which was used in the subsequent step without further purification.

Step 3: 3-[4-(2-bromoethoxy)phenyl]-3-(ethanesulfonyl)oxetane

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To a solution of 4-[3-(ethanesulfonyl)oxetan-3-yl]phenol (150 mg, 0.619 mmol) in MeCN (4 mL) were added K₂CO₃(428 mg, 3.10 mmol) and 1,2-dibromoethane (1.87 mL, 24.8 mmol). The mixture was stirred at 65° C. for 10 h. After cooling to room temperature, the reaction mixture was filtered, washed with MeCN (20 mL), and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-45% EtOAc:petroleum ether) to give 3-[4-(2-bromoethoxy)phenyl]-3-(ethanesulfonyl)oxetane (Intermediate A-37). MS=366.0/368.0 [M+NH₄]⁺.

General Procedure for Intermediate A-38

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Step 1: 1-{[(3-bromopropyl)sulfanyl]methyl}-4-methoxybenzene

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To a solution of (4-methoxyphenyl)methanethiol (9.01 mL, 64.8 mmol) and 1,3-dibromopropane (33.1 mL, 324 mmol) in MeOH (50 mL) was added NaOMe (5.25 g, 97.3 mmol). The reaction mixture stirred at room temperature for 16 h. After cooling to 0° C., the reaction mixture was quenched with H₂O (200 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over (Na₂SO₄), filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 120 g cartridge, 0-10% EtOAc:petroleum ether) to give 1-{[(3-bromopropyl)sulfanyl]methyl}-4-methoxybenzene.

Step 2: 1-[(3-bromopropanesulfonyl)methyl]-4-methoxybenzene

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To a 0° C. solution of 1-{[(3-bromopropyl)sulfanyl]methyl}-4-methoxybenzene (5.00 g, 18.2 mmol) in DCM (100 mL) was added m-CPBA (9.22 g, 85% purity, 45.4 mmol). The mixture was stirred at 0° C. for 2 h and was then quenched with saturated Na₂SO₃(50 mL). The organic layer was separated, washed with saturated NaHCO₃(2×100 mL), brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 120 g cartridge, 0-50% EtOAc:petroleum ether) to give 1-[(3-bromopropanesulfonyl)methyl]-4-methoxybenzene.

Step 3: 2-(4-methoxyphenyl)-1λ⁶-thiolane-1,1-dione

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To a 0° C. solution of 1-[(3-bromopropanesulfonyl)methyl]-4-methoxybenzene (3.00 g, 9.77 mmol) in DMA (30 mL) was added NaH (898 mg, 60 wt % in mineral oil, 22.5 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with ice water (20 mL), diluted with H₂O (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 25 g cartridge, 0-100% EtOAc:petroleum ether) to give 2-(4-methoxyphenyl)-1λ⁶-thiolane-1,1-dione. MS=227.2 [M+H]⁺.

Step 4: 2-(4-hydroxyphenyl)-1λ⁶-thiolane-1,1-dione

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A solution of 2-(4-methoxyphenyl)-1λ⁶-thiolane-1,1-dione (1.00 g, 4.42 mmol) in HBr in H₂O (10 mL, 45 wt %) was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with H₂O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 25 g cartridge, 0-100% EtOAc:petroleum ether) to give 2-(4-hydroxyphenyl)-1λ⁶-thiolane-1,1-dione. MS=213.1 [M+H]⁺.

Step 5: 2-[4-(2-bromoethoxy)phenyl]-1λ⁶-thiolane-1,1-dione

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To a mixture of 2-(4-hydroxyphenyl)-1λ⁶-thiolane-1,1-dione (660 mg, 3.11 mmol) and 1,2-dibromoethane (2.35 mL, 31.1 mmol) in DMF (5 mL) was added Cs₂CO₃(3.04 g, 9.33 mmol). The reaction mixture was stirred at 100° C. for 16 h. After cooling to room temperature, the mixture was diluted with H₂O (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 25 g cartridge, 0-100% EtOAc:petroleum ether) to give 2-(4-hydroxyphenyl)-1λ⁶-thiolane-1,1-dione (Intermediate A-38). MS=319.0/321.0 [M+H]⁺.

General Procedure for Intermediate A-39

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Step 1: 5-(benzyloxy)-2-bromobenzonitrile

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To a solution of 2-bromo-5-hydroxybenzonitrile (15.0 g, 75.8 mmol) in MeCN (160 mL) were added benzyl bromide (10.8 mL, 90.9 mmol) and K₂CO₃(15.7 g, 114 mmol). The mixture was stirred at 60° C. for 15 h. After cooling to room temperature, the reaction mixture was filtered to remove solids. The filtrate was diluted with water (60 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was triturated with petroleum ether and dried in vacuo to give 5-(benzyloxy)-2-bromobenzonitrile, which was used in the subsequent step without further purification.

Step 2: 5-(benzyloxy)-2-(3-hydroxyoxetan-3-yl)benzonitrile

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To a 0° C. solution of 5-(benzyloxy)-2-bromobenzonitrile (10.0 g, 34.7 mmol) in THF (120 mL) was slowly added 1.3 M i-PrMgCl·LiCl in THF (34.71 mL, 45.1 mmol). After stirring for 10 min, oxetan-3-one (3.50 g, 48.59 mmol) was added to the mixture, and stirring was continued for another 2 h. The reaction mixture was quenched with saturated aqueous NH₄C₁(80 mL) and stirred for 30 min, and then was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 120 g cartridge, 0-20% EtOAc:petroleum ether) to give 5-(benzyloxy)-2-(3-hydroxyoxetan-3-yl)benzonitrile. MS=282.2 [M+H]⁺.

Step 3: 5-(benzyloxy)-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one

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To a 0° C. solution of 5-(benzyloxy)-2-(3-hydroxyoxetan-3-yl)benzonitrile (1.50 g, 5.33 mmol) in DCM (20 mL) was added sodium methanesulfinate (2.72 g, 26.7 mmol) followed by the dropwise addition of TFA (3.95 mL, 53.3 mmol). The mixture was stirred at 40° C. for 15 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-25% EtOAc:petroleum ether) to give 5-(benzyloxy)-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one. MS=283.2 [M+H]⁺.

Step 4: 5-hydroxy-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one

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To a solution of 5-(benzyloxy)-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one (900 mg, 3.19 mmol) in MeOH (25 mL) was added Pd/C (200 mg, 10 wt %, 0.189 mmol). The mixture was stirred at room temperature for 15 h under H₂(15 psi). The reaction mixture was filtered and concentrated in vacuo to give 5-(benzyloxy)-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one, which was used in the subsequent step without further purification. MS=193.2 [M+H]⁺.

Step 5: 5-(2-bromoethoxy)-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one

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To a solution of 5-(benzyloxy)-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one (420 mg, 2.19 mmol) in MeCN (5 mL) were added K₂CO₃(1.51 g, 10.9 mmol) and 1,2-dibromoethane (6.60 mL, 87.4 mmol). The mixture was stirred at 65° C. for 15 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-33% EtOAc:petroleum ether) to give 5-(2-bromoethoxy)-3H-spiro[2-benzofuran-1,3′-oxetan]-3-one (Intermediate A-39). MS=299.0/301.1 [M+H]⁺.

General Procedure for Intermediate A-40

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Step 1: 1-[4-(benzyloxy)phenyl]cyclobutan-1-ol

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To a −78° C. solution of 1-(benzyloxy)-4-bromobenzene (5.00 g, 19.0 mmol) in THF (50 mL) was added 2.5 M n-BuLi in THF (12.16 mL, 30.4 mmol). After stirring at −78° C. for 30 min, cyclobutanone (1.70 mL, 22.8 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0° C., quenched with saturated aqueous NH₄Cl (50 mL), and then extracted with EtOAc (3×70 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 40 g cartridge, 0-15% EtOAc:petroleum ether) to give 1-[4-(benzyloxy)phenyl]cyclobutan-1-ol. ¹H NMR (400 MHz, DMSO-d₆, 17/18 H): δ 7.46-7.38 (m, 7H), 6.99 (d, J=8.8 Hz, 2H), 5.09 (s, 2H), 2.57-2.54 (m, 2H), 2.40-2.35 (m, 2H), 2.00-1.98 (m, 1H), 1.69-1.64 (m, 1H).

Step 2: 1-(benzyloxy)-4-(1-methanesulfonylcyclobutyl)benzene

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To a 0° C. solution of 1-[4-(benzyloxy)phenyl]cyclobutan-1-ol (3.80 g, 14.9 mmol) and sodium methanesulfinate (10.7 g, 105 mmol) in DCM (40 mL) was added TFA (22.1 mL, 299 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was cooled to 0° C. and quenched with H₂O (50 mL). The resulting biphasic mixture was adjusted to pH=6-7 with saturated aqueous Na₂CO₃and then extracted with DCM (3×50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was triturated with 1:1 petroleum ether:EtOAc. The mixture was filtered, the filter cake was washed with EtOAc, and dried in vacuo to give 1-(benzyloxy)-4-(1-methanesulfonylcyclobutyl)benzene, which was used in the subsequent step without further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 7.46-7.34 (m, 7H), 7.04 (d, J=8.8 Hz, 2H), 5.12 (s, 2H), 2.94-2.91 (m, 2H), 2.61-2.55 (m, 5H), 2.09-2.07 (m, 1H), 1.89-1.86 (m, 1H).

Step 3: 4-(1-methanesulfonylcyclobutyl)phenol

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To a solution of 1-(benzyloxy)-4-(1-methanesulfonylcyclobutyl)benzene (2.60 g, 8.22 mmol) in EtOAc (100 mL) under a N₂environment was added Pd/C (2.00 g, 10 wt %, 1.89 mmol). The suspension was degassed under vacuum and purged with H₂(3×). The mixture was stirred under H₂(15 psi) at room temperature for 5 h. The reaction mixture was filtered through Celite, the filter cake was washed with EtOAc, and the filtrate was concentrated in vacuo to give 1-(benzyloxy)-4-(1-methanesulfonylcyclobutyl)benzene, which was used in the subsequent step without further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 7.20 (d, J=6.8 Hz, 2H), 6.77 (d, J=6.8 Hz, 2H), 2.91-2.87 (m, 2H), 2.58 (s, 3H), 2.56-2.52 (m, 2H), 2.08-2.05 (m, 1H), 1.88-1.84 (s, 1H).

Step 4: 1-(2-bromoethoxy)-4-(1-methanesulfonylcyclobutyl)benzene

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A mixture of 1-(benzyloxy)-4-(1-methanesulfonylcyclobutyl)benzene (500 mg, 2.21 mmol), 1,2-dibromoethane (6.67 mL, 88.4 mmol) and K₂CO₃(1.53 g, 11.1 mmol) in MeCN (10 mL) was stirred at 65° C. for 16 h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-30% EtOAc:petroleum ether) to give 1-(2-bromoethoxy)-4-(1-methanesulfonylcyclobutyl)benzene (Intermediate A-40). MS=350.1/352.1 [M+NH₄]⁺.

The following intermediate in Table 8 was prepared according to procedures similar those described for Intermediate A-40 using the appropriate starting materials.

General Procedure for Intermediate A-41

TABLE 8

Intermediate #
Structure
Name
Exact Mass [M + H]⁺

A-41

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4-[4-(2- bromoethoxy)phenyl]-4- methanesulfonyloxane
Calc'd 380.1/382.1 Found 380.1/382.1 [M + NH₄]⁺

General Procedure for Intermediate A-42

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Step 1: 6-[4-(benzyloxy)phenyl]-2-oxaspiro[3.3]heptan-6-ol

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To a −78° C. solution of 1-(benzyloxy)-4-bromobenzene (2.68 g, 10.2 mmol) in THF (10 mL) was added 2.5 M n-BuLi in THF (4.74 mL, 11.9 mmol). After stirring for 20 min, a solution of 2-oxaspiro[3.3]heptan-6-one (950 mg, 8.47 mmol) in THF (3 mL) was added. The mixture was stirred at −78° C. for 30 min. The reaction mixture was warmed to 0° C., quenched with saturated aqueous NH₄Cl (15 mL), and then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 6-[4-(benzyloxy)phenyl]-2-oxaspiro[3.3]heptan-6-ol. MS=279.1 [M-OH]⁺.

Step 2: 6-[4-(benzyloxy)phenyl]-6-methanesulfonyl-2-oxaspiro[3.3]heptane

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To a solution of 6-[4-(benzyloxy)phenyl]-2-oxaspiro[3.3]heptan-6-ol (2.00 g, 6.75 mmol) in DCM (30 mL) were added sodium methanesulfinate (3.44 g, 33.7 mmol), and TFA (9.99 mL, 135 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C., quenched with H₂O (50 mL), and then extracted with DCM (2×15 mL). The combined organic layers were washed with brine (30 mL×2), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-50% EtOAc:petroleum ether) to give 6-[4-(benzyloxy)phenyl]-6-methanesulfonyl-2-oxaspiro[3.3]heptane. MS=359.1 [M+H]⁺.

Step 3: 4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenol

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To a solution of 6-[4-(benzyloxy)phenyl]-6-methanesulfonyl-2-oxaspiro[3.3]heptane (400 mg, 1.12 mmol) in EtOAc (10 mL) under N₂atmosphere was added Pd/C (200 mg, 10 wt %, 1.89 mmol). The suspension was degassed under vacuum and purged with H₂(3×). The mixture was stirred under H₂(15 psi) at room temperature for 3 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give 4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenol, which was used in the subsequent step without further purification.

Step 4: methyl 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)acetate

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A mixture of 4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenol (240 mg, 0.894 mmol), methyl 2-bromoacetate (0.169 mL, 1.79 mmol), and K₂CO₃(309 mg, 2.24 mmol) in DMF (5 mL) was degassed and purged with N₂(3×). The mixture was stirred at 50° C. for 3 h under N₂atmosphere. The reaction mixture was cooled to 0° C., quenched with H₂O (15 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give methyl 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)acetate. MS=341.1 [M+H]⁺.

Step 5: 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethan-1-ol

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To a 0° C. solution of methyl 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)acetate (300 mg, 0.881 mmol) in THF (10 mL) under a N₂environment was added LiAlH₄(66.9 mg, 1.76 mmol). The mixture was stirred at 0° C. for 30 min, and then was quenched with H₂O (15 mL). The resulting biphasic mixture was adjusted to pH=6-7 with 2.0 M aqueous HCl solution, and then was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethan-1-ol, which was used in the subsequent step without further purification. MS=313.1 [M+H]⁺.

Step 6: 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethyl methanesulfonate

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To a solution of 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethan-1-ol (280 mg, 0.896 mmol) in DCM (5 mL) was added TEA (0.250 mL, 1.79 mmol) and methanesulfonic anhydride (234 mg, 1.34 mmol). The mixture was stirred at room temperature for 1 h, and then was quenched with H₂O (10 mL). The resulting biphasic mixture was adjusted to pH=6-7 with 2.0 M aqueous HCl solution, and then was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 2-(4-{6-methanesulfonyl-2-oxaspiro[3.3]heptan-6-yl}phenoxy)ethyl methanesulfonate (Intermediate A-42), which was used in the subsequent step without further purification. MS=391.1 [M+H]⁺.

General Procedure for Intermediate A-43

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Step 1: 5-(benzyloxy)-2-chloropyrimidine

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To a solution of 2-chloropyrimidin-5-ol (5.00 g, 38.3 mmol) and benzyl bromide (5.46 mL, 46.0 mmol) in MeCN (50 mL) was added K₂CO₃(7.94 g, 57.5 mmol). The mixture was stirred at 60° C. for 2 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 40 g cartridge, 0-15% EtOAc:petroleum ether) to give 5-(benzyloxy)-2-chloropyrimidine. MS=221.1 [M+H]⁺.

Step 2: 5-(benzyloxy)-2-[(3-methyloxetan-3-yl)oxy]pyrimidine

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To a solution of 3-methyloxetan-3-ol (1.20 g, 13.6 mmol) and 5-benzyloxy-2-chloropyrimidine (1.00 g, 4.53 mmol) in DMF (20 mL) was added Cs₂CO₃(4.43 g, 13.6 mmol). The mixture was stirred at room temperature for 6 h. Solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-15% EtOAc:petroleum ether) to give 5-(benzyloxy)-2-[(3-methyloxetan-3-yl)oxy]pyrimidine. MS=273.1 [M+H]⁺.

Step 3: 2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-ol

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To a suspension of Pd/C (150 mg, 10 wt %, 0.14 mmol) in MeOH (15 mL) was added 5-(benzyloxy)-2-[(3-methyloxetan-3-yl)oxy]pyrimidine (600 mg, 2.20 mmol) under an atmosphere of N₂. The suspension was degassed and purged with H₂(3×). The mixture was stirred at room temperature under H₂(15 psi) for 3 h. The mixture was filtered through a pad of Celite, and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo to give 2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-ol. MS=183.1 [M+H]⁺.

Step 4: 5-(2-bromoethoxy)-2-[(3-methyloxetan-3-yl)oxy]pyrimidine

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To a solution of 2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-ol (370 mg, 2.03 mmol) and 1,2-dibromoethane (6.13 mL, 81.2 mmol) in MeCN (8 mL) was added K₂CO₃(1.40 g, 10.2 mmol). The mixture was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with H₂O (30 mL) and extracted with EtOAc (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-15% EtOAc:petroleum ether) to give 2-[(3-methyloxetan-3-yl)oxy]pyrimidin-5-ol (Intermediate A-43). MS=289.0/291.0 [M+H]⁺.

General Procedure for Intermediate A-44

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Step 1: N-(2,6-difluoro-4-methoxyphenyl)methanesulfonamide

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To a 0° C. mixture of 2,6-difluoro-4-methoxyaniline (3.00 g, 18.9 mmol) and TEA (3.15 mL, 22.6 mmol) in DCM (30 mL) was added methanesulfonic anhydride (8.21 g, 47.1 mmol) dropwise. The mixture was stirred at room temperature for 10 h. The reaction mixture was quenched with H₂O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 40 g cartridge, 0-50% EtOAc:petroleum ether) to give N-(2,6-difluoro-4-methoxyphenyl)methanesulfonamide. MS=236.1 [M−H]⁻.

Step 2: N-(2,6-difluoro-4-methoxyphenyl)-N-methylmethanesulfonamide

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To a 0° C. solution of N-(2,6-difluoro-4-methoxyphenyl)methanesulfonamide (1.00 g, 4.22 mmol) in THF (10 mL) was added NaH (184 mg, 60 wt % in mineral oil, 4.59 mmol). After stirring at 0° C. for 15 min, MeI (2.62 mL, 42.2 mmol) was added. The mixture was stirred at room temperature for 5 h. The reaction mixture was cooled to 0° C., quenched with H₂O (30 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-30% EtOAc:petroleum ether) to give N-(2,6-difluoro-4-methoxyphenyl)-N-methylmethanesulfonamide. MS=252.1 [M+H]⁺.

Step 3: N-(2,6-difluoro-4-hydroxyphenyl)-N-methylmethanesulfonamide

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To a 0° C. solution of N-(2,6-difluoro-4-methoxyphenyl)-N-methylmethanesulfonamide (786 mg, 3.13 mmol) in DCM (8 mL) was added BBr₃(0.904 mL, 9.39 mmol) dropwise. The mixture was stirred at room temperature for 6 h. The reaction mixture was cooled to 0° C. and quenched with H₂O (10 mL). The resulting biphasic mixture was concentrated in vacuo to remove DCM and the remaining aqueous phase was adjusted to pH=8-9 with saturated aqueous NaHCO₃. The resulting solid was isolated via filtration and washed with MTBE. The filter cake was dried in vacuo to give N-(2,6-difluoro-4-hydroxyphenyl)-N-methylmethanesulfonamide. MS=238.1 [M+H]⁺.

Step 4: N-[4-(2-bromoethoxy)-2,6-difluorophenyl]-N-methylmethanesulfonamide

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To a solution of N-(2,6-difluoro-4-hydroxyphenyl)-N-methylmethanesulfonamide (710 mg, 2.99 mmol) in 1,2-dibromoethane (10 mL) was added Cs₂CO₃(1.95 g, 5.99 mmol). The mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled to 0° C., quenched with H₂O (20 mL), and extracted with EtOAc (3×15 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-30% EtOAc:petroleum ether) to give N-[4-(2-bromoethoxy)-2,6-difluorophenyl]-N-methylmethanesulfonamide (Intermediate A-44). MS=361.1/363.1 [M+NH₄]⁺.

General Procedure for Intermediate A-45

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Step 1: 1-methanesulfinyl-4-methoxybenzene

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To a 0° C. solution of 1-methoxy-4-(methylsulfanyl)benzene (15.3 mL, 110 mmol) in THF (160 mL) and H₂O (160 mL) was added NaIO₄(12.2 mL, 220 mmol) portionwise. The mixture was allowed to warm to room temperature and stirred for 16 h, and then solids were removed by filtration. The filtrate was cooled to 0° C., quenched with saturated aqueous Na₂SO₃solution (200 mL), and extracted with EtOAc (5×200 mL). The combined organic layers were washed with saturated aqueous Na₂SO₃solution (2×200 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 1-methanesulfinyl-4-methoxybenzene, which was used in the subsequent step without further purification. MS=171.1 [M+H]⁺.

Step 2: imino(4-methoxyphenyl)methyl-λ⁶-sulfanone

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To a 0° C. solution of 1-methanesulfinyl-4-methoxybenzene (110 mmol) and PhI(OAc)₂(15 g, 470 mmol) in MeOH (200 mL) was added ammonium carbamate (13.8 g, 176 mmol). The mixture was stirred at 0° C. for 1 h, and then was concentrated in vacuo. The residue was diluted with H₂O (100 mL) and adjusted to pH=6-7 with the dropwise addition of saturated aqueous Na₋₂CO₃. Solids were removed by filtration, and the filtrate was extracted with EtOAc (5×200 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 330 g cartridge, 80-100% EtOAc:petroleum ether) to give imino(4-methoxyphenyl)methyl-λ⁶-sulfanone. MS=186.1 [M+H]⁺.

Step 3: [(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene](methyl)amine

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A solution of imino(4-methoxyphenyl)methyl-λ⁶-sulfanone (10.0 g, 54.0 mmol) and formaldehyde aqueous solution (29.7 mL, 37 wt %, 1.08 mol) in formic acid (100 mL) was stirred at 100° C. for 30 h. The mixture was cooled to 0° C. and then diluted with H₂O (120 mL). The solution was adjusted to pH=6-7 with the dropwise addition of 5.0 M aqueous NaOH. The mixture was extracted with EtOAc (3×120 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give [(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene](methyl)amine, which was used in the subsequent step without further purification. MS=200.2 [M+H]⁺.

Step 4: 4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenol

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To a 0° C. solution of [(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene](methyl)amine (11.0 g, 55.2 mmol) in DCM (120 mL) was added BBr₃(21.3 mL, 221 mmol). The mixture was stirred at room temperature for 2 h, then was cooled to 0° C. and quenched by the addition of H₂O (15 mL). The solution was adjusted to pH=6-8 with the dropwise addition of saturated aqueous NaHCO₃. The resulting solids were removed by filtration and the filter cake was washed with THF (3×200 mL). The resulting filtrate was concentrated in vacuo, and the resulting residue was triturated with a 1:1 mixture of petroleum ether and EtOAc, then dried in vacuo to give 4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenol. MS=186.0 [M+H]⁺.

Step 5: {[4-(2-bromoethoxy)phenyl](methyl)oxo-)⁶-sulfanylidene}(methyl)amine

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To a mixture of 4-[methyl(methylimino)oxo-λ⁶-sulfanyl]phenol (900 mg, 4.86 mmol) and 1,2-dibromoethane (10.0 mL, 133 mmol) was added Cs₂CO₃(3.17 g, 9.72 mmol). The mixture was stirred at 100° C. for 16 h. After cooling to room temperature, solids were removed via filtration and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-50% EtOAc:petroleum ether) to give {[4-(2-bromoethoxy)phenyl](methyl)oxo-λ⁶-sulfanylidene}(methyl)amine (Intermediate A-45). MS=291.9/293.9 [M+H]⁺.

General Procedure for Intermediate A-46

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Step 1: 4-(2-bromoethoxy)-2-(trifluoromethyl) aniline

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To a solution 4-amino-3-(trifluoromethyl)phenol (3.00 g, 16.9 mmol) in 1,2-dibromoethane (30 mL, 399 mmol) was added Cs₂CO₃(16.6 g, 50.8 mmol). The mixture was stirred at 100° C. for 12 h. After cooling to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 40 g cartridge, 0-50% EtOAc:petroleum ether) to give 4-(2-bromoethoxy)-2-(trifluoromethyl) aniline. MS=284.0/286.0 [M+H]⁺.

Step 2: N-[4-(2-bromoethoxy)-2-(trifluoromethyl)phenyl]-N-methanesulfonylmethanesulfonamide

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To a solution of 4-(2-bromoethoxy)-2-(trifluoromethyl) aniline (600 mg, 2.11 mmol) in DCM (10 mL) was added methanesulfonic anhydride (736 mg, 4.22 mmol), TEA (0.882 mL, 6.34 mmol) and DMAP (25.8 mg, 0.211 mmol). The mixture was stirred at 40° C. for 16 h. After cooling to temperature, the reaction mixture was quenched with H₂O (20 mL), and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (25 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-50% EtOAc:petroleum ether) to give N-[4-(2-bromoethoxy)-2-(trifluoromethyl)phenyl]-N-methanesulfonylmethanesulfonamide.

Step 3: N-[4-(2-bromoethoxy)-2-(trifluoromethyl)phenyl]methanesulfonamide

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To a solution of N-[4-(2-bromoethoxy)-2-(trifluoromethyl)phenyl]-N-methanesulfonylmethanesulfonamide (521 mg, 1.18 mmol) in THF (6 mL) was added a solution of NaOH (237 mg, 5.92 mmol) in H₂O (1.5 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with H₂O (10 mL), and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give N-[4-(2-bromoethoxy)-2-(trifluoromethyl)phenyl]methanesulfonamide (Intermediate A-46). MS=359.9/362.0 [M−H]⁻.

General Procedure for Intermediate A-47

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Step 1: 2-[4-(2-bromoethoxy)phenyl]-2-methylpropanenitrile

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To a solution of 2-(4-hydroxyphenyl)-2-methylpropanenitrile (500 mg, 3.10 mmol) in 1,2-dibromoethane (8.0 mL, 106 mmol) was added Cs₂CO₃(3.03 g, 9.31 mmol). The mixture was stirred at 100° C. for 12 h. After cooling to room temperature, the mixture was filtered to remove solids, and the resulting filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-50% EtOAc:petroleum ether) to give 2-[4-(2-bromoethoxy)phenyl]-2-methylpropanenitrile (Intermediate A-47). MS=241.1/243.0 [M-CN]⁺.

General Procedure for Intermediates A-48 & A-49

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Step 1: 2-bromo-4-fluorobenzene-1-sulfonamide

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A solution of 2-bromo-4-fluorobenzene-1-sulfonyl chloride (1.07 mL, 7.31 mmol) in MeOH (30 mL) was cooled to 0° C. and NH₃was bubbled into the reaction mixture over a period of 15 min. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was concentrated in vacuo and diluted with H₂O (100 mL). The reaction mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo give 2-bromo-4-fluorobenzene-1-sulfonamide, which was used in the subsequent step without further purification.

Step 2: N′-(2-bromo-4-fluorobenzenesulfonyl)-N,N-dimethylmethanimidamide

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To a mixture of 2-bromo-4-fluorobenzene-1-sulfonamide (1.00 g, 3.94 mmol) in MeCN (10 mL) was added a solution N,N-dimethylformamide dimethyl acetal (0.627 mL, 4.72 mmol) in MeCN (1 mL). The mixture was stirred at room temperature for 1 h, and was then concentrated in vacuo to give N′-(2-bromo-4-fluorobenzenesulfonyl)-N,N-dimethylmethanimidamide, which was used in the subsequent step without further purification. MS=309.0/311.0 [M+H]⁺.

Step 3: N′-{2-[(1E)-2-ethoxyethenyl]-4-fluorobenzenesulfonyl}-N,N-dimethylmethanimidamide

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A solution of 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (895 mg, 4.52 mmol), N′-(2-bromo-4-fluorobenzenesulfonyl)-N,N-dimethylmethanimidamide (700 mg, 2.26 mmol), K₂CO₃(937 mg, 6.78 mmol), Pd(PPh₃)₄(261 mg, 0.226 mmol), and PCy₃(73.3 μL, 0.226 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) was purged with N₂(2×) and heated via microwave for 1 h at 100° C. After cooling to room temperature, the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 10 g cartridge, 0-30% EtOAc:petroleum ether) to give N′-{2-[(1E)-2-ethoxyethenyl]-4-fluorobenzenesulfonyl}-N,N-dimethylmethanimidamide. MS=301.1 [M+H]⁺.

Step 4: 6-fluoro-2H-1λ⁶,2-benzothiazine-1,1-dione

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A solution of N′-{2-[(1E)-2-ethoxyethenyl]-4-fluorobenzenesulfonyl}-N,N-dimethylmethanimidamide (500 mg, 1.66 mmol) in 6.0 M aqueous HCl (2.77 mL, 16.6 mmol) and THF (5 mL) was stirred at 50° C. for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give 6-fluoro-2H-1λ⁶,2-benzothiazine-1,1-dione, which was used in the subsequent step without further purification. MS=198.1 [M−H]⁻.

Step 5: 6-fluoro-3,4-dihydro-2H-1%⁶,2-benzothiazine-1,1-dione

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To a mixture of Pd/C (10.0 mg, 10 wt %, 0.0094 mmol) in MeOH (3 mL) was added 6-fluoro-2H-1λ⁶,2-benzothiazine-1,1-dione (50.0 mg, 0.251 mmol). The mixture was purged with H₂(2×). The mixture was stirred at room temperature for 16 h under an atmosphere of H₂(15 psi). The reaction mixture filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-50% EtOAc:petroleum ether) to give 6-fluoro-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione (Intermediate A-48). MS=200.0 [M−H]⁻.

Step 6: 6-fluoro-2-methyl-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione

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To a solution of 6-fluoro-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione (500 mg, 2.48 mmol) and Cs₂CO₃(891 mg, 2.73 mmol) in DMF (10 mL) was added MeI (1.55 mL, 24.9 mmol). The mixture was stirred at room temperature for 3 h and was then diluted with H₂O (10 mL). The mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give 6-fluoro-2-methyl-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione, which was used in the subsequent step without further purification. MS=216.1 [M+H]⁺.

Step 7: 6-(2-hydroxyethoxy)-2-methyl-3,4-dihydro-2H-1′⁶,2-benzothiazine-1,1-dione

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A solution of 6-fluoro-2-methyl-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione (700 mg, 3.25 mmol), ethylene glycol (1.82 mL, 32.5 mmol) and Cs₂CO₃(3.18 g, 9.76 mmol) in DMF (3 mL) was stirred at 100° C. for 5 h. After cooling to room temperature, the mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-60% EtOAc:petroleum ether) to give 6-(2-hydroxyethoxy)-2-methyl-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione. MS=258.0 [M+H]⁺.

Step 8: 2-[(2-methyl-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2-benzothiazin-6-yl)oxy]ethyl methanesulfonate

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To a 0° C. solution of 6-(2-hydroxyethoxy)-2-methyl-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione (180 mg, 0.700 mmol) and TEA (0.146 mL, 1.05 mmol) in DCM (5 mL) was added methanesulfonic anhydride (146 mg, 0.839 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with H₂O (3 mL). The solution was adjusted to pH=6 with the dropwise addition of 2.0 M aqueous HCl. The mixture was extracted with DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give 2-[(2-methyl-1,1-dioxo-3,4-dihydro-2H-1,6,2-benzothiazin-6-yl)oxy]ethyl methanesulfonate, which was used in the subsequent step without further purification (Intermediate A-49). MS=336.1 [M+H]⁺.

General Procedure for Intermediate A-50

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Step 1: 6-(2-hydroxyethoxy)-3,4-dihydro-2H-1′⁶,2-benzothiazine-1,1-dione

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A solution of 6-fluoro-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione (Intermediate A-48, 2.50 g, 12.4 mmol), ethylene glycol (3.47 mL, 62.1 mmol) and t-BuOK (6.97 g, 62.1 mmol) in NMP (15 mL) was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction was quenched with H₂O (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 20 g cartridge, 0-100% EtOAc:petroleum ether) to give 6-(2-hydroxyethoxy)-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione. MS=242.1 [M−H]⁻.

Step 2: 2-[(1,1-dioxo-3,4-dihydro-2H-1λ⁶,2-benzothiazin-6-yl)oxy]ethyl methanesulfonate

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To a 0° C. solution of 6-(2-hydroxyethoxy)-3,4-dihydro-2H-1λ⁶,2-benzothiazine-1,1-dione (400 mg, 1.64 mmol) and TEA (0.343 mL, 2.47 mmol) in DCM (5 mL) was added methanesulfonic anhydride (344 mg, 1.97 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with H₂O (3 mL). The solution was adjusted to pH=6 with the dropwise addition of 2.0 M aqueous HCl. The mixture was extracted with DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-80% EtOAc:petroleum ether) to give 2-[(1,1-dioxo-3,4-dihydro-2H-1)⁶,2-benzothiazin-6-yl)oxy]ethyl methanesulfonate (Intermediate A-50). MS=320.1 [M−H]⁺.

General Procedure for Intermediate A-51

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Step 1: N-(4-methoxy-2-methylphenyl)methanesulfonamide

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To a 0° C. solution of 4-methoxy-2-methylaniline (7.41 mL, 58.3 mmol) and TEA (12.2 mL, 87.4 mmol) in DCM (50 mL) was added methanesulfonic anhydride (11.2 g, 64.2 mmol). After stirring at room temperature for 1 h, the reaction mixture was quenched with H₂O (35 mL). The solution was adjusted to pH=6 with the dropwise addition of 1.0 M aqueous HCl. The mixture was extracted with DCM (3×25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was triturated with EtOAc, and the solid was isolated via filtration then concentrated in vacuo to give N-(4-methoxy-2-methylphenyl)methanesulfonamide. MS=214.2 [M−H]⁻.

Step 2: N-(4-methoxy-2-methylphenyl)-N-methylmethanesulfonamide

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A solution of N-(4-methoxy-2-methylphenyl)methanesulfonamide (10.0 g, 46.5 mmol), MeI (4.34 mL, 69.68 mmol) and K₂CO₃(12.8 g, 92.9 mmol) in DMF (30 mL) was stirred at for 2 h. The reaction mixture was quenched with H₂O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give N-(4-methoxy-2-methylphenyl)-N-methylmethanesulfonamide, which was used in the subsequent step without further purification.

Step 3: N-[2-(bromomethyl)-4-methoxyphenyl]-N-methylmethanesulfonamide

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A solution N-(4-methoxy-2-methylphenyl)-N-methylmethanesulfonamide (5.00 g, 21.8 mmol), NBS (4.66 g, 26.2 mmol) and AIBN (71.6 mg, 0.436 mmol) in CCl₄(50 mL) was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 40 g cartridge, 0-80% EtOAc:petroleum ether) to give N-[2-(bromomethyl)-4-methoxyphenyl]-N-methylmethanesulfonamide. MS=308.0/310.0 [M+H]⁺.

Step 4: 6-methoxy-1-methyl-3,4-dihydro-1H-2X⁶,1-benzothiazine-2,2-dione

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To a 0° C. solution of N-[2-(bromomethyl)-4-methoxyphenyl]-N-methylmethanesulfonamide (2.60 g, 8.44 mmol) in DMA (15 mL) was added NaH (371 mg, 60 wt % in mineral oil, 9.28 mmol) in portions. The mixture was stirred at 75° C. for 4 h. After cooling to room temperature, the reaction was quenched with H₂O (20 mL). The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-30% EtOAc:petroleum ether) to give 6-methoxy-1-methyl-3,4-dihydro-1H-2λ⁶,1-benzothiazine-2,2-dione. MS=228.1 [M+H]⁺.

Step 5: 6-hydroxy-1-methyl-3,4-dihydro-1H-2λ⁶,1-benzothiazine-2,2-dione

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To a −20° C. solution of 6-methoxy-1-methyl-3,4-dihydro-1H-2λ⁶,1-benzothiazine-2,2-dione (1.20 g, 5.28 mmol) in DCM (15 mL) was added BBr₃(1.53 mL, 15.8 mmol) dropwise. The mixture was warmed to 0° C. and stirred for 1 h. The reaction mixture was quenched by the addition of H₂O (15 mL), warmed to room temperature, and then adjusted to pH=8 with saturated aqueous NaHCO₃. The mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 10 g cartridge, 0-30% EtOAc:petroleum ether) to give 6-hydroxy-1-methyl-3,4-dihydro-1H-2X⁶,1-benzothiazine-2,2-dione. MS=212.1 [M−H]⁻.

Step 6: 6-(2-bromoethoxy)-1-methyl-3,4-dihydro-1H-2′⁶,1-benzothiazine-2,2-dione

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A solution of 1,2-dibromoethane (1.59 mL, 21.1 mmol), 6-hydroxy-1-methyl-3,4-dihydro-1H-2λ⁶,1-benzothiazine-2,2-dione (900 mg, 4.22 mmol) and Cs₂CO₃(2.06 g, 6.33 mmol) in DMF (2 mL) was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 10 g cartridge, 0-30% EtOAc:petroleum ether) to give 6-(2-bromoethoxy)-1-methyl-3,4-dihydro-1H-2λ⁶,1-benzothiazine-2,2-dione (Intermediate A-51). MS=319.9/321.9 [M+H]⁺.

General Procedure for Intermediate A-52

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Step 1: 5-hydroxy-1λ⁶-benzothiophene-1,1-dione

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To a 0° C. solution of Oxone (1.84 g, 3.00 mmol) in H₂O (15 mL) was added a solution of 1-benzothiophen-5-ol (300 mg, 2.00 mmol) in MeOH (15 mL) dropwise. The mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo, diluted with H₂O (10 mL), and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-50% EtOAc:petroleum ether) to give 5-hydroxy-1λ⁶-benzothiophene-1,1-dione. MS=181.1 [M−H]⁻.

Step 2: 5-hydroxy-2,3-dihydro-1λ⁶-benzothiophene-1,1-dione

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To a solution of 5-hydroxy-1λ⁶-benzothiophene-1,1-dione (270 mg, 1.48 mmol) in EtOAc (30 mL) was added Pd/C (27 mg, 10 wt %, 0.025 mmol) under N₂atmosphere. The mixture was purged with H₂(3×). The mixture was stirred at room temperature for 3 h under an atmosphere of H₂(15 psi). The reaction mixture filtered through Celite, and the filtrate was concentrated in vacuo to give 5-hydroxy-2,3-dihydro-1λ⁶-benzothiophene-1,1-dione (Intermediate A-52), which was used in the subsequent step without further purification. MS=183.1 [M−H]⁻.

General Procedure for Intermediate A-53

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Step 1: 5-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one

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To a solution of 5-methoxy-2,3-dihydro-1H-isoindol-1-one (750 mg, 4.60 mmol,) in DMF (15 mL) were added Cs₂CO₃(2.25 g, 6.89 mmol) and MeI (0.343 mL, 5.52 mmol). The mixture was stirred at room temperature for 16 h. The mixture was filtered to remove solids, and the resulting filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 25 g cartridge, 50-100% EtOAc:petroleum ether) to give 5-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one. MS=178.0 [M+H]⁺.

Step 2: 5-hydroxy-2-methyl-2,3-dihydro-1H-isoindol-1-one

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To a 0° C. solution of 5-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (800 mg, 4.51 mmol) in DCM (10 mL) was added BBr₃(1.31 mL, 13.5 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and quenched by the addition of MeOH (5 mL), and then concentrated in vacuo. The crude residue was triturated with EtOAc to give 5-hydroxy-2-methyl-2,3-dihydro-1H-isoindol-1-one, which was taken to the next step without further purification. MS=164.0 [M+H]⁺.

Step 3: 5-(2-bromoethoxy)-2-methyl-2,3-dihydro-1H-isoindol-1-one

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To a solution of 5-hydroxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.25 g, 7.66 mmol) in 1,2-dibromoethane (12.5 mL, 166 mmol) was added Cs₂CO₃(4.99 g, 15.3 mmol). The mixture was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 25 g cartridge, 70-100% EtOAc:petroleum ether) to give 5-(2-bromoethoxy)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Intermediate A-53). MS=270.0/272.0 [M+H]⁺.

General Procedure for Intermediates A-54 & A-55

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Step 1: 2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-6-ol

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A mixture of 1,2,3,4-tetrahydroisoquinolin-6-ol (500 mg, 3.35 mmol), methanesulfonic anhydride (1.17 g, 6.70 mmol), and TEA (0.933 mL, 6.70 mmol) in DCM (10 mL) was degassed and purged with N₂(3×). After stirring at room temperature for 3 h under N₂atmosphere, the reaction mixture was quenched with H₂O (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 12 g cartridge, 0-50% EtOAc:petroleum ether) to give 2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-6-ol (Intermediate A-54). MS=228.1 [M+H]⁺.

Step 2: 6-(2-bromoethoxy)-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinoline

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To a solution of 2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-6-ol (100 mg, 0.440 mmol) in 1,2-dibromoethane (5 mL) was added Cs₂CO₃(430 mg, 1.32 mmol). The mixture was stirred at 100° C. for 5 h. After cooling to room temperature, solids were removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography (Biotage 4 g cartridge, 0-100% EtOAc:petroleum ether) to give 6-(2-bromoethoxy)-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinoline (