This application is a Continuation U.S. patent application of and claims benefit to U.S. patent application Ser. No. 12/287,791 filed Oct. 14, 2008, which is a continuation-in-part of U.S. patent application Ser. No. 12/009,123 filed Jan. 15, 2008, which is a continuation-in-part of U.S. patent application Ser. No. 11/879,034 filed Jul. 13, 2007 which claims benefit of Provisional Application No. 60/830,882 filed Jul. 14, 2006, the entirety of which each is incorporated herein by reference.

FIELD OF THE INVENTION

This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cancer.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes ab1, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70 Inhibition of such kinases has become an important therapeutic target.

The hepatocyte growth factor receptor (â€œc-Metâ€ ) is a unique receptor tyrosine kinase shown to be overexpressed in a variety of malignancies. c-Met typically comprises, in its native form, a 190-kDa heterodimeric (a disulfide-linked 50-kDa Î±-chain and a 145-kDa Î²-chain) membrane-spanning tyrosine kinase protein (Proc. Natl. Acad. Sci. USA, 84:6379-6383 (1987)). c-Met is mainly expressed in epithelial cells and stimulation of c-Met leads to scattering, angiogenesis, proliferation and metastasis. (See Cytokine and Growth Factor Reviews, 13:41-59 (2002)).

The ligand for c-Met is hepatocyte growth factor (also known as scatter factor, HGF and SF). HGF is a heterodimeric protein secreted by cells of mesodermal origin (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990)).

Various biological activities have been described for HGF through interaction with c-met (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the c-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 67-79 (1993). The biological effect of HGF/SF may depend in part on the target cell. HGF induces a spectrum of biological activities in epithelial cells, including mitogenesis, stimulation of cell motility and promotion of matrix invasion (Biochem. Biophys. Res. Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419 (1991)). It stimulates the motility and invasiveness of carcinoma cells, the former having been implicated in the migration of cells required for metastasis. HGF can also act as a â€œscatter factorâ€ , an activity that promotes the dissociation of epithelial and vascular endothelial cells (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBO J., 10:2867-2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)). Therefore, HGF is thought to be important in tumor invasion (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)).

HGF and c-Met are expressed at abnormally high levels in a large variety of solid tumors. High levels of HGF and/or c-Met have been observed in liver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate, gallbladder and myeloma tumors in addition to many others. The role of HGF/c-Met in metastasis has been investigated in mice using cell lines transformed with HGF/c-Met (J. Mol. Med., 74:505-513 (1996)). Overexpression of the c-Met oncogene has also been suggested to play a role in the pathogenesis and progression of thyroid tumors derived from follicular epithelium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen (Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and a potent angiogenic factor (J. Cell Biol., 119:629-641 (1992)).

Recent work on the relationship between inhibition of angiogenesis and the suppression or reversion of tumor progression shows great promise in the treatment of cancer (Nature, 390:404-407 (1997)), especially the use of multiple angiogenesis inhibitors compared to the effect of a single inhibitor. Angiogenesis can be stimulated by HGF, as well as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).

Angiogenesis, the process of sprouting new blood vessels from existing vasculature and arteriogenesis, the remodeling of small vessels into larger conduit vessels are both physiologically important aspects of vascular growth in adult tissues. These processes of vascular growth are required for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling. They are also required for the development of pathological conditions such as the growth of neoplasias, diabetic retinopathy, rheumatoid arthritis, psoriasis, certain forms of macular degeneration, and certain inflammatory pathologies. The inhibition of vascular growth in these contexts has also shown beneficial effects in preclinical animal models. For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.

The ability to stimulate vascular growth has potential utility for treatment of ischemia-induced pathologies such as myocardial infarction, coronary artery disease, peripheral vascular disease, and stroke. The sprouting of new vessels and/or the expansion of small vessels in ischemic tissues prevents ischemic tissue death and induces tissue repair. Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias). Treatment of malaria and related viral diseases may also be mediated by HGF and cMet.

Elevated levels of HGF and c-Met have also been observed in non-oncological settings, such as hypertension, myocardial infarction and rheumatoid arthritis. It has been observed that levels of HGF increase in the plasma of patients with hepatic failure (Gohda et al., supra) and in the plasma (Hepatol., 13:734-750 (1991)) or serum (J. Biochem., 109:8-13 (1991)) of animals with experimentally induced liver damage. HGF has also been shown to be a mitogen for certain cell types, including melanocytes, renal tubular cells, keratinocytes, certain endothelial cells and cells of epithelial origin (Biochem. Biophys. Res. Commun., 176:45-51 (1991); Biochem. Biophys. Res. Commun., 174:831-838 (1991); Biochem., 30:9768-9780 (1991); Proc. Natl. Acad. Sci. USA, 88:415-419 (1991)). Both HGF and the c-Met proto-oncogene have been postulated to play a role in microglial reactions to CNS injuries (Oncogene, 8:219-222 (1993)).

Metastatic SCC cells overexpress c-Met and have enhanced tumoregenesis and metastasis in vivo [G. Gong et al., Oncogene, 23:6199-6208 (2004)]. C-Met is required for tumor cell survival [N. Shinomiya et al., Cancer Research, 64:7962-7970 (2004)]. For a general review see C. Birchmeier et al., Nature Reviews/Molecular Biology 4:915-925 (2003).

In view of the role of HGF and/or c-Met in potentiating or promoting such diseases or pathological conditions, it would be useful to have a means of substantially reducing or inhibiting one or more of the biological effects of HGF and its receptor. Thus a compound that reduces the effect of HGF would be a useful compound. Compounds of the current invention have not been previously described as inhibitors of angiogenesis such as for the treatment of cancer.

Sugen application WO 05/010005 describes certain Triazolotriazine compounds that are c-met inhibitors. Diamon Shamrock Corp. application WO 83/00864 discloses certain Triazolotriazine compounds that are useful as anti-inflammatory agents. Yamanouchi applications EP 1481955 and US 2005/0261297 disclose certain nitrogen-containing heterocyclic compounds that are therapeutic agents having a bone formation-stimulating effect.

Compounds of the current invention are inhibitors of c-Met.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating cancer and angiogenesis is defined by Formulae I, II, III, IV, V, VI and VII

[Image Omitted]

enantiomers, diastereomers, salts and solvates thereof wherein

J is N or CR³;
W is N or CR^2b;
W* is N or CR^2b;
X is O or S;
Z and Z* are independently â€”Oâ€”, â€”S(O)_vâ€”, or â€”NR⁵â€”;
R^a, R^b, R^cand R^dare each independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, â€”NO₂, â€”CN, â€”NR⁵R^5a, â€”OR⁴, â€”C(â• O)R⁴, â€”C(â• O)OR⁴; â€”C(â• O)NR⁵R^5a, â€”N(R⁵)C(â• O)NR⁵R^5a, â€”OC(â• O)NR⁵R^5a, â€”S(O)_vR⁴, â€”S(O)₂NR⁵R^5a, â€”N(R⁵)SO₂R⁴any of which may be optionally independently substituted with one or more R¹⁰groups as allowed by valance;
or R^aand R^btogether with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R¹⁰groups as allowed by valance;
or R^cand R^dtogether with the carbon atom to which they are bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may be optionally substituted with one or more R¹⁰groups as allowed by valance;
or R^aand/or R^bmay combine with any R^cor R^dto form a partially or fully saturated 3-8 membered cycloalkyl ring or heterocyclo ring, either of which may be optionally substituted with one or more R¹⁰groups as allowed by valance;
or R^aand R^bmay combine to form a carbonyl group;
or R^cand R^dattached to the same carbon atom may combine to form a carbonyl group;
R¹is aryl, heteroaryl or heterocyclo any of which may be optionally independently substituted with one or more R¹⁰groups as allowed by valance;
R²is
- (i) H, halo, cyano, nitro, or
- (ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, â€”OR⁴, â€”S(O)_vR⁴, â€”NR⁵R^5a, â€”C(â• O)R⁴, â€”C(â• S)R⁴, â€”C(â• O)OR⁴, â€”C(â• S)OR⁴, â€”C(â• O)NR⁵R^5a, â€”C(â• S)NR⁵R^5a, â€”N(R⁵)C(â• O)NR⁵R^5a, â€”N(R⁵)C(â• S)NR⁵R^5a, â€”N(R⁵)C(â• O)R⁴, â€”N(R⁵)C(â• S)R⁴, â€”OC(â• O)NR⁵R^5a, â€”OC(â• S)NR⁵R^5a, â€”SO₂NR⁵R^5a, â€”N(R⁵)SO₂R⁴, â€”N(R⁵)SO₂NR⁵R^5a, â€”N(R⁵)C(â• O)OR⁴, â€”N(R⁵)C(â• S)OR⁴, â€”N(R⁵)SO₂R⁴, any of which may be optionally independently substituted with one or more R¹⁰as allowed by valance,
provided that in compounds of formula I when W and J are both N, R²is other than
- (a) â€”NR⁵R^5awhere R⁵and R^5aare independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl; and
- (b) phenyl substituted with a group

[Image Omitted]

- - where G¹and G²are independently alkyl, cycloalkyl, or G¹and G²together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring;
R^2a, R^2band R³are independently selected at each occurrence from H, halo, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, â€”OR⁴, â€”S(O)_vR⁴, â€”NR⁵R^5a, â€”C(â• O)R⁴, â€”C(â• S)R⁴, â€”C(â• O)OR⁴, â€”C(â• S)OR⁴, â€”C(â• O)NR⁵R^5a, â€”C(â• S)NR⁵R^5a, â€”N(R⁵)C(â• O)NR⁵R^5a, â€”N(R⁵)C(â• S)NR⁵R^5a, â€”N(R⁵)C(â• O)R⁴, â€”N(R⁵)C(â• S)R⁴, â€”OC(â• O)NR⁵R^5a, â€”OC(â• S)NR⁵R^5a, â€”SO₂NR⁵R^5a, â€”N(R⁵)SO₂R⁴, â€”N(R⁵)SO₂NR⁵R^5a, â€”N(R⁵)C(â• O)OR⁴, â€”N(R⁵)C(â• S)OR⁴, â€”N(R⁵)SO₂R⁴, any of which may be optionally independently substituted with one or more R¹⁰groups as allowed by valance;
R⁴is independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally independently substituted as allowed by valance with one or more R¹⁰groups;
R⁵and R^5aare independently selected at each occurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which may be optionally substituted as allowed by valance with one or more R¹⁰;
- or R⁵and R^5amay combine to form a heterocyclo ring optionally substituted with one or more R¹⁰;
R¹⁰at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)_m-OR⁴, -(alkylene)_m-S(O)_vR⁴, -(alkylene)_m-NR⁵R^5a, -(alkylene)_m-C(â• O)R⁴, -(alkylene)_m-C(â• S)R⁴, -(alkylene)_m-C(â• O)OR⁴, -(alkylene)_m-OC(â• O)R⁴, -(alkylene)_m-C(â• S)OR⁴, -(alkylene)_mC(â• O)NR⁵R^5a, -(alkylene)_mC(â• S)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• S)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)R⁴, -(alkylene)_m-N(R⁵)C(â• S)R⁴, -(alkylene)_m-OC(â• O)NR⁵R^5a, -(alkylene)_m-OC(â• S)NR⁵R^5a, -(alkylene)_m-SO₂NR⁵R^5a, -(alkylene)_m-N(R⁵)SO₂R⁴, -(alkylene)_m-N(R⁵)SO₂NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)OR⁴, -(alkylene)_m-N(R⁵)C(â• S)OR⁴, or -(alkylene)_m-N(R⁵)SO₂R⁴;
wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)_m-OR⁴, -(alkylene)_m-S(O)_vR⁴, -(alkylene)_m-NR⁵R^5a, -(alkylene)_m-C(â• O)R⁴, -(alkylene)_m-C(â• S)R⁴, -(alkylene)_m-C(â• O)OR⁴, -(alkylene)_m-OC(â• O)R⁴, -(alkylene)_m-C(â• S)OR⁴, -(alkylene)_m-C(â• O)NR⁵R^5a, -(alkylene)_m-C(â• S)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• S)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)R⁴, -(alkylene)_m-N(R⁵)C(â• S)R⁴, -(alkylene)_m-OC(â• O)NR⁵R^5a, -(alkylene)_m-OC(â• S)NR⁵R^5a, -(alkylene)_m-SO₂NR⁵R^5a, -(alkylene)_m-N(R⁵)SO₂R⁴, -(alkylene)_m-N(R⁵)SO₂NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)OR⁴, -(alkylene)_m-N(R⁵)C(â• S)OR⁴, or -(alkylene)_m-N(R⁵)SO₂R⁴;
and further wherein any two R¹⁰groups attached to the same atom or attached to adjacent atoms may combine to form an optionally substituted 3- to 8 membered ring system;
m is 0 or 1;
n is 0, 1 or 2;
q and t are each independently 0 or 1;
v is 0, 1 or 2.

Preferred compounds include compounds wherein R¹is phenyl, naphthyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrimidinyl, pyrazidinyl, isoquinolinyl, quinolinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, indolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, pyridopyrimidinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyrazinyl, triazolopyrazinyl and triazolopyridinyl any of which may be optionally independently substituted with one or more R¹⁰groups as allowed by valance.

Preferred R¹groups include

[Image Omitted]

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.

Especially preferred R¹groups include

[Image Omitted]

where R^10a, R^10b, R^10yand R^10zare independently absent, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)_m-OR⁴, -(alkylene)_m-NR⁵R^5a, -(alkylene)_m-C(â• O)R⁴, -(alkylene)_m-C(â• O)OR⁴, -(alkylene)_m-OC(â• O)R⁴, -(alkylene)_m-C(â• O)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)R⁴, -(alkylene)_m-OC(â• O)NR⁵R^5a, or -(alkylene)_m-N(R⁵)C(â• O)OR⁴;
or where R^10aand R^10bcombine to form an optionally substituted 3- to 8-membered ring system.

Preferred R¹groups further include

[Image Omitted]

wherein a is a bond or is absent;

U⁵is C or N;U⁶is NH, O or S; and

m+ is 0, 1, 2 or 3.

Most preferred R¹groups include moieties that are either unsubstituted or independently substituted as allowed by valance with one or more halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, -(alkylene)_m-OR⁴, -(alkylene)_m-NR⁵R^5a, -(alkylene)_m-C(â• O)R⁴, -(alkylene)_m-C(â• O)OR⁴, -(alkylene)_m-OC(â• O)R⁴, -(alkylene)_m-C(â• O)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)NR⁵R^5a, -(alkylene)_m-N(R⁵)C(â• O)R⁴, -(alkylene)_m-OC(â• O)NR⁵R^5a, or -(alkylene)_m-N(R⁵)C(â• O)OR⁴.

Preferred compounds of the present invention further include compounds wherein R²is H, halo, cyano, alkynyl, â€”C(â• O)NR⁵R^5a, â€”N(R⁵)C(â• O)R⁴, â€”N(R⁵)C(â• O)OR⁴, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl, tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which may be optionally independently substituted with one or more R¹⁰groups as allowed by valance.

Preferred R²groups include

- (a) halo, alkynyl, â€”C(â• O)NR⁵R^5a, â€”N(R⁵)C(â• O)R⁴or â€”N(R⁵)C(â• O)OR⁴any of which may be optionally independently substituted with one or more R¹⁰groups as allowed by valance; and
- (b) an aryl, heteroaryl or heterocyclo ring system selected from

[Image Omitted]

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.

Preferred compounds of the present invention include compounds having either or both of preferred R¹groups and preferred R²groups either alone or in any combination thereof.

Preferred compounds of the present invention include compounds wherein R^a, R^b, R^cand R^dgroups are independently hydrogen, alkyl (especially methyl), and halogen (especially fluorine).

Preferred compounds within the scope of formula I and II include compounds of the following formualae IA, IB, IC, ID and IIA

[Image Omitted]

enantiomers, diastereomers, salts and solvates thereof, wherein variables R^a, R^b, R^c, R^d, R¹, R², R^2a, R^2b, R³, Z, Z*, n, q and t are as previously defined above. Preferred compounds of formulae IA, IB, IC, ID and IIA include compounds having any of the preferred R¹groups and R²groups, either alone or in any combination thereof.

Preferred compounds within the scope of formula I and II also include compounds having the following formula IE, IF, IIB and IIC

[Image Omitted]

enantiomers, diastereomers, salts and solvates thereof
wherein variables R^a, R^b, R^c, R^d, R², R^2a, R^2b, and Z*, are as previously defined above, provided that in compounds of formula IE R²is not phenyl substituted with a group

[Image Omitted]

where G¹and G²are independently alkyl, cycloalkyl, or G¹and G²together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring; and further wherein
q is 0, 1, 2 or 3;
n* is 0, 1 or 2;
t* is 0 or 1
U¹, U², U³and U⁴are each independently C, or N; and
R^10cat each occurrence is independently selected from the groups listed in the definition of R¹⁰previously described above.
Preferred compounds of formulae IE, IF, IIB and IIC include compounds having any of the preferred R²groups described above.

Preferred compounds within the scope of formulae IE and IF include compounds of the following formula IEi, IEii, IEiii, IEiv, IFi, IFii, IFiii and IFiv

[Image Omitted]

enantiomers, diastereomers, salts and solvates thereof.

Preferred compounds within the scope of formula I further include compounds of the following formula IEA and IFA

[Image Omitted]

enantiomers, diastereomers, salts and solvates thereof wherein variables R^a, R^b, R^c, R^d, R², R^2a, R^2b, R^10c, U¹, U², U³, Z*, n*, q, and t*are as previously defined above provided that in compounds of formula IEA R²is not phenyl substituted with a group

[Image Omitted]

where G¹and G²are independently alkyl, cycloalkyl, or G¹and G²together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring. Preferred compounds of formulae IEA and IFA include compounds having any of the preferred R²groups described above.

Preferred compounds of formulae IEA and IFA include compounds of formulae IEAi, IEAii, IEAiii, IFAi, IFAii and IFAiii

[Image Omitted]

enantiomers, diastereomers, salts and solvates thereof.

Preferred compounds within the scope of formula I further include compounds of the following formula IG or IH

[Image Omitted]

Wherein U is CR^10cor N, and variables R^a, R^b, R², R^2a, R^2b, R^10a, R^10b, R^10c, and Z*, are as previously defined above, provided that in compounds of formula IG R²is not phenyl substituted with a group

[Image Omitted]

where G¹and G²are independently alkyl, cycloalkyl, or G¹and G²together with the nitrogen atom to which they are attached combine to form a 5- to 8-membered heterocyclo ring. Preferred compounds of formulae IG and IH include compounds having any of the preferred R²groups described above.

Preferred compounds within the scope of formula I further include compounds of the following formula IG or IH

[Image Omitted]

Where a is a bond or is absent; U⁵is C or N; U⁶is NH, O or S; and m+ is 0, 1, 2 or 3. Preferred compounds of formulae IJ and IK include compounds having any of the preferred R²groups described above.

Preferred compounds of the present invention include the compounds exemplified herein.

The invention also relates to pharmaceutical compositions containing the above compounds, together with a pharmaceutically acceptable vehicle or carrier.

The invention also relates to a method of treating cancer in a subject using the above compounds.

The invention also relates to a method of reducing tumor size in a subject using the above compounds.

The invention also relates to a method of reducing metastasis in a tumor in a subject, using the above compounds.

The invention also relates to a method of treating HGF-mediated disorders in a subject using the above compounds.

Indications

Compounds of the present invention would be useful for, but not limited to, the prevention or treatment of angiogenesis related diseases. The compounds of the invention have c-Met inhibitory activity. The compounds of the invention are useful in therapy as antineoplasia agents or to minimize deleterious effects of HGF.

Compounds of the invention would be useful for the treatment of neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).

Preferably, the compounds are useful for the treatment of neoplasia selected from lung cancer, colon cancer and breast cancer.

The compounds also would be useful for treatment of ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis. The compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability.

The compounds of the invention are useful in therapy of proliferative diseases. These compounds can be used for the treatment of an inflammatory rheumatoid or rheumatic disease, especially of manifestations at the locomotor apparatus, such as various inflammatory rheumatoid diseases, especially chronic polyarthritis including rheumatoid arthritis, juvenile arthritis or psoriasis arthropathy; paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, such as systemic Lupus erythematosus, poly-myositis, dermato-myositis, systemic sclerodermia or mixed collagenosis; postinfectious arthritis (where no living pathogenic organism can be found at or in the affected part of the body), seronegative spondylarthritis, such as spondylitis ankylosans; vasculitis, sarcoidosis, or arthrosis; or further any combinations thereof. An example of an inflammation related disorder is (a) synovial inflammation, for example, synovitis, including any of the particular forms of synovitis, in particular bursal synovitis and purulent synovitis, as far as it is not crystal-induced. Such synovial inflammation may for example, be consequential to or associated with disease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis deformans. The present invention is further applicable to the systemic treatment of inflammation, e.g. inflammatory diseases or conditions, of the joints or locomotor apparatus in the region of the tendon insertions and tendon sheaths. Such inflammation may be, for example, consequential to or associated with disease or further (in a broader sense of the invention) with surgical intervention, including, in particular conditions such as insertion endopathy, myofasciale syndrome and tendomyosis. The present invention is further especially applicable to the treatment of inflammation, e.g. inflammatory disease or condition, of connective tissues including dermatomyositis and myositis.

These compounds can be used as active agents against such disease states as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, fractures, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy or macular degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome)) since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.

Further, some of these compounds can be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, brain tumor-associated cerebral edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, and other diseases where vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease. The compounds will also be useful in treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g. fibrosis, cirrhosis and carpal tunnel syndrome).

The compounds of the present invention are also useful in the treatment of ulcers including bacterial, fungal, Mooren ulcers and ulcerative colitis.

The compounds of the present invention are also useful in the treatment of conditions wherein undesired angiogenesis, edema, or stromal deposition occurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis, following trauma, radiation, stroke, endometriosis, ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis, synovitis, Crohn's disease, sickle cell anemia, Lyme disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic inflammation, chronic occlusive pulmonary disease, asthma, and inflammatory rheumatoid or rheumatic disease. The compounds are also useful in the reduction of subcutaneous fat and for the treatment of obesity.

The compounds of the present invention are also useful in the treatment of ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, glaucoma, conjunctivitis, Stargardt's disease and Eales disease in addition to retinopathy and macular degeneration.

The compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, arteriosclerosis, vascular occlusion and carotid obstructive disease.

The compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.

The compounds of the present invention are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also useful in the reduction of blood flow in a tumor in a subject.

The compounds of the present invention are also useful in the reduction of metastasis of a tumor in a subject.

The compounds of this invention may also act as inhibitors of other protein kinases, e.g. tie-2, lck, src, fgf, c-Met, ron, ckit and ret, and thus be effective in the treatment of diseases associated with other protein kinases.

Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

As used herein, the compounds of the present invention include the pharmaceutically acceptable derivatives thereof.

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt and the like.

DEFINITIONS

â€œAngiogenesisâ€ is defined as any alteration of an existing vascular bed or the formation of new vasculature, which benefits tissue perfasion. This includes the formation of new vessels by sprouting of endothelial cells from existing blood vessels or the remodeling of existing vessels to alter size, maturity, direction or flow properties to improve blood perfusion of tissue.

As used herein, â€œHGFâ€ refers to hepatocyte growth factor/scatter factor. This includes purified hepatocyte growth factor/scatter factor, fragments of hepatocyte growth factor/scatter factor, chemically synthesized fragments of hepatocyte growth factor/scatter factor, derivatives or mutated versions of hepatocyte growth factor/scatter factor, and fusion proteins comprising hepatocyte growth factor/scatter factor and another protein. â€œHGFâ€ as used herein also includes hepatocyte growth factor/scatter factor isolated from species other than humans.

As used herein â€œc-Metâ€ refers to the receptor for HGF. This includes purified receptor, fragments of receptor, chemically synthesized fragments of receptor, derivatives or mutated versions of receptor, and fusion proteins comprising the receptor and another protein. â€œc-Metâ€ as used herein also includes the HGF receptor isolated from a species other than humans.

As used herein, the terms â€œhepatocyte growth factorâ€ and â€œHGFâ€ refer to a growth factor typically having a structure with six domains (finger, Kringle 1, Kringle 2, Kringle 3, Kringle 4 and serine protease domains). Fragments of HGF constitute HGF with fewer domains and variants of HGF may have some of the domains of HGF repeated; both are included if they still retain their respective ability to bind a HGF receptor. The terms â€œhepatocyte growth factorâ€ and â€œHGFâ€ include hepatocyte growth factor from humans (â€œhuHGFâ€ ) and any non-human mammalian species, and in particular rat HGF. The terms as used herein include mature, pre, pre-pro, and pro forms, purified from a natural source, chemically synthesized or recombinantly produced. Human HGF is encoded by the cDNA sequence published by Miyazawa et al. (1989), supra, or Nakamura et al. (1989), supra. The sequences reported by Miyazawa et al. and Nakamura et al. differ in 14 amino acids. The reason for the differences is not entirely clear; polymorphism or cloning artifacts are among the possibilities. Both sequences are specifically encompassed by the foregoing terms. It will be understood that natural allelic variations exist and can occur among individuals, as demonstrated by one or more amino acid differences in the amino acid sequence of each individual. The terms â€œhepatocyte growth factorâ€ and â€œHGFâ€ specifically include the delta 5 huHGF as disclosed by Seki et al., supra.

The terms â€œHGF receptorâ€ and â€œc-Metâ€ when used herein refer to a cellular receptor for HGF, which typically includes an extracellular domain, a transmembrane domain and an intracellular domain, as well as variants and fragments thereof which retain the ability to bind HGF. The terms â€œHGF receptorâ€ and â€œc-Metâ€ include the polypeptide molecule that comprises the full-length, native amino acid sequence encoded by the gene variously known as p190.sup.MET. The present definition specifically encompasses soluble forms of HGF receptor, and HGF receptor from natural sources, synthetically produced in vitro or obtained by genetic manipulation including methods of recombinant DNA technology. The HGF receptor variants or fragments preferably share at least about 65% sequence homology, and more preferably at least about 75% sequence homology with any domain of the human c-Met amino acid sequence published in Rodrigues et al., Mol. Cell. Biol., 11:2962-2970 (1991); Park et al., Proc. Natl. Acad. Sci., 84:6379-6383 (1987); or Ponzetto et al., Oncogene, 6:553-559 (1991).

The terms â€œagonistâ€ and â€œagonisticâ€ when used herein refer to or describe a molecule which is capable of, directly or indirectly, substantially inducing, promoting or enhancing HGF biological activity or HGF receptor activation.

The terms â€œcancerâ€ and â€œcancerousâ€ when used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, sarcoma, blastoma and leukemia. More particular examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. While the term â€œcancerâ€ as used herein is not limited to any one specific form of the disease, it is believed that the methods of the invention will be particularly effective for cancers which are found to be accompanied by increased levels of HGF or expression of c-Met in the mammal.

The terms â€œtreating,â€ â€œtreatment,â€ and â€œtherapyâ€ as used herein refer to curative therapy, prophylactic therapy, and preventative therapy.

The term â€œmammalâ€ as used herein refers to any mammal classified as a mammal, including humans, cows, horses, dogs and cats. In a preferred embodiment of the invention, the mammal is a human.

Given that elevated levels of c-Met and HGF are observed in hypertension, arteriosclerosis, myocardial infarction, and rheumatoid arthritis, nucleic acid ligands will serve as useful therapeutic agents for these diseases.

The term â€œtreatmentâ€ includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals).

A â€œpharmaceutically-acceptable derivativeâ€ denotes any salt, ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to inhibit angiogenesis.

The phrase â€œtherapeutically-effectiveâ€ is intended to qualify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. For example, effective neoplastic therapeutic agents prolong the survivability of the patient, inhibit the rapidly proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm.

The term â€œHâ€ denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term â€œalkylâ€ is used, either alone or within other terms such as â€œhaloalkylâ€ and â€œalkylaminoâ€ , it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are â€œlower alkylâ€ radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term â€œalkylenylâ€ embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl. The term â€œlower alkyl substituted with R²â€ does not include an acetal moiety.

The term â€œalkenylâ€ embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are â€œlower alkenylâ€ radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms â€œalkenylâ€ and â€œlower alkenylâ€ , embrace radicals having â€œcisâ€ and â€œtransâ€ orientations, or alternatively, â€œEâ€ and â€œZâ€ orientations.

The term â€œalkynylâ€ denotes linear or branched radicals having at least one carbon-carbon triple bond and having two to about twelve carbon atoms. More preferred alkynyl radicals are â€œlower alkynylâ€ radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.

Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

The term â€œhaloâ€ means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term â€œhaloalkylâ€ embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. â€œLower haloalkylâ€ embraces radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. â€œPerfluoroalkylâ€ means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

The term â€œhydroxyalkylâ€ embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are â€œlower hydroxyalkylâ€ radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.

The term â€œalkoxyâ€ embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are â€œlower alkoxyâ€ radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide â€œhaloalkoxyâ€ radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term â€œarylâ€ , alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner. The term â€œarylâ€ embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl. Said â€œarylâ€ group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like. Phenyl substituted with â€”Oâ€”CH₂â€”Oâ€” forms the aryl benzodioxolyl substituent.

The term â€œheterocyclylâ€ (or â€œheterocycloâ€ ) embraces saturated, and partially saturated and heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing â€”Oâ€”Oâ€”, â€”Oâ€”Sâ€” or â€”Sâ€”Sâ€” portions. Said â€œheterocyclylâ€ group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.

Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl, and the like.

Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1Î»â€²-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like.

The term heterocyclyl, (or heterocyclo) also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl].

The term â€œheteroarylâ€ denotes aryl ring systems that contain one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term â€œsulfonylâ€ , whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals â€”SO₂â€”.

The terms â€œsulfamyl,â€ â€œaminosulfonylâ€ and â€œsulfonamidyl,â€ denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (â€”SO₂NH₂).

The term â€œalkylaminosulfonylâ€ includes â€œN-alkylaminosulfonylâ€ where sulfamyl radicals are independently substituted with one or two alkyl radical(s). More preferred alkylaminosulfonyl radicals are â€œlower alkylaminosulfonylâ€ radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms â€œcarboxyâ€ or â€œcarboxylâ€ , whether used alone or with other terms, such as â€œcarboxyalkylâ€ , denotes â€”CO₂H.

The term â€œcarbonylâ€ , whether used alone or with other terms, such as â€œaminocarbonylâ€ , denotes â€”(Câ• O)â€”.

The term â€œaminocarbonylâ€ denotes an amide group of the formula â€”C(â• O)NH₂.

The terms â€œN-alkylaminocarbonylâ€ and â€œN,N-dialkylaminocarbonylâ€ denote aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are â€œlower alkylaminocarbonylâ€ having lower alkyl radicals as described above attached to an aminocarbonyl radical.

The terms â€œN-arylaminocarbonylâ€ and â€œN-alkyl-N-arylaminocarbonylâ€ denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical.

The terms â€œheterocyclylalkylenylâ€ and â€œheterocyclylalkylâ€ embrace heterocyclic-substituted alkyl radicals. More preferred heterocyclylalkyl radicals are â€œ5- or 6-membered heteroarylalkylâ€ radicals having alkyl portions of one to six carbon atoms and a 5- or 6-membered heteroaryl radical. Even more preferred are lower heteroarylalkylenyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl.

The term â€œaralkylâ€ embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are â€œlower aralkylâ€ radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are â€œphenylalkylenylâ€ attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term â€œalkylthioâ€ embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of â€œalkylthioâ€ is methylthio, (CH₃Sâ€”).

The term â€œhaloalkylthioâ€ embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of â€œhaloalkylthioâ€ is trifluoromethylthio.

The term â€œalkylaminoâ€ embraces â€œN-alkylaminoâ€ and â€œN,N-dialkylaminoâ€ where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are â€œlower alkylaminoâ€ radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.

The term â€œarylaminoâ€ denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radicals may be further substituted on the aryl ring portion of the radical.

The term â€œheteroarylaminoâ€ denotes amino groups, which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The â€œheteroarylaminoâ€ radicals may be further substituted on the heteroaryl ring portion of the radical.

The term â€œaralkylaminoâ€ denotes amino groups, which have been substituted with one or two aralkyl radicals. More preferred are phenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion.

The terms â€œN-alkyl-N-arylaminoâ€ and â€œN-aralkyl-N-alkylaminoâ€ denote amino groups, which have been independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.

The term â€œaminoalkylâ€ embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are â€œlower aminoalkylâ€ radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.

The term â€œalkylaminoalkylâ€ embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are â€œlower alkylaminoalkylâ€ radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.

The term â€œalkylaminoalkoxyâ€ embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are â€œlower alkylaminoalkoxyâ€ radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like.

The term â€œalkylaminoalkoxyalkoxyâ€ embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxy radicals are â€œlower alkylaminoalkoxyalkoxyâ€ radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy and the like.

The term â€œcarboxyalkylâ€ embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are â€œlower carboxyalkylâ€ radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH₂groups.

The term â€œhalosulfonylâ€ embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.

The term â€œarylthioâ€ embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of â€œarylthioâ€ is phenylthio.

The term â€œaralkylthioâ€ embraces aralkyl radicals as described above, attached to a divalent sulfur atom. More preferred are phenyl-C₁-C₃-alkylthio radicals. An example of â€œaralkylthioâ€ is benzylthio.

The term â€œaryloxyâ€ embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.

The term â€œaralkoxyâ€ embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are â€œlower aralkoxyâ€ radicals having optionally substituted phenyl radicals attached to lower alkoxy radical as described above.

The term â€œheteroaryloxyâ€ embraces optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom.

The term â€œheteroarylalkoxyâ€ embraces oxy-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals. More preferred heteroarylalkoxy radicals are â€œlower heteroarylalkoxyâ€ radicals having optionally substituted heteroaryl radicals attached to lower alkoxy radical as described above.

The term â€œcycloalkylâ€ includes saturated carbocyclic groups. Preferred cycloalkyl groups include C₃-C₆rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.

The term â€œcycloalkylalkylâ€ embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are â€œlower cycloalkylalkylâ€ radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are â€œ5-6-membered cycloalkylalkylâ€ attached to alkyl portions having one to three carbon atoms. Examples of such radicals include cyclohexylmethyl. The cycloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.

The term â€œcycloalkenylâ€ includes carbocyclic groups having one or more carbon-carbon double bonds including â€œcycloalkyldienylâ€ compounds. Preferred cycloalkenyl groups include C₃-C₆rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

The term â€œcomprisingâ€ is meant to be open ended, including the indicated component but not excluding other elements.

The term(s) â€œFormulas I, II, III, IV, V, VI and VIIâ€ either alone or in combination includes any sub formulas.

The compounds of the invention are endowed with c-Met inhibitory activity.

The present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of an angiogenesis mediated disease state, including those described previously. The compounds of the present invention are useful in the manufacture of an anti-cancer medicament. The compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of c-Met.

The present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the current invention in association with a least one pharmaceutically acceptable carrier, adjuvant or diluent.

The present invention also comprises a method of treating angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of the current invention.

Combinations

While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.

The phrase â€œco-therapyâ€ (or â€œcombination-therapyâ€ ), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.

Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of the current invention may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anticancer or cytotoxic agent.

Currently, standard treatment of primary tumors consists of surgical excision followed by either radiation or IV administered chemotherapy. The typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents, CDK inhibitors, or microtubule poisons. The chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like.

There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.

A first family of antineoplastic agents, which may be used in combination with compounds of the present invention, consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from but not limited to the group consisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2â€²-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents, which may be used in combination with compounds of the present invention, consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1 esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

A fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of Î±-carotene, Î±-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534.

Alternatively, the present compounds may also be used in co-therapies with other anti-neoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofuran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or valspodar.

Alternatively, the present compounds may also be used in co-therapies with VEGFR inhibitors including:

AMG 706 (motesanib diphosphate);
N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-phthalazinamine;
4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide;
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide;
3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[[[[4-(1-pyrrolidinyl)butyl]amino]carbonyl]amino]-4-isothiazolecarboxamide;
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine;
3-[5,6,7,13-tetrahydro-9-[(1-methylethoxy)methyl]-5-oxo-12H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-12-yl]propyl ester N,N-dimethyl-glycine;

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;

N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine

4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide

N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine

N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine

N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((3-(1,3-oxazol-5-yl)phenyl)amino)-3-pyridinecarboxamide;

2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;
N-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.
6-fluoro-N-(4-(1-methylethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;
2-((4-pyridinylmethyl)amino)-N-(3-(((2S)-2-pyrrolidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;
N-(3-(1,1-dimethylethyl)-1H-pyrazol-5-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;
N-(3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;
N-(3-((((2S)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;
2-((4-pyridinylmethyl)amino)-N-(3-((2-(1-pyrrolidinyl)ethyl)oxy)-4-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;
N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;
N-(4-(pentafluoroethyl)-3-(((2S)-2-pyrrolidinylmethyl)oxy)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;
N-(3-((3-azetidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;
N-(3-(4-piperidinyloxy)-5-(trifluoromethyl)phenyl)-2-((2-(3-pyridinyl)ethyl)amino)-3-pyridinecarboxamide;
N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;
2-(1H-indazol-6-ylamino)-N-[3-(1-methylpyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;
N-[1-(2-dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(1H-indazol-6-ylamino)-nicotinamide;
2-(1H-indazol-6-ylamino)-N-[3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;
N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;
N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;
N-[4-(tert-butyl)-3-(3-piperidylpropyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide;
N-[5-(tert-butyl)isoxazol-3-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide; and
N-[4-(tert-butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide.

Other compounds described in the following patents and patent applications can be used in combination therapy: U.S. Pat. No. 6,258,812, US 2003/0105091, WO 01/37820, U.S. Pat. No. 6,235,764, WO 01/32651, U.S. Pat. No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat. No. 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, U.S. Pat. No. 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO 04/05279, WO 04/07481, WO 04/07458, WO 04/09784, WO 02/59110, WO 99/45009, WO 00/59509, WO 99/61422, U.S. Pat. No. 5,990,141, WO 00/12089 and WO 00/02871.

In some embodiments, the combination comprises a composition of the present invention in combination with at least one anti-angiogenic agent. Agents are inclusive of, but not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth.

Exemplary anti-tumor agents include HERCEPTINâ„¢ (trastuzumab), which may be used to treat breast cancer and other forms of cancer, and RITUXANâ„¢ (rituximab), ZEVALINâ„¢ (ibritumomab tiuxetan), and LYMPHOCIDEâ„¢ (epratuzumab), which may be used to treat non-Hodgkin's lymphoma and other forms of cancer, GLEEVACâ„¢ which may be used to treat chronic myeloid leukemia and gastrointestinal stromal tumors, and BEXXARâ„¢ (iodine 131 tositumomab) which may be used for treatment of non-Hodgkins's lymphoma.

Exemplary anti-angiogenic agents include ERBITUXâ„¢ (IMC-C225), KDR (kinase domain receptor) inhibitory agents (e.g., antibodies and antigen binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind VEGF, or soluble VEGF receptors or a ligand binding region thereof) such as AVASTINâ„¢ or VEGF-TRAPâ„¢, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as ABX-EGF (panitumumab), IRESSAâ„¢ (gefitinib), TARCEVAâ„¢ (erlotinib), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2/Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). The pharmaceutical compositions of the present invention can also include one or more agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor â€œc-metâ€ .

Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., US Publication No. 2003/0162712; U.S. Pat. No. 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see, Wiley, U.S. Pat. No. 6,727,225), ADAM distintegrin domain to antagonize the binding of integrin to its ligands (Fanslow et al., US Publication No. 2002/0042368), specifically binding anti-eph receptor and/or anti-ephrin antibodies or antigen binding regions (U.S. Pat. Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent family members thereof), and anti-PDGF-BB antagonists (e.g., specifically binding antibodies or antigen binding regions) as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto).

Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide. (Merck KGaA, Germany, EPO 770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat, (Arriva, USA, U.S. Pat. No. 5,892,112); emaxanib, (Pfizer, USA, U.S. Pat. No. 5,792,783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA); TLC ELL-12, (Elan, Ireland); anecortave acetate, (Alcon, USA); alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn Mab, (Crucell, Netherlands) DAC:antiangiogenic, (ConjuChem, Canada); Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan); SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, EP 970070); ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson, USA); fibrinogen-E fragment, (BioActa, UK); angiogenesis inhibitor, (Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA); angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan); 2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00, (WAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan); TAN-1120, (Takeda, Japan); FR-111142, (Fujisawa, Japan, JP 02233610); platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist, (Borean, Denmark); cancer therapy, (University of South Carolina, USA); bevacizumab (pINN), (Genentech, USA); angiogenesis inhibitors, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha5beta3 integrin, second generation, (Applied Molecular Evolution, USA and MedImmune, USA); gene therapy, retinopathy, (Oxford BioMedica, UK); enzastaurin hydrochloride (USAN), (Lilly, USA); CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitor, (Alchemia, Australia); VEGF antagonist, (Regeneron, USA); rBPI 21 and BPI-derived antiangiogenic, (XOMA, USA); PI 88, (Progen, Australia); cilengitide (pINN), (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); cetuximab (INN), (Aventis, France); AVE 8062, (Ajinomoto, Japan); AS 1404, (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); Endostatin, (Boston Childrens Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (Boston Childrens Hospital, USA); 2-methoxyestradiol, (Boston Childrens Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine, angiogenesis, (EntreMed, USA); urokinase plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-1 alfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA); anginex, (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI, (ProteomTech, USA); tumor necrosis factor-alpha inhibitors, (National Institute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN USA); ABT 518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems, USA); MAb, alpha5 beta1, (Protein Design, USA); KDR kinase inhibitor, (Celltech Group, UK, and Johnson & Johnson, USA); GFB 116, (South Florida University, USA and Yale University, USA); CS 706, (Sankyo, Japan); combretastatin A4 prodrug, (Arizona State University, USA); chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM 1470, (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925, (Agouron, USA); Tetrathiomolybdate, (University of Michigan, USA); GCS 100, (Wayne State University, USA) CV 247, (Ivy Medical, UK); CKD 732, (Chong Kun Dang, South Korea); MAb, vascular endothelium growth factor, (Xenova, UK); irsogladine (INN), (Nippon Shinyaku, Japan); RG 13577, (Aventis, France); WX 360, (Wilex, Germany); squalamine (pINN), (Genaera, USA); RPI 4610, (Sirna, USA); cancer therapy, (Marinova, Australia); heparanase inhibitors, (InSight, Israel); KL 3106, (Kolon, South Korea); Honokiol, (Emory University, USA); ZK CDK, (Schering AG, Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis, Switzerland, and Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102, (Taisho, Japan); VEGF receptor modulators, (Pharmacopeia, USA); VE-cadherin-2 antagonists, (ImClone Systems, USA); Vasostatin, (National Institutes of Health, USA);vaccine, Flk-1, (ImClone Systems, USA); TZ 93, (Tsumura, Japan); TumStatin, (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1), (Merck & Co, USA); Tie-2 ligands, (Regeneron, USA); and, thrombospondin 1 inhibitor, (Allegheny Health, Education and Research Foundation, USA).

Alternatively, the present compounds may also be used in co-therapies with other anti-neoplastic agents, such as VEGF antagonists, other kinase inhibitors including p38 inhibitors, KDR inhibitors, EGF inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors including celecoxib, NSAID's, or Î±_vÎ²₃inhibitors.

The present invention comprises processes for the preparation of a compound of Formula I, II, III, IV, V, VI and VII.

Also included in the family of compounds of the current are the pharmaceutically acceptable salts and solvates thereof. The term â€œpharmaceutically-acceptable saltsâ€ embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of the current invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic, Î²-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of the current invention include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of the current invention. When a basic group and an acid group are present in the same molecule, a compound of the current invention may also form internal salts.

General Synthetic Procedures

The compounds of the invention can be synthesized according to the following procedures.

The following abbreviations are used throughout the specification:

HOAcâ€”acetic acid
MeCN, CH₃CNâ€”acetonitrile
NH₃â€”ammonia
NH₄Clâ€”ammonium chloride
Arâ€”argon
HBTAâ€”O-benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetramethyluronium hexafluorophosphate
HATU Oâ€”(7-azabenzotriazol-1-yl)-N,N,Nâ€²,Nâ€²-tetramethyluronium hexafluorophosphate
PyBopâ€”benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate
Pd₂(dba)₃-bis(dibenzylideneacetone) palladium
BINAPâ€”2,2â€²-bis(diphenylphosphino)-1,1â€²-binaphthyl
TEACâ€”bis(tetra-ethylammonium)carbonate
BBr₃â€”boron tribromide
BSAâ€”bovine serum albumin
Br₂-bromine
BOCâ€”butyloxycarbonyl
Cs₂CO₃â€”cesium carbonate
CHCl₃â€”chloroform
CDCl₃â€”chloroform deuterated
Cuâ€”copper
CuIâ€”copper(I) iodide
Et₂Oâ€”diethyl ether
DBUâ€”1,8-diazabicyclo[5.4.0]undec-7-ene
DIBALâ€”diisobutylaluminum hydride
DIADâ€”diisopropyl azodicarboxylate
DIEAâ€”diisopropylethylamine
DMFâ€”dimethylformamide
DMAPâ€”4-dimethylaminopyridine
DMSOâ€”dimethylsulfoxide
EDC, EDCIâ€”1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
dppaâ€”diphenylphosphoryl azide
EtOAcâ€”ethyl acetate
FBSâ€”fetal bovine serum
gâ€”gram
hâ€”hour
HBrâ€”hydrobromic acid
HClâ€”hydrochloric acid
HOBtâ€”1-hydroxybenzotriazole hydrate
H₂â€”hydrogen
H₂O₂â€”hydrogen peroxide
Feâ€”iron
LiHMDSâ€”lithium bis(trimethylsilyl)-amide
LDAâ€”Lithium diisopropylamide
MCPBAâ€”meta-chloroperbenzoic acid
MgSO₄â€”magnesium sulfate
MeOH, CH₃OHâ€”methanol
MeIâ€”methyl iodide
CH₂Cl₂, DCMâ€”methylene chloride

NMPâ€”N-methylpyrrolidinone

ML, mlâ€”milliliter
N₂â€”nitrogen
Pd/Câ€”palladium on carbon
Pd(OAc)₂â€”palladium acetate
Pd(OH)₂â€”palladium hydroxide
Pd(PPh₃)₄â€”palladium tetrakis triphenylphosphine
Pd(dppf)Cl₂â€”1,1-bis(diphenylphosphino)ferrocene palladium chloride
PBSâ€”phosphate buffered saline
POCl₃â€”phosphorous oxychloride
K₂CO₃â€”potassium carbonate
KOHâ€”potassium hydroxide
RTâ€”room temperature
NaHCO₃â€”sodium bicarbonate
NaBH₄â€”sodium borohydride
NaBH₃CNâ€”sodium cyanoborohydride
NaOtBuâ€”sodium tert-butoxide
NaOHâ€”sodium hydroxide
NaClO₂â€”sodium chlorite
NaClâ€”sodium chloride
NaHPO₄â€”sodium biphospate
NaHâ€”sodium hydride
NaIâ€”sodium iodide
Na₂SO₄â€”sodium sulfate
TBTUâ€”O-benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetramethyluronium tetrafluoroborate
THFâ€”tetrahydrofuran
Et₃N, TEAâ€”triethylamine
TFAâ€”trifluoroacetic acid
P(t-bu)₃â€”tri(tert-butyl)phosphine
H₂Oâ€”water

General Method A

[Image Omitted]

Example 14-((6-(3-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinolineStep 12-(7-methoxyquinolin-4-yloxy)acetic acid

A 250-mL, 3-neck, rb flask equipped with a magnetic stirbar, a reflux condenser and a powder funnel was charged with potassium hydroxide (6.0 g, 90 mmol) then 2-hydroxyacetic acid (5.0 g, 65 mmol) with stirring. The solid reactants gradually reacted and liquified as significant heat was generated. Upon dissolution of all the reagents, flask containing the hot syrupy liquid was immersed in a 170Â° C. oil bath, then a solution of 4-chloro-7-methoxyquinoline (5.0 g, 26 mmol) in anhydrous DMSO (20 mL, 4 vol wrt quinoline) was added dropwise over 20-30 min via addition funnel. The resulting brown solution was maintained in the oil bath with stirring. After 2.5 h, the flask was removed from the oil bath, then quenched by the addition of water (100 mL, 5 vol wrt DMSO). The resulting brown solution was immersed in an ice bath, and the mixture was neutralized by the dropwise addition of 6 N HCl (15 mL, 1 equiv to KOH), which resulted in the formation of a thick yellow ppt and brought the mixture to pH 3. The mixture was filtered and washed with water and ACN. The solid products were dried under vacuum to yield 2-(7-methoxyquinolin-4-yloxy)acetic acid (2.16 g, 36% yield) as a yellow solid. (ESI, pos. ion) m/z: 234.1 (M+H).

Step 2Nâ€²-(6-chloropyridazin-3-O-2-(7-methoxyquinolin-4-yloxy)acetohydrazide

A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (0.372 g, 2.57 mmol), 1-hydroxy-7-aza-benzotriazole (0.350 g, 2.57 mmol), EDC (0.641 g, 3.34 Î¼mol), 2-(7-methoxyquinolin-4-yloxy)acetic acid (0.600 g, 2.57 mmol) and diisopropylethylamine (1.34 ml, 7.72 mmol) in DMF (20 mL) was allowed to stir at 50Â° C. for 2 h. Concentrated. Reconstitued in MeCN (30 mL). Concentrated with cooling. Product crashed out of solution and was isolated by filtration. Used without further purification. (ESI, pos. ion) m/z: 234.1 (M+H).

Step 34-((6-chloro-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

Nâ€²-(6-chloropyridazin-3-yl)-2-(7-methoxyquinolin-4-yloxy)acetohydrazide (2.53 g, 7 0 mmol) was suspended in tetrahydrofuran (50 mL) then added triphenylphosphine (2.8 g, 11 mmol) and trimethylsilyl azide (1.4 ml, 11 mmol). To this suspension, was added diethylazodicarboxylate (2.0 ml, 13 mmol) in rapid drops with a syringe. The mixture became clear and hot to the touch. The reaction mixture was heated at 50Â° C. for 30 minutes. The reaction mixture was concentrated in vacuo. The remaining oil was triturated with diethyl ether. A gel-like solid formed which was collected on a glass frit, washing with diethyl ether. The solid was then triturated with ethyl acetate, and finally acetonitrile. An amorphous solid formed which was collected on a glass frit, washing with acetonitrile. The solid was further dried under high vacuum. In addition, the ethyl acetate filtrate was concentrated in vacuo. The remaining oil was then triturated with acetonitrile. An amorphous solid formed and was collected on a glass frit, washing with acetonitrile. The solid was further dried under high vacuum affording 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline as a tan solid. MS (ESI, pos. ion) m/z: 342.1 (M+1).

Step 44-((6-(3-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

3-fluorophenylboronic acid (0.092 g, 0.66 mmol) was added to a suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.44 mmol) in 2.5 mL dimethylformamide, followed by the addition of potassium carbonate (0.18 g, 1.3 mmol) in 0.6 mL water. PdCl₂(dppf)-CH₂Cl₂adduct (0.018 g, 0.022 mmol) was added and the flask was purged with argon, sealed and heated at 80Â° C. for four hours. Purification by MPLC (eluted with 5 then 10% MeOH in CH₂Cl₂) afforded the product as an off-white solid (78 mg, 44%). (ESI, pos. ion) m/z: 402.1 (M+H).

General Method B

[Image Omitted]

Example 24-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinolineStep 1(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol

A mixture of 1-(6-phenylpyridazin-3-yl)hydrazine (2.00 g, 10.7 mmol), glycolic acid (0.825 g, 10.8 mmol), p-TsOH.H₂O (2.55 g, 13.4 mmol) in PhMe (50 mL) was refluxed for 14 h. PhMe was removed in vacuo. The resulting solids were diluted with water (30 mL). The mixture was brought to pH Ëœ10 with 2N NaOH. The solids were isolated solid by filtration, washed with water and dried under vacuum to give an off white solid which was used without further purification. (ESI, pos. ion) m/z: 227.0 (M+H).

Step 24-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

Cesium carbonate (335 mg, 1027 mmol) was added to a mixture of 4-chloroquinoline (465 mg, 2054 Î¼mol) and above alcohol (112 mg, 685 Î¼mol) in DMSO (1.8 mL) at RT. The reaction mixture was stirred at 120Â° C. under microwave irradiation for 2 h. The reaction mixture was diluted with EtOAc and washed with water. The water layer was extracted with EtOAC. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. Purification by MPLC (CH₂Cl₂/MeOH+1% NH₄OH: 100/0 to 95/5) afforded the title compound. (ESI, pos. ion) m/z: 354.1 (M+H).

In addition to the above reaction, potassium hydride in DME can also be utilized in a similar manner.

General Method C

[Image Omitted]

Example 3N-(4-((6-phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-2-yl)pyrrolidine-1-carboxamideStep 14-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-2-amine

To an argon purged flask was added cesium carbonate (0.24 g, 0.73 mmol), 3-((2-chloropyridin-4-yloxy)methyl)-5-phenyl-3 aH-pyrazolo[4,3-b]pyridine (0.0820 g, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.0056 g, 0.0061 mmol), rac-2,2â€²-bis(diphenylphosphino)-1,1â€²-binaphthyl (0.0091 g, 0.015 mmol). The mixture was taken up in dioxane (8 mL) followed by the addition of benzophenone imine (0.049 ml, 0.29 Î¼mol). The mixture was heated to reflux for 6 h. The mixture was cooled to room temperature and filtered through a plug of silica gel which was washed with a large amount of 10% MeOH in CH₂Cl₂. The resulting mixture was concentrated. The mixture was reconstitued in THF (5 mL) and 1M HCl (5 mL) and allowed to stir for 3 h then concentrated under reduced pressure. The resulting residue was triturated with ether (3Ã—20 mL) and suspended in 9% sodium carbonate. The solid was isolated by filtration and utilized without further purification. (ESI, pos. ion) m/z: 319.1 (M+H).

Step 2N-(4-((6-phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

To the resulting solid in THF (5 mL) was added TRIETHYLAMINE (0.17 ml, 1.2 mmol) followed by phenyl chloroformate (0.15 ml, 1.2 mmol). The mixture was allowed to stir for 2 h. Added pyrrolidine (0.14 ml, 1.7 mmol) and stirred for an additional 2 h. The reaction mixture was concentrated, reconstituted in DMSO and purified via HPLC. (ESI, pos. ion) m/z: 416.2 (M+H).

General Method D

[Image Omitted]

Example 47-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine1) Preparation of 3-methyl-5-trimethylstannyl)isothiazole

[Image Omitted]

Butyllithium (1.6M in hexanes, 18.9 ml, 30 3 mmol) was added to a stirred solution of 3-methylisothiazole (2.73 g, 27.5 mmol) in THF (80 mL) at âˆ’78Â° C. The reaction mixture was stirred at âˆ’78Â° C. for 30 min and chlorotrimethylstannane (1M in THF, 27.5 ml, 27 5 mmol) was added dropwise. After 1 h at âˆ’78Â° C. for 1 h, the reaction mixture was quenched with a saturated aqueous solution of NaHCO₃. The water layer was extracted with Et₂O. The organic extracts were combined, dried over MgSO₄, filtered and concentrated in vacuo. The material (6.97 g) was taken forward without further purification MS m/z=264.1. Calc'd for C7H₁₃NSSn: 261.94

2) Preparation of tert-butyl (6-(3-methylisothiazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

[Image Omitted]

A pressure vessel was purged with Ar and charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (5.00 g, 17 6 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.807 g, 0.881 mmol), 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol). DMF (50 mL) was added, immediately followed by 3-methyl-5-(trimethylstannyl)isothiazole (6.46 g, 24.7 mmol). The reaction mixture was stirred at 100Â° C. for 1 h. Two more portions of tris(dibenzylideneacetone)dipalladium(0) (0.807 g, 0.881 mmol) and 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol) were added every hour for the first two hours of stirring. Reaction was then stirred was at 100Â° C. overnight, cooled to room temperature and concentrated in vacuo. Purification by MPLC (EtOAC/MeOH: 100/0 to 90/10) afforded the title compound (1.80 g, 30% yield). MS m/z=347.1 [M+H]⁺. Calc'd for C15H18N6O2S: 346.41

3) Preparation of (6-(3-methylisothiazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methanamine

[Image Omitted]

Trifluoroacetic acid (2889 Î¼l, 37505 mmol) was added to a stirred suspension of tert-butyl (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (464 mg, 1339 mmol) in DCM (10 mL) at RT. The reaction mixture was stirred at RT for 45 min. and then concentrated in vacuo. 2M NH₃in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH₄OH) afforded the title compound (226 mg, 69% yield). MS m/z=247.1 [M+H]⁺. Calc'd for C₁₀H₁₀N₆S: 246.30.

4) 7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

[Image Omitted]

(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (548 mg, 2225 mmol) and 8-chloro-3-methoxy-1,5-naphthyridine (576 mg, 2959 mmol) were charged in a microwave vial. 2-butanol (7 mL) was added and the reaction mixture was stirred at 120Â° C. under micro-waves irradiation for 8 h. 2M NH₃in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH₄OH: 100/0 to 90/10) afforded the title compound (720 mg, 80% yield). MS m/z=405.1 [M+H]⁺. Calc'd for C19H16N80S: 404.46

General Method E

[Image Omitted]

Example 57-methoxy-4-(2-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinolineStep 1Ethyl 3-(7-methoxyquinolin-4-yl)propanoate

4-chloro-7-methoxyquinoline (0.35 g, 2 mmol), tri-t-butylphosphonium tetrafluoroborate (0.05 g, 0.2 mmol), and tris(dibenzylideneacetone)dipalladium (o) (0.08 g, 0.09 mmol) were combined. The reaction vessel was purged and flushed with nitrogen three times, followed by addition of 3-ethoxy-3-oxopropylzinc bromide in THF (10 mL, 5 Î¼mol, 0.5 M). The reaction mixture was microwaved at 150Â° C. for 60 minutes. Upon completion, ammonium hydroxide (10 mL) was added. After 30 minutes the mixture was filtered and the filtrate was partitioned between water and ethyl acetate. Extracted with ethyl acetate (3Ã—20 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated. Purified by MPLC with a gradient of 20 to 50% EtOAc in CH₂Cl₂. (ESI, pos. ion) m/z: 354.1 (M+H).

Step 27-methoxy-4-(2-(6-phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

Ethyl 3-(7-methoxyquinolin-4-yl)propanoate (156 mg, 0.60 mmol) was combined with 1-(6-phenylpyridazin-3-yl)hydrazine (115 mg, 0.62 mmol) and pTsOH.H₂O (140 mg, 0.72 mmol). The mixture was microwaved at 150Â° C. for 60 minutes. The residue was taken up in DMSO and purified by HPLC and neutralized to yield the desired product as an off-white solid. (ESI, pos. ion) m/z: 382.1 (M+H).

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Example 6

(4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-N,N-dimethylmethanamine. A mixture of 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzaldehyde (prepared according to General Method A) (0.150 g, 0.36 mmol) and dimethylamine, 2.0 m solution in thf (0.36 ml, 0.73 mmol) in THF (5 mL) was allowed to stir for 20 min. Added sodium triacetoxyborohydride (0.15 g, 0.73 mmol) and stirred for 4 h. Concentrated. Suspended in DMSO, filtered through a 0.45 uM acrodisc. Purified on RPHPLC. Took fractions that contained product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=441.2 [M+1]⁺. Calc'd for C₂₅H₂₄N₆O₂: 440.2.

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Example 7

7-methoxy-4-((6-(4-(pyrrolidin-1-ylmethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline. Prepared in a similar manner as (4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-N,N-dimethylmethanamine.

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Example 8

4-((6-(3-fluoro-4-(morpholinomethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline. Prepared in a similar manner as above (4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-N,N-dimethylmethanamine

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Example 9

2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide

A mixture of methyl 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoate (0.488 g, 1.06 mmol) (prepared according to General Method A) and lithium hydroxide hydrate (0.223 g, 5.31 mmol) in THF (20 mL), water (5 mL) and MeOH (5 mL) was heated to 40Â° C. for 3 h. Brought to near neutral pH with 1M HCl. Concentrated. Azeotroped with MeCN (20 mL) and PhMe (20 mL). Used without further purification. A mixture of 2-methoxyethylamine (0.033 ml, 0.38 mmol), HATU (0.24 g, 0.62 mmol), Hunig'sBase (0.24 ml, 1.4 mmol), 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.153 g, 0.34 Î¼mol) in DMF was allowed to stir at room temperature for 1 h. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. The volatiles were removed in vacuo and the product was isolated by filtration. Dried under vacuum. MS m/z=503.2 [M+1]⁺. Calc'd for C₂₆H₂₃FN₆O₄: 502.5.

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Example 10

2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylbenzamide. Prepared in a similar manner as 2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.

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Example 11

2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide. Prepared in a similar manner as 2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.

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Example 12

4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline-7-carboxamide. A mixture of 4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline-7-carbonitrile (0.300 g, 0.793 mmol) and SULFURIC ACID (3.00 ml, 56 3 mmol) was heated at 90Â° C. for 30 min. Quenched onto ice and sodium bicarbonate. Isolated solid by filtration and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles. Product crashed out and was isolated by filtration. MS m/z=397.1 [M+1]⁺. Calc'd for C₂₂H₁₆N₆O₂: 396.4.

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Example 13

1-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridine. Step 1. To a solution of ethyl 2-(3-nitropyridin-4-ylamino)acetate (1.41 g, 6.26 mmol) (prepared according to J. Med. Chem. (1991), 34, 2993.) in THF (10 mL), MeOH (10 mL) and water (5 mL) at 0Â° C. was added lithium hydroxide, monohydrate (0.522 ml, 18.8 mmol). Stirred at 0Â° C. for 30 min. Acidified to pH Ëœ4 with conc. HCl. Concentrated. Azeotroped with MeCN (40 mL) followed by PhMe (30 mL). Took up in DMF (30 mL). Added 1-(6-phenylpyridazin-3-yl)hydrazine (1.17 g, 6.26 mmol), diisopropylethylamine (3.27 ml, 18.8 mmol) followed by HATU (3.57 g, 9.39 mmol). Stirred for 30 min. Concentrated. Partitioned between DCM (30 mL) and water (30 mL). Filtered and isolated solid material. Washed with water (10 mL) and DCM (10 mL). Dried under vacuum. MS m/z=366.1 [M+1]⁺. Calc'd for C₁₇H₁₅N₇O₃: 365.4.

Step 2. To a mixture of 2-(3-nitropyridin-4-ylamino)-Nâ€²-(6-phenylpyridazin-3-yl)acetohydrazide (0.663 g, 1.81 mmol), triphenylphosphine (0.952 g, 3.63 mmol) and trimethylsilyl azide (0.482 ml, 3.63 mmol) in THF (10 mL) at room temperature was added diisopropyl azodicarboxylate (0.715 ml, 3.63 mmol). Heated to Ëœ70Â° C. for 30 min. Reaction is complete. Concentrated. Purified on silica gel. 0 to 7% MeOH in CH₂Cl₂with 1% NH₄OH. MS m/z=348.1[M+1]⁺. Calc'd for C₁₇H₁₃N₇O₂: 347.3.

Step 3. To a mixture of 3-nitro-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridin-4-amine (0.373 g, 1.07 mmol) in THF (10 mL), MeOH (5 mL), EtOH (10 mL) was added Raney Nickel (wet, washed, Ëœ1 g wet). Stirred for 20 min. Reaction is complete. Filtered through a 0.45 Î¼m acrodisc. Concentrated. Used without further purification. MS m/z=318.1 [M+1]⁺. Calc'd for C₁₇H₁₅N₇: 317.4.

Step 3. To a solution of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0640 g, 0.202 mmol) in HOAc (5 mL) was added sodium nitrite (0.0153 g, 0.222 mmol) in water (2 mL). Stirred for 1 h. Concentrated. Took up in DMSO and purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate and removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=329.2[M+1]⁺. Calc'd for C₁₇H₁₂N₈: 328.3.

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Example 14

3-((1H-imidazo[4,5-c]pyridin-1-yl)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine. A mixture of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0650 g, 0.20 mmol), triethyl orthoformate (5.0 ml, 30 mmol), and p-TsOH (0.0039 g, 0.020 mmol) was heated at 60Â° C. After 2 h reaction is complete. Reaction was concentrated. Took up in DMSO and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate and volatiles removed. Collected product by filtration. MS m/z=328.1 [M+1]⁺. Calc'd for C₁₈H₁₃N₇: 327.3.

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Example 15

4-((6-(3-fluoro-4-(2-morpholinoethoxy)phenyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline. To a mixture of 4-(2-hydroxyethyl)morpholine (0.0964 ml, 0.788 mmol),triphenylphosphine (0.238 g, 0.909 mmol), 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenol (0.253 g, 0.606 mmol)(prepared according to General Method A) in THF (10 mL) was added DEAD (0.144 ml, 0.909 mmol). Stirred at room temperature for 1 h. Concentrated. Purifed on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=531.2 [M+1]⁺. Calc'd for C₂₈H₂₇FN₆O₄: 530.5.

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Example 16

2-chloro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide. Prepared in a similar manner as 2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide. MS m/z=519.1 [M+1]⁺. Calc'd for C₂₆H₂₃ClN₆O₄: 518.9.

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Example 17

4-((6-(3-chloro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline. HATU (0.370 g, 0.974 mmol) and 2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.300 g, 0.650 mmol) were taken up in DMF (5 mL). Added Hunig'sBase (0.339 ml, 1.95 mmol). Stirred for 10 min. Added (Z)-Nâ€²-hydroxyacetamidine (0.289 g, 3.90 mmol). Stirred for an additional 30 min. Removed DMF in vacuo. Suspended in water. Isolated product by filtration. The resulting solid was allowed to try under vacuum. Split into 3 portions and separately took up in dioxane (4 mL) in a microwave tube and heated for 12 min at 150Â° C. Combined all 3 reactions. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=500.0 [M+1]⁺. Calc'd for C₂₅H₁₈ClN₇O₃: 499.1.

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Example 18

7-methoxy-4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline. Step 1. Tri-t-butylphosphonium tetrafluoroborate (0.0377 g, 0.130 mmol), tris(dibenzylideneacetone)dipalladium (0.0594 g, 0.0649 mmol), trimethylsilyl acetylene (1.82 ml, 13 0 mmol), 4-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.500 g, 1.30 mmol) were taken up in dioxane (10 mL) and triethylamine (3 mL). Added CuI. Sealed in a tube and heated at 80Â° C. for 3 h. Concentrated. Took up in MeOH and added solid potassium carbonate (large excess). Allowed to stir for 30 min. Filtered through a plug of Celite and concentrated. Took up in 10% MeOH in DCM and filtered through a plug of silica gel to afford 4-((6-ethynyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline. MS m/z=331.0 [M+1]⁺. Calc'd for C₁₉H₁₄N₄O₂: 330.3. Step 2. To a mixture of 4-((6-ethynyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.200 g, 0.605 mmol), trimethylsilylmethyl azide (0.156 g, 1.21 mmol), sodium ascorbate (0.240 g, 1.21 mmol) in THF (4 mL) and water (1 mL) was added 1 drop of a copper sulfate (0.00966 g, 0.0605 mmol) solution. Stirred for 1 h. Concentrated. Suspended in water and extracted with CH₂Cl₂(3Ã—5 mL). Dried over sodium sulfate and concentrated. Took up crude mixture in DMF (4 mL). Added cesium fluoride (0.368 g, 2.42 mmol) and heated to 60Â° for 1 h. Concentrated. Purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate and volatiles were removed in vacuo. Product crashed out of solution and was isolated by filtration. MS m/z=388.1 [M+1]⁺. Calc'd for C₂₀H₁₇N₇O₂: 387.4.

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Example 19

(R/S)-7-methoxy-4-((6-phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylsulfinyl)quinoline. In a 50 mL round bottom flask under N₂were dissolved 7-methoxy-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylthio)quinoline (prepared according to General Method B) (220 mg, 551 Î¼mol) in 5.5 mL of DCM then cooled down at âˆ’78Â° C. and treated with solid m-CPBA (77%) (124 mg, 716 mmol) then warmed slowly to rt over 3 h. The reaction mixture was diluted with DCM then neutralized with NaHCO₃(sat.). The aqueous phase was extracted 3Ã— with DCM then the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with DCM/DCM:MeOH:NH₄OH (90:10:1)100:0 to 90:10 to afforded 7-methoxy-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylsulfinyl)quinoline (109 mg, 47.6% yield) as a white solid. MS m/z=415.1 [M+1]⁺. Calc'd for C₂₂H₁₇N₅O₂S: 416.0.

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Example 20

3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylprop-2-yn-1-amine. In a 10 mL sealed tube under N₂were dissolved dichlorobis(triphenylphosphine)palladium (41 mg, 59 mmol), N,N-dimethylprop-2-yn-1-amine (97 mg, 1170 mmol), 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (prepared according to General Method A) (200 mg, 585 Î¼mol), TRIETHYLAMINE (1631 Î¼l, 11704 mmol) and COPPER(I) IODIDE (11 mg, 59 mmol) in 3 mL of MeCN then stirred and heated at 80Â° C. for 10 h. The crude reaction mixture was directly purified by MPLC (ISCO) with DCM/DCM:MeOH:NH₄OH (90:10:1) 95:5 to afforded 3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylprop-2-yn-1-amine (26 mg, 11% yield) as a yellow solid. MS m/z=388.2 [M+1]⁺. Calc'd for C₂₁H₂₀N₆O₂: 389.2.

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Example 21

8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol. In a 25 mL sealed tube was dissolved 7-methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (prepared according to General Method D) (300 mg, 782 mmol) in 5 mL of concentrated HBr then stirred and heated at 100Â° C. for 48 h. The reaction mixture was diluted with DCM and H₂O then neutralized with NaOH (1N) to neutral pH. The aqueous phase was extracted 3Ã— with DCM then the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with DCM:MeOH:NH₄OH (90:10:1) and then triturated with hot EtOH to afforded 8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (230 mg, 79.6% yield) as a tan solid. MS m/z=369.1 [M+1]⁺. Calc'd for C₂₀H₁₅N₂O: 370.0.

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Example 22

N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(2-(pyrrolidin-1-yl)ethoxy)-1,5-naphthyridin-4-amine. In a 10 mL sealed tube under N₂were dissolved CESIUM CARBONATE (221 mg, 677 mmol), 8#6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (50 mg, 135 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (46 mg, 271 mmol) and SODIUM IODIDE (41 mg, 271 mmol) in 1 mL of DMSO then stirred and heated at 75Â° C. for 3 h. The reaction mixture was diluted with H₂O and the aqueous phase was extracted 3Ã— with DCM then the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with DCM/DCM:MeOH:NH₄OH (90:10:1)100:0 to 90:10 to afforded N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(2-(pyrrolidin-1-yl)ethoxy)-1,5-naphthyridin-4-amine (7 mg, 11% yield) as a yellow solid. MS m/z=466.2 [M+1]⁺. Calc'd for C₂₆H₂₆N₈O: 467.0.

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Example 237-Methoxy-4-((5-phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)quinoline

a) 5-Phenyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate. To a solution of methyl 2-(4-phenylpyridin-2-yl)acetate (see Lohse, O.; Thevenin, P.; Waldvogel, E. Synlett 1999, 1, 45-48) (0.504 g, 2.22 mmol) in 12 mL CH₃CN was added DBU (0.501 ml, 3.33 mmol) and the mixture cooled in an ice bath. To the solution, 4-acetamidobenzenesulfonyl azide (0.533 g, 2.22 mmol) was added and the mixture allowed to warm to rt. The mixture was stirred at rt for 5 h then evaporated. The residue was diluted with CH₂Cl₂, washed with water, brine, dried over Na₂SO₄, and filtered. The title compound was obtained after purification via flash chromatography.

b) (5-Phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol. To a cooled (ice bath) suspension of lithium tetrahydroaluminate (0.0929 g, 2.45 mmol) in 2 mL THF (anhy) was added slowly a solution of methyl 5-phenyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (0.310 g, 1.22 mmol) in 20 mL THF (internal temp remained <20 C). The mixture was allowed to stir in the ice bath 10 minutes. The mixture was diluted with EtOAc, washed with water, sat. NaHCO₃, the organic layer dried over Na₂SO₄, and filtered. The aqueous layer still had uv activity so a solution of Rochelle's salt and EA were added and the mixture stirred 30 min. The organic layer was washed with sat NaHCO₃, dried over Na₂SO₄, filtered, combined with main portion and evaporated. The title compound was isolated as a yellow solid.

c) 7-Methoxy-4-((5-phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)quinoline. A sealable tube was charged with Pd₂dba₃(0.219 g, 0.239 mmol), di-tert-butyl(1-(naphthalen-1-yl)naphthalen-2-yl)phosphine (0.190 g, 0.477 mmol), (5-phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol (0.215 g, 0.955 mmol), 4-chloro-7-methoxyquinoline (0.222 g, 1.15 mmol), Cs₂CO₃(0.622 g, 1.91 mmol) and dioxane (3 mL). The tube was blanketed with N₂, sealed and heated at 100 C for 45 min. The mixture was allowed to cool to rt and evaporated. The residue was purified via flash chromatography using a 1% NH₄OH in MeOH in CH₂Cl₂gradient. The title compound was collected as a tan solid. M/Z=405.1 [M+Na], calc 382.415 for C₂₃H₁₈N₄O₂.

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Example 24N-((6-(3-Chloro-4-fluorophenyl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

a) Nâ€²-(5-bromopyridin-2-yl)-2-(tert-butoxycarbonylamino)acetohydrazide. A suspension of 1-(5-bromopyridin-2-yl)hydrazine (4.00 g, 21 mmol), 2-(tert-butoxycarbonyl)acetic acid (3.7 g, 21 mmol), and HATU (12 g, 32 mmol) in 50 mL CH₃CN was cooled to âˆ’78 (solid precipitates to prevent stirring). The flask was removed from bath gradually allow to warm. When stirring resumed, triethylamine (8.9 ml, 64 mmol) was added and the mixture stirred for 1 h, then evaporated. The residue was dissolved with CH₂Cl₂, washed with water, brine, and the organic layer dried over Na₂SO₄, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in hexanes gradient. The title compound was collected as a yellow oil.

b) tert-Butyl (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methylcarbamate. To a solution of Nâ€²-(5-bromopyridin-2-yl)-2-(tert-butoxycarbonylamino)acetohydrazide (2.2 g, 6.4 mmol) in THF (30 mL) was added triphenylphosphine (2.5 g, 9.6 mmol) and TMS azide (1.3 ml, 9.6 mmol). DEAD (1.8 ml, 11 mmol) was added dropwise rapidly and the mixture heated at 55 C 1 h. The solvent was evaporated and the residue dissolved in CH₂Cl₂, washed with water, brine, dried over Na₂SO₄, and filtered. The mixture was purified via flash chromatography using a EtOAc in CH₂Cl₂gradient. The title compound obtained as a tan solid (664 mg, 32%).

c) N-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine. To a suspension of tert-butyl (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methylcarbamate (0.900 g, 2.75 mmol) in CH₂Cl₂(10 mL) was added TFA (0.848 ml, 11.0 mmol) and the mixture stirred at rt. After 30 minutes additional TFA (0.848 ml, 11.0 mmol) was added, and the mixture stirred at rt 2 h more then concentrated. The residue was taken up into 2-butanol (5 mL) and combined with 8-chloro-3-methoxy-1,5-naphthyridine (0.535 g, 2.75 mmol) in a 5 mL microwave vessel. The vessel was sealed and the mixture heated in the microwave for 10 min at 120 C with a 60 sec prestir. The mixture was concentrated, diluted with DCM and stirred with 2N NaOH (pH 14) for 30 minutes. The solid was filtered to afford the title compound as a beige solid.

d) N-((6-(3-Chloro-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine A sealable tube was charged with PdCl₂(dppf)-CH₂Cl₂Adduct (0.064 g, 0.078 mmol), N-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.120 g, 0.31 mmol), 3-chloro-4-fluorophenylboronic acid (0.057 g, 0.33 mmol), sat NaHCO₃(0.75 ml, >0.69 mmol) and dioxane (2 mL). The vessel was sealed and the mixture heated at 80 for 2.5 h. The mixture was allowed to cool to rt and diluted with water, causing a tan solid to precipitate. CH₂Cl₂(1 mL) was added and the solid filtered. The title compound was obtained after purification via flash chromatography (using a MeOH in CH₂Cl₂gradient) as a tan solid. M/Z=435.1 [M+H], calc 434.8604 for C₂₂H₁₆ClFN₆O. The following compounds were prepared using the same method as described for N-((6-(3-chloro-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine:

[Image Omitted]

Example 25

N-((6-(3-Fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine. M/Z=401.2 [M+H], calc 401.4153 for C₂₂H₁₂FN₆O.

[Image Omitted]

Example 26

7-Methoxy-N-((6-phenyl-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methyl)-1,5-naphthyridin-4-amine M/Z=383.2 [M+H], calc 382.4252 for C₂₂H₁₈N₆O.

[Image Omitted]

Example 28

(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(pyrrolidin-1-yl)methanone: Prepared by a method similar to (5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone. MS m/z=487.1 [M+1]⁺. Calc'd for C₂₅H₂₂N₆O₃S: 486.2

[Image Omitted]

Example 29

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylthiophene-2-carboxamide: To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonyl chloride (0.260 g, 0.58 mmol) in dichloromethane was added N-ethyl-N-isopropylpropan-2-amine (0.20 ml, 1.2 mmol) and dimethylamine (1.4 ml, 2.9 mmol). The solution was stirred at room temperature for one hour then was concentrated in vacuo. The residue was triturated with water and filtered; the resulting precipitate was triturated with acetonitrile and filtered to yield the product as an off-white solid. MS m/z=461.0 [M+1]⁺. Calc'd for C₂₃H₂₀N₆O₃S: 460.1.

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Example 30

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-methylthiophene-2-carboxamide: Prepared by a method similar to (5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone. MS m/z=447.0 [M+1]⁺. Calc'd for C₂₂H₁₈N₆O₃S: 446.1

[Image Omitted]

Example 31

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carboxamide: Prepared by a method similar to (5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone. MS m/z=433.0 [M+1]⁺. Calc'd for C₂₁H₁₆N₆O₃S: 432.1.

[Image Omitted]

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carbonyl chloride: To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carboxylic acid (prepared by General Method A)(0.150 g, 0.335 mmol) in dichloromethane (2 mL) was added thionyl chloride (0.734 ml, 10.1 Î¼mol and DMF (1 drop). The solution was stirred at room temp for three hours then concentrated and taken forward without further purification.

[Image Omitted]

Example 32

(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophen-2-yl)(morpholino)methanone: To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carbonyl chloride (0.100 g, 0.21 mmol) in dichloromethane (2 mL) at 0Â° C. was added morpholine (0.19 g, 2.1 mmol). The solution was stirred at room temperature twenty minutes, then was concentrated and purified by MPLC chromatography (eluted with 3% methanol in dichloromethane) to yield a yellow solid. Trituration in acetonitrile and filtration afforded the product as a white solid. MS m/z=517.2 [M+1]⁺. Calc'd for C₂₆H₂₄N₆O₄S: 516.2.

[Image Omitted]

7-methoxy-N-((6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine: To an argon flushed pressure vial (15 mL) was added copper (I)iodide (0.0070 g, 0.037 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.012 g, 0.015 mmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.050 g, 0.15 mmol), and triethyl(ethynyl)silane (0.13 ml, 0.73 mmol) in acetonitrile (2 mL) followed by triethylamine (0.61 ml, 4.4 mmol). The vial was sealed and stirred at room temperature overnight The solution was concentrated and purified by MPLC (eluted with 0-10% (90:10:1 DCM:MeOH:NH₄OH)) to yield the product as a light yellow solid. MS m/z=446.1 [M+1]⁺. Calc'd for C₂₃H₂₇N₇OSi: 445.2.

[Image Omitted]

Example 33

N-((6-ethynyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine: To a solution of 7-methoxy-N-((6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (0.360 g, 0.808 mmol) in acetic acid (8 mL) was added TBAF (1.21 ml, 1.21 mmol). The mixture was stirred at room temperature overnight, additional TBAF (1.21 ml, 1.21 mmol) was added and the mixture was heated to 50Â° C. for five hours. The mixture was concentrated and purified via MPLC (eluted with 0-10% (1:10:90 NH₄OH:MeOH:DCM) in dichloromethane) to yield the product as an off-white solid. MS m/z=332.0 [M+1]⁺. Calc'd for C₁₇H₁₃N₇O: 331.1.

[Image Omitted]

tert-butyl(6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate: A 1 L-round-bottomed flask flushed with argon was charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (12.00 g, 42 3 mmol), Pd(dppf)Cl₂-CH₂Cl₂adduct (3.45 g, 4.23 mmol), copper iodide (2.01 g, 10 6 mmol) at room temperature. Acetonitrile (400 mL) was added followed by triethyl(ethynyl)silane (37.9 ml, 211 Î¼mol). Upon stirring the reaction mixture turned dark red. Triethylamine (177 ml, 1269 mmol) was added via cannula over five minutes. The first drops resulted in a change of color to light yellow/orange. At the end of the addition, the reaction mixture was dark red again. After stirring at 50Â° C. for one hour, the mixture was cooled to room temperature and concentrated in vacuo. Purification by MPLC (ISCO, EtOAc/MeOH: 100/0 to 90/10) afforded the desired product. The material was taken forward without further purification. MS m/z=388.3 [M+1]⁺. Calc'd for C₁₉H₂₉N5O₂Si: 387.2.

[Image Omitted]

tert-butyl(6-ethynyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate: Potassium fluoride (2M in water, 27.6 ml, 55 3 mmol) was added to a stirred suspension of tert-butyl6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.57 g, 9.21 mmol) in acetonitrile (56 mL) at room temperature. The reaction mixture turned dark immediately, and was stirred at room temp for twenty minutes until complete. The mixture was concentrated in vacuo, triturated with water and filtered to yield the product as a brown solid (2.46 g). MS m/z=274.1 [M+1]⁺. Calc'd for C₁₃H₁₅N₅O₂: 273.1.

[Image Omitted]

tert-butyl(6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate: To a solution of nitroethane (1.02 ml, 14 3 mmol) in benzene (50 mL) was added phenyl isocyanate (3.12 ml, 28.5 mmol). The mixture was stirred at 50Â° C. for twenty minutes followed by the addition of tert-butyl (6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.00 g, 11.0 mmol) and triethylamine (0.0765 ml, 0.549 mmol). The mixture was stirred at 50Â° C. for six hours then at room temperature overnight. The mixture was cooled to room temperature, filtered and the resulting brown precipitate was washed with additional benzene. The filtrate was concentrated to yield the product as a black solid. MS m/z=331.1 [M+1]⁺. Calc'd for C₁₅H₁₈N₆O₃: 330.1.

[Image Omitted]

(6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methanamine: To a solution of tert-butyl (6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.63 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (16.9 ml, 220 mmol) and the mixture was stirred at room temperature for one hour. The mixture was concentrated, taken up in a solution of ammonia in methanol (2.0 M) and purified by MPLC chromatography (eluted with 0-10% (1:10:90 NH₄OH:MeOH:DCM) in DCM) to yield the product as a brown solid. MS m/z=230.8 [M+1]⁺. Calc'd for C₁₀H₁₀N₆O: 230.1.

[Image Omitted]

Example 34

7-methoxy-N-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine: To a microwave vial (10-20 mL) was added (6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (1.00 g, 4.34 Î¼mol) and 8-chloro-3-methoxy-1,5-naphthyridine (1.10 g, 5.65 mmol) in 2-butanol (12 mL). The suspension was stirred at 120Â° C. under microwave irradiation for four hours. The mixture was concentrated and taken up in ammonia in methanol (2.0 M) then purified by MPLC chromatography (eluted with 0-10% methanol in dichloromethane) to yield the product as a tan solid. MS m/z=389.0 [M+1]⁺. Calc'd for C₁₉H₁₆N₈O₂: 388.1

[Image Omitted]

Example 35

Ethyl-5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylate: Prepared by a method similar to 7-methoxy-N-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine MS m/z=446.6 [M+1]⁺. Calc'd for C₂₁H₁₈N₈O₄: 446.2.

[Image Omitted]

Example 36

5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylic acid: To a solution of ethyl 5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylate (0.045 g, 0.10 mmol) in methanol (1 mL) and water (0.5 mL) was added sodium hydroxide (6M, 0.050 ml, 0.30 mmol). The mixture was stirred at 50Â° C. for two hours, then was concentrated and diluted with water (2 mL). 2M HCL was added dropwise until precipitation was observed, the tan solid was collected by filtration. The solid was taken up in isopropanol and heated to 100Â° C. The resulting suspension was cooled to room temperature and filtered to yield the product as a tan solid. MS m/z=418.6 [M+1]⁺. Calc'd for C₁₉H₁₄N₈O₄: 418.1.

[Image Omitted]

tert-butyl-(6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate: Prepared by a method similar to tert-butyl-(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. MS m/z=430.7 [M+1]⁺. Calc'd for C₂₀H₂₆N₆O₅: 430.2.

[Image Omitted]

(5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazol-3-yl)methanol: To a solution of tert-butyl (6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (4.73 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (16.9 ml, 220 mmol). The mixture was stirred at room temperature for one hour, then was concentrated, taken up in 2.0 M ammonia in methanol and purified by MPLC chromatography (eluted with 0-10% (1:10:90 NH₄OH:MeOH:DCM) in DCM) to yield the product as a tan solid. MS m/z=246.9 [M+1]⁺. Calc'd for C₁₀H₁₀N₆O₂: 246.1.

[Image Omitted]

Example 37

(5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazol-3-yl)methanol: Prepared by a method similar to 7-methoxy-N-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine MS m/z=404.6 [M+1]⁺. Calc'd for C₁₉H₁₆N₈O₃: 404.1.

[Image Omitted]

5-(tributylstannyl)-2-(trimethylsilyl)thiazole: To a stirred solution of butyllithium (0.763 ml, 1.91 mmol) in diethyl ether (10 mL) at âˆ’78Â° C. was added dropwise over 30 minutes a solution of 2-(trimethylsilyl)thiazole (0.300 ml, 1.91 mmol) in ether (5 mL). The solution was stirred at âˆ’78Â° C. for one hour, followed by the addition of chlorotrimethylstannane (1.59 ml, 1.59 mmol) in THF over 15 minutes. After an additional hour at âˆ’78Â° C., the solution was washed with saturated bicarbonate and extracted with diethyl ether. Organic extracts were dried over magnesium sulfate and filtered then concentrated in vacuo to yield the product as a colorless oil.

[Image Omitted]

5-(tributylstannyl)thiazole: To a solution of 2-(trimethylsilyl)-5-(trimethylstannyl)thiazole (0.509 g, 1.6 mmol) in 5 mL THF was added 2 N HCl (1.0 mL). The solution was stirred at room temperature for one hour. The solution was diluted with diethyl ether and washed with sodium bicarbonate. Organic extracts were dried over magnesium sulfate and filtered then concentrated to yield the product as a colorless oil.

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3-methyl-5-(tributylstannyl)isoxazole: To a solution of nitroethane (0.0952 ml, 1.33 mmol) in benzene (2 mL) was added phenyl isocyanate (0.291 ml, 2.66 mmol). The solution was stirred at 50Â° C. for ten minutes followed by the addition of triethylamine (0.00925 ml, 0.0666 mmol) and tributyl(ethynyl)stannane (0.365 ml, 1.27 mmol). The mixture was left to stir at 50Â° C. overnight. The solution was diluted with water and filtered though a celite plug, the resulting filtrate was extracted with toluene. Organic extracts were dried over magnesium sulfate and filtered then concentrated to yield the product as a yellow oil.

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Example 38

In a pressure vessel, 3N HCl (1.2 ml, 3 5 mmol) was added to 4-((6-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.071 g, 0.18 mmol) in dioxane (0.60 mL). The reaction mixture was then heated at 100Â° C. for 3.5 h. Concentrated HCl (0.300 mL, 9.9 mmol) was added and the reaction was heated at 100Â° C. for 2 h. The reaction mixture was concentrated in vacuo, and then dried on high vacuum. Triethylamine (0.74 ml, 5 3 mmol) was added to the compound, and it was allowed to stir for one hour until the free base crashed out of solution.

The compound was dissolved partially in DCM/MeOH, however, fully dissolved after addition of hot DMSO. The compound was purified via flash chromatograph, eluting with 0-10% MeOH/NH₄OH in DCM. The compound was sonicated in DCM and filtered to remove the triethylamine-hydrochloride salt, and yielded 6-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2(1H)-one.

[Image Omitted]

Example 396-((6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (1.67 g, 12 mmol), 2-(quinolin-6-yl)acetic acid (1.65 g, 8.8 mmol), and HCl (2000 Î¼l, 24 mmol) was heated in an oil bath at 110Â° C. for 20 min before it was heated in a microwave (Personal Chemistry) at 180Â° C. & 15 min. The mixture was quenched with a solution of NaOH (1.2 g, 5 mL) slowly until the suspension is Ëœneutral in pH. The mixture was filtered and washed with H₂O (2Ã—5 mL). A brown solid was obtained (2.2 g). The solid was treated with aqueous Na₂CO₃(3 g, 20 mL, pH Ëœ11) and heated at 50Â° C. for 30 min. The blue mixture was cooled to room temperature, and filtered. The black solid was washed with H₂O and lyophilized to give the product.

LCMS: calc'd for C₁₅H₁₀ClN₅: 295.1. found 296.1 (M+1).

[Image Omitted]

Example 403-Methoxy-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A mixture of tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (148 mg) and 1-(6-phenylpyridazin-3-yl)hydrazine (126 mg) in HCl (conc., 0.3 mL) was heated at 100Â° C. for 5 min and was subject to microwave heating (180Â° C., 15 min). The yellow sludge was quenched with NaOH (5N, 1 mL). The pink mixture was filtered and washed with NaOH (1 N, 1 mL), H₂O (2 mL). The solid was suspended in DMF (2 mL)-DCM (2 mL). MeI (0.2 mL) was added followed by the addition of NaOH (2N, 1 mL). After 2 h, the mixture was partitioned between DCM (10 mL) and aqueous Na₂SO₃(5 mL). The organic was dried over MgSO₄, concentrated, and purified in silica (1-15% MeOH in DCM) to give the product as a yellow powder.

LCMS: calc'd for C₂₂H₁₇N₅O: 367.1. found 368.2 (M+1).

[Image Omitted]

Example 414-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol1) 6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde

[Image Omitted]

A 250 mL RB flask was charged with DMF (21.3 ml, 274 mmol) and cooled to 0Â° C.; phosphorus oxychloride (2.46 ml, 26.4 mmol) was added dropwise. This was stirred for 1 hour, then 6-bromoH-imidazo[1,2-a]pyridine (2.00 g, 10.2 mmol) was added in one portion. This was stirred at 100Â° C. for 5 hours and at room temperature for 16 hours. The flask was cooled to 0Â° C. and slowly neutralized with 6N aq. NaOH and sat. aq. NaHCO₃, resulting in the formation of a precipitate which was collected by filtration to give 6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde as a yellow-orange solid.

2) (6-bromoH-imidazo[1,2-a]pyridin-3-yl)methanol

[Image Omitted]

A 50 mL RB flask was charged with sodium borohydride (0.074 g, 2.0 mmol) and water (0.84 ml, 47 mmol), then cooled to 0Â° C. A solution of 6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde (0.8792 g, 3.9 mmol), methanol (6.3 ml, 156 mmol), and DCM was added slowly. This was allowed to warm to room temperature. The mixture was concentrated, then the yellow residue was triturated with water and filtered to give (6-bromoH-imidazo[1,2-a]pyridin-3-yl)methanol as a yellow solid.

3) 4-((6-bromoH-imidazo[1,2-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

[Image Omitted]

A 10-20 mL microwave vial was charged with (6-bromoH-imidazo[1,2-a]pyridin-3-yl)methanol (0.756 g, 3.3 mmol), 4-chloro-7-methoxyquinoline (0.81 g, 4 2 mmol), cesium carbonate (2.2 g, 6.7 mmol), and DMSO (8.00 ml, 113 mmol), sealed, and placed in a Personal Chemistry microwave at 100Â° C. for 2 hours. The reaction mixture was added dropwise to a flask containing water, resulting in the formation of a precipitate which was collected by filtration. The solid was dissolved in a combination of MeOH/DCM and filtered. The filtrate was concentrated and triturated with EtOAc/DCM. The solid was dissolved in a small amount of hot MeOH and DCM and purified by chromatography using a 40 g ISCO column, eluting with a gradient of 1-7% MeOH (with 10% NH₄OH)/DCM over 40 minutes.

4) 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol

A 16 mm test tube was charged with 4-((6-bromoH-imidazo[1,2-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.0607 g, 0.16 mmol), phenylboronic acid (0.039 g, 0.32 mmol), SPhos (0.0065 g, 0.016 mmol), Potassium phosphate (0.10 g, 0.47 mmol), Pd2(dba)₃(0.0036 g, 0.0039 mmol), and 1-butanol (0.014 ml, 0.16 mmol), then stirred at 100Â° C. for 16 hours. The reaction mixture was diluted with chloroform (15 mL) and washed with water (15 mL), sat. aq. NaHCO₃(15 mL), and brine (15 mL); the organic layer was dried with MgSO₄, filtered, and concentrated. This was purified using the prep HPLC machine using a gradient of 10% MeCN/water to 95% MeCN/water over 20 min. The fractions were combined and the product free based by diluting with 10% MeOH/HCCl₃(30 mL) and washing with sat. aq. NaHCO₃(30 mL). The organic layer was dried with MgSO₄, filtered, and concentrated, then the resulting yellow solid was submitted to the Analytical Chemistry group for purification. This was returned as the formic acid salt in water, which was concentrated, free based with sat. NaHCO₃(5 mL), diluted with water (15 mL), and extracted with 10% MeOH/HCCl₃(3Ã—25 mL). The combined organics were dried with MgSO₄, filtered, and concentrated to yield 7-methoxy-4-((6-phenylH-imidazo[1,2-a]pyridin-3-yl)methoxy)quinoline.

MS (ESI pos. ion) m/z: 382 (MH+). Calc'd exact mass for C₂₄H₁₉N₃O₂: 381.

[Image Omitted]

Example 42N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7H-purin-6-amine

A 15 mL tube was charged with (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (0.100 g, 0.444 mmol), 6-chloropurine (0.103 g, 0.666 mmol), and sec-butanol (3.00 ml, 32.4 mmol), sealed, then heated in a 100Â° C. oil bath for 5 hours. The reaction mixture was concentrated and the yellow residue was purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-8% MeOH/DCM over 80 minutes. N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7H-purin-6-amine (0.0500 g, 32.8% yield) was isolated as the hydrochloride salt.

MS (ESI pos. ion) m/z: 344 (MH+). Calc'd exact mass for C₂₃H₁₈FN₅O₂: 343.

[Image Omitted]

Example 435-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine

A 48 mL tube was charged with 6-(dimethylamino)pyridin-3-ylboronic acid (0.109 g, 0.658 mmol), 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.439 mmol), and DMF (3.00 ml, 38.6 mmol), and stirred for 10 minutes. A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38 6 mmol) was added, followed by PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, and heated in a 80Â° C. oil bath for 5 hours. The mixture was concentrated, and the residue was triturated with water to give a brown solid which was purified by MPLC using a 40 g column, eluting with 1-5% MeOH/DCM over 40 minutes to give 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine as a dark green solid.

MS (ESI pos. ion) m/z: 428 (MH+). Calc'd exact mass for C₂₃H₁₈FN₅O₂: 427.

[Image Omitted]

Example 447-methoxy-4-((6-(6-morpholinopyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

Prepared in a similar manner as 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine

MS (ESI pos. ion) m/z: 470 (MH+). Calc'd exact mass for C₂₃H₁₈FN₅O₂: 469.

[Image Omitted]

Example 454-((6-(H-imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

Prepared in a similar manner as 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine

MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C₂₃H₁₇N₇O₂: 423.

[Image Omitted]

Example 46tert-butyl 4-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-yl)piperazine-1-carboxylate

Prepared in a similar manner as 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine

MS (ESI pos. ion) m/z: 569 (MH+). Calc'd exact mass for C₃₀H₃₂N₈O₄: 568.

[Image Omitted]

Example 477-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

A 50 mL recovery flask was charged with tert-butyl 4-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (0.250 g, 0.44 mmol), TFA (0.75 ml, 9.6 mmol), and DCM (1.50 ml, 23 mmol), then stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, then quenched with sat. aq. NaHCO₃. The mixture was diluted with DCM (60 mL), resulting in an emulsion. The emulsion was filtered to give a brown solid. The solid was triturated with a combination of DCM/MeOH/MeCN and filtered to give 7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.

MS (ESI pos. ion) m/z: 469 (MH+). Calc'd exact mass for C₂₅H₂₄N₈O₂: 468.

[Image Omitted]

Example 48tert-butyl 3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate1) 4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

[Image Omitted]

Prepared in a similar manner as 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine

2) tert-butyl 3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate

A 0.5-2 mL microwave vial was charged with 4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.100 g, 0.249 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (0.116 g, 0.622 mmol), and DMSO (4.00 ml, 56 4 mmol), sealed and placed in a Personal Chemistry microwave for 1 hour at 100Â° C. and then 30 minutes at 120Â° C. Water was added slowly to the reaction mixture until a precipitate formed. The solid was collected and purified by MPLC using a 0 g RediSep column, eluting with a gradient of 3-6% MeOH/DCM over 40 minutes. The solid was triturated with MeCN and filtered; the mother liquor was concentrated to give tert-butyl 3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate.

[Image Omitted]

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonyl chloride: To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carboxylic acid (prepared according to general method A) (0.500 g, 1.15 mmol) in dichloromethane at 0Â° C. was added thionyl chloride (1.26 ml, 17.3 mmol) dropwise. Three drops DMF were added and the solution was stirred at room temp for three hours. The solution was concentrated to a brown residue and taken forward without further purification.

[Image Omitted]

Example 27

(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone: To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonyl chloride (0.260 g, 0.58 mmol) in dichloromethane (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.15 ml, 0.86 mmol) and morpholine (0.15 ml, 1.7 mmol). The solution was stirred at room temperature for two hours then was concentrated in vacuo. The brown residue was purified via MPLC chromatography (eluted with 0-5% methanol in dichloromethane) to yield the product as a tan solid. MS m/z=503.0 [M+1]⁺. Calc'd for C₂₅H₂₂N₆O₄S: 502.1.

MS (ESI pos. ion) m/z: 569 (MH+). Calc'd exact mass for C₃₀H₃₂N₈O₄: 568.

[Image Omitted]

Example 495-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-(pyrrolidin-3-yl)pyridin-2-amine

Prepared in a similar manner as 7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.

MS (ESI pos. ion) m/z: 469 (MH+). Calc'd exact mass for C₂₅H₂₄N₈O₂: 468.

[Image Omitted]

Example 504-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl-2-methylbut-3-yn-2-ol

A 25Ã—200 mm test tube was charged with 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.439 mmol), 2-methylbut-3-yn-2-ol (0.213 ml, 2.19 mmol), copper (I) iodide (0.0209 g, 0.110 mmol), triethylamine (1.83 ml, 13 2 mmol), and acetonitrile (5.00 ml, 96 2 mmol), flushed with argon, sealed, and placed in a 90Â° C. oil bath for 30 minutes. PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol) was added in one portion, the tube flushed with argon, sealed, then heated in a 90Â° C. oil bath for 4 hours. The reaction mixture was filtered thru a pad of silica gel (eluting with EtOAc/DCM/MeOH), then concentrated to yield a dark brown oil. This was purified by MPLC, using a 0 g RediSep column, eluting with 1-7% MeOH/DCM over 40 minutes. The appropriate fractions were collected to give 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol (0.0877 g, 51.3% yield).

MS (ESI pos. ion) m/z: 390 (MH+). Calc'd exact mass for C₂₁H₁₉N₅O₃: 389.

[Image Omitted]

Example 511-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one1) 1-(4-chloro-2-fluorophenyl)pyrrolidin-2-one

[Image Omitted]

A 100 mL sealed tube was charged with 4-chloro-2-fluoro-1-iodobenzene (0.498 ml, 3.90 mmol), pyrrolidin-2-one (0.598 ml, 7.80 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.0703 ml, 0.585 Î¼mol), potassium phosphate (1.66 g, 7.80 mmol), copper (I) iodide (0.0223 g, 0.117 mmol), and 1,4-dioxane (4.00 ml, 46 8 mmol), then flushed with argon, sealed, and placed in a 110Â° C. oil bath for 17 hours. The reaction mixture was filtered through a pad of silica gel, eluting with EtOAc and DCM, then the filtrate was concentrated to yield a brown oil This was purified by column chromatography using a 0 g ISCO column, eluting with a gradient of 3-5% MeOH/DCM over 30 minutes to give 1-(4-chloro-2-fluorophenyl)pyrrolidin-2-one (0.903 g, 108% yield) as a yellow solid.

2) 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

[Image Omitted]

A 48 mL sealed tube was charged with 1-(4-chloro-2-fluorophenyl)pyrrolidin-2-one (0.444 g, 2.08 mmol), pinacol diborane (1.06 g, 4.16 mmol), X-Phos (0.0991 g, 0.208 mmol), Pd2 dba3 (0.0571 g, 0.0623 mmol), potassium acetate (0.408 g, 4.16 mmol), and 1,4-dioxane (4.62 ml, 54.0 mmol), flushed with argon, sealed, then placed in a 90Â° C. oil bath for 5 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL), sat. NaHCO₃(100 mL), and brine (100 mL), dried with MgSO₄, filtered, and concentrated. This was purified by MPLC using a 0 g RediSep column, eluting with 1-5% MeOH/DCM over 40 minutes. The fractions were concentrated to give 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one, Ëœ85% pure, as an orange oil that solidified upon standing.

3) tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

[Image Omitted]

A 48 mL sealed tube was charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.150 g, 0.529 Î¼mol), 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.242 g, 0.793 mmol), PdCl2(dppf)-CH₂Cl₂Adduct (0.0432 g, 0.0529 Î¼mol), cesium carbonate (0.689 g, 2.11 mmol), 1,4-dioxane (3.62 ml, 42.3 mmol), and water (0.905 ml, 50 2 mmol), flushed with argon, sealed, then placed in a 80Â° C. oil bath for 5 hours. The contents were transferred to a flask and concentrated. The solid was triturated with water to give a red residue, which was purified by MPLC using a 0 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.117 g, 51.9% yield) was isolated as a tan solid.

4) 1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one

[Image Omitted]

A 50 mL recovery flask was charged with tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.117 g, 0.274 mmol), TFA (0.0211 ml, 0.274 mmol), and DCM (0.0177 ml, 0.274 mmol), then stirred open to air at room temperature for 2 hours. The mixture was concentrated, then taken up in MeOH. K₂CO₃was added, and this was stirred for 1 hour. The mixture was concentrated, then the residue was taken up in MeOH/CHCl₃then filtered. The filtrate was evaporated, taken up in water, then passed through a reverse phase C₁₈column, eluting with MeOH/DCM, then concentrated.

5) 1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one

A 0.5-2 mL microwave vial was charged with 1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one (0.0792 g, 0.243 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (0.0590 g, 0.303 mmol), and butan-2-ol (1.00 ml, 0.243 mmol), sealed, then placed in a Personal Chemistry Microwave for 4 hours at 120Â° C. The mixture was concentrated, then triturated with MeOH to give 1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one as the hydrochloric salt.

MS (ESI pos. ion) m/z: 485 (MH+). Calc'd exact mass for C₂₅H₂₁FN₈O₂: 484.

[Image Omitted]

Example 525-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylisoindolin-1-one1) 4-bromo-2-(hydroxymethyl)-N-methylbenzamide

[Image Omitted]

A 500 mL RB flask was charged with aluminum(III) chloride (4.1 g, 31 mmol) and 10 mL of 1,2-dichloroethane (90 ml, 1142 mmol), then cooled to 0Â° C. A separate 250 mL flask was charged with 90 mL of 1,2-dichloroethane (90 ml, 1142 mmol) and cooled to 0Â° C.; methylamine (gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes. The dichloroethane solution was slowly poured into the aluminum chloride solution, resulting in the formation of a thick white slush. This was warmed to room temperature. 5-bromoisobenzofuran-1(3H)-one (5.00 g, 23 mmol) was added in one portion and the reaction mixture was stirred for 2.5 hours and quenched with water. The mixture was filtered to remove the solid impurities, then the filtrate was washed with 0.5N aqueous HCl (100 mL) and brine (200 mL). The organic layer was dried with MgSO₄, filtered, and concentrated to give a white solid. This was triturated with EtOAc and filtered to give 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 58% yield) as a white solid.

2) 5-bromo-2-methylisoindolin-1-one

[Image Omitted]

A 150 mL sealed tube was charged with 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 13.7 mmol) and 1,3-dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 0Â° C. and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) was added slowly. The tube was capped and the reaction mixture was stirred at room temperature for 30 minutes. This was recooled to 0Â° C. and N,N,N,N-tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) was added in one portion; this mixture was stirred at room temperature for 4 hours. The tube was placed in a 150Â° C. oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL), then washed with 1M aqueous HCl. The aqueous layer was extracted with ethyl acetate (3Ã—100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL), dried with MgSO₄, filtered, then concentrated to give a yellow oil. This was purified by column chromatography, eluting with 1-4% MeOH/DCM to give 5-bromo-2-methylisoindolin-1-one (1.774 g, 57.3% yield) as a yellow solid.

3) 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

[Image Omitted]

Prepared in a similar manner as 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one.

4) tert-butyl (6-(2-methyl-1-oxoisoindolin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

[Image Omitted]

Prepared in a similar manner as tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.

5) 5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylisoindolin-1-one

[Image Omitted]

Prepared in a similar manner as 1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one.

6) 5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylisoindolin-1-one

Prepared in a similar manner as 1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one.

MS (ESI pos. ion) m/z: 453 (MH+). Calc'd exact mass for C₂₄H₂₀N₈O₂: 452.

[Image Omitted]

Example 53N-((6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine1) tert-butyl (6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

[Image Omitted]

Prepared in a similar manner as tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.

2) (6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine hydrochloride

[Image Omitted]

Prepared in a similar manner as 1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one.

3) N-((6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

Prepared in a similar manner as 1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one.

MS (ESI pos. ion) m/z: 416 (MH+). Calc'd exact mass for C₂₁H₂₁N₉O₂: 415.

[Image Omitted]

Example 54N-((6-(1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

A 48 mL sealed tube was charged with N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.150 g, 0.439 mmol), 1H-pyrazol-4-ylboronic acid (0.0737 g, 0.658 mmol), and DMF (3.00 ml, 38.6 mmol). A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38 6 mmol) was added, followed by PdCl2(dppf)-CH₂Cl₂Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, then placed in a 90Â° C. oil bath for 5 hours. The mixture was concentrated and the black solid was triturated with water to remove K₂CO₃, then purified by column chromatography using a 0 g RediSep column, eluting with 30-70% (90:10:1 DCM:MeOH:NH₄OH solution) in DCM over 40 minutes. Pure fractions were collected to give N-((6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine as a white solid.

MS (ESI pos. ion) m/z: 374 (MH+). Calc'd exact mass for C₁₈H₁₅N₉O: 373.

[Image Omitted]

Example 557-methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)-1,5-naphthyridin-4-amine1) 3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine

[Image Omitted]

A 16 mm test tube was charged with (6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanol (0.500 g, 2.20 mmol), Reactant 2 (0.951 ml, 4.40 mmol), DBU (0.663 ml, 4.40 mmol), and toluene (8.16 ml, 77 0 mmol), flushed with argon, sealed, then stirred at room temperature for 3 hours. The dark maroon mixture was concentrated and the resulting dark purple/black oil was purified by column chromatography using a gradient of 3-5% MeOH/DCM over 20 minutes. 3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine was isolated as a brown solid.

2) (6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanamine

[Image Omitted]

A 50 mL RB flask was charged with 3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine (0.3492 g, 1.38 mmol) and THF (14.0 ml, 171 mmol), resulting in a dark brown solution. Triphenylphosphine (0.545 g, 2.08 mmol) and water (0.0998 ml, 5.54 mmol) were added, and the flask was placed in a 65Â° C. oil bath for 2 hours. The reaction mixture was concentrated to give a thick brown oil, which was purified by column chromatography using an 80 g ISCO column, eluting with a gradient of 5% MeOH (containing NH₄OH)/DCM to 10% MeOH (containing NH₄OH)/DCM over 40 minutes. (6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanamine was isolated as a yellow solid.

3) 7-methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)-1,5-naphthyridin-4-amine

Prepared in a similar manner as 1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one.

MS (ESI pos. ion) m/z: 385 (MH+). Calc'd exact mass for C₂₀H₁₆N₈O: 384.

[Image Omitted]

Example 56(6-Phenylimidazo[1,2-b]pyridazin-3-yl)methanol

To a mixture of (6-chloroimidazo[1,2-b]pyridazin-3-yl)methanol (see Galtier, C. et al, Antiviral Chemistry & Chemotherapy, 2003, 14, 177-182) (0.200 g, 1.09 mmol), phenylboronic acid (0.133 g, 1.09 mmol), PdCl₂(dppf)-CH₂Cl₂(0.0445 g, 0.0545 mmol) in dioxane was added sat NaHCO₃(1.20 ml, >2.40 mmol). The mixture was blanketed with N₂, the vessel sealed and heated at 80 C for 1 h. The mixture was allowed to cool to rt and diluted with EtOAc. The organic phase was washed with water, then sat. NaHCO₃, dried over Na₂SO₄, filtered and evaporated. The mixture was purified via flash chromatography using a gradient of 0% to 10% MeOH in EtOAc. The title compound was collected as a white solid.

The following compounds were prepared according to the method described for (6-phenylimidazo[1,2-b]pyridazin-3-yl)methanol:

(6-(3-Fluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol
(6-(3,4-Difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol
(6-(3,4,5-Trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol

7-Methoxy-4-((6-phenylimidazo[1,2-b]pyridazin-3-yl)methoxy)quinoline. In a microwave vessel, (6-phenylimidazo[1,2-b]pyridazin-3-yl)methanol (0.075 g, 0.33 mmol), 4-chloro-7-methoxyquinoline (0.19 g, 1.00 mmol), Cs₂CO₃(0.22 g, 0.67 mmol) and 0.7 mL DMSO were combined and the vessel sealed. The mixture was pre-stirred for 2 min, followed by microwave heating for 2 h at 120 C, then 1 h at 130 C. The mixture was allowed to cool to rt, diluted with water to precipitate a cream solid. The solid was collected and rinsed with water. The solid was purified via flash chromatography using a 0% to 5% MeOH in EtOAc gradient to afford the title compound as a yellow solid. M/Z=383.2 [M+H], calc 382.4212 for C₂₃H₁₈N₄O₂.

The following compounds were prepared using the method described for 7-methoxy-4-((6-phenylimidazo[1,2-b]pyridazin-3-yl)methoxy)quinoline:

[Image Omitted]

Example 57

4-((6-(3-Fluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline. M/Z=401.2 [M+H], calc 400.4113 for C₂₃H₁₇FN₄O₂.

[Image Omitted]

Example 584-((6-(3,4-Difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

M/Z=419.2 [M+H], calc 418.4014 for C₂₃H₁₆F₂N₄O₂.

[Image Omitted]

Example 59

7-Methoxy-4-((6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline. In a 50 mL sealable flask was charged with PdCl₂(dppf)-CH₂Cl₂adduct (0.011 g, 0.013 mmol), 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.44 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.18 g, 0.48 mmol), sat NaHCO₃(0.75 ml, >0.97 mmol) and 4 mL dioxane. The vessel was sealed and the mixture heated at 80 C for 22 h. The mixture was allowed to cool to rt and diluted with EtOAc, the organic layer washed with water, sat. NaHCO3, dried over Na₂SO₄, filtered and evaporated. The residue was dissolved in 5 mL CH₂Cl₂and TFA (1.20 ml, 16 mmol) was added. The mixture was stirred at rt for 10 min and evaporated. The residue was taken up into CH₂Cl₂and stirred with minimal 2N NaOH for 1 h (ph basic). The mixture was evaporated and purified by prep hplc. The title compound was obtained as an off-white solid. M/Z=457.3 [M+H], calc 456.5076 for C₂₄H₂₄N₈O₂.

[Image Omitted]

Example 603-Fluoro-7-methoxy-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

A sealable tube was charged with Pd₂dba₃(0.20 g, 0.22 mmol), racemic-2-(di-t-butylphosphino)-1,1â€²-binaphthyl (0.18 g, 0.44 mmol), (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (0.100 g, 0.44 mmol), 4-chloro-3-fluoro-7-methoxyquinoline (0.14 g, 0.66 mmol), cesium carbonate (0.29 g, 0.88 mmol), and toluene and sealed. The mixture was heated at 100 C for 12 h. The mixture was allowed to cool to rt and the solid filtered, and rinsed with toluene. The solid was stirred with a mixture of EA, MeOH, CH₂Cl₂and filtered. The filtrate was purified via flash chromatography using a MeOH in CH₂Cl₂gradient. The resulting solid was triturated with CH₂Cl₂/Hexanes then purified by prep hplc. The title compound was collected as a white solid. M/Z=402.1 [M+H], calc 401.3994 for C₂₂H₁₆FN₅O₂.

[Image Omitted]

Example 61

N2-Phenyl-N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyrimidine-2,4-diamine hydrochloride. 2-Chloro-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyrimidin-4-amine (0.036 g, 0.11 mmol) was combined with 500 mL aniline and heated at 70 C for 2 h, at which point 300 mL aniline more was added and stirred an additional 30 minutes. The mixture was allowed to cool to rt. Ether (5 mL) was added and the mixture stirred. The title compound was collected as a white solid. M/Z=395.2 [M+H], calc 394.4402 for C₂₂H₁₈N₈.

[Image Omitted]

Example 627-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

a) (6-(3,4,5-Trifluorophenyl)imidazo[1,2-h]pyridazin-3-yl)methanamine. To a suspension of (6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol (0.442 g, 1.6 mmol) in CH₂Cl₂(5 mL) was added Mesyl-Cl (0.37 ml, 4.7 mmol) and triethylamine (0.66 ml, 4.7 mmol)-slight exotherm, place flask in water bath- and the mixture stirred at rt 1 h. The mixture was concentrated in vacuo (without heating the flask) and the residue dissolved in DMF (2 mL) and azidosodium (0.23 g, 3.5 mmol) was added in one portion. After 45 minutes, additional azidosodium (0.40 g, 6.0 mmol) was added and the mixture stirred 1 h longer. The mixture was diluted with EtOAc, washed with water, brine, (back extract aq layer) and dry organic layer over Na₂SO₄, filter and evaporate. The azide intermediate was dissolved in THF (4 mL) and trimethylphosphine 1M in THF (2.4 ml, 2.4 mmol) was added. The reaction mixture was stir at rt until the bubbling stops, plus an additional 2 minutes, then water (1 mL) was added. The mixture was diluted with EtOAc, washed with NaHCO₃solution, sat. NaHCO3, (back extract aq layer), then dry organic layer over Na₂SO₄, filter and evaporate. The residue was purified via flash chromatography using a1% NH₄OH in MeOH in CH₂Cl₂gradient to afford the title compound as a tan solid.

b) 7-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-h]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine. The title compound was prepared according to Method D, with the addition of 1 equivalent TFA. M/Z=437.1 [M+H], calc 436.3955 for C₂₂H₁₅F₃N₆O.

2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. In a sealable tube was combined Pd₂dba₃(0.0270 g, 0.0295 mmol), 2-(dicyclohexylphosphino)-2â€², 4â€², 6â€²-tri-1-propyl-1,1â€²-biphenyl (0.0563 g, 0.118 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.450 g, 1.77 mmol), 5-bromo-2-methylisoindolin-1-one (see Tsuritani, T., et al Synlett 2006, 5 801-803) (0.267 g, 1.18 mmol), potassium acetate (0.232 g, 2.36 mmol) and 2 mL dioxane. The mixture was blanketed with N₂, sealed and heated at 80 C for 22 h. The mixture was allowed to cool to rt then diluted with EtOAc, and the organic layer washed with water, sat. NaHCO₃, then dried over Na₂SO₄, filtered and evaporated. The residue was purified via flash chromatography using a EtOAc in CH₂Cl₂gradient. The title compound was collected as a tan solid.

tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-O-1H-pyrazol-1-yl)piperidine-1-carboxylate. The title compound was prepared according procedures known in the art.

1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. A 150 mL sealable tube was charged with Pd₂dba₃(0.216 g, 0.235 mmol), 2-(dicyclohexylphosphino)-2â€², 4â€², 6â€²-tri-1-propyl-1,1â€²-biphenyl (0.224 g, 0.471 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.47 g, 29 4 mmol), 4-bromo-1-ethyl-1H-pyrazole (see Ivachtchenko, A. V., et al J. Het. Chem. 2004, 41, 931-939) (4.12 g, 23.5 mmol), potassium acetate (4.62 g, 47.1 mmol) and dioxane (10 mL). The mixture was blanketed with N₂, the vessel sealed and heated at 85 C for 22 h. Allow the mixture to cool to rt and dilute with EtOAc, wash with water, sat. NaHCO₃, then dry organic layer over Na₂SO₄, filter and evaporate. The mixture was purified via flash chromatography using an EtOAc in CH₂Cl₂gradient. Use I₂stain to develop tlc (compound not uv active at 254). The title compound was collected as a mixture with pinacol diborane.

1-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, using 1-(2-methoxyethyl)-4-bromo-1H-pyrazole (see Ivachtchenko, A. V., et al J. Het. Chem. 2004, 41, 931-939).

[Image Omitted]

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole. Prepared from 6-bromobenzo[d]thiazole according to the above procedures.

1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

a) 4-Bromo-1-cyclobutyl-1H-pyrazole. To a cooled (0 C) stirred solution of 4-bromo-1H-pyrazole (5.360 g, 36.47 mmol) in DMF (50 mL) was added sodium hydride (1.925 g, 80.23 mmol) slowly. The mixture was allowed to stir in the ice bath 30 min and bromocyclobutane (3.433 ml, 36.47 mmol) was added. The vessel was sealed and the reaction mixture heated at 95 C for 23 h. The mixture was allowed to cool to rt and diluted with 200 mL EtOAc, washed with 500 mL water, then 2Ã—100 mL water, sat NaHCO₃, then the organic layer dried over Na₂SO₄, filtered and evaporated. The mixture was purified via flash chromatography using a CH₂Cl₂in hexanes gradient. (12 stain for visualization). The title compound was collected as a colorless liquid.

b) 1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1â€²-pyrazole. The title compound was prepared in the same manner as described for 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

a) 4-bromo-1-isopropyl-1H-pyrazole. A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo-1H-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt. The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na₂SO₄, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The desired compound (as determined by TLC, 12 stain) was collected as a colorless liquid.

b) 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1â€²-pyrazole. The title compound was prepared in the same manner as described for 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[Image Omitted]

Example 63

Intermediate 4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline was prepared as described in general Method A.

5-(3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one

4-((6-(6-Fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.121 g, 0.30 mmol) was suspended in dioxane (1 mL) then added 3M aqueous hydrochloric acid (2.0 ml, 6.0 mmol). The reaction mixture was then heated at 100Â° C. for 1 hour. The mixture was concentrated under vacuum and the remaining solid was dissolved in methanol (4 mL) then added triethylamine (0.42 ml, 3.0 mmol). The mixture was stirred at room temperature for 1 hour then concentrated under vacuum. The sample was purified by flash chromatography eluting with 15% 7N NH₃in methanol/dichloromethane to afford 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one as a pale orange solid.

[Image Omitted]

Example 64

4-(3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one was prepared as previously described for 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one.

[Image Omitted]

Example 65Synthesis of the Hydrazine Intermediate

[Image Omitted]

Step 1. 3,6-Dichloro-4-methylpyridazine (1.00 g, 6.1 mmol) was mostly dissolved in dioxane (22.5 mL) then added phenylboronic acid (0.82 g, 6 7 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.25 g, 0.31 mmol) and a solution of cesium carbonate (6.0 g, 18 mmol) in water (7.5 mL). The reaction mixture was heated at 80Â° C. for 6 hours. The reaction mixture was concentrated under vacuum and the remaining solid was triturated with water. The solid was collected on a glass frit, washing well with water. The sample was purified by flash chromatography eluting with 1:4 ethyl acetate/hexane to afford 3-chloro-4-methyl-6-phenylpyridazine as an off-white solid.

MS (ESI pos. ion) m/z: 205.2 (MH⁺).

Step 2. 3-Chloro-4-methyl-6-phenylpyridazine (0.510 g, 2.49 mmol) was dissolved in hydrazine (1.56 ml, 49.8 mmol) then the reaction mixture was heated at 100Â° C. for 1.5 hours. The precipitate that had formed in the mixture was collected and washed with ⁱPrOH. The solid was dried under high vacuum to afford 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine as a pale yellow solid.

MS (ESI pos. ion) m/z: 201.1 (MH⁺).

The remaining synthesis of 7-methoxy-N-((8-methyl-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine was conducted as described in general Method B.

Synthesis of the 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one Intermediate

[Image Omitted]

Step 1. 5-Bromopyridin-2(1H)-one (0.250 g, 1.44 mmol) was dissolved in DMF (3 mL) then added iodomethane (0.0943 ml, 1.51 Î¼mol) and potassium carbonate (0.218 g, 1.58 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The remaining residue was dissolved in ethyl acetate then washed with water and brine. The aqueous layer was back-extracted with ethyl acetate (3Ã—). The organic layers were combined and dried over sodium sulfate then concentrated under vacuum to afford 5-bromo-1-methylpyridin-2(1H)-one as an orange waxy solid.

MS (ESI pos. ion) m/z: 188.0 and 190.0 (MH⁺).

Step 2. 5-Bromo-1-methylpyridin-2(1H)-one (0.100 g, 0.532 mmol) was suspended in dioxane (2 mL) then added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.203 g, 0.798 mmol), PdCl2(dppf)-CH₂Cl₂Adduct (0.0217 g, 0.0266 mmol) and sodium acetate (0.109 g, 1.33 mmol). The reaction mixture was heated at 120Â° C. for 5.5 hours then at 130Â° C. for 3 hours. The reaction mixture was filtered through a pad of Celite, washing with MeOH. The filtrate was concentrated under vacuum. The remaining black residue was then dissolved in dichloromethane and filtered through another pad of Celite, washing well with dichloromethane. The filtrate was concentrated under vacuum and the remaining black residue was further dried under high vacuum to afford 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one as a black solid.

MS (ESI pos. ion) m/z: 236.1 (MH⁺).

[Image Omitted]

Example 66

Intermediate 3-(4-methoxybenzyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyridine was prepared as described in general Method A.

4-((6-phenyl-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methyl)phenol

3-(4-Methoxybenzyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyridine (0.057 g, 0.18 mmol) was dissolved in dichloromethane (2.5 mL) then cooled to 0Â° C. A 1M solution of boron tribromide (0.72 ml, 0.72 mmol) in dichloromethane was added slowly. The reaction mixture was stirred at 0Â° C. for 2 hours. A precipitate was present in the reaction mixture. The reaction was quenched with ice chips and stirred overnight at room temperature. A solid remained in the mixture. The reaction mixture was diluted with dichloromethane/methanol to give a clear mixture then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The sample was purified by preparative TLC eluting with 7% methanol in dichloromethane which afforded 4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol as an off-white solid

[Image Omitted]

Example 67

4-((6-(Pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol was prepared as previously described for 4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol.

[Image Omitted]

Example 68

4-((6-(Pyrazin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol was prepared as previously described for 4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol.

[Image Omitted]

Example 69

4-((6-(1H-Pyrrol-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol was prepared as previously described for 4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol.

6-bromoquinoxaline

To a solution of 4-bromobenzene-1,2-diamine (4.0 g, 21 mmol) in 60 mL of EtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) solution in water. The resulting mixture was refluxed for 10 hours. The mixture was concentrated in vacuo and the residue was diluted in 100 mL of EtOAc. The organic solution was washed with 40 mL of satd. NaHCO₃and 40 mL of brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) to give light yellow solid 6-bromoquinoxaline. MS (ESI, pos. ion) m/z: 208.9 (M+1).

tert-butyl 2-(quinoxalin-6-yl)acetate

To a solution of 6-bromoquinoxaline (1.40 g, 7 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.6 g, 0.7 mmol) and Q-phos (1.0 g) in 25 mL of THF was added Reactant 2 (27 ml, 27 mmol) three time in 3 hours. The reaction was heated at 50 oC for 16 hours and was quenched with 50 mL of satd. NH4Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give red oil. The residue was purified by a silica gel column chromatography (5% EtOAc/hex to EtOAC) twice to give red solid tert-butyl 2-(quinoxalin-6-yl)acetate. MS (ESI, pos. ion) m/z: 245.1 (M+1).

6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxaline

A mixture of tert-butyl 2-(quinoxalin-6-yl)acetate (0.15 g, 0 6 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0.7 mmol) and p-toluenesulfonic acid monohydrate (0.1 g, 0 6 mmol) in 3 mL of dioxane was heated with microwave at 150Â° C. for 1 hour in a microwave tube. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow solid as desired product 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxaline.

6-bromoquinazolin-4(3H)-one

A solution of 5-bromoisatoic anhydride (5.0 g, 21 mmol) and formamidinium acetate (2.2 g, 21 mmol) in 60 mL of i-PrOH was heated at reflux for 10 hours. The reaction mixture was cooled to rt and the white solid was collected by filtration. The white solid was washed with small amount of i-PrOH and dried in air to give desired product 6-bromoquinazolin-4(3H)-one. MS (ESI, pos. ion) m/z: 224.9 (M+1).

tert-butyl 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate

To a solution of 6-bromoquinazolin-4(3H)-one (1.00 g, 4 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.4 g, 0.4 mmol) and Q-phos (0.8 g) in 25 mL of THF was added Reactant 2 (27 ml, 13 mmol) three time in 5 hours. The reaction was heated at 50Â° C. for 16 hours and was quenched with 50 mL of satd. NH₄Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give red oil. The residue was purified by a silica gel column chromatography (5% EtOAc/hex to EtOAC) twice to give orange solid tert-butyl 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate. MS (ESI, pos. ion) m/z: 261.1 (M+1).

2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetic acid

A solution of tert-butyl 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate (0.25 g, 0.96 mmol) in 10 mL of satd.HCl in EtOAc was stirred at rt for 4 hours. The mixture was concentrated in vacuo at rt, and the residue was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 205.1 (M+1).

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Example 706-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one

A mixture of 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetic acid (0.10 g, 0 5 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0 6 mmol) and p-toluenesulfonic acid monohydrate (0.09 g, 0 5 mmol) in 3 mL of dioxane was heated with microwave at 150Â° C. for 1 hour in a microwave tube. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow solid as desired product 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one. MS (ESI, pos. ion) m/z: 355.1 (M+1).

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Example 716-(1-(6-(3-methylisothiazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5 6 mmol) in 10 mL of THF at âˆ’45Â° C. (CH₃CN/dry ice) was added isopropylmagnesium chloride LiCl complex (7.9 ml, 7.9 mmol) (LiCl complex, 1M in THF). The mixture was stirred at âˆ’45Â° C. for 20 minutes and was added zinc chloride, 0.5m in thf (17 ml, 8.4 mmol) slowly via a syringe. The mixture was then warmed up to rt and continued to stir for additional 30 minutes. 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (0.5787 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.51 g, 0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N,N-dimethyl acetamide was added to the reaction mixture. The reaction was warmed up to 50Â° C. for 6 h and was quenched with 50 mL of satd. NH₄Cl aq. solution. The mixture was extracted with 150 mL of EtOAc and the organic phase was washed with 60 mL of brine. The aqueous phases were extracted with 100 mL EtOAc again. The combined organic phases were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc) to give red solid as desired product 6-(1-(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. MS (ESI, pos. ion) m/z: 373.2 (M+1).

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Methyl 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoate (0.368 g, 0.803 mmol) was diluted with dioxane (17 mL) and to the solution was added lithium hydroxide (0.03 84 g, 1.61 mmol) in water (8 mL). The reaction mixture was heated at 40Â° C. for 4.5 hours. The reaction mixture was concentrated in vacuo to remove most of the dioxane and water (not concentrated to dryness).

To the crude mixture, water (8 mL) was added. Dropwise, 1N HCl was added to pH=7. The neutral solution was then filtered through a frit and the crude solid product was washed with MeCN and a small amount of MeOH. The final acid product was concentrated, and carried on to the acid chloride.

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To a suspension of 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (0.150 g, 0.338 mmol) in DCM (1.5 mL) at 0Â° C. was added dropwise thionyl chloride (0.370 ml, 5.06 mmol). DMF (1 drop) was added and the solution was allowed to stir at room temperature for 5 h. The reaction mixture was concentrated in vacuo to a light brown solid. The material was taken on crude for synthesis of the following amide.

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Example 722-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide

To a solution of N-ethyl-N-isopropylpropan-2-amine (0.077 ml, 0.44 mmol) and 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoyl chloride-HCl (0.088 g, 0.18 mmol) in DCM (1.25 mL) was added 2-methoxyethanamine (0.023 ml, 0.26 mmol) dropwise. The solution was stirred at room temperature for 5 h. The crude material was concentrated and then triturated with sodium bicarbonate and washed with water. The resultant solid was dissolved in DCM/MeOH and concentrated.

The crude material was dissolved in DCM/MeOH and was purified via flash chromatography, eluting with 0-10% MeOH/NH₄OH in DCM to yield 2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide.

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Example 73

tert-butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl(methyl)carbamate (0.067 g, 0.13 mmol) was dissolved in MeOH (1.7 mL) and to the solution was added concentrated HCl (0.50 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight. Upon completion, the crude mixture was concentrated in vacuo.

The solid that remained after concentration was dissolved in MeOH and to the solution was added triethylamine (0.23 ml, 1.6 mmol). The reaction was allowed to stir for 1 h. The crude mixture was concentrated in vacuo.

The compound was purified using via flash chromatography, eluting with 5-8% MeOH/NH₄OH in DCM to yield 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylbenzenamine as a yellow solid.

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Example 74

A solution of 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (0.192 g, 0.43 mmol), HATU (0.26 g, 0.69 mmol), and Hunig'sBase (0.30 ml, 1.7 mmol) in DMF (10.75 mL) was allowed to stir for 30 minutes. Ammonia (0.0093 ml, 0.43 mmol) was then bubbled through the mixture for another 30 minutes.

The solution was concentrated in vacuo and purified using via flash chromatography, eluting with 5-10% MeOH/NH₄OH in DCM. There remained an unidentified peak in the NMR, so the solid was triturated in MeCN, filtered, and quickly washed with DCM to wash through the impurities. Concentration in vacuo yielded 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide as an off-white solid.

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Example 75

To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carbonyl chloride (0.150 g, 0.33 mmol) and Hunig's Base (0.17 ml, 1.00 mmol) in DCM (2.5 mL) was added methanamine (0.17 ml, 0.33 mmol) in THF dropwise. The solution was stirred at room temperature for 3 hours, at which point an additional 1.5 equivalents of amine were added.

The solution was concentrated in vacuo and purified via flash chromatography eluting with 3-8% MeOH:NH₄OH in DCM. There remained an impurity, so the product was triturated with MeCN, filtered and washed with DCM to yield 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylthiophene-2-carboxamide (0.0276 g, 19% yield) as an amorphous tan solid.

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Example 76

6-((6-Phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline. To a 50 ml round-bottomed flask was added 2-(quinolin-6-yl)acetic acid (0.60 g, 3 2 mmol), CH₂Cl₂(20 ml) and oxalyl chloride (4.0 ml, 8.0 Î¼mol, 2 M in CH₂Cl₂) and DMF (0.2 mL of a solution of 1 drop DMF in 1 mL CH₂Cl₂). After 3 d, an additional 2.5 eq. of oxalyl chloride was added. After 4 h, toluene (1 mL) was added and the mixture was concentrated. Toluene (3 mL) was added and again concentrated. The residue was taken up in CH₂Cl₂(20 mL) and 1-(6-phenylpyridazin-3-yl)hydrazine (0.60 g, 3.2 mmol) was added. The mixture was stirred for 17 h and then concentrated. The mixture was then taken up in phosphorous oxychloride (20 ml, 220 mmol) and heated at 100Â° C. for 15 h. Toluene (5 mL) was added and the solution was concentrated. Another 5 mL toluene was added to the residue and once again it was concentrated. The brown solid residue was taken up in sat. NaHCO₃and extracted with EtOAc (4Ã—150 mL) and 25% iPrOH/CHCl₃(3Ã—150 mL). The combined extracts were washed with brine, dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (0 to 5% MeOH (2M in NH₃)/CH₂Cl₂) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 338 (M+1).

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Methyl 2-(quinolin-6-yl)propanoate. To a 250 ml round-bottomed flask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml). The mixture was cooled to âˆ’78Â° C. and methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. This was stirred at âˆ’78Â° C. for 30 min and then methyl iodide (0.75 ml, 12 mmol) was added. This was stirred for 30 min at âˆ’78Â° C. and then allowed to warm to rt. The mixture was quenched with sat NH₄Cl (40 mL) and diluted with water (200 mL). The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2Ã—100 ml). The combined extracts were washed with brine (50 ml), dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a brown oil (1.8 g, 85%). MS (ESI, pos. ion) m/z: 216 (M+1).

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2-(quinolin-6-yl)propanoic acid. To a 15 ml round-bottomed flask was added methyl 2-(quinolin-6-yl)propanoate (1.0 g, 4.7 mmol), methanol (5.0 ml, 12 mmol) and aq. sodium hydroxide (5 M, 2.3 ml, 12 mmol). The mixture was stirred at 25Â° C. for 24 h. The mixture was neutralized with aq. HCl (5 M, 2.3 mL, 12 mmol). After sitting overnight a white precipitate had formed. The mixture was filtered and the filtercake was washed with water and then dried in vacuo to afford the title compound as a white solid (0.72 g, 77%). MS (ESI, pos. ion) m/z: 202 (M+1).

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Example 77

6-(1-(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. To a 2-5 ml Personal Chemistry microwave vial was added 2-(quinolin-6-yl)propanoic acid (0.25 g, 1.2 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.42 g, 2.2 mmol) and conc. HCl (2 mL). The mixture was heated in the microwave at 160Â° C. for 8 h. After cooling to rt, the mixture was poured into sat. NaHCO₃(100 mL) and then extracted with EtOAc (4Ã—75 mL). The combined extracts were washed with brine, dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (1.0 to 4.5% MeOH (2 M in NH₃)/CH₂Cl₂) afforded the title compound as an off-white solid (0.23 g, 53% yield). MS (ESI, pos. ion) m/z: 352 (M+1).

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Example 78

(S)-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. Isolated from chiral separation of 6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. Column: Chiralpak AS-H (250Ã—21 mm) Mobile Phase: A: Liquid CO₂. B: Methanol (0.1% DEA). Isocratic: 75:25 (A:B). Flow rate: 70.0 mL/min. Outlet Pressure: 100 bar. Retention time: 4.38 min. Enantiomeric purity: >99% ee. MS (ESI, pos. ion) m/z: 352 (M+1).

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Example 79

(R)-6-(1-(6-phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (AMG 2121451). Isolated from chiral separation of 6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. Column: Chiralpak AS-H (250Ã—21 mm). Mobile Phase: A: Liquid CO₂. B: Methanol (0.1% DEA). Isocratic: 75:25 (A:B). Flow rate: 70.0 mL/min. Outlet Pressure: 100 bar. Retention time: 4.90 min. Enantiomeric purity: 96.8% ee. MS (ESI, pos. ion) m/z: 352 (M+1).

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Methyl 2-fluoro-2-(quinolin-6-yl)acetate. To a 250 ml round-bottomed flask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml). The mixture was cooled to âˆ’78Â° C. and methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. After stirring at âˆ’78Â° C. for 30 min, n-fluorobenzenesulfonimide (3.8 g, 12 mmol) was added as a 1 M solution in THF. This was stirred for 30 min at âˆ’78Â° C. and then allowed to warm to rt. The mixture was quenched with sat NH₄Cl (50 mL) and diluted with water (200 mL). The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2Ã—100 ml). The combined extracts were washed with brine (100 ml), dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 220 (M+1).

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2-Fluoro-2-(quinolin-6-yl)acetic acid. To a solution containing methyl 2-fluoro-2-(quinolin-6-yl)acetate (0.49 g, 2.2 mmol) in methanol (3.0 ml) was added sodium hydroxide (5 M, 1.0 ml, 5.0 mmol). The mixture was stirred at rt for 48 h and then neutralized with 5 N HCl (1.0 mL). The solution was allowed to sit overnight during which time a precipitate formed. The solution was filtered and the filtercake washed with cold water then dried under vacuum to afford the title compound as a tan solid. MS (ESI, pos. ion) m/z: 206 (M+1).

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Example 80

(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanol TFA salt. To a 2-5 ml Personal Chemistry microwave vial was added 2-fluoro-2-(quinolin-6-yl)acetic acid (0.20 g, 0.98 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.27 g, 1.5 mmol) and conc. hydrochloric acid (2.0 ml, 66 mmol). The mixture was heated at 160Â° C. for 6 h in the microwave. After cooling to rt, the mixture was poured into sat. NaHCO₃(100 mL) and extracted with 25% iPrOH/CHCl₃(4Ã—50 mL). The combined extracts were dried (Na₂SO₄) and concentrated onto silica. Purification by silica gel chromatography (2.0 to 6.5% MeOH (2 M in NH₃)/CH₂Cl₂) followed by further purification by Prep-HPLC (Phenomenex Synergi 4u MAX-RP 80A 150Ã—21.20 mm, 10 to 65% CH₃CN (0.1% TFA)/H₂O (0.1% TFA) over 15 min then 65% CH₃CN for 5 minutes at 20 ml/min) with the fractions containing product concentrated to afford the title compound as a tan solid (0.10 g, 22% yield). MS (ESI, pos. ion) m/z: 354 (M+1).

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Example 81

(R)-(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanol. Isolated from chiral separation of racemic (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanol TFA salt (AMG 2120533). Column: Chirotechnology AS-H column, 4.6 mmÃ—15 cm. Mobile phase: 70/30 Carbon dioxide/0.2% diethylamine in ethanol. Flow rate: 4.0 mL/min. Temperature: 40Â° C. Back pressure: 100 bar. Retention time: 1.65 min. Enantiomeric purity: >99% ee. MS (ESI, pos. ion) m/z: 354 (M+1).

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Example 82

(S)-(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanol. Isolated from chiral separation of racemic (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanol TFA salt (AMG 2120533). Column: Chirotechnology AS-H column, 4.6 mmÃ—15 cm. Mobile phase: 70/30 Carbon dioxide/0.2% diethylamine in ethanol. Flow rate: 4.0 mL/min. Temperature: 40Â° C. Back pressure: 100 bar. Retention time: 2.22 min. Enantiomeric purity: >99% ee. MS (ESI, pos. ion) m/z: 354 (M+1).

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Step 1: 4-amino-3-bromo-2-chloropyridine. 4-amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To this solution was added N-bromosuccinamide (75 g, 426 mmol,) portionwise at room temperature (water bath cooling was provided to control the exothermicity). The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC). Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.

Step 2: 4-amino-3-bromo-2-methoxypyridine. Methanol (350 mL) was charged in a two-neck round bottom flask equipped with a guard tube and septum and cooled to 0Â° C. Sodium metal (23g) was added to it slowly in pieces. After all sodium metal had dissolved, 4-amino-3-bromo-2-chloro pyridine (23 g, 178 mmol) was added and the solution was heated at 180Â° C. in a pressure vessel for 5-6 h. The reaction mixture was then cooled to 0Â° C. and adjusted to pH 8 by addition of conc. HCl. Solvent was removed under reduced pressure and the residue was suspended in ethyl acetate. Undissolved impurities were removed by filtration and the filtrate was concentrated under reduced pressure to obtain pure product.

Step 3: 5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione. A two necked round bottomed flask equipped with a reflux condenser was charged with Meldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL). The reaction mixture was heated 100Â° C. for 2 h. 4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was added and heating was continued for an additional 4 h at 100Â° C. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as a yellow solid.

Step 4: 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one. A two neck round bottomed flask equipped with an air condenser was charged with 5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (23 g, 64 mmol) and diphenyl ether (230 mL). The reaction mixture was heated at 250Â° C. for 30 min under nitrogen atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtained 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one as a brown solid.

Step 5: 7-Methoxy-1H-[1,6]naphthyridin-4-one. 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one (12g, 33 5 mmol) was dissolved in anhydrous methanol (240 mL) and 10% Dry Pd/C (2.4 g) was added carefully in portions. This was followed by portionwise addition of ammonium formate (24 g) which caused an exotherm. The reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with hot methanol. The filtrate was concentrated and the residue purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate-methanol.

Step 6: 4-Chloro-7-methoxy-[1,6]naphthyridine. A two neck round bottomed flask equipped with CaCl₂guard tube was charged with 7-Methoxy-1H-[1,6]naphthyridin-4-one (28 g, 159 mmol) and POCl₃(280 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into ice water and the pH was carefully adjusted to 8 with solid sodium carbonate (highly exothermic reaction). The product was extracted with EtOAc. The combined organic layer was washed with water, dried over Na₂SO₄and concentrated. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.

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Step 1: 3-Bromo-5-methoxypyridine. Sodium (12g) was dissolved in methanol (150 mL) while cooling, and excess MeOH was removed under reduced pressure to obtain NaOMe, which was azeotroped with toluene (2Ã—100 mL). A solution of 3,5-dibromopyridine (100 g) in DMSO (500 mL) was added to sodium methoxide and the mixture was stirred at 90Â° C. for 2 h. After cooling to RT, aqueous NaOH solution (3 M, 300 mL) was added and the mixture was extracted with Et₂O. The ethereal layer was washed with brine and dried over Na₂SO₄. After concentration the crude product obtained was purified by flash column chromatography (Hexane:EtOAc 85:15) to afford pure product 3-bromo-5-methoxy pyidine.

Step 2: 3-amino-5-methoxypyridine. 3-Bromo-5-methoxypyridine (15g) was added to a pressure vessel, and CuSO₄(3.9 g) and 25% aq. ammonia (150 mL) were added. The reaction mixture was stirred for 4 h at 135Â° C., then cooled to RT, basified with aqueous NaOH solution, and extracted with CH₂Cl₂. After evaporation of volatiles, 3-amino-5-methoxypyridine was obtained as yellow solid.

Step 3: 5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione. A two-necked round bottomed flask equipped with a reflux condenser was charged with Meldrum's acid (14.4 g, 100 mmol) and trimethylorthoformate (100 mL). The reaction mixture was heated at 100-105Â° C. for 2 h. 5-amino-3-methoxy pyridine (12.5 g, 100 mmol) was added to the reaction mixture and heating was continued for an additional 4 h at the same temperature. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as light yellow solid.

Step 4: -Methoxy-1H-[1,5]naphthyridin-4-one. A two-necked round bottomed flask equipped with an air condenser was charged with 5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (18g) and diphenyl ether (180 mL). The reaction mixture was heated at 240-250Â° C. for 5 min under N₂atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtain product as a brown solid.

Step 5: 8-chloro-3-methoxy-1,5-naphthyridine. A two-necked round bottomed flask equipped with an air condenser (protected with CaCl₂guard tube) was charged with 7-Methoxy-1H-[1,5]naphthyridin-4-one (13g) and POCl₃(65 mL). The reaction mixture was allowed to reflux at 120Â° C. for 12 h. The POCl₃was removed in vacuo and azeotroped twice with toluene. EtOAc (75 mL) was added and the reaction mixture was stirred at 50-60Â° C. for 15-20 min. EtOAc removed separated by decantation. The organic layers were combined and concentrated. The obtained crude was dissolved in EtOAc (50 ml) and a washed with satd. aqueous sodium bicarbonate. The organic layer was dried over Na₂SO₄and concentrated. The resulting solids were suspended in hexane, stirred for 15 min, filtered and dried under vacuum.

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Example 837-(difluoromethoxy)-N-((6-phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

DMF (0.5 mL) and water (0.1 mL) were added to a pressure vessel containing 8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol (50 mg, 135 Î¼mol), sodium 2-chloro-2,2-difluoroacetate (47 mg, 311 Î¼mol), cesium carbonate (62 mg, 190 Î¼mol). The reaction mixture was stirred at 100Â° C. for 18 h, cooled to RT and concentrated in vacuo. Purification by MPLC (DCM/MeOH+1% NH₄OH: 100/0 to 90/10) afforded the title compound (10 mg, 17% yield). MS m/z=420.1 [M+H]⁺. Calc'd for C21H15F2N₇O: 419.40.

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Example 84N-((6-(3H-1,2,3-triazol-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine1) Preparation of tert-butyl (6-(3H-1,2,3-triazol-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

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tert-Butyl (6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.109 g, 0.399 mmol) and sodium azide (0.0285 g, 0.439 mmol) were dissolved DMF (2 mL) at RT. The reaction mixture was stirred overnight at RT then at 70Â° C. for 3 h. Water was added at RT and the aqueous layer was extracted with EtOAc and 1-butanol. The organic extracts were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. Used without further purification.

2) Preparation of N-((6-(3H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

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Prepared by a method similar to 7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine MS m/z=375.1

[M+H]⁺. Calc'd for C17H14N₁₀O: 374.37

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Example 854-((8-fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

Dioxane (3.6 mL) was added to 4-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (175 mg, 488 Î¼mol), X-Phos (32.6 mg, 68.3 Î¼mol), 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 Î¼mol), palladium acetate (7.67 mg, 34.1 Î¼mol). The flask was purged with argon and sealed. The reaction mixture was stirred at 80Â° C. for 2d. More X-Phos (32.6 mg, 68.3 Î¼mol), palladium acetate (7.67 mg, 34.1 Î¼mol) and 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 Î¼mol) were added and stirring was continued at 80Â° C. overnight. The reaction mixture was cooled at RT, concentrated in vacuo and urified by MPLC (CH₂Cl₂/MeOH: 100/0 to 90/10). Further purification by MPLC (ISCO, EtOAc/MeOH:9/1, isocratic) afforded the title compound (105 mg, 51% yield). MS m/z=422.0 [M+H]⁺. Calc'd for C₂₁H₁₆FN₅O₂S: 421.46

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Example 864-((8-fluoro-6-(2-methylthiazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline1) Preparation of 2-methyl-5-(trimethylstannyl)thiazole

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Butyllithium (1.6M in THF, 3.5 ml, 5.5 mmol) was added to a stirred solution of 2-methylthiazole (0.45 ml, 5.0 mmol) in THF (15 mL) at âˆ’78Â° C. The reaction mixture was stirred at âˆ’78Â° C. for 40 min. Chlorotrimethylstannane (1M in THF, 5.0 ml, 5.0 mmol) was added. Stirring was continued at âˆ’78Â° C. for 45 min. The reaction mixture was quenched with a satured aqueous solution of NaHCO₃. The aqueous layer was extracted with Et₂O. The organic extracts were dried over MgSO₄, filtered and concentrated in vacuo. Used in the next step without purification (obtained 1.29 g). MS m/z=264.1. Calc'd for C₇H13NSSn: 261.94.

2) Preparation of 4-((8-fluoro-6-(2-methylthiazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

Prepared by a method similar to 4-((8-fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline. MS m/z=422.1 [M+H]⁺. Calc'd for C21H16FN5O2S: 421.46

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Example 87N,N-dimethyl-3-(4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-3-yl)prop-2-yn-1-amine1) Preparation of 3-((3-iodopyridin-4-yloxy)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine

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Cesium carbonate (354 mg, 1087 mmol) was added to a mixture of (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (123 mg, 544 Î¼mol) (named 77289-19-99) and (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (123 mg, 544 Î¼mol) in DMSO (1.8 mL). The reaction mixture was stirred at 120Â° C. for 2 h under micro-waves irradiation. The reaction mixture was diluted with EtOAc. The organic layer was washed with water. The water layer extracted with EtOAc. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. Purification by MPLC afforded the title compound (161 mg, 69% yield).

2) Preparation of N,N-dimethyl-3-(4-((6-phenyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-3-yl)prop-2-yn-1-amine

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Tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.5 Î¼mol) was added to a suspension of 3-((3-iodopyridin-4-yloxy)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (107 mg, 249 Î¼mol) and 1-dimethylamino-2-propyne (80.4 Î¼l, 748 mmol) in THF (0.6 mL) and triethylamine (591 Î¼l, 4238 Î¼mol) at RT. Copper(i) iodide, 99.999% (4.75 mg, 24.9 Î¼mol) was added and the reaction mixture was stirred at 75Â° C. (oil bath) for Ëœ75 min. The reaction mixture was cooled at RT, concentrated in vacuo. Purification by MPLC (ISCO, CH₂Cl₂/MeOH: 100/0 to 90/10) afforded the title compound. MS m/z=385.1 [M+H]⁺. Calc'd for C22H20N₆O: 384.44

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Example 88

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Preparation of 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-a]pyridine-6-carbonitrile

4-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline was prepared as previously described in general Method A.

4-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.050 g, 0.13 mmol) was dissolved in DMF (1 mL) then added zinc cyanide (0.023 g, 0.19 mmol), 1,1â€²-bis(diphenylphosphino)ferrocene (0.0072 g, 0.013 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.0059 g, 0.0065 mmol). The reaction mixture was heated at 100Â° C. for 8 hours. Additional zinc cyanide (0.012 g, 0.095 mmol), 1,1â€²-bis(diphenylphosphino)ferrocene (0.004 g, 0.0065 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.003 g, 0.0032 mmol) were added and heating was continued at 100Â° C. for 6 hours. The reaction mixture was concentrated under vacuum. The sample was purified by preparative TLC eluting with 10% 7N ammonia in methanol/dichloromethane to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (23 mg, 53% yield) as a white solid.

MS (ESI pos. ion) m/z: 332.1 (MH⁺).

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Example 89

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Preparation of 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-a]pyridine-6-carboxamide

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile was prepared as previously described.

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.5 mL). The reaction mixture was heated at 50Â° C. for 30 minutes. The reaction mixture was slowly poured in to cold saturated aqueous sodium bicarbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was transferred with dichloromethane/methanol to a flask and dried under high vacuum to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.050 g, 95% yield) as a tan solid.

MS (ESI pos. ion) m/z: 350.2 (MH⁺).

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Example 90

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Preparation of 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-a]pyridine-6-carboxylic acid

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile was prepared as previously described.

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.375 mL) and water (0.125 mL). The reaction mixture was heated at 100Â° C. for 3.5 hours then slowly poured in to ice. The mixture was adjusted to approx. pH 7 with saturated aqueous sodium carbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was dried under high vacuum to afford 347-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.047 g, 89% yield) as a tan solid.

MS (ESI pos. ion) m/z: 351.1 (MH⁺).

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Preparation of N-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-a]pyridine-6-carboxamide. 3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.047 g, 0.13 mmol), cyclopropanamine (0.011 ml, 0.16 mmol), 1-hydroxy-7-azabenzotriazole (0.018 g, 0.13 mmol), and N-ethyl-Nâ€²-(3-dimethylaminopropyl)carbodiimide hydrochloride, (0.039 g, 0.20 mmol) were added to a reaction flask then suspended in DMF (1 mL). N-Ethyldiisopropylamine (0.070 ml, 0.40 mmol) was added to the reaction mixture. The clear reaction mixture was stirred at 20Â° C. overnight. The reaction mixture was concentrated under vacuum then triturated with water. The solid was collected on a glass frit, washing with water. The sample was purified by preparative TLC eluting with 8% 7N ammonia in methanol/dichloromethane to afford N-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.023 g, 44% yield) as a tan solid.

MS (ESI pos. ion) m/z: 390.2 (MH⁺).

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Example 91

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Preparation of 7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline

tert-Butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate was prepared as described in general Method A.

tert-Butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.113 g, 0.23 mmol) was dissolved in methanol (3 mL) then added concentrated hydrochloric acid (0.500 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The remaining solid was suspended in methanol (1 mL) then added triethylamine (0.40 ml, 2.9 mmol). The clear solution was stirred at room temperature for 2 hours then concentrated under vacuum. The sample was purified by flash chromatography eluting with 8% 7N ammonia in methanol/dichloromethane to afford 7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (0.038 g, 42% yield) as a tan solid.

MS (ESI pos. ion) m/z: 388.1 (MH⁺).

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Example 92

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Preparation of (S)-3-((7-methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide

(S)-tert-Butyl 3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)pyrrolidine-1-carboxylate was prepared as previously described for N-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

(S)-tert-Butyl 3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)pyrrolidine-1-carboxylate (0.050 g, 0.096 mmol) was dissolved in methanol (1.5 mL) then added concentrated hydrochloric acid (0.400 ml, 4.8 mmol). The reaction mixture was stirred at room temperature for 5 hours then concentrated under vacuum. The remaining solid was dissolved in methanol (1 mL) then added potassium carbonate (0.062 g, 0.45 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The sample was purified by flash chromatography eluting with 10%-15% 7N ammonia in methanol/dichloromethane to afford (S)-3-((7-methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.039 g, 97% yield) as a pale yellow solid.

MS (ESI pos. ion) m/z: 419.2 (MH⁺).

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Example 93

(R)-3-((7-Methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide was prepared as previously described for (S)-3-((7-methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

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Example 94

N-Ethyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide was prepared as previously described for N-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

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Example 95

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Preparation of tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid was prepared as previously described.

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.072 g, 0.21 mmol) was dissolved in DMF (1.5 mL) then added N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.054 ml, 0.31 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.12 g, 0.31 mmol) and triethylamine (0.043 ml, 0.31 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The sample was purified by flash chromatography eluting with 6% 7N ammonia in methanol/dichloromethane to afford tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate (0.097 g, 93% yield) as a pale yellow solid.

MS (ESI pos. ion) m/z: 507.3 (MH⁺).

Preparation of 3-((7-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide

tert-Butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate was deprotected as previously described for 7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline.

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Example 96

3-((7-Methoxyquinolin-4-yloxy)methyl)-N-phenyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide was prepared as described for 3-((7-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

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Example 97

N-(4-Fluorophenyl)-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide was prepared as described for 3-((7-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

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Example 98

N-(3-Fluorophenyl)-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide was prepared as described for 347-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

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(4-bromo-2-chlorophenyl)methanamine. To a solution of 4-bromo-2-chlorobenzonitrile (2500 mg, 11549 Î¼mol) in THF (20 mL) at 0Â° C. was added borane-methyl sulfide complex, 2.0 m sol in THF (28873 Î¼l, 57747 Î¼mol). Ice bath removed and reaction stirred overnight warming to 23Â° C. Reaction cooled to 0Â° C. and quenched with MeOH (15 mL). Reaction then partitioned between CHCl₃(100 mL) and 1M NaOH (100 mL). Organic dried with brine and MgSO₄. Organic then concentrated to an oil under reduced pressure and purified on silica (80 g) eluting with 0>6% 2M NH₃in MeOH/DCM and product isolated as a colorless oil. MS (ESI pos. ion) m/z: 220/222 (MH+). Calc'd exact mass for C₇H₇BrClN: 219/221

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tert-butyl 4-bromo-2-chlorobenzylcarbamate. To a stirring solution of (4-bromo-2-chlorophenyl)methanamine (2200 mg, 9978 Î¼mol) in DCM (10 mL) was added BOC-Anhydride (9978 Î¼l, 9978 Î¼mol) [1M in THF] and stirred for 1 h at 23Â° C. after which ethylenediamine (1 mL) added. Solvents removed under reduce pressure and residue purified on 80 g silica eluting product with 0>50% Hex/EtOAc.

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tert-butyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate. A suspension of tert-butyl 4-bromo-2-chlorobenzylcarbamate (1670 mg, 5209 mmol), bis(pinacolato)diboron (1455 mg, 5730 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (190.6 mg, 260.4 Î¼mol), and potassium acetate (1022 mg, 10418 Î¼mol) in dioxane (8 mL) was sparged with argon for 5 min then heated to 120Â° C. in an appropiately sealed vial with stirring. After 1 h, reaction partitioned between DCM (50 mL) and 5% NaHCO3 (25 mL). Organic dried over MgSO4, concentrated, then purified on 80 g silica eluting with 0>40% EtOAc/hexanes and product isolated as a viscous amber oil.

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(4-bromo-2-chlorophenyl)methanol. To a stirring solution of 4-bromo-2-chlorobenzoic acid (11.1 g, 47 mmol) in THF (100 mL) at 0Â° C. under nitrogen was added borane-methyl sulfide complex (9.4 ml, 94 mmol) via syringe over 10 min. Gas evolution quite evident. Ice bath removed, and once gas evolution subsided reaction gently heated to reflux for 1 h. Reaction slowly quenched with MeOH (50 mL) and 2M HCl (20 mL). Aqueous extracted with 9:1 CHCl₃/IPA (150 mL). Organic dried with sat NH₄Cl, MgSO₄, then concentrated to a colorless oil under reduced pressure. Product crystallized after 1 week sitting neat.

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(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-0)phenyl). A suspension of (4-bromo-2-chlorophenyl)methanol (1000 mg, 4515 Î¼mol), bis(pinacolato)diboron (1261 mg, 4967 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (165.2 mg, 225.8 Î¼mol), and potassium acetate (886.2 mg, 9030 mmol) in dioxane (5 mL) was sparged with argon for 10 min then heated to 120Â° C. with stirring in an appropiately sealed vial. After 1 h, reaction then partioned between DCM (50 mL) and 5% NaHCO₃(20 mL). Organic dried over MgSO₄, concentrated, then purified on 80 g silica eluting with 0>70% EtOAc/Hex. Product isolated as a light amber oil.

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To a stirring solution of 4-bromo-2-chlorobenzoic acid (3.45 g, 15 mmol) and DIEA (7.7 ml, 44 mmol) in DMF (30 mL) was added HATU (6.1 g, 16 mmol) at 23Â° C. under nitrogen. Darkened suspension stirred for 1 h, then added n,o-dimethylhydroxylamine hydrochloride (2.1 g, 22 mmol). Solution stirred overnight at 23Â° C. Reaction then partitioned between 2.5% NaHCO₃(250 mL) and diethyl ether (100 mL). Aqueous further extracted with ether (2Ã—50 mL). Combined ethereal extracts dried over MgSO₄, then concentrated an amber oil under reduced pressure. 4-bromo-2-chloro-N-methoxy-N-methylbenzamide isolated as a light amber oil.

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1-(4-bromo-2-chlorophenyl)ethanone. To a stirring solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (890 mg, 3195 Î¼mol) in THF (10 mL) at âˆ’5Â° C. under nitrogen was slowly added methylmagnesium bromide 3.0 m in diethyl ether (1278 Î¼l, 3834 Î¼mol). After 30 min another 1.3 mL (3.8 Î¼mol; 1.2 eq) of MeMgBr added at 23Â° C. After an additional hour, LCMS suggests 95% conversion. Reaction quenched with sat NH₄Cl (10 mL) and resulting white cake washed repeatedly with diethyl ether. Combined organics washed with water and sat NaCl then pushed through a plug of silica (10 g). 1-(4-bromo-2-chlorophenyl)ethanone isolated as a colorless oil.

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1-(4-bromo-2-chlorophenyl)ethanol. To a stirring solution of 1-(4-bromo-2-chlorophenyl)ethanone (700 mg, 2998 Î¼mol) in THF (20 mL) was added sodium borohydride (340 mg, 8994 Î¼mol) and methanol (5 mL). Reaction suspension stirred overnight at 30Â° C. Reaction then partioned between EtOAc (50 mL) and sat NH₄Cl (25 mL). Aqueous further extracted with EtOAc (2Ã—25 mL). Combined organics dried over MgSO₄, concentrated, then purified on silica (0 g) eluting with 10>40% EtOAc/hexanes. Product isolated as a colorless oil.

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1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol. A suspension of 1-(4-bromo-2-chlorophenyl)ethanol (600 mg, 2548 Î¼mol), bis(pinacolato)diboron (712 mg, 2802 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (93.2 mg, 127 mmol), potassium acetate (319 Î¼l, 5095 Î¼mol) in dioxane (5 mL) was sparged with argon for 5 min then heated to 120Â° C. in an appropiately sealed vial. Reaction then partitioned between EtOAc (25 mL) and 5% NaHCO₃(25 mL). Aqueous further washed with EtOAc (2Ã—20 mL). Combined organics dried with sat NH₄Cl, MgSO₄, concentrated, then purified on silica (80 g) eluting with 10>35% EtOAc/Hex. Product isolated as a colorless oil.

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4-bromo-2-chlorobenzaldehyde. To a stirring solution of (4-bromo-2-chlorophenyl)methanol (4.5 g, 20 mmol) in DCM (50 mL) was added Dess-Martin periodinane (9.3 g) at 23Â° C. Reaction refluxed after addition. After 20 min, TLC (1:4 EtOAc/Hex) suggests full conversion of alcohol. Suspension then washed with 5% NaHCO₃(100 mL plus 15g dry NaHCO₃). Organic dried over MgSO₄, concentrated onto dry silica (15g), then purified on silica (120 g) eluting with 0>10% EtOAc/hex. 4-bromo-2-chlorobenzaldehyde isolated as a white solid.

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1-(4-bromo-2-chlorophenyl)ethanamine. A solution of 1-(4-bromo-2-chlorophenyl)ethanone (2.430 g, 10 mmol), ammonia, 2.0 m solution in methanol (26 ml, 52 mmol) and titanium (iv) isopropoxide (6 ml, 21 mmol) was stirred for 16 h in a sealed vessel. Reaction then added to a freshly made suspension of sodium borohydride powder, 98% (4 g, 104 mmol) in MeOH (20 mL). Exothermic reaction started at 9:45 am, then continued to stir with a 45Â° C. external heating bath for 45 min. Water (10 mL) then added to reaction and stirred for an additional 10 min. Resulting white solid removed via filtration through Celite, and filtrated reduced in volume under reduced pressure. This suspension then partioned between 9:1 CHCl₃/IPA (30 mL) and 1M NaOH (10 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (2Ã—10 mL). Combined organics dried over MgSO₄, concentrated, then purified on silica (80 g) eluting with 0>5% 2M NH₃in MeOH/DCM. MS (ESI pos. ion) m/z: 234/236 (MH+). Calc'd exact mass for C₈H₉BrClN: 233/235. 1-(4-bromo-2-chlorophenyl)ethanamine isolated as a colorless oil.

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tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate. To a stirring solution of 1-(4-bromo-2-chlorophenyl)ethanamine (950 mg, 4051 Î¼mol) in DCM (5 mL) was added BOC-anhydride (4861 Î¼l, 4861 Î¼mol) [1M in THF]. Reaction stirred for 18 h at 23Â° C. Ethanolamine (0.25 mL) added and stirred for 5 min. Reaction then partitioned between diethyl ether (50 mL) and 5% NaHCO₃(25 mL). Organic dried over MgSO₄, concentrated, then purified on silica (80 g) eluting with 0>20% EtOAc/hexanes. BOC-1.10 g. A suspension of the Bromo-BOC intermediate, bis(pinacolato)diboron (1132 mg, 4456 mmol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (148 mg, 203 Î¼mol), and potassium acetate (795 mg, 8102 Î¼mol) in dioxane (8 mL) was sparged with argon for 5 min then heated to 120Â° C. in an appropiately sealed vessel for 2 h. Reaction then partitioned between 9:1 CHCl₃/IPA (50 mL) and sat. NH₄Cl (20 mL). Organic dried over MgSO₄, concentrated, and product purified on silica (80 g) eluting with 10>15% of EtOAc/Hex. tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate isolated as a white foam.

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(R,Z)-N-(4-bromo-2-chlorobenzylidene)-2-methylpropane-2-sulfinamide. A suspension of 4-bromo-2-chlorobenzaldehyde (1150 mg, 5240 Î¼mol), (r)-(+)-2-methyl-2-propanesulfinamide (1588 mg, 13100 Î¼mol), copper(ii) sulfate (696.4 Î¼l, 15720 Î¼mol) in DCM (10 mL) was stirred at 37Â° C. for 78 h. Reaction filtered through Celite, and solid washed repeatedly with DCM.

Filtrate concentrated then purified on silica (80 g) eluting product with 0>30% of EtOAc/Hex.

MS (ESI pos. ion) m/z: 322/324 (MH+). Calc'd exact mass for C₁₁H₁₃BrClNOS: 321/323.

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(R)â€”Nâ€”((S)-1-(4-bromo-2-chlorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. To a stirring solution of (R,Z)-N-(4-bromo-2-chlorobenzylidene)-2-methylpropane-2-sulfinamide (1370 mg, 4246 Î¼mol) and (trifluoromethyl)trimethylsilane (943 Î¼l, 6369 Î¼mol) in DMF (5 mL) was added 1,3-bis(1-adamantyl)imidazol-2-ylidene (143 mg, 425 Î¼mol). Reaction stirred at 35Â° C. for 18 h then quenched with sat NH₄Cl (10 mL). Reaction partitioned between EtOAc (40 mL) and 5% NaHCO₃(10 mL). Organic dried over MgSO4, concentrated to and oil from toluene, then purified on silica (80 g) eluting with 20>30% EtOAc/Hex. Product isolated as a white solid.

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(R)â€”Nâ€”((S)-1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide. A suspension of (R)â€”Nâ€”((S)-1-(4-bromo-2-chlorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (950 mg, 2419 Î¼mol), bis(pinacolato)diboron (676 mg, 2661 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (88.5 mg, 121 Î¼mol), and potassium acetate (475 mg, 4839 Î¼mol) in dioxane (6 mL) was sparged with argon for 5 min. Reaction then appropiately sealed and heated to 120Â° C. with stirring for 1 h. Reaction then partitioned between EtOAc (25 mL) and 5% NaHCO₃(10 mL). Organic dried over MgSO₄, concentrated, then purified on silica (120 g) eluting product with 10>20% of EtOAc/hexanes. Product isolated as a waxy white solid. MS (ESI pos. ion) m/z: 440 (MH+). Calc'd exact mass for C₁₈H₂₆BClF₃NO₃S: 439.

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Example 99

(2-chloro-4-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methanol. A suspension of 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (170 mg, 575 Î¼mol), (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (309 mg, 1150 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (126 mg, 172 mmol), cesium carbonate (749 mg, 2299 mmol) in Dioxane (0.3 mL) and water (0.3 mL) was sparged with argon for 5 min then heated to 100Â° C. with stirring. 1:30 am. After 90 min, LCMS suggests 95% conversion. Reaction then partitioned between 9:1 CHCl₃/IPA (25 mL) and 5% NaHCO₃(15 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (2Ã—10 mL). Combined organics dried with MgSO₄, concentrated onto dry silica (10 g), and then purified on silica (12g) eluting with 0>10% 2M NH₃in MeOH/DCM. Resulting solid triturated with methanol (2 mL) and collected by filtration. MS (ESI pos. ion) m/z: 402 (MH+). Calc'd exact mass for C₂₂H₁₆ClN₅O: 401.

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Example 100

(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methanol. A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (200 mg, 585 Î¼mol), (3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (173 mg, 644 mmol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (21 mg, 29 mmol), and sodium carbonate (2M; 1170 Î¼l, 2341 mmol) in DME (2 mL) was sparged with argon for 10 min then heated to 85Â° C. for 6 h. Reaction then partitioned between 9:1 CHCl₃/IPA (25 mL) and 5% NaHCO₃(10 mL) and aqueous further extracted with 9:1 CHCl₃/IPA (2Ã—10 mL). Combined organics dried with MgSO₄then concentrated onto dry silica under reduced pressure. Product purified on 40 g silica eluting with 0>12% of 2M NH₃in MeOH/DCM and isolated as an off white powder. MS (ESI pos. ion) m/z: 448 (MH+). Calc'd exact mass for C₂₃H₁₈ClN₅O₃: 447.

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Example 101

1-(2-chloro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanol. A suspension of 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (228 mg, 807 Î¼mol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (197 mg, 576 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (127 mg, 173 mmol), cesium carbonate (751 mg, 2306 mmol) in dioxane (3 mL) and water (0.6 mL) was sparged with argon for 5 min then heated to 100Â° C. for 6 h. Reaction cooled then partitioned between 9:1 CHCl₃/IPA (20 mL) and 1M NaOH (15 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (2Ã—10 mL). The combined organics dried over MgSO₄. concentrated, then purified on 40 g silica eluting with an isocratic 7% 2M NH₃in MeOH/DCM. Product further purified prep HPLC eluting with water/ACN (0.1% TFA). After collected fractions were reduced to a clear the residue was dissolved in 1:1 ACN/water and pH adjusted to 9 with 1M NaOH (3-4 drops). Resulting solid collected by filteration and solid washed with water (2 mL). MS (ESI pos. ion) m/z: 462 (MH+). Calc'd exact mass for C₂₃H₂₀ClN₇O₂: 461.

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Example 102

tert-butyl (2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methylcarbamate. A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (200 mg, 585 Î¼mol), tert-butyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (323 mg, 878 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (86 mg, 117 mmol), cesium carbonate (763 mg, 2341 mmol) in dioxane (3 mL) and water (0.3 mL) was sparged with argon for 10 min then heated to 100Â° C. for 18 h. Reaction then partitioned between 9:1 CHCl₃/IPA (50 mL) and 5% NaHCO₃(25 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (2Ã—10 mL). Combined organics then dried over MgSO₄, concentrated, and purified on silica (0 g) eluting with 0>6% 2M NH₃in MeOH/DCM. Product isolated as an off white solid. 84024-19-2 MS (ESI pos. ion) m/z: 547 (MH+). Calc'd exact mass for C₂₈H₂₇ClN₆O₄: 546.

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Example 103

2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methanamine. A solution of tert-butyl (2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methylcarbamate (85 mg, 155 Î¼mol) in DCM (2 mL) and TFA (2 mL) stirred for 30 min at 23Â° C. Solvents removed under reduced pressure, then residue partitioned between 9:1 DCM/IPA (10 mL) and 1M NaOH (5 mL). Aqueous further extracted with DCM (2Ã—5 mL). Combined organics dried over MgSO₄, then reduced to an off white solid under reduced pressure. MS (ESI pos. ion) m/z: 447 (MH+). Calc'd exact mass for C₂₃H₁₉ClN₆O₂: 446.

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Example 104(S)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethanamine

A solution of (R)â€”Nâ€”((S)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (135 mg, 218 mmol) in MeOH (2 mL) and 4M HCl (2 mL) was stirred for 30 min at 35Â° C. LCMS suggests full conversion. Solvents removed under reduced pressure with azeotroping from toluene. Residue dissolved in MeOH (10 mL) and Si-Carbonate (2g; 1.4 mmol) added. Suspension stirred for 30 min, then filtrated collected by filtration. Solvents removed under reduced pressure and residue purified on silica (12g) eluting product with 0>5% MeOH/DCM. MS (ESI pos. ion) m/z: 515 (MH+). Calc'd exact mass for C₂₄H₁₈ClF₃N₆O₂: 514.

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Example 105(R)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethanamine

A solution of (S)â€”Nâ€”((R)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (62 mg, 100 mmol) in MeOH (2 mL) and 5M HCl (2 mL) was stirred at 35Â° C. for 18h. LCMS suggests full conversion. Solvents removed under reduced pressure and residue dissolved in MeOH (20 mL). Si-Carbonate (1.3 g; 0.9 mmol) added to solution and stirred for 2 h. Filtrated isolated by filtration and reduced to a film under reduced pressure. Product purified on silica (4 g) eluting with 7% 2M NH₃in MeOH/DCM. MS (ESI pos. ion) m/z: 515 (MH+). Calc'd exact mass for C₂₄H₁₈ClF₃N₆O₂: 514.

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Example 106

tert-butyl 1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate. A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (180 mg, 527 mmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (302 mg, 790 mmol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (77.1 mg, 105 Î¼mol), cesium carbonate (686 mg, 2107 mmol) in DMF (2 mL) and water (0.4 mL) was first sparged with argon for 5 min then heated to 100Â° C. with stirring. 2:20 Î¼m After 10 min, LCMS suggests >95% conversion. Reaction then partitioned between 9:1 CHCl₃/IPA (20 mL) and 1M NaOH (5 mL). Organic then dried over MgSO4, concentrated, and purified on silica (0 g) eluting with isocratic 4% of 2M NH₃in MeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass for C₂₉H₂₉ClN₆O₄: 560.

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Example 107

1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanamine. A solution of tert-butyl 1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate (100 mg, 178 mmol) in DCM (2 mL) and TFA (2 mL) was stirred for 30 min at 23Â° C. Solvents removed under reduced pressure (not-toluene azeotroping is suggested!) and residue dissolved in CHCl₃/IPA (10 mL). Solution stirred as a suspension with Si-Carbonate (1.3 g; 1 mmol) for 30 min. Suspension filtered and filtrate reduced to an amber film (150 mg). Product purified on silica (12 g) eluting with 4-7% of 2M NH₃in MeOH/DCM. MS (ESI pos. ion) m/z: 461 (MH+). Calc'd exact mass for C₂₄H₂₁ClN₆O₂: 460.

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Example 108

N-((6-(4-(aminomethyl)-3-chlorophenol)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine. To a stirring solution of tert-butyl (2-chloro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methylcarbamate (70 mg, 128 mmol) in DCM (2 mL) was added TFA (2 mL). Reaction solution stirred for 30 min at 23Â° C. Solvents then removed under reduced pressure and residue purified on prep-HPLC using a water/ACN (0.1% TFA) gradient. Resulting solid was dissolved in 1:1 ACN/water (1 mL) and pH adjusted to 10 with 1M NaOH (approx 10 drops). Resulting solid collected by filtration and washed with water (5 mL). MS (ESI pos. ion) m/z: 447 (MH+). Calc'd exact mass for C₂₂H₁₉ClN₈O: 446.

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methyl 2-(3-methoxyquinolin-6-yl)-2-methylpropanoate. To a stirring solution of methyl 2-(3-methoxyquinolin-6-yl)acetate (450 mg, 1946 Î¼mol) in THF (5 mL) at âˆ’70Â° C. under nitrogen was added lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (5838 Î¼l, 5838 Î¼mol). Dark red solution stirred for 10 min, then added iodomethane (364 Î¼l, 5838 mmol) in THF (1 mL). Reaction removed from cooling bath, and monitored by LCMS after 45 min. LCMS suggests very clean conversion. Reaction quenched with sat NH₄Cl (5 mL) and NaHCO₃(5 mL). Aqueous extracted with EtOAc (3Ã—40 mL). Combined organics dried over MgSO4, concentrated, then purified on silica (0 g) eluting with 10>30% of EtOAc/Hex._MS (ESI pos. ion) m/z: 260 (MH+). Calc'd exact mass for C₁₅H₁₇NO₃: 259.

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2-(3-methoxyquinolin-6-yl)-2-methylpropanoic acid. A solution of methyl 2-(3-methoxyquinolin-6-yl)-2-methylpropanoate (400 mg, 1543 mmol), LiOH (1928 Î¼l, 7713 mmol) [4M], MeOH (2 mL), and THF (2 mL) was stirred at 50Â° C. overnight. LCMS suggests full conversion. Solution cooled, acidified to pH 1 with 5M HCl, and precipitate collected by filtration. White cake washed with water (2 mL) and EtOH (1 mL). Product air dried for 3 h and isolated as a white solid. MS (ESI pos. ion) m/z: 246 (MH+). Calc'd exact mass for C₁₄H₁₅NO₃: 245.

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2-(3-methoxyquinolin-6-yl)-2-methyl-Nâ€²-(6-phenylpyridazin-3-yl)propanehydrazide. A suspension of 2-(3-methoxyquinolin-6-yl)-2-methylpropanoic acid (92 mg, 375 mmol), DIEA (66 Î¼l, 375 mmol), and o-(7-azabenzotriazol-1-yl)-n,n,nâ€²,n-tetramethyl uronium hexafluorophosphate (143 mg, 375 mmol) in DMF was stirred for 2 h at 23Â° C. To the solution was added 1-(6-phenylpyridazin-3-yl)hydrazine (70 mg, 375 mmol) and stirred for 72 h at 23Â° C. Reaction partitioned between 9:1 CHCl₃/IPA (25 mL) and 1M NaOH (5 mL). Organic dried over MgSO₄the concentrated to a solid from toluene under reduced pressure. Solid triturated with ACN (2 mL) and collected by filtration. 2-(3-methoxyquinolin-6-yl)-2-methyl-Nâ€²-(6-phenylpyridazin-3-yl)propanehydrazide isolated as a white solid. MS (ESI pos. ion) m/z: 414 (MH+). Calc'd exact mass for C₂₄H₂₃N₅O₂: 413.

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Example 1093-methoxy-6-(2-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-yl)quinoline

A solution of 2-(3-methoxyquinolin-6-yl)-2-methyl-Nâ€²-(6-phenylpyridazin-3-yl)propanehydrazide (270 mg, 653 mmol) in TFA (2 mL) was heated to 150Â° C. in microwave (6 bar; 20W) for 2 h. LCMS suggests very good conversion: 89425-17-1. Reaction concentrated under reduced pressure then partitioned between CHCl₃/IPA (50 mL) and 1M NaOH (50 mL). Aqueous further extracted with CHCl₃/IPA (15 mL) and combined organics dried over MgSO₄, concentrated, then dissolved in ACN (2 mL). Crystallized solid washed with ACN (1 mL) and dried under reduced pressure. MS (ESI pos. ion) m/z: 396 (MH+). Calc'd exact mass for C₂₄H₂₁N₅O: 395.

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Example 110

6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. A solution of Nâ€²-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (4300 mg, 13119 mmol) in TFA (40 mL) was heated to 120Â° C. with microwaves for 40 min. LCMS suggests very good conversion. Solvents removed under reduced pressure and residue partitioned between 9:1 CHCl₃/IPA (75 mL) and 1M NaOH (100 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (2Ã—25 mL). Combined organics dried over MgSO4, concentrated, and oily residue dissolved in ACN/MeOH (2 mL). Resulting solid after 2h was isolated by filtration and washed with ACN (5 mL). 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline isolated as a white solid. MS (ESI pos. ion) m/z: 310 (MH+). Calc'd exact mass for C₁₆H₁₂ClN₅: 309.

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Example 1116-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

A suspension of 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (106 mg, 342 Î¼mol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (142 mg, 684 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (25 mg, 34 Î¼mol), and cesium carbonate (446 mg, 1369 Î¼mol) in DMF (1 mL) and water (0.5 mL) was sparged for 5 min with argon then heated to 100Â° C. in an appropriately sealed vial for 30 min. Reaction then partitioned between 9:1 CHCl₃/IPA (20 mL) and 1M NaOH (5 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (5 mL) and combined organics dried over MgSO4, concentrated to a solid from toluene, then purified on silica (12g) eluting with 30>50% of 10% 2M NH₃in MeOH/DCM. 6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline isolated as off white crystals from ACN (1 mL). MS (ESI pos. ion) m/z: 356 (MH+). Calc'd exact mass for C₂₀H₁₇N₇: 355.

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Example 112

3-(6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline. To a mixture of quinolin-3-ol (0.058 g, 0.40 mmol), (6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (0.104 g, 0.4 mmol), and triphenylphosphine (0.11 g, 0.44 mmol) in dry tetrahydrofuran (2 ml) and dry dichloromethane (2 ml) under argon, was added dropwise with stirring, diethyl azodicarboxylate (0.069 ml, 0.44 mmol). The resulting mixture was stirred at room temperature for 18 hours. The solvent was then stripped at reduced pressure, and the residue subjected to chromatography on Silica gel, eluent 5% methanol in dichloromethane to afford the title compound, which was recrystallised from hot toluene to give a colourless solid. M/e 390 (MH+)

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Example 113

N-((6-(4-(1-aminoethyl)-3-chlorophenyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy)-1,5-naphthyridin-4-amine. A suspension of N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (300 mg, 878 Î¼mol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (419 mg, 1097 Î¼mol), dichloro[1,1â€²bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (193 mg, 263 Î¼mol), cesium carbonate (1144 mg, 3511 Î¼mol) in dioxane (6 mL) and water (1 mL) was sparged with argon for 10 min then heated to 100Â° C. for 20 h with stirring. Reaction then partitioned between 9:1 CHCl₃/IPA (50 mL) and 1M NaOH (25 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (20 mL). Combined organics then dried over MgSO4, concentrated, and purified on 40 g silica eluting with 7>8% of 2M NH₃in MeOH/DCM. Product then further purified on prep HPLC eluting with water/ACN (0.1% TFA). BOC intermediate then stirred as a solution in DCM (1 mL) and TFA (3 mL) for 30 min. Solvents removed under reduced pressure and residue dissolved in MeOH (8 mL) and DCM (8 mL). Solution then stirred with Si-Carbonate from Silicycle (1 g/with a labeled loading of 0.77 Î¼mol/g) for 1 h at 23Â° C. Suspension filtered and filtrate reduced to a film under reduced pressure. Product was lyophilized from 1:1 ACN/water (1.5 mL) to provide N-((6-(4-(1-aminoethyl)-3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy)-1,5-naphthyridin-4-amine as an off white fluffy solid. MS (ESI pos. ion) m/z: 461 (MH+). Calc'd exact mass for C₂₃H₂₁ClN₈O: 460.

[Image Omitted]

Example 1146-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinoline

Step 1. tert-Butyl 2-(isoquinolin-6-yl)acetate. A dry, 25 mL, 1 neck round bottom flask was charged with a 0.5 M Et₂O solution of Zincate 2 (10.00 ml, 5 0 Î¼mol, Reike Metals), and concentrated in vacuo. The vacuum was released with nitrogen, and the flask was charged with a stirbar, 5 mL dry THF, fitted with a reflux condenser and an Ar inlet. Upon dissolution of the solids, 6-bromoisoquinoline (0.516 g, 2 5 mmol) and tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol) was added. The solution was heated with an 80Â° C. oil bath for 5 h, and cooled. The solution was treated with 30 mL of 10% aqueous EDTA (pH adjusted to 6.1 with NaOH), and stirred for 1 h. A precipitate had formed that was removed by filtration of the biphasic solution through a sintered glass funnel and discarded. The filtrate was concentrated to Ëœ35 mL, and extracted with DCM (4Ã—30 mL). The combined extracts were washed with water (1Ã—30 mL), and the water was back-extracted with DCM (1Ã—10 mL). The DCM layers were dried over MgSO₄, and the resultant slurry filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL DCM and treated with Si-carbonate (Silicycle, 5.5 g, 3.7 mmol). The slurry was swirled occasionally for 1 h, and filtered through a 0.22 uM PTFE membrane. The silica was washed with DCM (4Ã—20 mL), and the combined filtrates were concentrated in vacuo. The residue was purified in three injections using a Waters Spherisorb S5 column (PN PSS830195, 20Ã—250 mm, 60 â„« pore, 5 nm particle size); flow=20 mL/min; A=DCE, B=EtOH; isocratic at 5% B. A band that eluted from 3.9 to 5.9 minutes was isolated. The solvent was removed in vacuo to afford tert-butyl 2-(isoquinolin-6-yl)acetate.

Step 2. 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinoline hydrochloride. A 10 mL, CEM microwave vessel was charged with 3 (0.1040 g, 0.427 mmol), 1-(5-phenylpyridin-2-yl)hydrazine (4, 0.119 g, 0.641 mmol), a stirbar and 1 mL concentrated HCl. The vessel was sealed, and fitted with an 18-guage needle and an Argon inlet. The slurry was placed in a heating block at 115Â° C. for 15 minutes with stirring. A volatile substance evolved during this time. The vessel was briefly cooled, and the seal was replaced. The vessel was irradiated on a CEM Explorer using the following parameters: ramp time 20 s, hold time 10 min, hold temperature 150Â° C., powermax=on, 75 W max. The resultant turbid aqueous solution was filtered and concentrated in vacuo. The solids were suspended in 3 mL hot EtOH, and cooled. The precipitate was isolated by filtration and washed with EtOH (3Ã—3 mL). The solids were taken up in 2 mL H₂O, and filtered through a 0.1 Î¼m PVDF Ultra-free-CL centrifugal filter (Millipore Corp, PN UFC40W00, 2000 g for 5 minutes). The aqueous filtrate was lyophilized to afford 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinoline hydrochloride. Anal. Calcd for C₂₁H₁₅N₅.HCl0.1.1.7 H₂O: C, 62.36; H, 4.83; N, 17.31. Found: C, 62.39Â±0.08; H, 4.48Â±0.02; N, 17.28Â±0.03.

[Image Omitted]

Example 115

8-((6-(3,4,5-trifluorophenyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol. A sealed tube was charged with 7-methoxy-N-((6-(3,4,5-trifluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine hydrochloride (238 mg, 502 Î¼mol) and HBr (5966 Î¼l, 52740 Î¼mol), sealed, then placed in a 120Â° C. oil bath for 48 h.

Cooled to room temperature and brought to pH Ëœ14 with NaOH (6N). Isolated solid by filtration which was purified by RPHPLC to afford 8-((6-(3,4,5-trifluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol as its formate salt. MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C₂₀H₁₂F₃N₇O: 423.

[Image Omitted]

3-hydroxy-6-iodoquinoline-4-carboxylic acid. 5-iodoindoline-2,3-dione (50 g, 183 mmol) was dissolved in a hot solution containing potassium hydroxide (82 g, 1465 mmol) and water (250 mL). The reaction mixture was in homogeneous solution for 5 min then was precipitated out completely. Enough ethanol (30 ml) was added to redissolve the reaction mixture. After cooled to rt and mechanically stirred, 3-bromo-2-oxopropanoic acid hydrate (47 g, 256 mmol) was added portionwiseâ€”tremendous heat was generated (>80Â° C.). After the addition, the reaction mixture was cooled to rt and continued to stir for 3 days. The reaction mixture was treated with sat. solution of NaHSO₃(sodium bisulfate, 12g, 115.32 mmol) in order to prevent the development of color in the product. The resulting mixture was then acidified to pH=2 using concentrated HCl. After stirred for 1 h, the yellow ppt. that was formed in the solution mixture was collected by filtration. The solid was washed with water and suspended in water with SO₂bubbling in the solution. After 30 minutes the solid again was separated by filtration. This wet solid was suspended in water, stirred, and dissolved by gradual addition of solid Na₂CO₃. The solution was treated with a saturated solution of NaHSO₃and filtered. The filtrate was acidified to pH=2 using concentrated HCl. The solid that was formed in the solution mixture was collected by filtration. The solid was washed with water, then resuspended in water, and again filtered. The solid was suspended in EtOH, separated by filtration, and airdried to afford the desired product as a brown solid. MS m/z: 316.2 (M+H). Calc'd. for C₁₀H₆INO₃-315.06.

[Image Omitted]

6-iodoquinolin-3-ol. 3-hydroxy-6-iodoquinoline-4-carboxylic acid (22 g, 70 mmol) was suspended in 1-nitrobenzene (143 ml, 1397 mmol) followed by adding Hunig's base (25 mL)â€”the suspension was completely dissolved. The resulting mixture was heated to reflux (210Â° C.) under N₂. After 3 h, LC/MS showed no sign of starting material mass. The reaction mixture was cooled to rt; solvent was removed as much as possible in vacuo. The crude product was redissolved in DCM/MeOH and the solid was collected by filtration. The solid was rinsed with hexane and either and dried as brownish solid. The filtrate was removed excess solvent and purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-058, 330 g SiO₂, solvent system: hexanes:acetone=80%:20%, Flow=100 mL/min) to afford the desired product as brown solid. MS m/z: 272.3 (M+H). Calc'd. for C₉H₆INO-271.05.

[Image Omitted]

tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate. A stirred solution of 6-iodoquinolin-3-ol (1.76 g, 6 mmol) in THF (10 mL) was treated with 2-tert-butoxy-2-oxoethylzinc chloride (39 ml, 19 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.6 mmol). After the addition, it was heated to reflux (75Â° C.) under N₂. After 3 h, TLC 89368-3-1 showed no sign of starting material. Reaction was stop. The reaction was cooled to rt. Solvent was removed. The residue was stirred in EtOAc/10% EDTA (50 mL/50 mL) solution mixture. After 1 h, the organic layer was separated. The aqueous layer was extracted with more EtOAc (2Ã—25 mL). The combined organic layers were washed with water, brine, dried over MgSO₄, and removed solvent. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-026, 12 g SiO₂, hex:acetone=80%:20%, Flow=30 mL/min) to afford the desired product as brownish liquid. MS m/z: 260.3 (M+H). Calc'd. for C₁₅H₁₂NO₃-259.2.

[Image Omitted]

tert-butyl 2-(3-methoxyquinolin-6-yl)acetate. To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added methanol (0.05 ml, 1 mmol) and tributylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0Â° C. followed by adding 1,1â€²-(azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. The reaction mixture was continued to stir for 20 h. TLC showed about 80% conversion. More MeOH (1 ml), tibutylphosphine (0.05 mL), and ADDP (50 mg) were added and allowed to stir for 3 h.

Hexane was added to the reaction mixture and dihydro-ADDP separated out and was filtered off. The filtrate was concentrated. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-027, 40 g SiO₂) to afford the desired product as colorless liquid. MS m/z: 274.3 (M+H). Calc'd. for C₁₆H₁₉NO₃-273.2.

[Image Omitted]

6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolin-3-ol. To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.3 g, 1 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.3 g, 2 mmol), and HYDROCHLORIC ACID (0.3 ml, 11 mmol) as solvent. The vial was sealed and first heated at 100Â° C. for 20 min then placed into

CEM microwave for 20 min. at 180Â° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH. The ppt. was collected by filtration. The ppt. was washed with water and dried. The solid was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-027, 40 g SiO₂, DCM:MeOH=95%:5%, Flow=40 mL/min) to afford the desired product as gray solid. MS m/z: 354.2 (M+H). Calc'd. for C₂₁H₁₅N₅O-353.37.

[Image Omitted]

Example 116

N,N-dimethyl-2-(6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolin-3-yloxy)ethanamine. 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolin-3-ol (0.05 g, 0.1 mmol) was dissolved in DMF (8 mL). SODIUM HYDRIDE (0.01 g, 0 3 mmol) was added and allowed to stir for 1 h at rt. 2-chloro-N,N-dimethylethanamine hydrochloride (0.06 g, 0 4 mmol), which was free-based using 5 N NaOH then extracted with ether, was added. The resulting mixture was continued to stir for 20 h at rt. Solvent was removed in vacuo. The crude material was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-026, 12 g SiO₂, solvent system: DCM:MeOH (2M NH₃)=95%:5%, Flow=30 mL/min) to afford the title compound MS m/z: 425.3 (M+H). Calc'd. for C₂₅H₂₄N₆O-424.49.

[Image Omitted]

tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate. To a flame-dry 100 ml 3-neck round-bottomed flask was added lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (5 ml, 5 mmol) and THF (20 mL). The mixture was cooled to âˆ’78Â° C. followed by adding tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.88 g, 3 mmol) in THF (10 mL)dropwise via addition funnel. After stirring at âˆ’78Â° C. for 30 min, iodomethane (0.4 ml, 6 mmol) was added. The reaction mixture was stirred for 30 min at âˆ’78Â° C. then allowed to warm to rt and stir for 1 h. The mixture was then quenched with sat. NH₄Cl (3 mL). Solvent was removed. The residue was partitioned between EtOAc/water. The organic layer was washed with brine, dried over MgSO₄and removed solvent. The crude material was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-027, 40 g SiO₂, solvent system: hexane:acetone=90%:10%, Flow=30 mL/min) to afford a final product as yellowish liquid. MS m/z: 288.4 (M+H). Calc'd. for C₁₇H₂₁NO₃-287.3.

[Image Omitted]

Example 1173-methoxy-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate (0.130 g, 0.45 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.17 g, 0.90 mmol), HYDROCHLORIC ACID (0.11 ml, 1.4 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90Â° C. for 30 min then placed into CEM microwave for 15 min. at 140Â° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the solid was collected by filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO₄, and removed solvent in vacuo. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-027, 40 g SiO₂, DCM:MeOH=97%:3%, Flow=40 mL/min) to afford the desired product as light yellowish solid. MS m/z: 382.3 (M+H). Calc'd. for C₂₃H₁₉N₅O-381.43.

[Image Omitted]

Example 118

(S)-3-methoxy-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. Chiral separation. MS m/z: 382.3 (M+H). Calc'd. for C₂₃H₁₉N₅O-381.43.

[Image Omitted]

Example 119

(R)-3-methoxy-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. Chiral separation. MS m/z: 382.3 (M+H). Calc'd. for C₂₃H₁₉N₅O-381.43.

[Image Omitted]

tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate. To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0 4 mmol) in benzene (5 mL) was added 2-methoxyethanol (0.09 ml, 1 mmol) and tri-n-butylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0Â° C. followed by adding 1,1â€²-(azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. After 2 h, TLC showed there still existed 50% starting material. More methoxymethanol (2 eq, 0.06 mL) was added. The reaction mixture was continued to stir for 20 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out was filtered off. The filtrate was concentrated. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-027, 40 g SiO₂, hexane:acetone=85%:15%, Flow=40 mL/min) to afford the desired product as colorless liquid. MS m/z: 318.4 (M+H). Calc'd. for C₁₈H₂₃NO₄-317.38.

[Image Omitted]

Example 1203-(2-methoxyethoxy)-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

To a 5 ml CEM microwave tube was added tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (0.080 g, 0.25 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.094 g, 0.50 mmol), HYDROCHLORIC ACID (0.063 ml, 0.76 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90Â° C. for 30 min then placed into CEM microwave for 15 min. at 140Â° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the precipitate was collected via filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO₄, and removed solvent in vacuo. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-026, 12 g SiO₂, DCM:EtOAc:MeOH=60%:37%:3%, Flow=30 mL/min) to afford the desired product as light yellowish solid. MS m/z: 412.3 (M+H). Calc'd. for C₂₄H₂₁N₅O₂-411.45.

[Image Omitted]

methyl 2,2-difluoro-2-(quinolin-6-yl)acetate. To a stirring solution of methyl 2-(quinolin-6-yl)acetate (450 mg, 2236 mmol) in THF (2 mL) at âˆ’70Â° C. under nitrogen was added lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (5144 Î¼l, 5144 mmol) and stirred for 10 min. To this solution was added n-fluorobis(phenylsulfonyl)amine (1481 mg, 4696 mmol) in THF (5 mL) and slowly warmed to 0Â° C. over the course of 1 h. Reaction stirred for an additional 1 h at 23Â° C., and resulting solid (sulfonamide) removed by filtration. The filtrate was concentrated to a solid under reduced pressure. The resulting solid was then partitioned between EtOAc (20 mL) and sat NH₄Cl (10 mL). The organic layer was dried over MgSO₄then concentrated to a solid under reduced pressure and used without further purification.

[Image Omitted]

Example 121

6-(difluoro(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline. A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.39 g, 2.1 mmol) and p-toluenesulfonic acid monohydrate (0.20 g, 1.1 mmol) in 5 mL of dioxane was heated at 150Â° C. for 1 hour in a microwave tube in the microwave. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and washed with 40 mL of brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give yellow solid as desired product 6-(difluoro(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline. MS (ESI pos. ion) m/z: 374.1 (M+H). Calc'd Exact Mass for C₂₁H₁₃F₂N₅: 373.1.

[Image Omitted]

tert-butyl 2-(4-aminoquinazolin-6-yl)acetate

To a solution of 6-bromoquinazolin-4-amine (0.400 g, 1.79 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.163 g, 0.179 mmol) and Q-phos (0.20 g) in 10 mL of THF was added 2-tert-butoxy-2-oxoethylzinc chloride 0.5 m in diethyl ether (10.7 ml, 5.36 mmol). The reaction was heated at 50Â° C. for 16 hours and was quenched with 50 mL of satd. NH₄Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na₂SO₄and concentrated in vacuo to give red solid. The residue was purified by a silica gel column chromatography (5% EtOAc/hex to EtOAC) to give red solid tert-butyl 2-(4-aminoquinazolin-6-yl)acetate which was used without further purification. MS (ESI pos. ion) m/z: 260.1 (M+H). Calc'd Exact Mass for C₁₄H₁₇N₃O₂: 259.1.

[Image Omitted]

Example 122

6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4-amine. Prepared according to example 121 from tert-butyl 2-(4-aminoquinazolin-6-yl)acetate. MS (ESI pos. ion) m/z: 354 (M+H). Calc'd Exact Mass for C₂₀H₁₅N₇: 353.

MassGeneralEX.StructureMWFoundMethod123 [Image Omitted]

383384A 124 [Image Omitted]

304305A 125 [Image Omitted]

303304B 126 [Image Omitted]

318319C 127 [Image Omitted]

431432C 128 [Image Omitted]

388388A 129 [Image Omitted]

483483A 130 [Image Omitted]

440441A 131 [Image Omitted]

440441A 132 [Image Omitted]

458459A 133 [Image Omitted]

426427A 134 [Image Omitted]

402403B 135 [Image Omitted]

475475A 136 [Image Omitted]

378379B 137 [Image Omitted]

461461A 138 [Image Omitted]

436436A 139 [Image Omitted]

462462A 140 [Image Omitted]

454455A 141 [Image Omitted]

425426A 142 [Image Omitted]

465466A 143 [Image Omitted]

424424A 144 [Image Omitted]

414415B 145 [Image Omitted]

384385B 146 [Image Omitted]

413414B 147 [Image Omitted]

360361B 148 [Image Omitted]

359360B 149 [Image Omitted]

328329B 150 [Image Omitted]

354355B 151 [Image Omitted]

384385B 152 [Image Omitted]

384385B 153 [Image Omitted]

442443D 154 [Image Omitted]

385386A 155 [Image Omitted]

452453A 156 [Image Omitted]

486486A 157 [Image Omitted]

451452A 158 [Image Omitted]

398398B 159 [Image Omitted]

382383D 160 [Image Omitted]

399400B 161 [Image Omitted]

383384D 162 [Image Omitted]

412412B 163 [Image Omitted]

397398B 164 [Image Omitted]

397398B 165 [Image Omitted]

472473B 166 [Image Omitted]

397398D 167 [Image Omitted]

397398D 168 [Image Omitted]

398399B 169 [Image Omitted]

358359D 170 [Image Omitted]

409410D 171 [Image Omitted]

419420A 172 [Image Omitted]

437438A 173 [Image Omitted]

461461A 174 [Image Omitted]

401402A 175 [Image Omitted]

436436A 176 [Image Omitted]

403404A 177 [Image Omitted]

419420A 178 [Image Omitted]

436436A 179 [Image Omitted]

452452A 180 [Image Omitted]

425425A 181 [Image Omitted]

411411A 182 [Image Omitted]

401401C 183 [Image Omitted]

338337C 184 [Image Omitted]

389390A 185 [Image Omitted]

451452A 186 [Image Omitted]

414415A 187 [Image Omitted]

414415D 188 [Image Omitted]

402403A 189 [Image Omitted]

427428A 190 [Image Omitted]

411412A 191 [Image Omitted]

431432A 192 [Image Omitted]

531531A 193 [Image Omitted]

507507A 194 [Image Omitted]

415416A 195 [Image Omitted]

415416A 196 [Image Omitted]

411412A 197 [Image Omitted]

415416A 198 [Image Omitted]

486486A 199 [Image Omitted]

491491A 200 [Image Omitted]

414415A 201 [Image Omitted]

477477A 202 [Image Omitted]

452453A 203 [Image Omitted]

453454A 204 [Image Omitted]

402403A 205 [Image Omitted]

384385A 206 [Image Omitted]

389390A 207 [Image Omitted]

413414A 208 [Image Omitted]

372373A 209 [Image Omitted]

384385A 210 [Image Omitted]

462462A 211 [Image Omitted]

408409A 212 [Image Omitted]

401402A 213 [Image Omitted]

401402A 214 [Image Omitted]

373374A 215 [Image Omitted]

403404A 216 [Image Omitted]

451452A 217 [Image Omitted]

419420A 218 [Image Omitted]

467468A 219 [Image Omitted]

419420A 220 [Image Omitted]

437438A 221 [Image Omitted]

403404A 222 [Image Omitted]

404405A 223 [Image Omitted]

418418A 224 [Image Omitted]

452452A 225 [Image Omitted]

452452A 226 [Image Omitted]

404405A 227 [Image Omitted]

530530D 228 [Image Omitted]

436436A 229 [Image Omitted]

557557A 230 [Image Omitted]

453454A 231 [Image Omitted]

452453A 232 [Image Omitted]

441442A 233 [Image Omitted]

387388A 234 [Image Omitted]

387388D 235 [Image Omitted]

401402D 236 [Image Omitted]

440441A 237 [Image Omitted]

458459A 238 [Image Omitted]

445446A 239 [Image Omitted]

428429A 240 [Image Omitted]

416417A 241 [Image Omitted]

417418A 242 [Image Omitted]

458459A 243 [Image Omitted]

431432D 244 [Image Omitted]

427428D 245 [Image Omitted]

418419A 246 [Image Omitted]

436437A 247 [Image Omitted]

418 419D 248 [Image Omitted]

436437D 249 [Image Omitted]

396397A 250 [Image Omitted]

400401A 251 [Image Omitted]

450451A 252 [Image Omitted]

400401A 253 [Image Omitted]

466467A 254 [Image Omitted]

418419A 255 [Image Omitted]

466467A 256 [Image Omitted]

400401A 257 [Image Omitted]

460460A 258 [Image Omitted]

425426A 259 [Image Omitted]

474474A 260 [Image Omitted]

407408A 261 [Image Omitted]

384385A 262 [Image Omitted]

384385A 263 [Image Omitted]

388389A 264 [Image Omitted]

383384A 265 [Image Omitted]

418419A 266 [Image Omitted]

418419A 267 [Image Omitted]

436437A 268 [Image Omitted]

512512A 269 [Image Omitted]

468469A 270 [Image Omitted]

423423A 271 [Image Omitted]

389390A 272 [Image Omitted]

414415A 273 [Image Omitted]

414415A 274 [Image Omitted]

426427A 275 [Image Omitted]

430431A 276 [Image Omitted]

435435A 277 [Image Omitted]

417417A 278 [Image Omitted]

413414A 279 [Image Omitted]

403404A 280 [Image Omitted]

403404A 281 [Image Omitted]

384385A 282 [Image Omitted]

383384A 283 [Image Omitted]

371372A 284 [Image Omitted]

382383A 285 [Image Omitted]

388389A 286 [Image Omitted]

457458A 287 [Image Omitted]

402403A 288 [Image Omitted]

389390A 289 [Image Omitted]

488488A 290 [Image Omitted]

389390A 291 [Image Omitted]

403404A 292 [Image Omitted]

432433A 293 [Image Omitted]

403404A 294 [Image Omitted]

437438A 295 [Image Omitted]

421422D 296 [Image Omitted]

421422D 297 [Image Omitted]

387388A 298 [Image Omitted]

454455D 299 [Image Omitted]

419420A 300 [Image Omitted]

400401A 301 [Image Omitted]

475476A 302 [Image Omitted]

420421A 303 [Image Omitted]

418419A 304 [Image Omitted]

436437A 305 [Image Omitted]

432433A 306 [Image Omitted]

339â€‰339.1, 341.3B 307 [Image Omitted]

336337A 308 [Image Omitted]

341342A 309 [Image Omitted]

440441D 310 [Image Omitted]

437438D 311 [Image Omitted]

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363364D

[Image Omitted]

Example 403(R)â€”N-((6-(3,5-difluorophenyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine

a) (R)-tert-butyl 2-((8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate was prepared according to method D.

b) (R)â€”N-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine. The title compound was prepared from (R)-tert-butyl 2-((8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate following the procedure used to make 7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline. m/z: 489 (M+H). Calc'd. for C₂₅H₂₂F₂N₈O-488.

[Image Omitted]

Example 404(S)â€”N-((6-(3,5-difluorophenyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine

The title compound was prepared in the same manner as (R)â€”N-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine m/z: 489 (M+H). Calc'd. for C₂₅H₂₂F₂N₈O-488.

[Image Omitted]

Example 4057-methoxy-N-((6-(2-morpholinothiazol-4-0)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine1) 4-(4-bromothiazol-2-yl)morpholine

[Image Omitted]

To a microwave vial was added N,N-diisopropylethylamine (0.86 ml, 4.9 mmol), 2,4-dibromothiazole (1.00 g, 4.1 mmol), and morpholine (0.43 ml, 4.9 mmol) in EtOH (4 mL). The mixture was heated under microwave irradiation at 140Â° C. for 35 minutes. The reaction mixture was concentrated in vacuo. The crude material was dissolved in minimal DCM/MeOH and purified via MPLC (eluting with 0-30% EtOAc in hexanes) to yield 4-(4-bromothiazol-2-yl)morpholine (0.700 g, 68% yield) as a white solid.

2) 4-(4-(trimethylstannyl)thiazol-2-yl)morpholine

[Image Omitted]

Prepared in a method similar to 3-methyl-5-trimethylstannyl)isothiazole.

3) Bis-tert-butyl(6-chloro-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

[Image Omitted]

Di-tert-butyl dicarbonate (24.42 g, 111.9 mmol) was added to a stirred suspension of tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (10.58 g, 37 3 mmol) in acetonitrile (200 mL) at 0Â° C. followed by 4-dimethylaminopyridine (4.556 g, 37.3 mmol). Stirring was continued at 0Â° C. for Ëœ10 min then the cooling bath was removed and stirring was continued at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with EtOAc and washed with water. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. Purification via MPLC (EtOAc/MeOH: 100/0 to 90/10) afforded the title compound (14.3 g, 37.3 Î¼mol, 100% yield).

4)(6-(2-morpholinothiazol-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl di-tert-butyl carbamate

[Image Omitted]

To a pressure vessel purged with argon was added palladium (II) acetate (0.0029 g, 0.013 mmol), Xantphos (0.015 g, 0.026 mmol) and bis-tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.100 g, 0.26 mmol) in 1,4-dioxane (0.17 M, 1.5 mL). 4-(4-(trimethylstannyl)thiazol-2-yl)morpholine (0.13 g, 0.39 mmol) and degassed water (0.0094 ml, 0.52 mmol) were added, once more purging the flask with argon. The reaction mixture was stirred at 100Â° C. for 4 h until complete consumption of the starting material. The reaction mixture was concentrated in vacuo. The crude material was dissolved in minimal EtOAc and purified via MPLC (eluting with 100% EtOAc). (6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl di-tert-butyl carbamate (0.086 g, 64% yield) was obtained as a solid. The material was carried forward without further purification.

5) 7-methoxy-N-((6-(2-morpholinothiazol-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

[Image Omitted]

To a microwave vial was added (6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl di-tert-butyl carbamate (0.086 g, 0.17 mmol) and 8-chloro-3-methoxy-1,5-naphthyridine (0.036 g, 0.18 mmol) in 2-butanol (1.0 mL). The vial was sealed and heated under microwave irradiation at 120Â° C. for 6 h. The reaction was concentrated in vacuo. The crude material was dissolved in 2M ammonia in methanol and purified via MPLC (eluting with 0-10% 1% NH₄OH/in DCM). 7-methoxy-N-((6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (0.031 g, 39% yield) was obtained as a yellow solid. m/z: 476.0 (M+H). Calc'd. for C₂₂H₂₁N₉O₂S-475.53.

The following example compounds 406 and 407 were prepared using the method to make 7-methoxy-N-((6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine:

MassExStructureMWFound406 [Image Omitted]

390391 407 [Image Omitted]

390391

The following example compounds 408-428 were prepared using steps 1 and 2 of Method A. Where applicable, enantiomer was obtained via SFC:

MassExStructureMWFound408 [Image Omitted]

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422423

[Image Omitted]

1-(3-fluoro-5-(3-methylisothiazol-5-yl)pyridin-2-yl)hydrazine

5-chloro-2,3-difluoropyridine (0.069 ml, 0.67 mmol), X-Phos (0.045 g, 0.094 mmol) and palladium (II) acetate (0.011 g, 0.047 mmol) were combined in 1,4-dioxane (0.2 M, 3.4 mL). To the reaction vessel was added 3-methyl-5-(trimethylstannyl)isothiazole (0.53 g, 2.0 mmol) and, after purging with argon, the reaction was stirred at 100Â° C. for 2 h and then concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting first with 100% EtOAc followed by 20% EtOAc in hexanes-isocratic) to yield 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine (0.139 g, 98% yield) as a yellow solid. 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine was converted to the title compound using a procedure similar to 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine.

[Image Omitted]

1-(5-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)hydrazine

A mixture of palladium (II) acetate (0.0375 g, 0.167 mmol), potassium phosphate (2.13 g, 10.0 mmol), 3,5-difluorophenylboronic acid (1.58 g, 10.0 mmol), X-Phos (0.159 g, 0.334 Î¼mol) and 5-chloro-2,3-difluoropyridine (0.347 ml, 3.34 Î¼mol) was diluted with 1,4-dioxane (0.1M, 33.4 mL) and water (0.3M, 11.0 mL) and was heated under nitrogen at 100Â° C. for 45 minutes. The reaction was concentrated in vacuo. The concentrated material was triturated with water, filtered and rinsed with MeCN. The crude solid was taken up in dichloromethane and filtered over a plug of Celite to eliminate residual palladium. The material was dissolved in minimal DCM, and purified via MPLC (eluting with 0-10% EtOAc in hexanes) to yield 5-(3,5-difluorophenyl)-2,3-difluoropyridine. The material was converted to the hydrazine in a method similar to that in the synthesis of (5)-6-(1-(8-fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)quinoline.

The following compounds were prepared using a similar method as 1-(5-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)hydrazine:

1) 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazin

The following compounds were prepared using a similar method (using either the trimethyl- or tributyl-stannnane) as 1-(3-fluoro-5-(3-methylisothiazol-5-yl)pyridin-2-yl)hydrazine: 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine; and 1-(3-fluoro-5-(3-trifluoromethylisoxazol-5-yl)pyridin-2-yl)hydrazine.

[Image Omitted]

2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride

Tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate (0.865 g, 3.01 mmol) was dissolved in EtOAc (0.2M, 15 mL), and HCl (g) (0.0915 ml, 3.01 mmol) was bubbled through the solution for approximately 5 minutes. The reaction vessel was sealed and the reaction was stirred at room temperature for 1.5h until completion. The reaction mixture was concentrated in vacuo to yield 2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride (0.805 g, 99.9% yield) as an orange solid.

[Image Omitted]

2-fluoro-2-(quinolin-6-yl)propanoic acid

To a solution of methyl 2-(quinolin-6-yl)propanoate (0.868 g, 4.03 mmol) in THF (1.1M, 3.7 mL) at âˆ’78Â° C. was added LiHMDS (1M in THF) (5.24 ml, 5.24 mmol). The reaction was stirred at âˆ’78Â° C. for Ëœ15 minutes, then to it was added a solution of N-fluorobenzenesulfonimide (1.40 g, 4.44 mmol) in THF (1.0M, 4.5 mL). The reaction was allowed to warm to âˆ’10Â° C. over 2h. The reaction was filtered through a plug of Celite, washed with EtOAc and the filtrate was then concentrated in vacuo. The concentrated material was rediluted with EtOAc and washed with saturated NH₄Cl solution. The aqueous layer was then extracted with EtOAc, and the organic layers were dried over MgSO₄, filtered and concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with isocratic 40% EtOAc:Hexanes to yield methyl 2-fluoro-2-(quinolin-6-yl)propanoate (0.709 g, 75.4% yield) as a yellow oil.

To synthesize the corresponding acid, methyl 2-fluoro-2-(quinolin-6-yl)propanoate was saponified in a method similar to that of 2-(quinolin-6-yl)propanoic acid.

[Image Omitted]

2-(3-methoxyquinolin-6-yl)acetic acid hydrochloride

tert-Butyl 2-(3-methoxyquinolin-6-yl)acetate was saponified in a method similar to 2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride.

[Image Omitted]

(6-(2-methoxythiazol-4-0)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine

The di-tert-butyl carbonate precursor ((6-(2-methoxy-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl di-tert-butyl carbamate) was synthesized in a method similar to (6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl di-tert-butyl carbamate, using 2-methoxy-4-(tributylstannyl)thiazole as the organostannane, followed by TFA deprotection similar to the method described for (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine

[Image Omitted]

Example 4294-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline1) 2-(7-hydroxyquinolin-4-yloxy)acetic acid hydrobromide

[Image Omitted]

To a pressure vial was added 2-(7-methoxyquinolin-4-yloxy)acetic acid (1.00 g, 4.29 Î¼mol) in DCE (0.6 M, 7 mL). The vial was cooled in an ice bath and to the solution was added BBr₃(1.62 ml, 17.2 mmol). The reaction was allowed to warm to room temperature and stirred overnight. While some starting material remained, the reaction was stopped and diluted with DCM (keep in hood due to fuming). The solids were filtered and dried over high vacuum to yield a light brown crude solid (Ëœ1.8 g). The material was used without further purification.

2) 4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol

[Image Omitted]

The material was prepared using general method A (with 2-(7-hydroxyquinolin-4-yloxy)acetic acid hydrobromide and 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine

3) 4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline

[Image Omitted]

4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol (0.110 g, 0.28 mmol), PPh₃(polymer supported: 2.3 Î¼mol/g) (1.2 g, 2 8 mmol) and 2-methoxyethanol (0.11 ml, 1.3 mmol) were combined in DCM (11 ml, 0.28 mmol). The mixture was cooled to 0Â° C., and DEAD (0.089 ml, 0.56 mmol) was added dropwise. The reaction was removed from the ice bath, and stirred at RT for 1 h. The material was diluted with DCM, and the PSâ€”PPh₃was filtered off and washed thoroughly with DCM. The filtrate was concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with 0-100% 90:10:1 DCM:MeOH:NH₄OH in DCM) to yield 4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline (0.070 g, 55% yield) as a white solid. MS (ESI pos. ion) m/z: 450.0 (M+H). Calc'd Exact Mass for C₂₃H₂₀FN₅O₄: 449.44

[Image Omitted]

tert-Butyl (6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

In a 15-mL sealed tube flushed with nitrogen, tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (2.00 g, 7.0 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (0.58 g, 0.70 mmol), and copper (I) iodide (0.34 g, 1.8 mmol) were diluted in MeCN (70 mL). To the reaction mixture was first added 4-methylpent-1-yn-3-ol (3.7 ml, 35 mmol), followed by triethylamine (25 ml, 176 mmol). The reaction was then heated at 50Â° C. for 7.5 h. The crude material was dissolved in minimal DCM and purified via MPLC (twice)(eluting with 0-10% MeOH/NH₄OH:DCM) to yield tert-butyl (6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (1.823 g, 75% yield) as a light brown solid.

[Image Omitted]

tert-Butyl (6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

tert-Butyl (6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (1.82 g, 5.27 mmol) and manganese dioxide (activated) (9.16 g, 105 mmol) were dissolved in DCM (263 mL) and stirred at room temperature over two days. Additional manganese dioxide (activated) (4.58 g, 52 7 mmol) was added and stirring continued overnight. The reaction mixture was filtered over a plug of Celite and washed with DCM to yield tert-butyl (6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.917 g, 50.7% yield) after concentration in vacuo.

[Image Omitted]

tert-Butyl (6-(3-isopropylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

An aqueous mixture of tert-butyl (6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.800 g, 2.33 mmol) and hydroxylamine-O-sulfonic acid (0.263 g, 2.33 mol) in water (8.0 mL) and 1,4-dioxane (8.0 mL) was stirred at 0Â° C. until complete consumption of the organic starting material was observed. The mixture was then carefully treated with solid sodium bicarbonate (0.196 g, 2.33 mmol), followed by treatment with 1.4 M aqueous sodium hydrosulfide (1.83 ml, 2.56 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The concentrated crude material was dissolved in minimal DCM and was purified via MPLC (eluting with 0-10% MeOH/NH₄OH in DCM) to yield tert-butyl (6-(3-isopropylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.196 g, 22.5% yield) with 82% purity. MS (ESI pos. ion) m/z: 433.0 (M+H). Calc'd Exact Mass for C₂₁H₂₀N₈OS: 432.51.

[Image Omitted]

Example 4301-(6-Phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanola) N-methoxy-N-methylquinoline-6-carboxamide

A 250 mL RB flask was charged with quinoline-6-carboxylic acid (5.00 g, 28.9 mmol), DCM (100 ml, 1554 mmol), oxalyl chloride (3.79 ml, 43 3 mmol), and a few drops of DMF and stirred at RT for 2 hours, then concentrated. The residue was taken up in DCM (100 ml, 1554 mmol), cooled to 0Â° C., then Hunig's Base (17.7 ml, 101 mmol) and N-methoxymethanamine hydrochloride (2.96 g, 30.3 mmol) were added slowly. The mixture was stirred at room temperature for 16 hours (91463-3-1). The mixture was diluted with DCM (200 mL), then washed with water (250 mL), sat. NaHCO₃(250 mL), and brine (250 mL). The organic layer was dried with MgSO₄, filtered, and concentrated to give a brown oil, which was purified by MPLC eluting with 2-6% MeOH/DCM to give N-methoxy-N-methylquinoline-6-carboxamide (5.943 g, 95.2% yield) as a brown oil.

b) 1-(quinolin-6-yl)ethanone

A 250 mL RB flask was charged with N-methoxy-N-methylquinoline-6-carboxamide (5.943 g, 27.5 mmol) and THF (100 ml, 1220 mmol), then cooled to 0 C. Methylmagnesium bromide (18.3 ml, 55 0 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was not quite complete, so additional MeMgBr (3 mL) was added and the mixture was stirred overnight. The mixture was then neutralized using 2N HCl and the aqueous layer was extracted with DCM (200 mLÃ—2) and EtOAc (200 mLÃ—2). The organic layer was dried with MgSO₄, filtered, and concentrated to give a yellow oil. The aqueous layer contained some product, so the layer was concentrated and then filtered thru a reverse phase C₁₈column, first eluting with water than with MeOH. The MeOH layer was concentrated to give a yellow oil which was combined with the yellow oil from the organic layer. The combined portions were purified by MPLC eluting with a gradient of 2-6% MeOH/DCM. 1-(quinolin-6-yl)ethanone (4.074 g, 86.6% yield) was isolated as a yellow oil which solidified upon standing.

c) 2-bromo-1-(quinolin-6-yl)ethanone hydrobromide

A 250 mL RB flask was charged with 1-(quinolin-6-yl)ethanone (3.82 g, 22 3 mmol) and 30% HBr/AcOH (45.0 ml). Bromine (1.14 ml, 22.1 mmol) was added slowly. This was stirred at room temperature for 4 hours, at which point full conversion to product (with a small amount of dibrominated side product) was observed. The reaction mixture was filtered and the solid was washed with Et₂O to give 2-bromo-1-(quinolin-6-yl)ethanone hydrobromide (5.6359 g, 76.3% yield). The compound was used in the next step without further purification.

d) (E)-Nâ€²-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine

A 500 mL RB flask was charged with 6-chloropyridazin-3-amine (10.0 g, 77 2 mmol) and dimethoxy-N,N-dimethylmethanamine (206 ml, 1544 Î¼mol), equipped with a reflux condenser, then heated to 110Â° C. for 3 hours then left at room temperature for 16 hours. The precipitate was collected by filtration. The mother liqour was concentrated down to give an yellow solid, which was triturated with EtOAc and collected. The solids were combined to give (E)-Nâ€²-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine (11.81 g, 82.9% yield) as a white solid

e) (6-Chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone

A 100 mL RB flask was charged with 2-bromo-1-(quinolin-6-yl)ethanone (0.7011 g, 2.80 mmol), (E)-Nâ€²-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine (0.518 g, 2.80 mmol), and DMF (10.0 ml, 129 Î¼mol), equipped with a reflux condenser, then heated at 105Â° C. for 3 hours. The reaction mixture was concentrated, then triturated with MeOH to yield (6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g, 1.72 Î¼mol, 61%) as a brown solid.

f) (6-Phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone

A 48 mL sealed tube was charged with (6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g, 1.72 mmol), phenylboronic acid (0.314 g, 2.58 mmol), cesium carbonate (1.68 g, 5.15 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (0.0701 g, 0.0858 mmol), 1,4-dioxane (6.31 ml, 73.8 mmol), and water (1.11 ml, 61.8 mmol), flushed with argon, sealed, then placed in an 80Â° C. oil bath for 8 hours. The mixture was concentrated then triturated with water, followed by MeOH/DCM to give (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone as a reddish brown solid.

g) 1-(6-Phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanol

A 25 mL RB flask was charged with (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.200 g, 0.57 mmol) and THF (2.00 ml, 24 mmol), then cooled to 0Â° C. methylmagnesium bromide (0.76 ml, 2.2 mmol) was added dropwise and the mixture was stirred at room temperature for 5 hours. This was diluted with 2 N HCl (1 mL) and water (25 mL), then extracted with DCM (25 mLÃ—2) and EtOAc (25 mL). The combined organics were washed with brine and dried with MgSO₄, filtered, and concentrated. The resulting oil was purified by MPLC using a 0 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. 1-(6-phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanol (0.082 g, 39% yield) was isolated as a tan solid. MS (ESI pos. ion) m/z: 367 (MH+). Calc'd exact mass for C₂₃H₁₈N₄O: 366.

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Example 4316-((6-Phenylimidazo[1,2-b]pyridazin-3-yl)methyl)quinoline

A 10-20 mL microwave vial was charged with hydrazine hydrate (0.0312 ml, 0.642 mmol), (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.150 g, 0.428 mmol), KOH (0.0961 g, 1.71 mmol), and diethylene glycol (4.09 ml, 42 8 mmol), sealed, then placed in a Personal Chemistry microwave at 130Â° C. for 20 minutes after a 5 minute pre-stir. The mixture was diluted with water (75 mL), then extracted with DCM (2Ã—75 mL). The combined organics were washed with brine (75 mL), then dried with MgSO₄, filtered, and concentrated to give a brown solid, then purified by prep HPLC to give the product as the formic acid salt. MS (ESI pos. ion) m/z: 337 (MH+). Calc'd exact mass for C₂₂H₁₆N₄: 336.

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Example 4326-((6-(3-Methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)quinoline

A 16 mm test tube was charged with hydrazine hydrate (0.0273 ml, 0.563 mmol), (6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (prepared using a similar procedure as (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone) (0.100 g, 0.281 mmol), sodium tert-butoxide (0.0406 g, 0.422 mmol), and 1-butanol (0.670 ml, 7.32 mmol), sealed, then heated to 150Â° C. for 2 hours (96979-1-1). The mixture was diluted with water, neutralized with 2 N HCl, then extracted with DCM (3Ã—30 mL). The combined organics were dried with MgSO₄, filtered, then concentrated. 6-((6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)quinoline was purified by prep HPLC and isolated as the TFA salt. MS (ESI pos. ion) m/z: 341 (MH+). Calc'd exact mass for C₂₀H₁₅N₅O: 341.

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Example 4336-(difluoro(6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)quinoline

A 25 mm test tube was charged with 2,2-difluoro-1,3-dimethylimidazolidine (DFI) (0.24 g, 1.8 mmol), (6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.125 g, 0.35 mmol), and MeCN (2.00 ml, 38 mmol), sealed, then heated at 84Â° C. for 36 hours, adding additional 2,2-difluoro-1,3-dimethylimidazolidine (DFI) (0.24 g, 1.8 mmol) after 16 hours. The mixture was diluted with water (50 mL), then extracted with DCM (2Ã—40 mL). The combined organics were washed with brine (40 mL), dried with MgSO₄, filtered, then concentrated to give a brown residue. This was purified by MPLC using a 0 g RediSep column, eluting with 20-50% (90:10:1 DCM:MeOH:NH₄OH mixture) in EtOAc over 40 minutes. The purest fractions were collectedâ€”these still contained DFI, so the residue was triturated with EtOAc and decanted. 6-(difluoro(6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)quinoline was isolated as a light yellow solid.

MS (ESI pos. ion) m/z: 378 (MH+). Calc'd exact mass for C₂₀H₁₃F₂N₅O: 377.

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Example 4347-(difluoromethoxy)-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline

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1) 4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol hydrobromide

A 150 mL tube was charged with 7-methoxy-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (1.44 g, 3.72 mmol) and HBr (30.3 ml, 558 mmol), sealed, then placed in a 120Â° C. for 5 hours. The reaction mixture was slowly neutralized with 6N NaOH until a precipitate crashed out of solution (pH Ëœ5)â€”the solid was collected to give 4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol hydrobromide.

2) 7-(difluoromethoxy)-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline

A 48 mL tube was charged with sodium 2-chloro-2,2-difluoroacetate (0.15 g, 1.0 mmol), 4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol hydrobromide (0.200 g, 0.44 mmol), cesium carbonate (0.43 g, 1.3 mmol), and DMF (1.7 ml, 22 mmol), flushed with argon, sealed, then placed in a 100Â° C. oil bath for 5 hours. The reaction mixture was concentrated, then diluted with DCM and chloroform. This was washed with water, sat. NaHCO₃, and brine, then dried with MgSO₄, filtered, and concentrated to give a brown oil. This was purified by HPLC to give 7-(difluoromethoxy)-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (0.025 g, 13% yield) as the formic acid salt. MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C₂₁H₁₅F₂N₅O₃: 423.

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Example 435N-((6-(1H-indazol-6-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

a) 6-(3-((7-Methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-indazole-1-carboxylate. A tube was charged with N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.250 g, 0.732 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (0.378 g, 1.10 mmol), PdCl2(dppf)-CH₂Cl₂Adduct (0.0597 g, 0.0732 mmol), potassium carbonate (0.303 g, 2.19 mmol), DMF (5.01 ml, 64.4 mmol), and water (1.16 ml, 64 4 mmol), flushed with argon, sealed, then placed in a 60Â° C. oil bath for 6 hours. The reaction mixture was concentrated, then triturated with water to give a black solid. The material was used directly in the next step.

b) N-((6-(1H-indazol-6-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine. The title compound was prepared in the same manner as 7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C₂₂H₁₇N₉O: 423.

4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole

A 250 mL RB flask was charged with 4-bromo-1H-pyrazole (2.00 g, 13 6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.35 ml, 17.0 mmol), cesium carbonate (8.87 g, 27.2 mmol), and 1,4-dioxane (40.0 ml, 468 mmol), capped, and stirred at room temperature for 20 hours. The reaction mixture was filtered and the solid washed with dioxane; the filtrate was then concentrated to give 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.402 g, 77.1% yield) as a crude oil.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-O-1-(2,2,2-trifluoroethyl)-1H-pyrazole

The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole.

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Example 4367-methoxy-N-((6-(3-methylisothiazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

The title compound was prepared in the same manner as 7-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine MS (ESI pos. ion) m/z: 404 (MH+). Calc'd exact mass for C₂₀H₁₇N₇OS: 403.

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(5-(3-(aminomethyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)isothiazol-3-yl)methanol

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1) 5-bromo-3-(dibromomethyl)isothiazole. 5-Bromo-3-methylisothiazole (2.15 g, 12 mmol) was dissolved in dichloroethane (20 mL) then added N-bromosuccinimide (4.5 g, 25 mmol) and AIBN (0.50 g, 3.0 mmol). The reaction mixture was heated at 100Â° C. for 4 hours. Additional AIBN (0.50 g, 3.0 mmol) and bromine (0.062 ml, 1.2 mmol) were added to the mixture and continued heating at 100Â° C. for 4 hours. N-bromosuccinimide (4.5 g, 25 mmol) and AIBN (0.50 g, 3.0 mmol) were added then continued heating at 100Â° C. for 4 hours. Again, N-bromosuccinimide (4.5 g, 25 mmol) and AIBN (0.30 g, 1.8 mmol) were added and the mixture was heated at 100Â° C. for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The sample was purified by flash chromatography eluting with 0-10% ethyl acetate/hexane to afford 5-bromo-3-(dibromomethyl)isothiazole (2.07 g, 51% yield) as a colorless liquid.

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2) 5-bromoisothiazole-3-carbaldehyde. 5-Bromo-3-(dibromomethyl)isothiazole (1.00 g, 3.0 mmol) was dissolved in DME (10 mL) then added a solution of silver nitrate (0.56 g, 3.3 mmol) in water (1.6 mL). A white precipitate formed. The reaction mixture was heated at 100Â° C. for 1.5 hours. Additional silver nitrate (0.56 g, 3.3 mmol) in water (1.6 mL) was added and heating was continued at 100Â° C. for 2.5 hours. The reaction mixture was filtered through a pad of Celite washing with THF then ethyl acetate. The filtrate was concentrated under vacuum and the remaining oil was diluted with ethyl acetate. The organic layer was washed with water then dried over sodium sulfate and concentrated under vacuum to afford 5-bromoisothiazole-3-carbaldehyde (0.536 g, 94% yield) as alight yellow oil.

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3)(5-bromoisothiazol-3-yl)methanol. 5-Bromoisothiazole-3-carbaldehyde (0.533 g, 2 8 mmol) was dissolved in ethanol (40 mL) then added sodium borohydride (0.11 g, 2.8 mmol). The reaction mixture was stirred at room temperature for 3 hours. Added more sodium borohydride (0.026 g, 0.69 mmol) and continued stirring at room temperature for 4.5 hours. Additional sodium borohydride (0.11 g, 2 8 mmol) was added once again and stirring was continued at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride then concentrated under vacuum. The remaining aqueous layer was diluted with water then extracted with ethyl acetate (2Ã—). The organic layer was dried over sodium sulfate and concentrated under vacuum to afford (5-bromoisothiazol-3-yl)methanol (0.430 g, 80% yield) as an orange oil.

MS (ESI pos. ion) m/z: 194.0 and 196.0 (MH⁺).

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4) 5-bromo-3-((tert-butyldimethylsilyl oxy)methyl)isothiazole. (5-Bromoisothiazol-3-yl)methanol (0.380 g, 1.96 mmol) was dissolved in DMF (4 mL) then added tert-butyldimthylsilyl chloride (0.443 g, 2.94 mmol) and imidazole (0.400 g, 5.87 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was combined with previous reactions and concentrated under vacuum. The sample was purified by flash chromatography eluting with 0-15% ethyl acetate/hexane to afford 5-bromo-3-((tert-butyldimethylsilyloxy)methyl)isothiazole as a pale yellow liquid. MS (ESI pos. ion) m/z: 308.0 and 310.0 (MH⁺).

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5) 3-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)isothiazole. 5-Bromo-3-((tert-butyldimethylsilyloxy)methyl)isothiazole (0.100 g, 0.324 mmol) was dissolved in THF (1 mL) then cooled to âˆ’78Â° C. and added 1.6 M n-BuLi in hexane (0.223 ml, 0.357 mmol) dropwise via syringe. The reaction mixture became yellow and stirring was continued at âˆ’78Â° C. for 45 minutes. 1M Trimethyltin chloride in THF (0.324 ml, 0.324 mmol) was added to the mixture dropwise via syringe. No color change was observed. Continued stirring at âˆ’78Â° C. for 1.5 hours. The reaction was quenched with saturated aqueous sodium bicarbonate at âˆ’78Â° C. then warmed to room temperature. The mixture was diluted with water then extracted with ether. The organic layer was dried over sodium sulfate and concentrated under vacuum to afford 3-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)isothiazole (0.121 g, 95.1% yield) as a light yellow liquid.

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6) bis(1,1-dimethylethyl) (6-(3-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-5-isothiazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate. Bis(1,1-dimethylethyl) (6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate (0.200 g, 0.521 mmol) was suspended in dioxane (3 mL) then added 3-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)isothiazole (0.429 g, 1.09 mmol), xantphos (0.0301 g, 0.0521 mmol), palladium (II) acetate (0.00585 g, 0.0261 mmol), and water (0.0188 ml, 1.04 mmol). The reaction mixture was heated at 100Â° C. for 3 hours. The reaction mixture was concentrated under vacuum. The sample was purified by flash chromatography eluting with 0-100% ethyl acetate to afford bis(1,1-dimethylethyl) (6-(3-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-5-isothiazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate (0.170 g, 56.6% yield) as a yellow oil. MS (ESI pos. ion) m/z: 577.2 (MH⁺).

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7) (5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isothiazol-3-yl)methanol. Bis(1,1-dimethylethyl) (6-(3-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-5-isothiazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate (0.170 g, 0.29 Î¼mol) was dissolved in ethyl acetate (5 mL) then hydrochloric acid gas was bubbled through the mixture for approx. 5 minutes. A precipitate formed and stirring was continued at room temperature for 1.5 hours. The reaction was concentrated under vacuum then mostly redissolved in methanol (3.5 mL) and added ammonium hydroxide (0.052 ml, 1.3 mmol). The mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The sample was purified by flash chromatography eluting with 50-100% 90:10:1 dichloromethane/methanol/NH4OH followed by 100% 90:10:1 dichloromethane/methanol/NH4OH to afford (5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isothiazol-3-yl)methanol (0.066 g, 85% yield) as a white solid. MS (ESI pos. ion) m/z: 263.0 (MH⁺).

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Example 4376-((8-fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

1) 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline. A mixture of 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (500 mg, 3095 mmol) and methyl 2-(quinolin-6-yl)acetate (600 mg, 2982 mmol) in HCl (conc., 600 Î¼L, 7200 mmol) was heat at 100Â° C. for 20 min. The mixture was then heated in a microwave at 180Â° C. for 40 min. The mixture was quenched with NaOH (5 N, 1.5 mL) and the suspension was filtered and washed with H₂O. The resulting brown solid is mostly the desired product. The solid was then triturated with NaOH (5 N, 1 mL), filtered, and washed with H₂O. LCMS (ESI pos. ion): calc'd for C₁₆H₁₀ClFN₄: 312.0. found: 313.1 (M+1).

2) 6-((8-fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline. A mixture of Pd(OAc)₂(6.46 mg, 28.8 mmol), potassium phosphate (367 mg, 1727 Î¼mol), phenylboronic acid (211 mg, 1727 Î¼mol), dicyclohexyl(2-(2,4,6-triisopropylcyclohexa-1,3-dienyl)phenyl)phosphine (27.6 mg, 57.6 Î¼mol), and 6#6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline (180 mg, 576 Î¼mol) in dioxane (6 mL)-H₂O (2 mL) was heated to 100Â° C. under nitrogen for 20 h. The mixture was cooled to rt and partitioned between H₂O and CH₂Cl₂. The organic layer was dried over MgSO₄and concentrated. The residual was purified on silica using MeOH in DCM (0-5%) to give a pink solid. This solid was triturated with hexane-EtOAc-DCM (hot) to give a brown solid (105 mg). LCMS (ESI pos. ion): calc'd for C₂₂H₁₅FN₄: 354.1. found: 355.2 (M+1).

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Example 4386-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol

A mixture of crude 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline (200 mg, 584 Î¼mol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (600 mg, 2884 Î¼mol), PdCl₂(dppf)-CH₂Cl₂adduct (24 mg, 29 Î¼mol), and Na₂CO₃(500 mg, 4717 mmol) in DME (7 mL)-H₂O (5 mL) was heated at 100Â° C. under nitrogen. After overnight, the sludge was treated with DMSO (10 mL) and filtered. The DMSO solution was purified on HPLC (10-60%/10 min). The product fraction was concentrated to dryness with toluene. The solid was then triturated with MeOH-hexane (1:2) to give a brown powder (60 mg). LCMS (ESI pos. ion): calc'd for C₂₀H₁₅FN₆O: 374.1. found 375.1 (M+1).

General Method F

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Example 4396-((5-(3,5-difluorophenyl)isoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline

1) 2,2-difluoro-2-(quinolin-6-yl)acetic acid. To a solution of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (2.0 g, 8.4 mmol) in dioxane (4 mL) and water (12 mL) was added lithium hydroxide monohydrate (0.53 g, 12 mmol). After stirring at 50Â° C. for thirty minutes, the solution was brought to pH 4 with 2.0 N HCl. The solution was concentrated and dried on a lyophilizer overnight to yield the product as an orange solid. MS m/z=224.0 [M+1

2) 2,2-difluoro-2-(quinolin-6-yl)acetyl chloride hydrochloride. To a suspension of 2,2-difluoro-2-(quinolin-6-yl)acetic acid (1.9 g, 8.4 mmol) in dichloromethane (16 mL) was added oxalyl chloride (7.4 mL, 84 mmol). The mixture was stirred at 45Â° C. for one hour. The suspension was filtered and the resulting filtrate concentrated to yield the product as an orange oil (1.8 g, 73% step 1 and 2 combined).

3) 1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone. To a solution of 3,5-dibromo-2-fluoropyridine (3.1 g, 12 mmol) in anhydrous THF (12 mL) under argon was added isopropylmagnesium chloride (2.0 M in THF, 6.0 mL, 12 mmol). The solution was stirred at room temperature for ten minutes, then was added via cannula to a solution of 2,2-difluoro-2-(quinolin-6-yl)acetyl chloride hydrochloride (1.8 g, 6.1 mmol) in anhydrous THF (20 mL) at âˆ’78Â° C. The solution was allowed to rise to âˆ’40Â° C. over one hour; then was stirred at 0Â° C. for one hour. The reaction was quenched with water and extracted with ethyl acetate; organic extracts were dried over magnesium sulfate and concentrated. Purification by MPLC (eluted with a gradient of 20 to 80% ethyl acetate in hexanes) afforded the product as a tan solid (0.90 g, 38%).

4) 1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone oxime. To a pressure vessel was added hydroxylamine hydrochloride (1.6 g, 24 mmol), sodium acetate (2.9 g, 35 mmol) and 1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone (0.90 g, 2.4 mmol) in acetic acid (20 mL). The suspension was sealed and stirred at 100Â° C. for fifteen minutes, then was concentrated, triturated with water and filtered. Purification of the resulting solid by MPLC (eluted with a gradient of 0-10% methanol in dichloromethane) afforded the product as a beige solid (0.59 g, 63%). MS m/z=396.0 [M+1]⁺

5) 6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline. To a solution of 1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone oxime (0.59 g, 1.5 mmol) in anhydrous THF (10 mL) was added sodium hydride (0.090 g, 2.3 mmol) at 0Â° C. After ten minutes, the solution was diluted with ethyl acetate and washed with water, organic extracts were dried over magnesium sulfate. Purification by MPLC (eluted with a gradient of 20-50% ethyl acetate in hexanes) afforded the product as a white solid (0.39 g, 70%). MS m/z=377.0 [M+1]⁺ Calc'd for C₁₆H₈BrF₂N₃O: 376.2

6) 6-((5-(3,5-difluorophenyl)isoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline. To a pressure vessel was added PdCl₂(dppf)-CH₂Cl₂adduct (0.0076 g, 0.0093 mmol), cesium carbonate (0.13 g, 0.40 mmol), 6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline (0.050 g, 0.13 mmol) and 3,5-difluorophenylboronic acid (0.031 g, 0.020 mmol) in DMF (1.0 mL) water (0.25 mL). The vessel was purged with argon, sealed and stirred at 80Â° C. for two hours. The mixture was concentrated, triturated with water an filtered; purification of the resulting precipitate by MPLC (eluted with a gradient of 20 to 50% ethyl acetate in hexanes afforded the product as a white solid (27 mg, 53%).

General Method G

[Image Omitted]

Example 4406-(difluoro(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinoline

1) 2,2-difluoro-N-methoxy-N-methyl-2-(quinolin-6-yl)acetamide. To a solution of N-methoxymethanamine hydrochloride (3.7 g, 38 mmol) and methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (6.0 g, 25 mmol) in anhydrous THF (30 mL) was added isopropylmagnesium chloride (2.0 M, 38 mL, 76 mmol) at âˆ’20Â° C. After thirty minutes the reaction was quenched with saturated ammonium chloride and extracted with diethyl ether; organic extracts were dried over magnesium sulfate. Purification by MPLC (eluted with a gradient of 10 to 70% ethyl acetate in hexanes) afforded the product as an orange solid. MS m/z=267.2 [M+1]⁺.

2) 1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone. n-Butyllithium (2.5M in hexanes, 3.70 ml, 9.25 mmol) was added to a stirred solution of DABCO (1.04 g, 9.25 mmol) in Et₂O (46 mL) at âˆ’78Â° C. The reaction mixture was stirred 1 h at âˆ’20Â° C. and then cooled again at âˆ’78Â° C. 2-Chloro-5-fluoropyridine (0.939 ml, 9.25 mmol) in Et₂O (5 mL) was added. Stirring was continued at âˆ’78Â° C. for 1 h. 2,2-Difluoro-N-methoxy-N-methyl-2-(quinolin-6-yl)acetamide (2.24 g, 8.41 mmol) in Et₂O (20 mL) was added by cannula. The reaction mixture was stirred at âˆ’78Â° C. for 70 min. The cooling bath was replaced by an ice/water bath. After 10 min of stirring at 0Â° C., the reaction mixture was quenched with water. The water layer was extracted with EtOAc and DCM/MeOH (9/1). The organic layers were combined, dried over MgSO₄, filtered and concentrated in vacuo. Purification by MPLC (hexanes/EtOAc: 100/0 to 40/60) afforded the title compound (2.27 g, 80% yield).

3) 1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone oxime. To a pressure vessel was added 1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone (1.0 g, 3.0 mmol), sodium acetate (3.7 g, 45 mmol) and hydroxylamine hydrochloride (2.1 g, 30 mmol) in acetic acid (15 mL). The vessel was sealed and the suspension was stirred at 100Â° C. for twenty minutes. Following concentration and trituration with water, a white precipitate was collected via filtration. Purification of the solid by MPLC (eluted with 0-10% methanol in dichloromethane) afforded the product as a white solid (0.85 g, 82%) MS m/z=352.0 [M+1]⁺.

4) 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline. To a pressure vessel was added 1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone oxime (0.050 g, 0.14 mmol) and cesium carbonate (0.14 g, 0.43 mmol) in anhydrous DMF (1 mL). After stirring at 80Â° C. for 30 minutes, the solution was diluted with ethyl acetate and washed with water. Organic extracts were dried over magnesium sulfate and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) to yield the product as a white solid (35 mg, 74%) MS m/z=332.2 [M+1]⁺. Calc'd for C16H8ClF2N30: 331.7.

5) 6-(difluoro(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinoline. To a pressure vessel was added 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline) (0.10 g, 0.30 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (0.012 g, 0.015 mmol), cesium carbonate (0.29 g, 0.90 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.094 g, 0.45 mmol) in DMF (2 mL) and water (0.5 mL). The vessel was purged with argon, sealed and stirred at 80Â° C. for forty minutes. The mixture was diluted with ethyl acetate and washed with water, organic extracts were dried over magnesium sulfate. Purification by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) afforded the product as a light yellow solid (45 mg, 40%). MS m/z=378.2 [M+1]⁺ Calc'd for C₂₀H₁₃F₂N₅O: 377.3.

General Method H

[Image Omitted]

Example 4416-((R)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

1) Methyl 2-(quinolin-6-yl)propanoate. To a solution of methyl 2-(quinoline-6-yl)acetate (7.0 g, 35 mmol) in anhydrous THF (70 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 35 mL, 35 mmol) and solution of methyl iodide (2.2 mL, 35 mmol) in anhydrous THF (1 mL) at âˆ’78Â° C. The dry ice in acetone bath was removed and the mixture was stirred for 35 minutes, then was quenched with saturated ammonium chloride (30 mL), diluted with ethyl acetate and washed with saturated sodium bicarbonate. Organic extracts were dried over magnesium sulfate and purified via MPLC (eluted with a gradient of 10 to 30% ethyl acetate in hexanes) to yield the product as a light yellow oil (6.5 g, 87%).

2) 2-(quinolin-6-yl)propanoic acid. To a solution of methyl 2-(quinolin-6-yl)propanoate (1.4 g, 6.5 mmol) in methanol (7 mL) and water (1.5 mL) was added sodium hydroxide (6 N, 2.7 mL, 16 mmol) and the solution was stirred at 50Â° C. for one hour. The solution was concentrated, brought to pH 4 with 2.0 N HCl and the product was isolated via filtration as a white solid (0.94 g, 72%).

3) 2-(quinolin-6-yl)propanoyl chloride hydrochloride. To a suspension of 2-(quinolin-6-yl)propanoic acid (0.73 g, 3 6 mmol) in anhydrous dichloromethane (15 mL) was added thionyl chloride (1.3 mL, 18 mmol) and the solution was stirred at room temperature for ten minutes. The solution was concentrated to yield the product as an orange solid.

4) 1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one. To a solution of 3,5-dibromo-2-fluoropyridine (2.4 g, 9 3 mmol) in anhydrous THF (10 mL) was added isopropylmagnesium chloride (2.0 M in THF, 4.7 mL, 9 3 mmol) and stirred at room temperature for ten minutes. The solution was added via cannula to a solution of 2-(quinolin-6-yl)propanoyl chloride hydrochloride (0.79 g, 3.1 mmol) in anhydrous THF (10 mL) at âˆ’78Â° C. and the combined reaction mixture was allowed to rise to âˆ’40Â° C. over one hour. The mixture was stirred at âˆ’40Â° C. for an additional 90 minutes, then was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. Organic extracts were dried over magnesium sulfate and purified via MPLC (eluted with a gradient of 10-80% ethyl acetate in hexanes) to yield the product as a yellow oil (0.60 g, 54%).

5) 1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one oxime. To a pressure vial was added sodium acetate (2.0 g, 24 mmol), hydroxylamine hydrochloride (1.1 g, 16 mmol) and 1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one (0.58 g, 1.6 mmol) in acetic acid (10 mL). The vial was sealed and stirred at 100Â° C. for one hour, then was concentrated, diluted with ethyl acetate and washed with water. Organic extracts were concentrated and purified by MPLC (eluted with 0-10% methanol in dichloromethane) to yield the product as a tan oil (0.50 g, 83%).

6) 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline. To a solution of 1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one oxime (0.58 g, 1.6 mmol) in THF (15 mL) was added sodium hydride (60% in mineral oil, 0.093, 2.3 mmol) at 0Â° C. The solution was stirred at 0Â° C. for ten minutes, then was diluted with ethyl acetate and washed with water. Organic extracts were concentrated and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) to yield the product as a colorless oil (0.10 g, 19%). MS m/z=354.0 [M+1]⁺. Calc'd for C₁₇H₁₂BrN₃O: 354.2

7) 6-((R)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline. To a pressure vial was added 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.09 g, 0.25 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (0.010 g, 0.013 mmol), cesium carbonate (0.25 g, 0.76 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.079 g, 0.38 mmol) in DMF (2.5 mL) and water (0.5 mL). The vessel was flushed with argon, sealed and stirred at 90Â° C. for one hour. The mixture was concentrated, triturated in water and a brown solid was collected via filtration. Purification by MPLC (eluted with a gradient of 10 to 50% ethyl acetate) afforded a racemic mixture of the product. The desired enantiomer (>99% ee) was obtained via SFC. MS m/z=356.2 [M+1]⁺ Calc'd for C₂₁H₁₂N₅O: 355.4

[Image Omitted]

Example 442

N-((6-(3-(fluoromethyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine: To a suspension of (5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazol-3-yl)methanol (0.080 g, 0.20 mmol) in anhydrous dichloromethane (3 mL) was added deoxofluor (0.10 mL, 0.060 mmol) under argon at 0Â° C. The solution was brought to room temperature over one hour and stirred three additional hours. The reaction was quenched with saturated sodium bicarbonate and stirred for 15 minutes; a brown gum was collected by filtration. Purification via MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) afforded the product as an off-white solid (9.0 mg, 11%). MS m/z=407.2 [M+1]⁺. Calc'd for C₁₉H₁₅FN₈O₂: 406.4

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Example 4436-(difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[5,4-b]pyridin-3-yl)methyl)quinoline

To a pressure vial was added 2-(dicyclohexylphosphino)biphenyl (9.3 mg, 0.013 mmol), 6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.27 mmol), 3-methyl-5-(trimethylstannyl)isothiazole (0.14 g, 0.53 mmol) and Pd₂(dba)₃(12 mg, 0.013 mmol) in anhydrous DMF (5 mL). The vessel was purged with argon, sealed and stirred at 80Â° C. for ninety minutes. The mixture was concentrated and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) to yield the product as a light yellow solid. MS m/z=395.0 [M+1]⁺ Calc'd for C₂₀H₁₂F₂N₄OS: 394.4.

The following example compounds 444-448 were prepared using a method similar to 6-(difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[5,4-b]pyridin-3-yl)methyl)quinoline:

MassExStructureMWFound444 [Image Omitted]

374375 445 [Image Omitted]

380381 446 [Image Omitted]

378379 447 [Image Omitted]

363364 448 [Image Omitted]

377378

[Image Omitted]

Example 449N-cyclobutyl-3-(difluoro(quinolin-6-yl)methyl)isoxazolo[5,4-b]pyridin-5-amine

To a pressure vial was added sodium tert-butoxide (38 mg, 0.40 mmol), xantphos (0.12 g, 0.20 mmol), Pd₂(dba)₃(61 mg, 0.066 mmol), 6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.27 mmol), and cyclobutanamine (0.025 mL, 0.29 Î¼mol) in toluene (3 mL). The mixture was stirred at 80Â° C. for two hours then was diluted with dichloromethane and filtered through celite. Purification of the filtrate by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) afforded the product as a yellow oil (5.1 mg, 5%). MS m/z=367.0 [M+1]⁺ Calc'd for C₂₀H₁₆F₂N₄O: 366.4

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Example 4506-((5-(3,5-difluorophenyl)isoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline

To a pressure vessel was added cesium carbonate (0.61 g, 1.9 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (26 mg, 0.031 mmol), 1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone oxime (0.26 g, 0.63 mmol) and 3,5-difluorophenylboronic acid (0.15 g, 0.94 mmol) in anhydrous DMF (5 mL) and water (1 mL). The mixture flushed with argon, sealed and stirred at 80Â° C. for one hour. The suspension was concentrated, triturated with water and filtered to afford a tan solid, purification by MPLC (eluted with a gradient of 20 to 50% ethyl acetate in hexanes) afforded the product as a white solid (23 mg, 9%). MS m/z=410.0 [M+1]⁺ Calc'd for C₂₂H₁₁F₄N₃O: 409.3.

[Image Omitted]

Example 4516-(difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of 5-bromo-3-methylisothiazole (0.19 g, 1.1 mmol) in anhydrous THF (3 mL) was added isopropylmagnesium lithium chloride (1.0 M in THF, 1.5 mL, 1.5 mmol) at âˆ’40Â° C. The mixture was stirred at âˆ’40Â° C. for twenty minutes followed by the addition of zinc chloride (0.5 M in THF, 3.1 mL, 1.6 mmol). The mixture was brought to room temperature and stirred for thirty minutes followed by the addition of Q-Phos (0.12 g, 0.17 mmol), Pd₂(dba)₃(0.097 g, 0.110 mmol), 645-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.30 mmol), and anhydrous dimethylacetamide (3.5 mL). The mixture was stirred at 50Â° C. for ninety minutes then was diluted with ethyl acetate and washed with water. Organic extracts were dried over magnesium sulfate and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes), then purified by HPLC (eluted with a gradient of 15 to 90% acetonitrile in water) to afford the product as a white solid (4.2 mg, 3%). MS m/z=395.2 [M+1]⁺ Calc'd for C₂₃H₁₅F₂N₃O: 394.4.

[Image Omitted]

Example 4523-(difluoro(quinolin-6-yl)methyl)-N,N-dimethylisoxazolo[4,5-b]pyridin-5-amine

To a microwave vial was added dimethylamine (2.0 M in THF, 0.75 mL, 1.5 mmol) and, 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.30 mmol) in ethanol (3 mL). The mixture was stirred at 140Â° under microwave irradiation for two hours then was concentrated and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) to yield the product as a light yellow solid (87 mg, 85%). MS m/z=341.2 [M+1]⁺ Calc'd for C₁₈H₁₄F₂N₄O: 340.3.

MassExStructureMWFoundMethod453 [Image Omitted]

387388H 454 [Image Omitted]

387 388H

[Image Omitted]

Example 4556-(1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), and 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90Â° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to afford the product as an off-white solid. MS m/z=359.0 [M+1]⁺ Calc'd for C₂₀H₁₄N₄OS: 358.4.

[Image Omitted]

Example 4566-((R)-1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90Â° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield the racemic product as an off-white solid. The desired enantiomer (>99% ee) was obtained via SFC. MS m/z=359.0 [M+1]⁺ Calc'd for C₂₀H₁₄N₄OS: 358.4

[Image Omitted]

Example 4576-((S)-1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

Prepared by a method similar to 6-((R)-1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline. MS m/z=359.0 [M+1]⁺ Calc'd for C₂₀H₁₄N₄OS: 358.4.

[Image Omitted]

Example 4586-((S)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

Prepared by a method similar to 6-((R)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline. MS m/z=356.2 [M+1]⁺ Calc'd for C₂₁H₁₇N₅O: 355.4

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Example 4597-methoxy-4-((6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

To a solution of tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (0.27 g, 0.50 mmol) (prepared according to general method A) was added trifluoroacetic acid (0.77 mL, 10 mmol). The mixture was stirred at room temperature for 90 minutes, then was concentrated, taken up in 2.0 M ammonia in methanol and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield the product as a pink solid. MS m/z=445.0 [M+1]⁺ Calc'd for C₂₃H₂₀N₆O₂S: 444.51.

[Image Omitted]

5-bromo-N,N-dimethylthiazol-2-amine: To a microwave vial was added N-ethyl-N-isopropylpropan-2-amine (0.72 mL, 4.1 mmol), 2,5-dibromothiazole (1.00 g, 4.1 mmol) and dimethylamine (40% in water, 0.52 mL, 4.1 mmol) in ethanol (10 mL). The vial was sealed and stirred at 140Â° C. under microwave irradiation for one hour, then was concentrated and purified by MPLC (eluted with a gradient of 0-50% ethyl acetate in hexanes) to yield the product as a white, crystalline solid (0.25 g, 29%).

[Image Omitted]

tert-butyl (6-(2-(dimethylamino)thiazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate: To a solution of 5-bromo-N,N-dimethylthiazol-2-amine (0.73 g, 3.53 mmol) in anhydrous THF (9 mL) was added isopropylmagnesium lithium chloride (1.0 M in THF, 4.8 mL, 4.8 mmol) at âˆ’40Â° C. The solution was stirred for twenty minutes followed by the dropwise addition of zinc chloride (0.5 M in THF, 10 mL, 5.2 mmol). The mixture was brought to room temperature and stirred for thirty minutes followed by the addition of dimethylacetamide (12 mL), Pd₂(dba)₃, (0.32 g, 0.35 mmol), Q-Phos (0.34 g, 0.56 mmol), and tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.29 g, 1.0 mmol). The mixture was stirred at 50Â° for two hours then was quenched with saturated ammonium chloride and purified by MPLC chromatography (eluted with a gradient of 0 to 10% (1:10:90 NH₄OH:MeOH:DCM) in DCM) to yield the product as a light orange solid (0.27 g, 71%).

General Method I

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Example 4606-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-0)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline

[Image Omitted]

1) tert-butyl 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetate. The title compound was made from tert-butyl 2-(3-methoxyquinolin-6-yl)acetate in a similar fashion to the procedure reported for the synthesis of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate.

[Image Omitted]

2) 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid. A 200 mL round bottom flask was charged with tert-butyl 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetate (5.06 g, 16 mmol) then CH₂Cl₂, then trifluoroacetic acid (16 ml, 213 mmol) followed by triethylsilane (6.5 ml, 41 mmol). The solution was maintained at rt for 24 h until LCMS showed disappearance of starting material. The solution was concentrated and was subjected to high vacuum for 40 h to give 4.1 g (99% yield) of 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid as a brown solid. The material was of sufficient purity for use in subsequent steps.

[Image Omitted]

3) 2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine. A sealable flask was charged with 5-chloro-2,3-difluoropyridine (1.541 g, 10.3 mmol), palladium(ii) acetate (0.116 g, 0.515 mmol), potassium phosphate tribasic (6.56 g, 30.9 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.57 g, 12.4 mmol), and X-Phos (0.491 g, 1.03 mmol). The flask was sealed with a septum cap, then dioxane (20 mL) and H2O 2O (2 mL) were added. The resulting mixture was sparged with N₂for 10 min, and then heated at 100Â° C. for 2 h. The solution was cooled to rt and then concentrated and purified by flash chromatography using eluent 99:1 Hexanes:EtOAc to 60:40 Hexanes:EtOAc gradient to afford 2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (1.78 g, 88.5% yield) as a colorless film. LRMS (ESI) m/z calcd for C₉H₇F₂N₃(M+H) 197.1. found 197.4.

[Image Omitted]

4) 2,2-difluoro-Nâ€²-(2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(3-methoxyquinolin-6-yl)acetohydrazide. A round bottom flask was charged with 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid (389 mg, 1536 Î¼mol) and DMF (8 mL). The solution was cooled to 0 C, thionyl chloride (224 Î¼l, 3073 Î¼mol), was added and the resulting solution was maintained 1 h at 0Â° C. Then, triethylamine (641 Î¼l, 4609 Î¼mol)was added via syringe, followed by 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (382 mg, 1844 Î¼mol) and 4-(dimethylamino)pyridine (18.8 mg, 154 Î¼mol); both added as solids. The heterogeneous solution was stirred at 0Â° C. for 1 h, then allowed to warm to rt and stir for 18 h. The mixture was quenched with saturated aqueous NaHCO₃(50 mL) and the resulting mixture was extracted with CH₂Cl₂(3Ã—50 mL). The combined organic layers were concentrated (heating to 50Â° C.) and the residue purified by SiO₂chromatography solvent system: CH₂Cl₂:MeOH 99%:1% gradient 90:10 CH₂Cl₂to yield 2,2-difluoro-Nâ€²-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide (225 mg, 33.1% yield) as a brown amorphous solid.

5) 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline. A sealable microwave vial was charged with 2,2-difluoro-Nâ€²-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide (225 mg, 509 Î¼mol) and polymer supported triphenylphosphine (2.3 mmol/g, 221 mg, 509 Î¼mol). The flask was sealed and dichloroethane (4 mL) was added followed by diisopropylethylamine (89 Î¼l, 509 Î¼mol) and 2,2,2-trichloroacetonitrile (127 Î¼l, 1271 Î¼mol). The resulting mixture was irradiated in a microwave (Biotage Initiator) at 150Â° C. for 40 min. The reaction mixture was filtered and the filter cake was washed with CH₂Cl₂(15 mL) and MeOH (10 mL). The filtrate was concentrated in vacuo and the resulting crude residue was purified by MPLC using 100% CH₂Cl₂to 98:2 CH₂Cl₂: MeOH to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline (94 mg, 44% yield) as a tan amorphous solid. LRMS (ESI) m/z calcd for C₂₁H₁₆F₃N₆O (M+H) 425.1. found 425.4.

[Image Omitted]

Example 4616-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol

To a flask charged with 3-(benzyloxy)-6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline (10 mg, 20 mmol) was added trifluoroacetic acid (1.5 mL, 20 mmol). The resulting solution was heated at 65Â° C. for 18 h. The solution was concentrated for purification by MPLC using 98:2 CH₂Cl₂: MeOH to 90:10 CH₂Cl₂: MeOH gradient to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol (3.6 mg, 44% yield) as a colorless solid. LRMS (ESI) m/z calcd for C₂₀H₁₄F₃N₆O (M+H) 411.1. found 411.3.

[Image Omitted]

Example 4626-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-(3-morpholinopropoxy)quinoline

To a flask charged with 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol (17.3 mg, 42 mmol), was added triphenylphosphine (55 mg, 211 Î¼mol), THF (1 mL), and 4-(3-hydroxypropyl)-morpholine, 95% (31 Î¼l, 211 Î¼mol). The mixture was placed under N₂and cooled to 0Â° C. Di-tert-butyl azodicarboxylate (49 mg, 211 Î¼mol) was added as a solid in a single portion and the solution was allowed to warm to rt and was maintained for 48 h. The solution was concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH₂Cl₂and absorbed onto a 5g loading cartridge and passed through a Redi-SepÂ® pre-packed silica gel column (0 g) using 99:1 CH₂Cl₂: MeOH to 90:10 CH₂Cl₂: MeOH gradient to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-(3-morpholinopropoxy)quinoline (7.5 mg, 33% yield) as a colorless solid; LRMS (ESI) m/z calcd for C₂₇H₂₇F₃N₇O₂(M+H) 538.2. found 538.2.

[Image Omitted]

Example 4636-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline

[Image Omitted]

a) Nâ€²-(5-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetohydrazide. This compound was assembled from 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid and 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine according to General Method I. LRMS (ESI) m/z calcd for C₁₇H₁₃ClF₃N₄O₂S (M+H) 397.1. found 397.2.

[Image Omitted]

b) 6-((6-chloro-8-fluoro-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline. This compound was made from Nâ€²-(5-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetohydrazide according to General Method I. LRMS (ESI) m/z calcd for C₁₇H₁₁ClF₃N₄O (M+H) 379.1. found 379.2.

c) 6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline. A sealable microwave vial was charged with 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline (342.05 mg, 903 mmol), palladium(II) acetate (30 mg, 135 mmol), potassium phosphate (575 mg, 2709 mmol), 3,5-difluorophenylboronic acid (285 mg, 1806 mmol), and X-Phos (129 mg, 271 mmol). The tube was sealed, and flushed with N₂. Dioxane (9 mL), then H₂O (1 mL) were added and the mixture was sparged with N₂for 10 min, then heated at 100Â° C. for 24 h. The mixture was cooled to rt and concentrated absorbed onto a 5g loading cartridge for MPLC purification using a 98:2 CH₂Cl₂: MeOH to 90:10 CH₂Cl₂: MeOH gradient to give 6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline (72 mg, 17% yield). LRMS (ESI) m/z calcd for C₂₃H₁₄F₅N₄O (M+H) 457.1. found 457.0.

[Image Omitted]

tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate

A flask was charged with tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (581.04 mg, 2.241 mmol) and triphenylphosphine (1.175 g, 4.482 mmol) then sealed with a septum and an placed under N₂. Benzene (10 mL) was added, followed by 2-methoxyethanol (0.8838 ml, 11.20 mmol). The heterogeneous solution was cooled to 0Â° C., and di-tert-butyl azodicarboxylate (1.032 g, 4.482 mmol) was added as a solid in a single portion. The solution was allowed to warm to rt and maintained 20 h. The solution was then partitioned between saturated aqueous. NH₄Cl, and the layers separated. The aqueous layer was extracted with EtOAc (2Ã—50 mL), and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by MPLC (Teledine Isco combiFlash Companion), 80 g SiO₂, solvent system: 90:10 hexanes:EtOAc gradient to 50:50 hexanes:EtOAc to give tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (585. 2 mg, 82% yield). LRMS (ESI) m/z calcd for C₁₈H₂₄NO₄(M+H) 318.2. found 318.3.

[Image Omitted]

tert-butyl 2-(3-((1,4-dioxan-2-yl)methoxy)quinolin-6-yl)acetate (racemate)

The title compound was assembled from tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate and (1,4-dioxan-2-yl)methanol according to the procedure described for tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate.

[Image Omitted]

Nâ€²-(6-chloropyridazin-3-yl)-2,2-difluoro-2-(3-(2-methoxyethoxy)quinolin-6-yl)acetohydrazide

The title compound was assembled from 1-(6-chloropyridazin-3-yl)hydrazine and tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate as described in General Method I. LRMS (ESI) m/z calcd for C₁₈H₁₇ClF₂N₅O₃(M+H) 424.1. found 424.2.

[Image Omitted]

Example 4646-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline

A sealable microwave vial was charged with Nâ€²-(6-chloropyridazin-3-yl)-2,2-difluoro-2-(3-(2-methoxyethoxy)quinolin-6-yl)acetohydrazide (46.98 mg, 111 mmol), 1,2-dimethoxyethane (1.5 mL), and 1 drop of conc. HCl. The vial was sealed and heated at 130Â° C. for 40 min. The solution was concentrated and purified by MPLC (Teledine Isco combiFlash Companion). The residue was taken up in minimal CH₂Cl₂and absorbed onto a 5g loading cartridge and passed through a Redi-SepÂ® pre-packed silica gel column (12g) using 98:2 CH₂Cl₂: MeOH to 90:10 CH₂Cl₂: MeOH to afford 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline (25.3 mg, 56.2% yield) as a colorless solid. LRMS (ESI) m/z calcd for C₁₈H₁₅ClF₂N₅O₂(M+H) 406.1. found 406.2.

[Image Omitted]

Example 4656-((6-(3,5-difluorophenyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline

The title compound was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline and 3,5-difluorophenylboronic acid in a similar manner as that described for 6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline. LRMS (ESI) m/z calcd for C₂₄H₁₈F₄N₅O₂(M+H) 484.1. found 484.2.

General Method J

[Image Omitted]

Example 466N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

[Image Omitted]

1) methyl 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate. A sealable microwave vial was charged with methyl 2-(5-chlorofuro[3,2-b]pyridin-3-yl)acetate (1.30 g, 5.74 mmol), palladium(II) acetate (0.129 g, 0.574 mmol), potassium phosphate (3.66 g, 17 2 mmol), 3,5-difluorophenylboronic acid (1.81 g, 11.5 mmol), and X-Phos (0.548 g, 1.15 mmol). The vial was sealed, flushed with N₂, then dioxane (20 mL) and H₂O (2 mL) were added. The solution was sparged with N₂for 10 min, then heated at 100Â° C. for 24 h. The mixture was then cooled to rt and concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH₂Cl₂and absorbed onto a 25g loading cartridge and passed through a Redi-SepÂ® pre-packed silica gel column (120 g) using 98:2 Hexanes:EtOAc to 70:30 Hexanes:EtOAc gradient to afford methyl 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate (1.46 g, 83.8% yield) as a colorless amorphous solid. LRMS (ESI) m/z calcd for C₁₆H₁₂F₂NO₃(M+H) 304.1. found 304.2.

[Image Omitted]

2) 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetic acid. To a flask charged with methyl 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate (1.46 g, 5 mmol) was added MeOH (1.5 mL), H₂O (0.5 mL), followed by NaOH (2 mL, 6 M, 12 mmol) to generate a yellow solution, which was capped and maintained at rt for 18 h. The solution was acidified with conc. HCl to pH=3 and poured into CH₂Cl₂. The layers were separated and the organic layer was extracted with CH₂Cl₂(2Ã—10 mL), followed by EtOAc (2Ã—10 mL). The combined organic extracts were dried over Na₂SO₄and concentrated in vacuo to produce a colorless solid, which was of sufficient purity for use in the next step.

[Image Omitted]

3) methyl (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methylcarbamate. To a flask under N2 charged with 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetic acid (1.033 g, 3.57 mmol) was added anhydrous CH₂Cl₂(40 mL). The heterogeneous solution was cooled to 0Â° C. and oxalyl chloride (1.6 mL, 17.8 mmol) was added, followed by a catalytic amount of DMF. The solution was warmed to rt and maintained for 1 h. The solution was concentrated, then taken up in anhydrous acetone and added to a stirring aqueous solution of sodium azide (1.62 g, 25.0 Î¼mol, in 10 mL H₂O) at 0Â° C. to generate a homogeneous orange solution. After 15 min at 0Â° C., the mixture was diluted further with CH₂Cl₂and stirred an additional 5 min to give a homogeneous solution. The solution was then partitioned between H₂O and CH₂Cl₂, and the layers were separated. The aqueous layer was extracted with CH₂Cl₂(2Ã—10 mL) and the combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The residue was transferred to a dry flask, evacuated and flushed with N₂(5Ã—), and anhydrous CH₂Cl₂(30 mL) was added. The solution was cooled to âˆ’78Â° C., and boron trichloride (5.4 mL, 5.4 Î¼mol, 1.0 M in CH₂Cl₂) was added dropwise. The cold bath was removed and the solution was allowed to warm to rt, and maintained 48 h. Anhydrous methanol (5 mL) was added and the solution maintained at rt for 3 h at which time it was concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The residue was taken up in minimal CH₂Cl₂and absorbed onto a 25g loading cartridge and passed through a Redi-SepÂ® pre-packed silica gel column (80 g) using 99:1 CH₂Cl₂: MeOH to 90:10:1 CH₂Cl₂: MeOH:NH₄OH to afford methyl (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methylcarbamate (680 mg, 60% yield) as a brown amorphous solid. LRMS (ESI) m/z calcd for C₁₆H₁₃F₂N₂O₃(M+H) 319.1. found 319.2.

[Image Omitted]

4) (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine. To a flask charged with methyl (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methylcarbamate (680 mg, 2137 Î¼mol) was added MeOH (20 mL), then aqueous NaOH (18 mL, 6 N, 106 mmol). The solution was heated at reflux for 60 h. The solution was concentrated to remove MeOH, then partitioned between CH₂Cl₂(30 mL) and NaHCO₃(10 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂(1Ã—10 mL), then EtOAc (4Ã—25 mL). The combined organic layers were concentrated to give a total of (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine (306.6 mg, 55% yield) as a brown foam. LRMS (ESI) m/z calcd for C₁₄H₁₁F₂N₂O (M+H) 261.1. found 261.2.

5) N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine A sealable microwave vial was charged with (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine (177.6 mg, 682 Î¼mol), 8-chloro-3-methoxy-1,5-naphthyridine (146 mg, 751 Î¼mol), and potassium phosphate (435 mg, 2047 Î¼mol). A septum was attached and the vial was flushed with N₂, then toluene (5 mL) and H2O 2O (1 mL) were added and the was solution sparged with N₂for 5 min. The septum was then quickly removed and tris(dibenzylideneacetone)dipalladium (o) (15.6 mg, 17.1 Î¼mol) and rac-2,2â€²-bis(diphenylphosphino)-1,1â€²-binaphthyl (42.5 mg, 68.2 Î¼mol) were added together as solids. The vial was then sealed and the resulting purple solution was sparged again for 5 min. The mixture was then heated at 100Â° C. for 20 h. The mixture was concentrated in vacuo for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH₂Cl₂and absorbed onto a 25g loading cartridge and passed through a Redi-SepÂ® pre-packed silica gel column (80 g) using 98:2 CH₂Cl₂: MeOH to 90:10 CH₂Cl₂: MeOH gradient to afford a tan amorphous solid. This solid was additionally triturated with CH₂Cl₂(2Ã—0.5 mL) to give N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (103 mg, 36.1% yield). LRMS (ESI) m/z calcd for C₂₃H₁₂F₂N₄O₂(M+H) 419.1. found 419.2.

[Image Omitted]

Example 467N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-(2-methoxyethoxy)-1,5-naphthyridin-4-amine

The title compound was assembled from (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine and 8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine in the manner described for 7-methoxy-N-((5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)methyl)-1,5-naphthyridin-4-amine LRMS (ESI) m/z calcd for C₂₅H₂₁F₂N₄O₃(M+H) 463.2. found 463.2.

[Image Omitted]

Methyl 2-(5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)acetate

A sealable flask was charged with methyl 2-(5-chlorofuro[3,2-b]pyridin-3-yl)acetate, palladium (II) acetate (49.8 mg, 222 mmol), X-Phos (211 mg, 443 mmol), and 3-methyl-5-(tributylstannyl)isoxazole (1319 mg, 3546 mmol). The flask was sealed and dioxane (20 mL) was added. The mixture was sparged with N₂for 10 min, then heated at 100Â° C. for 48 h. The mixture was cooled to rt and concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH₂Cl₂and absorbed onto a 25g loading cartridge and passed through a Redi-SepÂ® pre-packed silica gel column (0 g) using 98:2 CH₂Cl₂: MeOH to 90:10 CH₂Cl₂: MeOH to afford methyl 2-(5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)acetate (581 mg, 96.3% yield). LRMS (ESI) m/z calcd for C₁₄H₁₃N₂O₄(M+H) 273.1. found 273.3.

MWMassMeth-ExStructure(M + H)Foundod468 [Image Omitted]

426426I 469 [Image Omitted]

442442I 470 [Image Omitted]

396396I 471 [Image Omitted]

428428I 472 [Image Omitted]

501501I 473 [Image Omitted]

512512I 474 [Image Omitted]

388388J

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8-chloro-3-fluoro-1,5-naphthyridine

1) 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. A 150 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (6.0 g, 41.6 mmol) and trimethyl orthoformate (41.6 mL, 41.6 mmol). This was heated to 100Â° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30Â° C. and 5-fluoropyridin-3-amine (4.7 g, 41.6 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100Â° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.1 g, 82% yield) as a bright yellow solid. MS [M+H]=267.2. Calc'd for C₁₂H₁₁FN₂O₄=266.2.

2) 7-fluoro-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.0 g, 30.0 mmol) and diphenyl ether (83.5 mL). This was heated to 250Â° C. in heating mantle and allowed to stay at this temperature for five minutes. Cooled to room temperature, diluted with hot hexanes, and filtered to afford 7-fluoro-1,5-naphthyridin-4(1H)-one (2.2 g, 45% yield) as a crude brown solid. The title compound was used without further purification. MS [M+H]=165.2, Calc'd for C₈H₅FN₂O=164.14.

3) 8-chloro-3-fluoro-1,5-naphthyridine. A pressure resistant vial was charged with 7-fluoro-1,5-naphthyridin-4(1H)-one (600 mg, 3.66 mmol) and POCl₃(6.8 mL, 73.1 mmol). Vessel sealed and stirred at 110Â° C. for 16 hrs. Reaction mixture was cooled to room temperature and poured onto ice while stirring vigorously. While keeping reaction mixture at 0Â° C., it was basified to pH Ëœ8 with 6N NaOH. Product extracted with dichloromethane. Organic layer collected, dried over sodium sulfate and concentrated to afford desired material. This was passed through a silica plug in 1-5% (90:10:1 DCM/MeOH/NH₄OH)/DCM to afford 8-chloro-3-fluoro-1,5-naphthyridine (430 mg, 64% yield) as a tan solid. MS [M+H]=182.9. Calc'd for C₈H₄ClFN₂=182.58

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7-chloro-3H-imidazo[4,5-b]pyridine

1) 4-azabenzimidazole N-oxide. Hydrogen peroxide (30 wt % solution in water, 38.0 ml, 372 mmol) was added to a suspension of 3H-imidazo[4,5-b]pyridine (4.93 g, 41.4 mmol) in AcOH (40 mL) at room temperature. The resulting reaction mixture was stirred at 80Â° C. for 3 h, cooled to RT and concentrated in vacuo to a volume Ëœ50 mL. Concentration to dryness was done using a stream of N₂. The resulting residue was suspended in water (Ëœ10 mL). Filtration afforded the title compound (4.61 g, 82.4% yield).

2) 7-chloro-3H-imidazol[4,5-b]pyridine. A 50 mL round bottom flask set up with a reflux condenser under nitrogen atmosphere was charged 4-azabenzimidazole N-oxide (1.2 g, 8.88 mmol) and 11 mL of DMF. This was heated to 50Â° C. and methanesulfonyl chloride (1.86 ml, 23.98 mmol) was added dropwise via syringe. The resulting mixture was heated to 80Â° C. and stirred at this temperature for 16 hours. This was cooled to room temperature and quenched with water (approximately 10 mL) and reaction mixture brought to pH 7 by adding 6N NaOH aqueous solution. The reaction was extracted four times with dichloromethane (50 mL). Some product was present in aqueous layer; this was concentrated and residue set aside. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 0 g column, gradient elution 0-10% MeOH:DCM) to afford 7-chloro-3H-imidazo[4,5-b]pyridine (450 mg, 33.0% yield). MS [M+H]=154.2. Calc'd C₆H₄ClN₃=153.56.

[Image Omitted]

8-chloro-1,5-naphthyridin-3-ol

A pressure-resistant vial was charged with 8-chloro-3-methoxy-1,5-naphthyridine (2.5 g, 12.8 mmol), boron tribromide (13.4 mL, 141.3 mmol) and dichloroethane (0.6M, 21.4 mL). Vessel sealed and mixture stirred at 60Â° C. for 16 hrs. Next day the reaction mixture was chilled in ice bath and diluted with dichloromethane (200 mL). This was allowed to sit under nitrogen system until all fuming ceased. The resulting yellow solid material was then filtered and dried under high vacuum. This was suspended in 40% (90:10:1 DCM/MeOH/NH4OH)/DCM and purified in this system by ISCO silica gel chromatography (80 g) afford 8-chloro-1,5-naphthyridin-3-ol (1.3 g, 56% yield). MS [M+H]=181.2. Calc'd for C₈H₅ClN₂O=180.59.

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3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine

A resealable pressure bottle was charged with 8-chloro-1,5-naphthyridin-3-ol (400 mg, 2.2 mmol), 2-dibromoethane (3.2 mL, 37.7 mmol), and DMF (0.15M, 14.8 mL). Vessel sealed and placed in a pre-heated at 65Â° C. oil bath. Reaction allowed to stir at this temperature for 4 hrs. Reaction cooled to room temperature and passed through a pad of celite. Filtrate concentrated and purified by ISCO silica gel chromatography (20-40% EtOAc/Hexanes) to afford 3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine (460 mg, 72% yield). MS [M+H]=289.0 Calc'd for C₁₀H₈BrClN₂O=287.54

The following compound was prepared using the procedure for 3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine:

8-chloro-3-((tetrahydrofuran-2-yl)methoxy)-1,5-naphthyridine; 8-chloro-3-((tetrahydrothiophen-1,1-dioxide-3-yl)methoxy)-1,5-naphthyridine (starting with the alkyl chloride).

[Image Omitted]

(R)-8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine

A 25 mL round bottom flask at rt was charged with (R)-3-fluoropyrrolidine hydrochloride (124 mg, 0.99 mmol). To this was added potassium carbonate (365 mg, 2.64 mmol), 3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine (190 mg, 0.66 mmol), sodium iodide (149 mg, 0.99 mmol) and DMF (2 mL). Reaction mixture placed in oil bath preheated to 60Â° C. and allowed to stir for 16 hrs. Reaction mixture passed through celite cake, rinsed with 10% MeOH/DCM and filtrate concentrated to afford yellow oil. This was purified by ISCO silica gel chromatography (20-40% EtOAC/Hexanes) to afford (R)-8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine (105 mg, 54% yield). MS [M+H]=296.2. Calc'd for C₁₄H₁₅ClFN₃O=295.7.

The following compounds were prepared in a similar fashion as 8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine:

8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine;
8-chloro-3-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine;
1-(2-(8-chloro-1,5-naphthyridin-3-yloxy)ethyl)pyrrolidin-3-ol;
3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-8-chloro-1,5-naphthyridine (using NaH as the base);
3-(2-(1H-pyrazol-1-yl)ethoxy)-8-chloro-1,5-naphthyridine;
3-(2-(1H-1,2,3-triazol-1-yl)ethoxy)-8-chloro-1,5-naphthyridine.

[Image Omitted]

8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine

A resealable pressure bottle was charged with 8-chloro-1,5-naphthyridin-3-ol (80 mg, 0.44 mmol), cesium carbonate (433 mg, 1.3 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (360 mg, 1.55 mmol), and DMF (0.9 ml). Vessel sealed and placed in a pre-heated at 50Â° C. oil bath. Reaction allowed tostir at this temperature for 45 minutes. LC/MS shows complete conversion. Quench with water, dilute with aqueous sodium bicarbonate solution and dichloromethane. Layers separated, organic layer collected and dried over sodium sulfate. This was concentrated to afford yellow oil; which was purified by ISCO silica gel chromatography (20-40% EtOAc/Hexanes) to afford 8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine (65 mg, 56% yield). MS [M+H]=263.0@1.89 minutes. Calc'd for C₁₀H₆ClF₃N₂O=262.6.

[Image Omitted]

8-chloro-3-(2,2-difluoroethoxy)-1,5-naphthyridine

The title compound was prepared using the method described for 8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine.

[Image Omitted]

8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine

A round bottom flask under nitrogen environment was charged with 8-chloro-1,5-naphthyridin-3-ol (1.05 g, 5.8 mmol), 22.8 g of PS-Triphenylphosphine (loading: 2.2 Î¼mol/g), 2-methoxyethanol (2.2 mL, 27.9 mmol), and THF (29.1 ml, 5814 mmol)/DCM (58.1 mL). Mixture cooled to 0Â° C. and to this was added DEAD (1.84 mL) dropwise via syringe. Reaction mixture allowed to stir at room temperature for 16 hours. Diluted with 50 mL of 10% MeOH/dichloromethane and resin bound reagent filtered. Filtrate concentrated under reduced pressure and purified by ISCO silica gel chromatography (10-30% EtOAc/Hexanes) to afford 8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine (770 mg, 55% yield) as white solid.

MS [M+H]=238.9. Calc'd for C_HH_HClN₂O₂=238.67.

The following compounds were prepared in a similar fashion as 8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine:

8-chloro-3-(2-(pyrrolidin-1-yl)ethoxy)-1,5-naphthyridine;
8-chloro-3-(3-morpholinopropoxy)-1,5-naphthyridine;
3-((1,4-dioxan-2-yl)methoxy)-8-chloro-1,5-naphthyridine;
8-chloro-3-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridine.

[Image Omitted]

8-chloro-3-(difluoromethoxy)-1,5-naphthyridine

A round bottom flask under nitrogen atmosphere was charged with sodium 2-chloro-2,2-difluoroacetate (0.49 g, 3.2 mmol), 8-chloro-1,5-naphthyridin-3-ol (0.25 g, 1.4 mmol), cesium carbonate (1.4 g, 4.2 mmol), and DMF (2.8 mL, 0.5M). This was then placed in a 100Â° C. preheated oil bath and stirred at this temperature for 3 hours. Reaction mixture diluted with 10% Methanol/Dichloromethane and filtered over celite. Filtrate concentrated and purified by ISCO silica gel chromatography (0 g) in 1% MeOH/DCM to afford pure 8-chloro-3-(difluoromethoxy)-1,5-naphthyridine (0.18 g, 56% yield) as white solid. MS [M+H]=231.2. Calc'd for C₉H₅ClF₂N₂O=230.60.

[Image Omitted]

8-chloro-3-((2-methyl-2H-1,2,4-triazol-3-yl)methoxy)-1,5-naphthyridine

1) 2-methyl-2H-1,2,4-triazole-3-carbaldehyde. A dry round bottom flask under nitrogen atmosphere was charged with 1-methyl-1H-1,2,4-triazole (1.0 g, 12.04 mmol) and THF (6.0 ml, 2M). This was cooled to 0Â° C. followed by addition of 2M solution of isopropylmagnesium chloride in THF (6.6 mL, 13.24 mmol) via syringe. Ice bath removed and reaction allowed to stir at room temperature for 1.5 hours. Reaction mixture cooled back to 0Â° C. and N,N-dimethylformamide (1.39 ml, 18.05 mmol) added dropwise via syringe. Reaction mixture allowed to warm up to room temperature over 1 hour and stirred at this temperature for 16 hours. Next day reaction mixture was quenched with 2N HCl and mixture diluted with dichloromethane. Layers separated, and aqueous layer neutralized with aq. sodium bicarbonate solution and extracted with dichloromethane. All organic layers combined, dried over sodium sulfate and concentrated at room temperature (most THF remains) to afford clear material. This was purified by ISCO silica gel chromatography (10-40% EtOAc/Hex) to afford 2-methyl-2H-1,2,4-triazole-3-carbaldehyde (1.0 g, 75% yield). Yield was estimated based on Hâ€²NMR. Product was isolated as a solution in EtOAc (did not remove all EtOAc due to volatility of aldehyde, b.p. Ëœ60Â° C.). MS [M+H]=112.2; MS [M+H+H₂O]=130.2@0.23 minutes. Calc'd for C₄H₅N₃O=111.10.

2) (2-methyl-2H-1,2,4-triazol-3-yl)methanol. 2-methyl-2H-1,2,4-triazole-3-carbaldehyde (0.50 g, 4.50 mmol) in MeOH (10 mL)was treated with sodium borohydride (0.17 g, 4.50 mmol) at room temperature and allowed to stir for 2 hours. Reaction mixture was quenched with aqueous sodium bicarbonate solution, diluted with 10% MeOH/DCM, and organic layer collected. Aqueous layer was saturated with sodium sulfate and extracted with 50 mL of dichloromethane (3 times). Organic portions combined, dried over sodium sulfate and concentrated to Â¼ volume at room temp. This was then diluted with ether, causing a precipitate to form. This was concentrated yielding 2-methyl-2H-1,2,4-triazol-3-yl)methanol as a foamy white solid (0.44 g, 86.4% yield). This was used â€˜as isâ€™ for next step. MS [M+H]=114.2. Calc'd for C₄H₂N₃O=113.1.

3) 8-chloro-3-((2-methyl-2H-1,2,4-triazol-3-yl)methoxy)-1,5-naphthyridine. The title compound was prepared in a similar fashion as 8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine.

[Image Omitted]

3-bromo-8-chloro-1,5-naphthyridine

1) 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. A 350 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (21.6 g, 150 0 mmol) and triethyl orthoformate (150 mL, 150.0 mmol). This was heated to 100Â° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30Â° C. and 55-bromopyridin-3-amine (25.95 g, 150.0 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100Â° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (41.5 g, 85% yield) as a yellow solid. MS [M+H]=327.0. Calc'd for C₁₂H₁₁BrN₂O₄=327.1.

2) 7-bromo-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.5 g, 32.1 mmol) and diphenyl ether (84.5 mL, 32.1 mmol). This was heated to 250Â° C. in heating mantle and allowed to stay at this temperature for 1 hour. Reaction mixture was cooled to room temperature and diluted with 300 mL of Hexanes. This was heated to 60Â° C. and triturated in this system for 3 hrs to afford 7-bromo-1,5-naphthyridin-4(1H)-one (6.05 g, 84% yield) as a crude brown solid. This was used without further purification.

MS[M+H]=227.0. Calc'd for C₈H₅BrN₂O=225.0.

3) 3-bromo-8-chloro-1,5-naphthyridine. 7-bromo-1,5-naphthyridin-4(1H)-one (23.8 g, 105.8 mmol), acetonitriel (192 mL, 105.8 mmol), and DMF (2.05 mL, 26 5 mmol) were placed in a 3-necked round bottom flask set up with a reflux condenser. Argon bubbled through. Reaction mixture brought to reflux (Ëœ95Â° C.). Oxalyl chloride (28.7 ml, 328.1 mmol) was added dropwise via addition funnel over 40 minutes and reaction allowed to stir at this temperature for 16 hrs. Reaction mixture cooled to 0Â° C. and basified to pH Ëœ8 with aqueous sodium bicarbonate solution. Product extracted with DCM (500 mL) three times. Organic layers combined, dried over sodium sulfate and concentrated to afford brown solid. This was purified by ISCO silica gel chromatography to afford 3-bromo-8-chloro-1,5-naphthyridine (3.6 g, 14% yield) as fluffy tan solid. MS[M+H]=245.0@. Calc'd for C₈H₄BrClN₂=243.5.

[Image Omitted]

8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine

A 25 ml round bottom flask set up under nitrogen was charged with Pd₂(dba)₃(301 mg, 0.33 mmol), BINAP (614 mg, 0.99 mmol) and sodium tert-butoxide (237 mg, 2.46 mmol). System was purged with Argon and 3-bromo-8-chloro-1,5-naphthyridine (400 mg, 1.64 mmol), diphenylmethanimine (0.28 mL, 1.64 mmol), and toluene (1M, 1.64 mL) were added. This was placed in a preheated oil bath at 80Â° C. and stirred at this temperature for 16 hours. Reaction cooled to room temperature, diluted with dichloromethane, and passed over a celite cake. Filtrate collected was concentrated to afford brown oil. This was purifed by ISCO silica gel chromatography (0 g, 1% MeOH/DCM over 50 mins) to afford clean 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (280 mg, 50% yield). MS[M+H]=344.0. Calc'd for C₂₁H₁₄ClN₃=343.8.

[Image Omitted]

8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine

[Image Omitted]

1) 8-chloro-1,5-naphthyridin-3-amine A round bottom flask under nitrogen was charged with 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (315 mg, 0.92 mmol), 2M aqueous HCl (1.42 mL, 2.84 mmol), and tetrahydrofuran (0.25M, 3.67 mL). This was stirred at RT for 30 minutes. Reaction basified with aq. sodium bicarbonate solution and product extracted with dichloromethane. This was dried over sodium sulfate and concentrated to afford orange solid; which was purified via ISCO silica gel chromatography, 0 g column, 30% (90/10/1 DCM:MeOH:NH4OH)/DCM over 40 minutes to afford 7-amino-1,5-naphthyridin-4-ol (140 mg, 95% yield) as yellow solid. MS[M+H]=180.2. Calc'd for C₈H₆ClN₃=179.6.

2) 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine A round bottom flask under nitrogen atmosphere was charged with 8-chloro-1,5-naphthyridin-3-amine (160 mg, 0.89 mmol), DMF (2.2 mL, 0.89 mmol). This was cooled to 0Â° C. and SODIUM HYDRIDE (60% dispersion in oil) (107 mg, 4.45 mmol) added portionwise. This was quickly followed by addition of 1-bromo-2-methoxyethane (0.12 mL, 1.25 mmol) dropwise via syringe. Ice bath removed and reaction mixture heated to 85Â° C. and stirred at this temperature for 16 hours. Reaction diluted with 5 mL of 5% MeOH/Dichloromethane, loaded onto silica gel column and eluted with 2% MeOH/DCM to afford 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine (70 mg, 33% yield) as a light yellow solid. MS[M+H]=238.2. Calc'd for C₁₁H₁₂ClN₃O=237.7.

[Image Omitted]

N-(8-chloro-1,5-naphthyridin-3-yl)-2-methoxyacetamide

A round bottom flask under nitrogen was charged with 8-chloro-1,5-naphthyridin-3-amine (41 mg, 0.23 mmol), triethylamine (64 Î¼l, 0.46 mmol), and dichloromethane (1 mL). To this was added 2-methoxyacetyl chloride (42 Î¼l, 0.46 mmol) dropwise via syringe and reaction allowed to stir overnight at room temperature. Next day reaction mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Layers separated and organic layer dried over sodium sulfate to afford yellow oil. This was purified by ISCO silica gel chromatography (2-5% MeOH/DCM) to afford N-(8-chloro-1,5-naphthyridin-3-yl)-2-methoxyacetamide (43 mg, 75% yield) as light yellow solid. MS[M+H]=251.9. Calc'd for C₁₁H₁₀ClN₃O₂=251.7.

[Image Omitted]

8-chloro-3-morpholino-1,5-naphthyridine

A round bottom flask under nitrogen atmosphere was charged with Pd₂(dba)₃(578 mg, 0.63 mmol), Xantphos (1.1 g, 1.89 mmol), and sodium tert-butoxide (364 mg, 3.79 mmol). This was purged with Argon followed by addition of 3-bromo-8-chloro-1,5-naphthyridine (615 mg, 2.53 mmol), morpholine (0.22 mL, 2.53 mmol), and toluene (1M, 2.53 mL). This was then placed in a preheated oil bath at 80Â° C. After 2.5 hours, reaction was stopped, cooled to room temp and diluted with Dichloromethane. This was passed over a celite cake and filtrate concentrated to afford brown oil; which was purifed by ISCO silica gel chromatography (0 g, 1% MeOH/DCM over 50 mins) to afford 8-chloro-3-morpholino-1,5-naphthyridine (200 mg, 32% yield). MS[M+H]=250.2. Calc'd for C₁₂H₁₂ClN₃O=249.7.

4-bromo-1-phenyl-1H-pyrazole

A sealable tube was charged with 4-bromopyrazole (4.000 g, 27.2 mmol), 1-iodobenzene (3.64 ml, 32.7 mmol), (+/âˆ’)-trans-1,2-diaminocyclohexane (0.654 ml, 5.44 mmol), Copper iodide (I) (0.518 g, 2.72 mmol), potassium carbonate (8.28 g, 59.9 mmol) and 13 mL dioxane added. The mixture was blanketed with N2, the vessel sealed and heated to 100 C for 16 h. The mixture was allowed to cool to rt, diluted with EtOAc, washed with water, and an emulsion formed. The organic layer separated and the aqueous emulsion mixture was filter through a pad of celite and rinsed with EtOAc, and sat. NaHCO₃. The combined organig layers were dried over Na₂SO₄, filtered and evaporate. The mixture was purified via flash chromatography using a 0% to 100% CH₂Cl₂in hexanes gradient. The title compound was collected as a yellow solid (3.18 g)

1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-O-1H-pyrazole

The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-phenyl-1H-pyrazole.

4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole

The title compound was prepared in the same manner as 4-bromo-1-(cyclobutyl)-1H-pyrazole, but using tetrahydrofuran-3-yl methanesulfonate (prepared according to procedures known in the art).

1-(tetrahydrofuran-3-O-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-O-1H-pyrazole

The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-cyclopropyl-1H-pyrazole

a) 1-cyclopropyl-1H-pyrazole. In a 1000 mL 3-neck flask, to a mixture of potassium hydroxide (104 g, 1857 mmol) in water (200 mL) was added cyclopropylamine (131 ml, 1857 mmol) and the mixture stirred at 50 C. A solution of hydroxylamine-O-sulfonic acid (HOS)(30.00 g, 265 mmol) in 100 mL water was added dropwise resulting in the formation of a white precipitate after the first few drops. The stirring stopped during the first half of the addition and some cyclopropylamine condensed on top of the HOS soln. Additional amine (10 mL) was added to the reaction and addition of HOS solution continuted. Mixture bubbles during the addition. The flask was remove from heat and cool in ice bath to 25 C. HCl (conc) was added slowly, 150-200 mL, to achieve PH 3. The mixture was filtered to remove the white solid and the filtrate heated with 1,1,3,3-tetramethoxypropane (43.7 ml, 265 mmol). The mixture took 1.5 h to reach 90 C, maintained the temperature at 90 for 1 h, then allowed the mixture to cool to 40 C with stirring for an additional 17 h. The mixture was allowed to cool to Ëœ35 C and extracted with Et₂O (400 mL then 2Ã—100 mL), the combined organic layers were with water, 6N NaOH, 2N NaOH, then sat NaHCO3, and the organic layer dried over Na₂SO₄, filtered and evaporate gently. Upon evaporation, when volume is reduced from Ëœ600 mL to Ëœ100 mL, the white solid that has precipitated was filtered. The title compound was obtained as a golden liquid (Ëœ2g).

b) 4-bromo-1-cyclopropyl-1H-pyrazole. To a golden solution of 1-cyclopropyl-1H-pyrazole (2.360 g, 22 mmol) in 100 mL chloroform, was added bromine (1.2 ml, 24 mmol) as a soln in 100 mL CHCl₃dropwise over 1.5 h. the mixture was heated in oil bath to 60 C for 2 h. The mixture was allowed to cool to RT, washed with sat NaHCO₃, dried over Na₂SO₄, filtered and evaporated to afford the title compound as a tan liquid (3.64 g).

c) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-cyclopropyl-1H-pyrazole. The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-cyclopropyl-1H-pyrazole.

[Image Omitted]

tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

A 2-L round bottom flask equipped with a magnetic stirbar was charged with di(1H-imidazol-1-yl)methanone (121 g, 749 mmol) and acetonitrile (500 mL). The stirred slurry was cooled by immersing the flask in an ice bath. A solution of N-Boc glycine (125 g, 714 mmol) in acetonitrile (500 mL) was added via a 500-mL addition funnel over the course of 30-45 min. The mixture was aged for 1 h while a 5-L, 3-neck, round bottom flask equipped with a mechanical overhead stirrer and a thermocouple w/adapter was charged with 1-(6-chloropyridazin-3-yl)hydrazine (108 g, 749 mmol) and acetonitrile (900 mL) and cooled to <5 deg C. in an ice bath. The cold solution of the acylimidazole was then transferred via a polyethylene cannula into the thick suspension of the hydrazine over a period of 30-45 min)

The ice bath was removed, and the mixture was allowed to warm. After 2.5 h of stirring, 4-methylbenzenesulfonic acid hydrate (143 g, 749 mmol) was added. The flask was then equipped with a heating mantle and a reflux condenser and was heated to reflux (82 deg C.) for 13 h, then cooled back to about 60 deg C. At this point, the warm solution was vacuum filtered through paper. The brown filtrate was then concentrated by rotary evaporation. The resulting thick yellow-brown slurry was stirred in an ice bath and diluted with ACN (about 100 mL). After stirring for 1 h, the solids were isolated by vacuum filtration, washed with ice-cold 1:1 ACN/H₂O (2Ã—150 mL) and air-dried on the filter until a freely flowing solid was obtained (159 g, 78.5% yield).

General Method K

[Image Omitted]

Example 4756-(Difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

To a stirring suspension of 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (190 mg, 917 mmol), methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (218 mg, 917 mmol), triphenylphosphine polymer supported (241 mg, 917 mmol), DIEA (200 Î¼l, 1146 mmol) in DCM (4 mL) was added 2,2,2-trichloroacetonitrile (92 Î¼l, 917 mmol). The reaction vessel was then appropriately sealed and heated to 150Â° C. with microwaves for 15 min. The reaction was then concentrated onto dry silica under reduced pressure and product purified on silica (0 g) eluting with 1-4% of 2 M NH₃in MeOH/DCM. The product was then further purified by RP-HPLC eluting with water/ACN (0.1% TFA). Collected fractions concentrated under reduced pressure, dissolved in MeOH/DCM (5 mL) and stirred with Si-Carbonated (300 mg; 0 2 mmol) for 30 min at 23Â° C. Solids were then removed by filtration, and washed with MeOH (3Ã—1 mL). The filtrate was then concentrated under reduced pressure, and product isolated as an off white solid. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact mass for C₂₀H₁₃F₃N₆: 394.

General Method L

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2,2-Difluoro-2-(quinolin-6-yl)acetohydrazide

A solution methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (400 mg, 1686 mmol) and anhydrous hydrazine (2153 Î¼l, 67453 Î¼mol) in MeOH (4 mL) was stirred for 1 h at 23Â° C. The solvents were then removed under reduced pressure to provide product as a white solid. MS (ESI pos. ion) m/z: 238 (MH+). Calc'd exact mass for C₁₁H₉F₂N₃O: 237.

[Image Omitted]

Example 4766-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline

A suspension of 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide (2000 mg, 8432 mmol) and 3,6-dichloropyridazine (3768 mg, 25295 mmol) in 1.25 M HCl in MeOH (20 mL) was heated to 90Â° C. with microwaves for 50 min. The solvents were then removed under reduced pressure and residue partitioned between 9:1 CHCl₃/IPA (60 mL) and 1 M NaOH (20 mL). The organic phase then dried over MgSO₄, concentrated, then purified on silica (120 g) eluting with 1>2.5% of 2 M NH₃in MeOH/DCM to provide product isolated as a dark tan solid. MS (ESI pos. ion) m/z: 332 (MH+). Calc'd exact mass for C₁₅H₈ClF₂N₅: 331.

MassMeth-ExStructureMWFound od477 [Image Omitted]

407408L 478 [Image Omitted]

427428L 479 [Image Omitted]

391392L 480 [Image Omitted]

407408L 481 [Image Omitted]

371372M 482 [Image Omitted]

408409M 483 [Image Omitted]

403404M

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tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate

A suspension of tert-butyl 4-bromophenethylcarbamate (2700 mg, 8994 Î¼mol), bis(pinacolato)diboron (2284 mg, 8994 Î¼mol), bis(pinacolato)diboron (2284 mg, 8994 Î¼mol), potassium acetate (1765 mg, 17989 Î¼mol) in dioxane (12 mL) was sparged with argon for 5 min then heated to 120Â° C. in an appropriately sealed vessel for 1 h. The reaction was then partitioned between ether (50 mL) and 5% NaHCO₃(25 mL). The organic phase was then dried over MgSO₄, concentrated, then purified on silica (120 g) eluting with 10>30% EtOAc/Hexanes. The product tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (2200 mg, 70% yield) was isolated as a white solid. MS (ESI pos. ion) m/z: 292 (MH+1-56). Calc'd exact mass for C₁₉H₃₀BNO₄: 347.

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Example 4842-(4-(3-(Difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanamine

a) tert-Butyl 2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate. A suspension of 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline (350 mg, 1055 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (733 mg, 2110 mmol), 1,1â€²-bis (diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (77 mg, 106 Î¼mol), Na2CO3 (447 mg, 4221 mmol) in DME (4 mL) and water (2 mL) was sparged with argon for 5 min then heated to 85Â° C. in an appropriately sealed vessel for 4 h. The reaction was then partitioned between DCM (30 mL) and 1 M NaOH (10 mL). The organic phase was then dried over MgSO₄, concentrated, then purified on silica (0 g) eluting with 1>4% of 2 M NH₃in MeOH/DCM. The product was isolated as an off white solid.

b) 2-(4-(3-(Difluoro(quinolin-6-yl)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanamine A solution of tert-butyl 2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate (70 mg, 136 mmol) in DCM (1 mL) and TFA (1 mL) was stirred for 30 min at 23Â° C. The solvents were then removed under reduced pressure and crude product purified by RP-HPLC eluting with water/ACN (0.1% TFA). The desired collected fractions were then concentrated under reduced pressure and the resulting residue dissolved in MeOH/DCM (5 mL). Solution was then stirred as a suspension with Si-Carbonated (300 mg; 0.2 mmol) for 30 min at 23Â° C. The solids were then removed by filtration, washed with MeOH (3Ã—1 mL), and filtrate concentrated under reduced pressure. The product was isolated as a white fluffy solid. MS (ESI pos. ion) m/z: 417 (MH+). Calc'd exact mass for C₂₃H₁₅F₂N₆: 416.

General Method M

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Nâ€²-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide

To a stirring solution of 2-(quinolin-6-yl)propanoic acid (3260 mg, 16201 Î¼mol) and DIEA (2830 Î¼l, 16201 Î¼mol) in DMF (25 mL) was added o-(7-azabenzotriazol-1-yl)-n,n,nâ€²,n-tetramethyl uronium hexafluorophosphate (6160 mg, 16201 Î¼mol) whole at 23Â° C. under nitrogen. The solution was stirred for 60 min, cooled to 0Â° C., then added 1-(6-chloropyridazin-3-yl)hydrazine (2342 mg, 16201 Î¼mol). After 20 h stirring at 23Â° C., the reaction was then partitioned between 9:1 CHCl₃/IPA (100 mL) and 5% NaHCO₃(50 mL). The organic phase was then dried over MgSO₄, concentrated to an oil, then purifed on silica (120 g) eluting with 0>10% of 2 M NH₃in MeOH/DCM. The product was isolated as an off white solid. MS (ESI pos. ion) m/z: 328 (MH+). Calc'd exact mass for C₁₆H₁₄ClN₅O: 327.

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6-(1-(6-chloro-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

A solution of Nâ€²-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (2700 mg, 8238 Î¼LÎ¼mol) in TFA (20 mL) was heated to 120Â° C. with microwaves (2 bar; 10 watts) for 40 min. The solution was concentrated under reduced pressure then partitioned between 9:1 CHCl₃/IPA (75 mL) and 1 M NaOH (100 mL). The aqueous layer was further extracted with 9:1 CHCl₃/IPA (2Ã—20 mL). The combined organics were dried over MgSO₄then concentrated to an amber oil under reduced pressure. The product was isolated as off white crystaline solid from ACN. MS (ESI pos. ion) m/z: 310 (MH+). Calc'd exact mass for C₁₆H₁₂ClN₅: 309. Enantiomer resolved with: Chiralpak AD-H (3Ã—25 cm) column using 45% ethanol (0.1% DEA)/CO2

The following compounds were prepared using same method as tert-Butyl 2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate and resolved from racemic mixtures:

MassExStructureMWFoundPeak #485 [Image Omitted]

355 3561 486 [Image Omitted]

3553562 487 [Image Omitted]

3853861 488 [Image Omitted]

385 3862 489 [Image Omitted]

372 3731 490 [Image Omitted]

372 3732

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Example 4916-(difluoro(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A suspension of 1-(6-(3-methylisoxazol-5-yl)pyridazin-3-yl)hydrazine hydrochloride (200 mg, 879 mmol) and methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (208 mg, 879 mmol) in 5 M HCl (1 mL) was appropriately sealed and heated to 150Â° C. with microwaves for 4 h. The reaction was then quenched by a dropwise into cold 5 M NaOH (2 mL) and aqueous extracted with CHCl₃/IPA (25 mL). The organic phase was then dried over MgSO₄, concentrated, and purified with silica (0 g) eluting with 1>5% 2 M NH₃in MeOH/DCM. The product was then further purified on RP-HPLC eluting with water/ACN (0.1% TFA). Combined fractions concentrated, dissolved in DCM (5 mL) and MeOH (5 mL), then stirred with Si-Carbonate (0.5 g; 35 mmol) for 1 h. Si-Carbonate removed by filtration and filtrated concentrated with <0.5 mL remaining with product isolated by trituration. MS (ESI pos. ion) m/z: 379 (MH+). Calc'd exact mass for C₁₉H₁₂F₂N₆O: 378.

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3-chloro-6-(3-methylisothiazol-5-yl)pyridazine

To a solution of 5-bromo-3-methylisothiazole (2.42 g, 14 mmol) in 20 mL of THF at âˆ’45Â° C. was added isopropylmagnesium chloride (19 ml, 19 mmol) in THF (1 M). After 20 minutes, zinc(II) chloride (41 ml, 20 mmol) in THF (0.5 M) was added and the solution was warmed up to rt. 3,6-dichloropyridazine (2.4 g, 16 mmol), 3,6-dichloropyridazine (2.4 g, 16 mmol) and Q-Phos (2.5 g) were added and the reaction was heated to 50Â° C. for 16 hours. The reaction was then cooled to 23Â° C. and quenched with 60 mL of satd. NH₄Cl aq. solution. The mixture was mixed with celite and 100 mL of EtOAc. The insoluble material was removed by filtration. The filtrate was diluted with 40 mL of EtOAc and 30 mL of water. The organic phase was separated and washed with 60 mL of brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10% to 80% hex/EtOAc) to afford red solid as desired product. MS (ESI pos. ion) m/z: 212 (MH+). Calc'd exact mass for C₈H₆ClN₃S: 211.

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1-(6-(3-methylisothiazol-5-yl)pyridazin-3-yl)hydrazine

A mixture of 3-chloro-6-(3-methylisothiazol-5-yl)pyridazine (0.85 g, 4 0 mmol) and anhydrous hydrazine (3.8 ml, 120 mmol) in 30 mL of sec-BuOH was heated at 130Â° C. for 3 hours. The mixture was cooled to 23Â° C. and diluted with 5 mL of water. The solid was collected by filtration and was washed by 2 mL of water to produce a yellow solid. MS (ESI pos. ion) m/z: 208 (MH+). Calc'd exact mass for C₈H₆ClN₃S: 207.

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Example 4926-(difluoro(6-(3-methylisothiazol-5-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1 mmol), 14643-methylisothiazol-5-yl)pyridazin-3-yl)hydrazine (0.25 g, 1.2 mmol) and p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) in 5 mL of dioxane was heated at 150Â° C. for 1 hour in a microwave. The mixture was then diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and washed with 40 mL of brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give yellow glass. The product was further purified by a prep-HPLC to give yellow glass. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact mass for C₁₉H₁₂F₂N₆S: 394.

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Example 4936-(1-(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5 6 mmol) in 10 mL of THF at âˆ’45Â° C. (CH₃CN/dry ice) was added isopropylmagnesium chloride LiCl complex (7.9 ml, 7.9 mmol) (LiCl complex, 1 M in THF). The mixture was stirred at âˆ’45Â° C. for 20 minutes and to this was added zinc chloride, 0.5 M in THF (17 ml, 8.4 mmol) slowly via a syringe. The mixture was then warmed up to rt and continued to stir for additional 30 minutes. 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (0.5787 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.51 g, 0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N,N-dimethyl acetamide was added to the reaction mixture. The reaction was warmed up to 50Â° C. for 6 hours and was quenched with 50 mL of satd. NH₄Cl aq. solution. The mixture was extracted with 150 mL of EtOAc and the organic phase was washed with 60 mL of brine. The aqueous phases were further extracted with 100 mL EtOAc. The combined organics were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH in EtOAc) to give afford a red solid. MS (ESI pos. ion) m/z: 373 (MH+). Calc'd exact mass for C₂₀H₁₆N₆S: 372.

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Example 4943-methyl-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxalin-2(1H)-one

(See Example 495)

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Example 4953-methyl-7-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxalin-2(1H)-one

A mixture of tert-butyl 2-(2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)acetate (0.10 g, 0.36 mmol), tert-butyl 2-(3-methyl-2-oxo-1,2-dihydroquinoxalin-6-yl)acetate (0.10 g, 0.36 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.081 g, 0.44 mmol) and p-toluenesulfonic acid monohydrate (0.069 g, 0.36 mmol) in 3 mL of dioxane was heated with microwave at 150Â° C. for 1 hour. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by prep-HPLC to resolve the regiostereomers as example compounds 494 and 495. For each regiosteroemer MS (ESI pos. ion) m/z: 369 (MH+). Calc'd exact mass for C₂₁H₁₆N₆O: 368.

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tert-butyl 2-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)acetate

To a solution of 6-bromo-3-methylquinazolin-4(3H)-one (0.485 g, 2.0 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.19 g, 0.20 mmol) and Q-phos (0.20 g) in 40 mL of THF was added 2-tert-butoxy-2-oxoethylzinc chloride 0.5 M in diethyl ether (8.1 ml, 4.1 mmol). The reaction was heated at 50Â° C. for 16 hours and was quenched with 40 mL of satd. NH₄Cl. The mixture was diluted with 60 mL of EtOAc. The organic phase was separated, washed with brine, dried over Na₂SO₄and concentrated in vacuo to give red solid. The residue was purified by a silica gel column chromatography (5% EtOAc/Hex to EtOAC) to provide a red solid. MS (ESI pos. ion) m/z: 275 (MH+). Calc'd exact mass for C₁₅H₁₈N₂O₃: 274.

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Example 4963-Methyl-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one

The title compound was prepared using the method for 3-methyl-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxalin-2(1H)-one. MS (ESI pos. ion) m/z: 369 (MH+). Calc'd exact mass for C₂₁H₁₆N₆O: 368.

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(6-(5-cyclopropylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine

[Image Omitted]

1) tert-butyl (6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. To an argon purged flask were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.65 ml, 45.1 mmol), tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.20 g, 11.3 mmol), cesium carbonate (11.0 g, 33.8 mmol), and PdCl₂(dppf)-CH₂Cl₂(0.461 g, 0.564 mmol). The mixture was dissolved in 38 mL of dioxane and 4 mL of water (0.25M 10:1) and was heated to 80Â° C. for 12 h. The mixture was cooled to room temperature, concentrated, and purified directly via MPLC (DCM/MeOH+1% NH₄OH) to afford the title compound (3.0 g, 95% yield).

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2) tert-butyl (6-formyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. Tert-butyl (6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (485 mg, 1.76 mmol) was dissolved in 5 mL of THF and 5 mL of water then osmium tetroxide (0.687 mL (4% water solution), 0.0176 mmol) was added and stirred for 5 min. Sodium periodate was added (141, 3.53 mmol) and the reaction was stirred for 2 h. The reaction was then extracted with dichloromethane (3Ã—10 mL), dried over Na₂SO₄and concentrated. Purification via MPLC (DCM/MeOH+1% NH₄OH) afforded title compound as a tan solid (350 mg, 72% yield).

[Image Omitted]

3) (E)-tert-butyl (6-((hydroxyimino)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. Tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (400 mg, 1.44 mmol) and hydroxylamine hydrochloride (200 mg, 2.86 mmol) were combined in a flask with 25 mL of THF and 25 mL of 1 N NaOH solution. Stirred at rt for 1 h. Then added dichloromethane (50 mL) and extracted the aqueous layer 3 times with DCM (50 mL), dried over Na₂SO₄and concentrated. Purified the oxime via MPLC (DCM/MeOH+1% NH₄OH) to give title compound (200 mg, 47% yield) as a tan solid.

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4) (Z)-tert-butyl (6-(chloro(hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. Dissolved (E)-tert-butyl (6-((hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (200 mg, 0.684 mmol) in 25 mL of DMF and added 1-chloropyrrolidine-2,5-dione (95.9 mg, 0.718 mmol). Let stir at rt for 2 h. Poured reaction mixture onto water (20 mL) and extracted with ether (3Ã—20 mL). Washed organics with water (2Ã—20 mL), brine (1Ã—20 ml), dried over sodium sulfate, filtered and concentrated. Title compound used without further purification (220 mg, 97% yield).

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5) (6-(5-cyclopropylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine Dissolved (Z)-tert-butyl (6-(chloro(hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (110 mg, 337 mmol), ethynylcyclopropane (28 Î¼l, 337 mmol), and potassium hydrogencarbonate (67.4 mg, 673 mmol) in 0.3 mL of EtOAc and heated to 60Â° C. for 12 h to afford the protected intermediate. The solvent was removed by rotary evaporation and the residue was redissolved in dicholoromethane (5 mL) and TFA (2 mL) and stirred for 30 min at room temperature. The solvent was then removed and the residue was redissolved in MeOH. Solid K₂CO₃was added and the mixture was stirred for 1 h to free base the title compound. Purified the amine via MPLC (DCM/MeOH+1% NH₄OH) to afford the title compound (20 mg, 23% yield).

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tert-butyl 4-(8-chloro-1,5-naphthyridin-3-O-4-hydroxypiperidine-1-carboxylate

Dissolved 3-bromo-8-chloro-1,5-naphthyridine (210 mg, 862 Î¼mol) in 8 mL of THF and cooled to âˆ’78Â° C. Then added butyllithium (517 Î¼l, 1294 Î¼mol) and stirred for 15 min. Added tert-butyl 4-oxopiperidine-1-carboxylate (258 mg, 1294 Î¼mol) and let warm to room temperature over 1 h. The reaction was quenched with saturated NH₄Cl and extracted with dichloromethane (3Ã—20 mL), dried over NaSO₄and concentrated. Intermediate was purified via MPLC (DCM/MeOH/NHOH) to yield tert-butyl 4-(8-chloro-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (120 mg, 38% yield.

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Example 4974-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)piperidin-4-ol

Deprotection of tert-butyl 4-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate using the method described for (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine. M/Z=489.2 [M+H], calc 488.19 for C₂₅H₂₂F₂N₈O.

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Example 498N-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(4-fluoropiperidin-4-0)-1,5-naphthyridin-4-amine

A solution of tert-butyl 4-(8-(0-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (30 mg, 51 Î¼mol) in 0.5 mL of DCM was cooled to âˆ’78 C. Then added DAST (13 Î¼l, 102 Î¼mol) and let stir to room temperature over 30 min. TFA was then added to the reaction mixture and stirred for 30 min. The solvent was then removed by rotary evaporation and the residue was redissolved in MeOH and free based through a cation exchange column. Purification via MPLC (DCM/MeOH+1% NH₄OH) yielded the title compound (15 mg, 60% yield). M/Z=491.2

[M+H], calc 490.18 for C₂₅H₂₁F₃N_s.

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Example 4996-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-3-methoxyquinoline

To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.05 g, 0.2 mmol), 1-(6-chloropyridazin-3-yl)hydrazine (0.04 g, 0.3 mmol), water (0.5 mL) and hydrochloric acid (0.05 ml, 0.5 mmol). The vial was sealed and first heated at 90Â° C. for 30 min then placed into CEM microwave for 10 min. at 100Â° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOHâ€”brown ppt. was generated. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO₄, and removed solvent in vacuo. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSepÂ®, P/N 68-2203-026, 12 g SiO₂, DCM:EtOAc:MeOH=75%:20%:5%, Flow=30 mL/min). A peak at 25 min was collected. The solvent was removed in vacuo to afford the desired product as light yellowish solid. Wt: 20.0 mg. MS (ESI pos. ion) m/z: 326.53. Calc'd exact mass for C₁₆H₁₂ClN₅O: 325.75.

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(R/S)-tert-butyl (6-(1-hydroxyethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

In a 10 mL round bottom flask under N₂was dissolved tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (200 mg, 721 mmol) in 3 mL of THF then cooled at âˆ’78Â° C. and treated with methylmagnesium bromide (721 Î¼l, 2164 Î¼mol). After 30 minutes, the reaction mixture was warmed to 0Â° C. over 1 h. After 1 h the reaction mixture based on LC-MS was neutralized with NH₄Cl (sat.). The aqueous phase was extracted 3Ã— with DCM then the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude tert-butyl (6-(1-hydroxyethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (202 mg, 95.5% yield) was used without further purification in the next step. MS m/z=294.4 [M+1]⁺. Calc'd for C₁₃H₁₉N₅O₃: 293.3.

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Example 500N-((6-chloro-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxyquinolin-4-amine

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a) 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride. In a 100 mL round bottom flask were dissolved 8-chloro-3-methoxy-1,5-naphthyridine (5.00 g, 25 7 mmol) and glycine tert-butyl ester hydrochloride (17.2 g, 103 mmol) in 50 mL of 2-BuOH then stirred and heated at 100Â° C. After 5 h the solvent based on LC-MS was removed by reduced pressure and then the solid was dissolved in 200 mL of HCl 1N and stirred at 60Â° C. overnight. After 10 h the reaction mixture based on LC-MS was cooled down to rt then 0Â° C. and the desired acid precipitate. Filtered the solid (3.97 g) then evaporated the aqueous solution and triturated in 75 mL of H₂O at 0Â° C. then filter again and washed with 25 mL of H₂O at 0Â° C. (1.58 g) to afforded total 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (5.55 g, 80.1% yield) as a tan solid. MS m/z=234.1 [M+1]⁺. Calc'd for C₁₁H₁₁N₃O₃: 233.1.

b) N-((6-chloro-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine. In a 250 mL round bottom flask under N₂were dissolved HATU (1762 mg, 4635 Î¼mol), 1-(6-chloropyridazin-3-yl)hydrazine (536 mg, 3708 Î¼mol), 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (1.00 g, 3708 Î¼mol) in 25 mL of MeCN then stirred and cooled down at âˆ’40Â° C. then treated with TRIETHYLAMINE (2584 Î¼l, 18540 Î¼mol) and warmed to rt. After 30 min the reaction mixture based on LC-MS was evaporated under reduced pressure and dry under high vacuum. The crude solid was dissolved in 100 mL of i-PrOH then treated with Ts-OH (2821 mg, 14832 Î¼mol) and heated at 80Â° C. After 3 h the reaction mixture based on LC-MS was diluted with DCM then neutralized with NaOH (1N). The aqueous phase was extracted 3Ã— with DCM with 10% MeOH then the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude mixture was triturated with hot i-PrOH then cooled down and filtered (662 mg) and the mother liquor was evaporated under reduced pressure and purified by MPLC (ISCO) (210 mg) with DCM:MeOH 100:0 to 90:10 to afforded in combined yields N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (872 mg, 69% yield) as a off-white solid. MS m/z=342.1 [M+1]⁺. Calc'd for C₁₅H₁₂ClN₂O: 341.7.

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tert-Butyl (6-carbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

a) 3-((tert-butoxycarbonyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid. In a 25 mL round bottom flask were dissolved 2-methyl-2-butene (21639 Î¼l, 43278 Î¼mol), potassium dihydrogen phosphate (2356 mg, 17311 Î¼mol) and tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (600 mg, 2164 Î¼mol) in 5 mL of t-BuOH and 5 mL of water then was added at 0Â° C. sodium chlorite (783 mg, 8656 Î¼mol) and the reaction mixture was warmed to rt. After 10 h the reaction mixture based on LC-MS was concentrated under reduced pressure and the crude acid was extract from the solid salts mixture with MeOH, filtered and the solvent was concentrated under reduced pressure. The crude 3-((tert-butoxycarbonyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid (635 mg, 100% yield) was used without further purification in the next step. MS m/z=294.2 [M+1]⁺. Calc'd for C₁₂H₁₅N₅O₄: 293.1

b) tert-butyl (6-carbamoyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. In a 10 mL round bottom flask under N₂were dissolved 3-((tert-butoxycarbonyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid (250 mg, 852 Î¼mol), HATU (389 mg, 1023 mmol), triethylamine (356 Î¼l, 2557 mmol) in 1.5 mL of DMF then was treated with a (92 Î¼l, 4262 Î¼mol) and stirred at rt. After 2 h the reaction mixture based on LC-MS was concentrated under reduced pressure and then purified by MPLC (ISCO) with DCM:MeOH+NH₄OH (1%) 100:0 to 90:10 to afforded tert-butyl (6-carbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (129 mg, 52% yield). MS m/z=293.2 [M+1]⁺. Calc'd for C₁₂H₁₆N₆O₃: 292.3.

3-(aminomethyl)-N-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxamide

The title compound was made using the same conditions as tert-butyl (6-carbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.

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Example 5016-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline

a) 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine. A mixture of 5-chloro-2,3-difluoropyridine (10.0 g, 66.9 mmol) and hydrazine (10.0 ml, 319 mmol) in ⁱPrOH (50 mL) was heated to 65-70Â° C. for 6 hours. The mixture was cooled to 23Â° C., filtered, and washed with Na₂CO₃(satd), and H₂O. Product isolated as a white solid. MS (ESI pos. ion) m/z: 162 (MH+). Calc'd exact mass for C₅H₅ClFN₃: 161.

b) 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinolin. To a mixture of 2-(3-methoxyquinolin-6-yl)acetic acid (0.22 g, 1.0 mmol), 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (0.11 g, 0.68 mmol) and triphenylphosphine (0.97 g, 2.0 mmol) (on solid support) in DCM (5 mL) was added DIEA (0.24 ml, 1.4 mmol) followed by 2,2,2-trichloroacetonitrile (0.14 ml, 1.4 mmol) via a syringe. The mixture was then heated to 150Â° C. for 15 minutes in an appropriately sealed vial. The mixture was filtered and the filtrate was diluted with 50 mL of EtOAc. The solution was washed with 30 mL of satd. NaHCO₃followed by 30 mL of brine, dried over Na₂SO₄and concentrated in vacuo. The crude product was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give light yellow solid as desired product. MS (ESI pos. ion) m/z: 343 (MH+). Calc'd exact mass for C₁₇H₁₂ClFN₄O: 3-((2.

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Example 5023-Methoxy-6-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A flask charged with 5-bromo-3-methylisothiazole (0.049 g, 0.28 mmol) and 0.3 mL dry THF was cooled to 0Â° C., and isopropylmagnesium chloride (0.30 ml, 0.30 mmol) added dropwise over 5 minutes and the mixture stirred an additional 5 minutes before allowing to warm to rt. The mixture was stirred at rt 10 minutes and the mixture cannulated to a solution of zinc(II) chloride (0.30 ml, 0.30 mmol) [1M] and the slurry stirred 10 minutes. The zincate was treated with 6-((6-iodo-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-3-methoxyquinoline (0.0890 g, 0.21 mmol), 1 mL dry THF, and a preformed solution of 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.012 g, 0.021 mmol) and Pd(OAc)₂(0.0024 g, 0.011 mmol) dissolved in 1 mL dry THF. The flask was fitted with a reflux condenser and heated with a 90Â° C. oil bath for 24 h. The zincate portion of this procedure was repeated, added to the reaction mixture, and the mixture heated at 90Â° C. for 1 h. The mixture was allowed to cool to rt and loaded onto 10 g of SiO₂wet-packed with THF, and eluted with 200 mL THF. The eluents were concentrated in vacuo, and taken up in 5 mL EtOH. To the solution was added Si-sulfonic acid (1.5 g, 1.1 mmol) and the mixture stirred at room temperature for 24 h, and the solid collected. The solid was washed with EtOH (discarded), and then 2M NH₃in EtOH (5Ã—5 mL). The ammoniacal eluents were concentrated and the residue purified by HPLC to afford 3-methoxy-6-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (0.0013 g, 1.6% yield).

General Method N

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Example 503(R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-0)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

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1. ethyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetate

1,6-naphthyridin-5-ol (1.00 g, 6.8 mmol), ethyl iodoacetate (1.6 ml, 14 mmol) and cesium carbonate (4.5 g, 14 mmol) were dissolved in 25 mL of THF then stirred and heated at 100Â° C. for 2 h until the reaction was complete. The reaction was concentrated and purified via MPLC using a gradient to 90% DCM:10% MeOH to afford ethyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetate (1.5 g, 94% yield).

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2. 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride

2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetate (32.0 g) was dissolved in 450 mL of a 6 N HCl solution, then stirred and heated at 100Â° C. for 1 hr until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and azeotroped 3 times with benzene (200 mL) to remove the water. The crude 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (30.56 g, 92.3% yield) was used without further purification.

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3. Nâ€²-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-O-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide

HATU (1053 mg, 2 7 mmol), 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (470 mg, 1.8 mmol) and 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (421 mg, 2 mmol) (step 1 of General Method K) were taken up in 6 mL of acetonitrile. DIPEA (967 Î¼l, 5.5 mmol) was added and the reaction was stirred for 30 minutes, until reaction was complete. The crude material was concentrated and then purified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH₄OH) to yield Nâ€²-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (500 mg, 67% yield).

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4. (R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Nâ€²-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (400 mg, 982 mmol) and triphenylphosphine (386 mg, 1.4 mmol) were taken up in THF (9.8 mL). TMS-azide (195 Î¼l, 1.4 mmol) was added, followed by slow addition of DEAD (233 Î¼l, 1.4 mmol) and the reaction was stirred at room temperature for 1 hr until complete. The reaction was concentrated and purified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH₄OH to yield racemic 6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (220 mg, 57% yield) as a tan solid. Separated by preperative SFC (ChiralPakÂ® OJ-H, (20Ã—150 mm, 5 m), 20% MeOH, 80% CO₂, 0.2% DEA; 100 bar system pressure; 70 mL/min; t_r: 3.5 min) to yield (R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (60 mg, 15% yield). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=390.2 [M+H], calc 389.14 for C₂₀H₁₆FN₂O. ¹H NMR (400 MHz, CHLOROFORM-d) ppm 2.16 (d, J=5.18 Hz, 3H) 3.97 (s, 3H) 6.82 (d, J=6.55 Hz, 1H) 7.01-7.13 (m, 2H) 7.41-7.49 (m, 1H) 7.54 (d, J=6.26 Hz, 1H) 7.61 (s, 1H) 7.71 (s, 1H) 8.33 (s, 1H) 8.78 (d, J=7.73 Hz, 1H) 8.93 (s, 1H).

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Example 504(S)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

The title compound was synthesized in the same general manner as that previously described for example 503. Separated by preperative SFC (ChiralPakÂ® OJ-H, (20Ã—150 mm, 5 m), 20% MeOH, 80% CO₂, 0.2% DEA; 100 bar system pressure; 70 mL/min; t_r: 4.3 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. MS m/z=390.2 [M+H], calc 389.14 for C₂₀H₁₆FN₇O.

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Example 505(R)-6-(1-(6-(5-chloropyridin-2-yl)-8-fluoro-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

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1. 1-(5-(5-chloropyridin-2-yl)-3-fluoropyridin-2-yl)hydrazine

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a. 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A 350 mL resealable pressure vial was charged with 5-chloro-2,3-difluoropyridine (5.0 g, 33 mmol), pinacol diborane (13 g, 50 mmol), x-phos (1.9 g, 4.0 mmol), Pd₂dba₃(1.8 g, 2.0 mmol), and 1,4-dioxane (215 ml, 0.16 M), flushed with argon, sealed, then heated at 100Â° C. for 16 hours. The mixture was concentrated and diluted with DCM (200 mL), then washed with water (50 mL). The organic layer was dried with MgSO₄, filtered, then concentrated to give a brown oil. The oil was purified by MPLC, eluting with 10-60% EtOAc/Hexanes. 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.6 g, 69% yield) was isolated as a light orange oil which solidified upon standing. LC/MS shows the product as the boronic acid. However, the structure of the product is as drawn above. MS m/z=160.2 [M+1]⁺. Calc'd for C₁₁H₁₄BP₂NO₂: 241.0

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b. 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine

To a pressure vessel was added 2-bromo-5-chloropyridine (3.0 g, 16 mmol), cesium carbonate (15 g, 47 mmol), 1,1â€²-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (2.5 g, 3.1 mmol), and 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.5 g, 19 mmol) in 1,4-dioxane (120 mL) and water (22 mL). The mixture was flushed with argon, sealed and stirred at 90Â° C. for three hours. The mixture was concentrated, diluted with dichloromethane and washed with water. Organic extracts were concentrated and purified by MPLC (eluted with 0-10% methanol in dichloromethane) to yield 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine as a yellow solid (2.4 g, 68%). MS m/z=227.2 [M+1]⁺. Calc'd for C₁₀H₅ClF₂N₂: 226.6.

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c. 1-(5-(5-chloropyridin-2-yl)-3-fluoropyridin-2-yl)hydrazine

To a solution of 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine (2.4 g, 11 mmol) in IPA (35 mL, 0.3 M) at room temperature was added hydrazine (4 mL, 127 mmol). The reaction mixture was stirred at 60Â° C. for 2 h, at which point the reaction was cooled to room temperature and concentrated in vacuo. The concentrated material was suspended in saturated NaHCO₃and filtered to obtain product as a white, fluffy solid. The material was re-suspended in water (30 mL), and filtered to obtain 1-(5-(5-chloropyridin-2-yl)-3-fluoropyridin-2-yl)hydrazine (2.1 g, 83% yield). MS m/z=239.2 [M+1]⁺. Calc'd for C₁₀H₈ClFN₄: 238.6.

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2. (R)-6-(1-(6-(5-chloropyridin-2-yl)-8-fluoro-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared according to General Method N. Chiral separation by preparative SFC (ChiralCelÂ® OD-H (20Ã—150 mm 5 m), 30% MeOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 4.0 mins) On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the R enantiomer.

MS m/z=420.8 [M+1]⁺. Calc'd for C₂₁H₁₄ClFN₆O: 420.8. ¹H NMR (400 MHz, DMSO-d₆) ppm 2.01 (d, J=7.04 Hz, 3H) 6.78 (d, J=7.82 Hz, 1H) 7.03 (d, J=6.94 Hz, 1H) 7.54 (dd, J=8.07, 4.55 Hz, 1H) 7.78 (d, J=7.82 Hz, 1H) 7.97-8.09 (m, 2H) 8.16 (dd, J=8.56, 2.49 Hz, 1H) 8.61 (dd, J=7.97, 1.71 Hz, 1H) 8.70-8.78 (m, 1H) 8.92 (dd, J=4.55, 1.81 Hz, 1H) 9.03 (d, 1H).

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Example 506(S)-6-(1-(6-(5-chloropyridin-2-yl)-8-fluoro-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared in the same general manner as that previously described for example 505 using General Method N. Chiral separation by preparative SFC (ChiralCelÂ® OD-H (20Ã—150 mm 5 m), 30% MeOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 5.8 mins) On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. MS m/z=420.8 [M+1]⁺. Calc'd for C₂₁H₁₄ClFN₆O: 420.8.

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Example 507(R)-6-(1-(8-fluoro-6-(1-methyl-1H-imidazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

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1. 1-(3-fluoro-5-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl)hydrazine

Prepared in the same general manner as that previously described for 1-(5-(5-chloropyridin-2-yl)-3-fluoropyridin-2-yl)hydrazine

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2. (R)-6-(1-(8-fluoro-6-(1-methyl-1H-imidazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared according to General Method N. Chiral separation by preparative SFC (ChiralPakÂ® AD-H (20Ã—250 mm 5 m), 40% MeOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r4.1 mins).

On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=389.8 [M+1]⁺. Calc'd for C₂₀H₁₆FN₇O: 389.4. ¹H NMR (400 MHz, DMSO-d₆) ppm 1.97 (d, J=6.94 Hz, 3H) 3.68 (s, 3H) 6.75 (d, J=7.73 Hz, 1H) 6.94 (d, J=6.85 Hz, 1H) 7.52-7.59 (m, 1H) 7.64 (dd, J=7.78, 0.54 Hz, 1H) 7.69-7.75 (m, 3H) 8.46 (s, 1H) 8.63 (dt, J=8.12, 0.88 Hz, 1H) 8.90-8.94 (m, 1H)

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Example 508(S)-6-(1-(8-fluoro-6-(1-methyl-1H-imidazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared in the same general manner as that previously described for example 507 using General Method N. Chiral separation by preparative SFC (ChiralPakÂ® AD-H (20Ã—250 mm 5 m), 40% MeOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 5.9 mins) On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. MS m/z=389.8 [M+1]⁺. Calc'd for C₂₀H₁₆FN₇O: 389.4.

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Example 509(R)-6-(1-(8-fluoro-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-0)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

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1. 1-(3-fluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine

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a. 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole

A mixture of cesium carbonate (20.7 g, 63.4 mmol) and 4-iodopyrazole (10.00 g, 51.6 mmol) in DMF (100 mL) was allowed to stir for 10 min. To the mixture was added 2-(2-bromoethoxy)tetrahydro-2h-pyran (9.98 ml, 63.4 mmol) and heated at 80Â° C. overnight. The mixture was diluted with water and extracted with EtOAc (3Ã—50 mL), and subsequently washed with water (2Ã—50 mL) and brine, dried over sodium sulfate, and filtered. The crude mixture was evaporated onto silica gel and purified via MPLC (0% to 50%; EtOAc in hexanes). Isolated 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (15.3 g, 92%) as a clear oil. MS m/z=323.0 [M+1]⁺. Calc'd for C₁₀H₁₅IN₂: 322.1.

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b. 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-O-1H-pyrazole

To a solution of 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (8.7 g, 27.1 mmol) in THF (75 mL) at 0Â° C. under argon was added isopropylmagnesium chloride as a 2 M solution in THF (27.1 mL, 54.3 mmol). The reaction was stirred for 1 h at 0Â° C. To it was added 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.7 mL, 40 7 mmol) and the mixture was stirred for an additional 1 h while allowing to warm to room temperature. It was then treated with saturated ammonium chloride (100 mL) solution and the product was extracted with EtOAc (3Ã—100 mL). The combined organics were washed with brine, dried over sodium sulfate, and filtered. Crude material was concentrated under reduced pressure to afford 7.1 g (81%) of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a clear yellow oil. The material was taken on crude to the next step. MS m/z=323.2 [M+1]⁺. Calc'd for C₁₆H₂₇BN₂O₄: 322.2

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c. 2,3-difluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine

A 48 mL tube was charged with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.4 g, 19.9 mmol), 5-chloro-2,3-difluoropyridine (1.7 mL, 16.6 mmol), X-Phos (1.6 g, 3.3 mmol), Potassium phosphate (3.5 g, 16.6 mmol), PdOAc₂(0.4 g, 1.7 mmol), 1,4-dioxane (50 mL), and water (5.0 mL), flushed with argon, sealed, then heated at 100Â° C. for 3 hours. The mixture was concentrated and purified by MPLC, eluting with 2.5% MeOH/DCM over 40 minutes to afford 2,3-difluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine as a clear oil which solidified upon standing at room temperature (3.1 g, 60.5% yield). LC/MS shows the product as the free alcohol. However, the structure of the product is as drawn above. MS m/z=226.2 [M+1]⁺. Calc'd for C₁₅H₁₇F₂N₃O₂: 309.3

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d. 1-(3-fluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine

To a solution of 2,3-difluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine (3.0 g, 9.5 mmol) in IPA (47.7 mL, 0.2 M) at room temperature was added hydrazine (3.6 mL, 114.4 mmol). The reaction mixture was stirred at 60Â° C. for 2 h, at which point the reaction was cooled to room temperature and concentrated in vacuo. The concentrated material was suspended in saturated NaHCO₃solution and filtered to obtain product as a white, fluffy solid. The material was re-suspended in water (30 mL), filtered, and driend under high vacuum to obtain 1-(3-fluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (2.2 g, 72% yield) as an orange solid. MS m/z=322.2 [M+1]⁺. Calc'd for C₁₅H₂₀FN₅O₂: 321.4.

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2. 6-(1-(8-fluoro-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-O-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

The THP-protected compound was synthesized according to the General Method N.

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3. (R)-6-(1-(8-fluoro-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

6-(1-(8-fluoro-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (0.5 g, 1.0 mmol) was dissolved in EtOH (12 mL) and to the solution was added hydrochloric acid (2.0 mL, 4.0 mmol). The reaction was stirred at rt for 3 hours at which time it was diluted with 5 mL of water and 10 mL of aq. saturated sodium bicarbonate solution. The product was extracted with DCM (30 mL) three times. The organic layers were combined, dried over sodium sulfate and concentrated to dryness to afford 6-(1-(8-fluoro-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (0.4 g, 96%). Chiral separation by preparative SFC (ChiralpakÂ® AD-H (20Ã—150 m, 5 m), 35% EtOH, 65% CO2, 0.2 DEA; 100 bar system pressure, 50 mL/min; t_r: 4.4 min). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. M/Z=420.2 [M+H], calc 419.15 for C₂₁H₁₈FN₇O₂. ¹H NMR (400 MHz, CHLOROFORM-d) ppm 2.17 (d, J=7.14 Hz, 3H) 4.00-4.09 (m, 2H) 4.29-4.33 (m, 2H) 6.91 (d, J=7.92 Hz, 1H) 7.04 (dd, 1H) 7.10 (dd, J=10.56, 1.17 Hz, 1H) 7.51 (dd, J=8.17, 4.74 Hz, 1H) 7.59 (d, J=7.82 Hz, 1H) 7.72 (d, J=0.68 Hz, 1H) 7.76 (d, J=0.78 Hz, 1H) 8.34 (d, J=1.17 Hz, 1H) 8.84 (dd, J=8.07, 1.22 Hz, 1H) 8.92 (dd, J=4.74, 1.81 Hz, 1H)

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Example 510(S)-6-(1-(8-fluoro-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared in the same general manner as that previously described for example 509 using General Method N. Chiral separation by preparative SFC (ChiralpakÂ® AD-H (20Ã—150 m, 5 m), 35% EtOH, 65% CO2, 0.2 DEA; 100 bar system pressure, 50 mL/min; t_r: 6.0 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. M/Z=420.2 [M+H], calc 419.15 for C₂₁H₁₈FN₇O₂.

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Example 511(R)-6-(1-(8-fluoro-6-(4-methylthiophen-2-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

The compound was prepared according to General Method N. The hydrazine was prepared in an analogous fashion to 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine. Chiral separation by preparative SFC (ChiralpakÂ® AD-H (20Ã—250 mm 5 m), 40% MeOH 0.2% DEA, 80 mL/min and 100 bar system backpressure, retention time=5.1 minutes. On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=406.0 [M+1]⁺. Calc'd for C₂₁H₁₆FN₅OS:405.5.

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Example 512(S)-6-(1-(8-fluoro-6-(4-methylthiophen-2-0)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

The compound was prepared according to General Method N. The hydrazine was prepared in an analogous fashion to 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine. Chiral separation by preparative SFC (ChiralpakÂ® AD-H (20Ã—250 mm 5 m), 40% MeOH 0.2% DEA, 80 mL/min and 100 bar system backpressure, retention time=6.1 minutes. On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. MS m/z=406.0 [M+1]⁺. Calc'd for C₂₁H₁₆FN₅OS:405.5.

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Example 5136-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1,6-naphthyridin-5(6H)-one

The title compound was synthesized in the same general manner as that previously described for example 503 using 1-(5-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)hydrazine. MS m/z=408.2 [M+H], calc 407.4 for C₂₁H₁₂F₃N₅O.

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Example 514(R)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-34(2-methoxyethoxy)methyl)-1,6-naphthyridin-5(6H)-one

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1. 3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one

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a. 2-chloro-5-hydroxynicotinonitrile

In a 300 mL sealed tube under N₂were dissolved potassium acetate (20 g, 207 mmol), 5-bromo-2-chloronicotinonitrile (15 g, 69 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (21 g, 83 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (1.7 g, 2.1 mmol) in 150 mL of p-dioxane then stirred and heated at 85Â° C. for 2 hrs. After completion, the reaction was cooled to 0Â° C. and treated with hydrogen peroxide (31.5%) (22 ml, 207 mmol) then stirred at rt for 1 hr. The reaction mixture was diluted with DCM (100 mL) then water was added (200 mL). The aqueous phase was extracted 3 times with DCM (100 mL), then the organic layer was washed with saturated sodium thiosulfate solution (300 mL). The organics were then dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude 2-chloro-5-hydroxynicotinonitrile (7.5 g, 70% yield) was carried through crude to the next step.

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b. 2-chloro-5-(2-methoxyethoxy)nicotinonitrile

In a 100 mL round bottom flask under N₂were dissolved triphenylphosphine (19 g, 73 mmol), 2-chloro-5-hydroxynicotinonitrile (7.5 g, 49 mmol), and 2-methoxyethanol (5.7 ml, 73 mmol) in THF (130 mL) followed by a slow addition of DEAD (27 ml, 68 mmol), and then stirred at room temperature. After 2 h the reaction showed full conversion to the desired compound. The crude mixture was purified by MPLC eluting with 100% DCM to 90% DCM:10% MeOH to afford 2-chloro-5-(2-methoxyethoxy)nicotinonitrile (6.46 g, 63% yield) as a tan solid.

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c. 5-(2-methoxyethoxy)-2-(2-(trimethylsilyl)ethynyl)nicotinonitrile

In a sealed tube, dichlorobis(triphenyl-phosphine)palladium (ii) (0.17 g, 0.24 mmol), trimethylacetylene (2.0 ml, 14 mmol), 2-chloro-5-(2-methoxyethoxy)nicotinonitrile (2.50 g, 12 mmol), and copper(I) iodide (0.11 g, 0.59 mmol) were dissolved in acetonitrile (0.5 M, 24 mL) and to the reaction was added triethylamine (3.3 ml, 24 mmol). The reaction mixture was heated to 85Â° C. for 12 hrs. The reaction was concentrated and purified directly via MPLC, eluting with 0-100% EtOAc in hexanes to yield 5-(2-methoxyethoxy)-2-(2-(trimethylsilyl)ethynyl)nicotinonitrile (1.9 g, 59% yield).

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d. 2-ethynyl-5-(2-methoxyethoxy)nicotinamide

5-(2-methoxyethoxy)-2-(2-(trimethylsilyl)ethynyl)nicotinonitrile (4.23 g, 15 mmol) was dissolved in acetone (60 mL). To the solution was added 3 M sodium carbonate (62 ml, 185 mmol) and hydrogen peroxide (31 ml, 308 mmol) dropwise, and it was stirred at room temperature for 4 h. After completion, the reaction was cooled to 0Â° C. and to it was slowly added sodium thiosulfate (200 mL) with stirring. The aqueous layer was extracted with DCM (Ã—3, 200 mL), and the combined organics were concentrated and purified via MPLC eluting with 100% DCM to 90% DCM:10% MeOH:1% NH₄OH to yield 2-ethynyl-5-(2-methoxyethoxy)nicotinamide (2.0 g, 59% yield).

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e. 3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one

2-ethynyl-5-(2-methoxyethoxy)nicotinamide (2.04 g, 9 mmol) was dissolved in 1M dimethylamine (in methanol or ethanol) (46 ml, 93 mmol). The reaction was heated to 85Â° C. for 12 hrs. The reaction was concentrated and purified via MPLC eluting with 100% DCM to 90% DCM:10% MeOH:1% NH₄OH to yield 3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (0.900 g, 44% yield).

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2. 2-(3-(2-methoxyethoxy)-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride

The compound was synthesized from 3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one similar to the synthesis of 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride in Method N (Example 503).

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3. 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine

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a. 2,3-difluoro-5-(3-methylisoxazol-5-yl)pyridine

A 330 mL pressure vessel was charged with 5-chloro-2,3-difluoropyridine (5.00 g, 33.4 mmol), 3-methyl-5-(tributylstannyl)isoxazole (14.9 g, 40.1 mmol), XPhos (2.23 g, 4.68 mmol), PdOAc₂(0.526 g, 2.34 Î¼mol), and 1,4-dioxane (167 ml, 33 4 mmol), flushed with argon, sealed, then heated at 100Â° C. for 16 hours. The mixture was concentrated; the black oil was absorbed onto silica gel and purified by MPLC, eluting with 20% EtOAc in hexanes isocratic to yield an orange solid; this was triturated with hexanes to give 2,3-difluoro-5-(3-methylisoxazol-5-yl)pyridine (3.6278 g, 55.3% yield) as a yellow solid.

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b. 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine

A 330 mL pressure vessel was charged with 4,5-difluoro-2-(3-methylisoxazol-5-yl)pyridine (3.6695 g, 18.7 mmol), hydrazine (3.53 ml, 112 mmol), and IPA (93.5 ml, 18 7 mmol), sealed, then heated at 65Â° C. for 3 hours. The mixture was filtered; the solid was triturated with sat. aqueous NaHCO₃solution and washed with water (2Ã—20 mL). 1-(4-fluoro-6-(3-methylisoxazol-5-yl)pyridin-3-yl)hydrazine (3.5668 g, 91.6% yield) was isolated as a white powder.

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4. (R)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-((2-methoxyethoxy)methyl)-1,6-naphthyridin-5(6H)-one

Using 3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one and 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine, the title compound was synthesized using General Method N to yield (R)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-((2-methoxyethoxy)methyl)-1,6-naphthyridin-5(6H)-one. Chiral separation by preparative SFC (ChiralpakÂ® AD-H (20Ã—150 mm, 5 m), 25% MeOH, 75% CO₂, 0.2% DEA; 100 bar system pressure; 75 mL/min; t_r5.78 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. M/Z=465.2 [M+H], calc 464.16 for C₂₃H₂₁FN₆O₄. ¹H NMR (400 MHz, CHLOROFORM-d) ppm 2.17 (d, J=7.14 Hz, 3H) 2.39 (s, 3H) 3.49 (s, 3H) 3.78-3.94 (m, 2H) 4.23-4.43 (m, 2H) 6.43 (s, 1H) 6.85 (d, J=7.82 Hz, 1H) 7.08 (q, J=7.11 Hz, 1H) 7.29 (dd, J=10.07, 1.17 Hz, 1H) 7.43 (d, J=7.82 Hz, 1H) 8.17 (d, J=2.93 Hz, 1H) 8.58-8.81 (m, 2H).

[Image Omitted]

Example 515(S)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-((2-methoxyethoxy)methyl)-1,6-naphthyridin-5(6H)-one

Synthesized in the same general manner as that previously described for example 509 using General Method N. Chiral separation by preparative SFC (ChiralpakÂ® AD-H (20Ã—150 mm, 5 m), 25% MeOH, 75% CO₂, 0.2% DEA; 100 bar system pressure; 75 mL/min; t_r4.75 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. M/Z=465.2 [M+H], calc 464.16 for C₂₃H₂₁FN₆O₄

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Example 516(R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-0)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one

The title compound was synthesized using General Method N. Chiral separation by preparative SFC (ChiralpakÂ® AS-H (20Ã—150 mm, 5 m), 20% iPrOH, 80% CO₂; 100 bar system pressure, 50 mL/min; t_r1.67 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. M/Z=464.2 [M+H], calc 463.18 for C₂₃H₂₂FN₂O₃. ¹H NMR (400 MHz, CHLOROFORM-d) ppm 2.15 (d, J=7.14 Hz, 3H) 3.49 (s, 3H) 3.80-3.90 (m, 2 H) 3.97 (s, 3H) 4.27-4.39 (m, 2H) 6.83 (d, J=7.73 Hz, 1H) 7.00-7.13 (m, 2H) 7.42 (d, J=7.82 Hz, 1H) 7.61 (s, 1H) 7.72 (s, 1H) 8.15 (d, J=2.84 Hz, 1H) 8.31 (s, 1H) 8.72 (d, J=3.03 Hz, 1H).

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Example 517(S)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one

The compound was synthesized in the same general manner as that previously described for example 516 according to General Method N. Chiral separation by preparative SFC (ChiralpakÂ® AS-H (20Ã—150 mm, 5 m), 20% iPrOH, 80% CO₂; 100 bar system pressure, 50 mL/min; t_r: 2.02 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. M/Z=464.2 [M+H], calc 463.18 for C₂₃H₂₂FN₂O₃

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Example 518(R)-3-(2-methoxyethoxy)-6-(1-(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

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1. 1-(5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine

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a. 2-fluoro-5-(3-methylisoxazol-5-yl)pyridine

A 48 mL tube was charged with 5-bromo-2-fluoropyridine (1.17 ml, 11.4 mmol), 3-methyl-5-(tributylstannyl)isoxazole (5.29 g, 14.2 mmol), cyclohexyl JohnPhos (0.398 g, 1.14 mmol), Pd₂dba₃(0.312 g, 0.341 mmol), and DMF (12.4 ml, 159 mmol), flushed with argon, sealed, then heated at 90Â° C. for 16 hours. Additional 3-methyl-5-(tributylstannyl)isoxazole (5.29 g, 14.2 mmol) (2g), Pd₂dba₃(0.312 g, 0.341 mmol), and cyclohexyl JohnPhos (0.398 g, 1.14 mmol) were added and the mixture was stirred at 90Â° C. for 10 more hours. This was concentrated and the brown residue was purified by MPLC, eluting with 15% ethyl acetate in hexanes isocratic. 2-fluoro-5-(3-methylisoxazol-5-yl)pyridine (1.1029 g, 54.5% yield) isolated as a light yellow solid.

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b. 1-(5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine

The hydrazine was synthesized similar to 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine (except heated to 60Â° C.) (84.2% yield).

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2. (R)-3-(2-methoxyethoxy)-6-(1-(6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

The title compound was synthesized according to General Method N. Chiral separation by preparative SFC (Chiralcel OHâ€”H (2 cm IDÃ—25 cm length, 5Î¼), 35-65% MeOH 0.2% DEA in CO₂, 80 mL/min; t_r=4.95 min) On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=447.2 [M+1]⁺. Calc'd for C₂₃H₂₂N₆O₄: 446.5. ¹H NMR (400 MHz, DMSO-d₆) Î´ ppm 8.89 (t, 1H), 8.68 (d, J=3.03 Hz, 1H), 8.01-8.02 (m, 1 H), 7.96 (dd, J=9.59, 1.08 Hz, 1H), 7.79 (dd, J=9.54, 1.61 Hz, 1H), 7.60 (d, J=7.82 Hz, 1H), 7.01-7.05 (m, 1H), 6.99 (s, 1H), 6.75 (d, J=7.63 Hz, 1H), 4.29-4.32 (m, 2H), 3.70-3.73 (m, 2H), 3.32 (s, 3H), 2.31 (s, 3H), 1.99 (d, J=7.04 Hz, 3H).

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Example 519(S)-3-(2-methoxyethoxy)-6-(1-(6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Compound was synthesized in the same general manner as that previously described for example 518 according to General Method N. Chiral separation by preparative SFC (Chiralcel OHâ€”H (2 cm IDÃ—25 cm length, 5Î¼), 35-65% MeOH 0.2% DEA in CO₂, 80 mL/min; t_r=7.05 min) On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. MS m/z=447.2 [M+1]⁺. Calc'd for C₂₃H₂₂N₆O₄: 446.5.

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Example 520(R)-6-(1-(6-(5-chloropyridin-2-yl)-8-fluoro-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-methoxy-1,6-naphthyridin-5(6H)-one

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1. 2-(3-methoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride

All steps for the synthesis of this acid are the same as for 2-(3-(2-methoxyethoxy)-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (Example 514). with the following exceptions:

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a. 2-chloro-5-methoxynicotinonitrile

2-chloro-5-hydroxynicotinonitrile (18.0 g, 116 mmol) was placed in a resealable pressure-resistant tube and suspended in DMF (146 ml, 116 mmol). To this was added cesium carbonate (76 g, 233 mmol) and methyl iodide (36 mL, 582 mmol). The vessel was sealed and the mixture stirred at 65Â° C. for 17 h. The reaction mixture was diluted with water (250 mL) and the product was extracted with DCM (3Ã—400 mL). The organic layers were combined, dried over sodium sulfate and concentrated to afford 0 g of brown thick oil. This was passed through a plug of silica to afford 13g of 85% pure material. This was triturated in 10% DCM/Hexanes (hot Ëœ40Â° C.) and solids filtered, rinsed with hexanes and dried to afford 2-chloro-5-methoxynicotinonitrile as brown solid (10.0 g, 51%). MS m/z=169[M+1]⁺. Calc'd for C₇H₅ClN₂O: 168.6.

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b. 5-methoxy-2-(2-(trimethylsilyl)ethynyl)nicotinonitrile

This step was run at 65Â° C. instead of 85Â° C.

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c. ethyl 2-(3-methoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoate

Ethyl 2-bromopropanoate was used instead of the iodide and the reaction temperature was also lower (60Â° C.).

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2. (R)-6-(1-(6-(5-chloropyridin-2-yl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-methoxy-1,6-naphthyridin-5(6H)-one

The title compound was synthesized according to General Method N. Chiral separation by preparative SFC (ChiralCelÂ® OD-H (20Ã—250 mm 5 m), 35% MeOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 6.3 mins) On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=450.8 [M+1]⁺. Calc'd for C₂₂H₁₆ClFN₆O₂: 450.8.

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Example 521(S)-6-(1-(6-(5-chloropyridin-2-0)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-methoxy-1,6-naphthyridin-5(6H)-one

Prepared according to General Method N. Chiral separation by preparative SFC (ChiralCelÂ® OD-H (20Ã—250 mm 5 m), 35% MeOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 8.0 mins). On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. m/z=450.8 [M+1]⁺. Calc'd for C₂₂H₁₆ClFN₆O₂: 450.8.

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Example 522(R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-methoxy-1,6-naphthyridin-5(6H)-one

Prepared according to General Method N. Chiral separation by preparative SFC (ChiralCelÂ® OD-H (20Ã—250 mm 5 m), 40% EtOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 5.2 mins). On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=419.8 [M+1]⁺. Calc'd for C₂₁H₁₈FN₇O₂: 419.4.

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Example 523(S)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-0)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-methoxy-1,6-naphthyridin-5(6H)-one

Prepared according to General Method N. Chiral separation by preparative SFC (ChiralCelÂ® OD-H (20Ã—250 mm 5 m), 40% EtOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 6.8 mins). On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. MS m/z=419.8 [M+1]⁺. Calc'd for C₂₁H₁₈FN₇O₂: 419.4.

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Example 524(R)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-methoxy-1,6-naphthyridin-5(6H)-one

Prepared according to General Method N. Chiral separation by preparative SFC (ChiralPakÂ® AD-H (20Ã—250 mm 5 m), 40% MeOH 0.2% DEA, 70 mL/min and 100 bar system backpressure (t_r: 4.7 mins). On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=420.8 [M+1]⁺. Calc'd for C₂₁H₁₇FN₆O₃: 420.4. ¹H NMR (400 MHz, DMSO-d₆) ppm 2.00 (d, J=7.04 Hz, 3H) 2.31 (s, 3H) 3.94 (s, 3H) 6.77 (dd, J=7.78, 0.54 Hz, 1H) 6.94-7.05 (m, 2H) 7.64 (d, J=7.82 Hz, 1H) 7.76-7.89 (m, 1 H) 7.98 (dd, J=3.08, 0.54 Hz, 1H) 8.68 (d, J=3.03 Hz, 1H) 8.80 (d, J=1.08 Hz, 1H).

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Example 525(S)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-methoxy-1,6-naphthyridin-5(6H)-one

[Image Omitted]

Example 5266-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-5(6H)-one

[Image Omitted]

1. 2-(5-oxo-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride

[Image Omitted]

a. 2-(3-hydroxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrobromide

A resealable pressure-resistant bottle was charged with ethyl 2-(3-methoxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoate (0.83 g, 3.0 mmol) (Example 515) and conc. HBr (0.16 ml, 3.0 mmol). The vessel was sealed and the mixture was stirred at 130Â° C. for 20 hours. The reaction mixture was then concentrated to afford 2-(3-hydroxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrobromide (0.95 g, 100% yield) as brown solid. This was carried through crude in the next step. Free base material MS m/z=235.0 [M+1]⁺. Calc'd for C₁₁H₁₁BrN₂O₄: 315.1.

[Image Omitted]

b. 2-(5-oxo-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride

A resealable pressurized vial was charged with 2-(3-hydroxy-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrobromide (0.54 g, 2 mmol), cesium carbonate (2 g, 7 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2 g, 7 mmol), and N,N-dimethylformamide (6 mL, 0.3M). The vessel was sealed and the mixture was stirred at 60Â° C. for 1 hr. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure to afford brown oil. This was purified via MPLC (10-50% EtOAC/Hexanes) to afford tan solid of bis alkylated material. This was suspended and refluxed in 5 mL of 6N HCl for 2 hours. Reaction mixture concentrated and dried under reduced pressure to afford 2-(5-oxo-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (0.3 g, 50% yield). This was concentrated under reduced pressure to dryness to afford 2-(5-oxo-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (0.3 g, 50% yield) as yellow solid. Free base material MS m/z=317.0 [M+1]⁺. Calc'd for C₁₃H₁₂ClF₃N₂O₄: 352.7.

[Image Omitted]

2. 6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-5(6H)-one

Prepared according to General Method N. MS m/z=488.8 [M+1]⁺. Calc'd for C₂₂H₁₆F₄N₆O₃: 488.4. ¹H NMR (400 MHz, DMSO-d₆) ppm 2.01 (d, J=7.04 Hz, 3H) 2.25-2.38 (m, 3H) 5.05 (q, J=8.77 Hz, 2H) 6.74-6.83 (m, 1H) 6.96-7.07 (m, 2H) 7.71 (d, J=7.82 Hz, 1H) 7.86 (dd, J=11.49, 1.12 Hz, 1H) 8.20 (d, J=2.74 Hz, 1H) 8.78 (d, J=3.03 Hz, 1H) 8.83 (d, J=1.08 Hz, 1H)

[Image Omitted]

Example 5276-((R)-1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5(6H)-one

[Image Omitted]

1. 2-(3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride

All steps for the synthesis of this acid are the same as for 2-(3-(2-methoxyethoxy)-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (Example 514) with the following exception:

[Image Omitted]

a. 2-chloro-5-(1-methyl-1H-pyrazol-4-yl)nicotinonitrile

A 48 mL tube was charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.42 g, 40.5 mmol), 5-bromo-2-chloronicotinonitrile (8.00 g, 36 8 mmol), potassium carbonate (15.3 g, 110 mmol), PdCl₂(dppf) (2.69 g, 3.68 mmol), 1,4-dioxane (135 mL, 1582 mmol) and water (23.9 mL, 1324 mmol), flushed with argon, sealed and then heated to 60Â° C. for 8 h. The reaction mixture was concentrated, adsorbed onto silica gel, and purified via MPLC eluting with 3% MeOH in DCM. 2-chloro-5-(1-methyl-1H-pyrazol-4-yl)nicotinonitrile (4.962 g, 61.7%) was obtained (with a small impurity). The material was taken forward crude.

[Image Omitted]

2. 6-((R)-1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(1-methyl-1H-pyrazol-4-O-1,6-naphthyridin-5(6H)-one

Synthesized using General Method N. Chiral separation by preparative SFC (ChiralpakÂ® OJ-H 5 m (20Ã—250 mm, 5 m), 45% MeOH, 55%, CO₂, 0.2% DEA, 70 mL/min; 120 bar system pressure; t_r: 8.3 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. M/Z=471.2 [M+H], calc 470.16 for C₂₄H₁₉FN₈O₂. ¹H NMR (400 MHz, DMSO-d₆) ppm 2.01 (d, J=7.04 Hz, 3H) 2.31 (s, 3H) 3.89 (s, 3H) 6.78 (d, J=8.41 Hz, 1H) 6.95-7.09 (m, 2H) 7.72 (d, J=7.82 Hz, 1H) 7.85 (d, J=12.62 Hz, 1H) 8.12 (s, 1H) 8.46 (s, 1H) 8.67 (dd, J=2.35, 0.68 Hz, 1H) 8.83 (d, J=1.08 Hz, 1H) 9.20 (d, J=2.45 Hz, 1H).

[Image Omitted]

Example 5286-((S)-1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5(6H)-one

Prepared in the same general manner as that previously described for example 527 according to General Method N. Chiral separation by preparative SFC (ChiralpakÂ® OJ-H 5 m (20Ã—250 mm, 5 m), 45% MeOH, 55%, CO₂, 0.2% DEA, 70 mL/min; 120 bar system pressure; t_r: 7.2 min). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. M/Z=471.2 [M+H], calc 470.16 for C₂₄H₁₉FN₈O₂.

General Method O

[Image Omitted]

Example 529(R)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

[Image Omitted]

1. (R)-methyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoate

Dissolved 1,6-naphthyridin-5(6H)-one (10.6 g, 73 mmol), (S)-methyl 2-hydroxypropanoate (8.6 ml, 91 mmol) and triphenylphosphine (30 g, 116 mmol) in 144 mL THF (0.5M) and cooled to 0Â° C. Then added DEAD (17 ml, 109 mmol) dropwise, monitoring temperature so as not to exceed 5Â° C. Then let warm to room temperature over 1 hr, where reaction was complete by LCMS. The reaction was concentrated on silica and purified via MPLC, first with a gradient of Hexanes:EtOAc (removes most of PPh₃O); then gradient of 100% DCM to 90% DCM:10% MeOH:1% NH₄OH to yield (R)-methyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoate (16g, 95% yield) where the ee was confirmed to be >95%.

[Image Omitted]

2. (R)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride

Dissolved (R)-methyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoate (3.20 g, 14 mmol) in 70 mL of THF and added 6 M HCl (23 ml, 138 mmol) and heated to 80Â° C. for 3 hrs until reaction was complete by LCMS. Reaction concentrated to remove water, and azeotroped 3 times with benzene to remove excess water, to yield (R)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride (3.4 g, 95% yield) which was >95% ee according to HPLC (conditions: 25/75 EtOH-TFA (0.1%):Heptane, ChiralPak AD-H, 1.0 mL/min, 20 min, 4.6Ã—150 mm column). Obtained (R)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride as a yellow solid, which was taken on crude to the next step.

[Image Omitted]

3. (2R)â€”Nâ€²-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide

HATU (9.0 g, 24 mmol), (R)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid hydrochloride and 1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine (3.6 g, 17 mmol) were taken up in acetonitrile (52 ml, 0.3 M) and cooled to 0Â° C. DIPEA (8.2 ml, 47 mmol) was added dropwise and the reaction was allowed to stir to room temperature for 30 minutes until complete by LCMS. The crude material was concentrated onto silica gel and then purified via MPLC eluting with 100% DCM to 90% DCM:10% MeOH:1% NH₄OH to yield (2R)â€”Nâ€²-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (4.927 g, 77% yield).

[Image Omitted]

4. (R)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

(2R)â€”Nâ€²-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (1.9 g, 4.7 mmol) and triphenylphosphine (1.8 g, 7 0 mmol) were taken up in THF (47 ml, 4.7 mmol). TMS-azide (0.93 ml, 7 0 mmol) was added, followed by slow addition of DEAD (1.1 ml, 7 0 mmol) and the reaction was stirred at room temperature for 50 minutes (monitored temperature so as not too exceed 30-40Â° C.) until reaction was complete. The reaction mixture was concentrated down, removing approximately Â½ volume of THF. The material was then redissolved in EtOAc (Ëœ100 mL), and 2 M HCl (Ëœ30 mL) was added. The mixture was shaken vigorously, and the aqueous layer (with product) was set aside. The EtOAc layer was extracted Ã—2 with HCl (30 mL) and all of the aqueous layers were combined. The aqueous layer was cooled to 0Â° C., and to it was added 6 M NaOH dropwise until pH was 7-8 (desired product crashed out as an off-white solid). The solid was filtered over vacuum to remove desired product from water. The solid was then dissolved through the frit into a new flask with DCM/MeOH, and dried over NaSO₄(to further dry). The product was then recrystallized from EtOH with heat, sonication and then cooling or scratching to promote rapid crystallization. (R)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (1.5 g, 60-80% yield) was isolated as a white solid with >95% ee by HPLC (conditions: 50/50 EtOH:Heptane, ChiralPakÂ® AD-H, 1.0 mL/min, 20 min, 4.6Ã—150 mm column, tr 6.61 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. M/Z=391.2 [M+H], calc 390.12 for C₂₀H₁₅FN₆O₂. ¹H NMR (400 MHz, DMSO-d₆) ppm 2.00 (d, J=7.04 Hz, 3H) 2.31 (s, 3H) 6.78 (d, J=7.92 Hz, 1H) 6.95-7.12 (m, 2H) 7.54 (dd, J=8.22, 4.50 Hz, 1H) 7.77 (d, J=7.73 Hz, 1H) 7.85 (d, J=11.54 Hz, 1H) 8.62 (d, J=9.59 Hz, 1H) 8.82 (s, 1H) 8.92 (dd, J=4.55, 1.71 Hz, 1H).

[Image Omitted]

Example 5303-(1-methyl-1H-pyrazol-4-yl)-6-((R)-1-(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared in the same general manner as that previously described for example 527 according to General Method N. Chiral separation by preparative SFC (ChiralCel OD-H (20Ã—250 mm 5), 35:65:0.2 MeOH:CO₂:DEA, 80 mL/min and 100 bar system backpressure (t_r: 12 mins). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. M/Z=453.0 [M+H], calc 452.5 for C₂₄H₂₀N₈O₂.

[Image Omitted]

Example 5313-(1-methyl-1H-pyrazol-4-yl)-6-((S)-1-(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared in the same general manner as that previously described for example 527 according to General Method N. Chiral separation by preparative SFC (ChiralCel OD-H (20Ã—250 mm 5), 35:65:0.2 MeOH:CO₂:DEA, 80 mL/min and 100 bar system backpressure (t_r: 18 mins). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. M/Z=453.0 [M+H], calc 452.5 for C₂₄H₂₀N₈O₂.

[Image Omitted]

Example 532(S)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Synthesized according to General Method N. Seperated by preperative HPLC (ChiralPakÂ® IA, (50Ã—250 mm, 5 m), 50% Heptane, 50% EtOH; 100 mL/min; t_r: 14.0 min) to yield (S)-6-(1-(8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one. On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. M/Z=391.2 [M+H], calc 390.12 for C₂₀H₁₅FN₆O₂.

[Image Omitted]

Example 533(R)-3-(2-methoxyethoxy)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Synthesized using General Method N. Chiral separation by preparative SFC (ChiralpakÂ® OD-H (20Ã—250 mm, 5 m), 30% MeOH, 70%, CO₂, 0.2% DEA, 70 mL/min; 100 bar system pressure; t_r: 6.8 min) On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. M/Z=446.2 [M+H], calc 445.19 for C₂₃H₂₃N₂O₃.

[Image Omitted]

Example 534(S)-3-(2-methoxyethoxy)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]-triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one

Prepared in the same general manner as that previously described for example 533 according to General Method N. Chiral separation by preparative SFC (ChiralpakÂ® OD-H (20Ã—250 mm, 5 m), 30% MeOH, 70%, CO₂, 0.2% DEA, 70 mL/min; 100 bar system pressure; t_r: 9.9 min). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the S enantiomer. M/Z=446.2 [M+H], calc 445.19 for C₂₃H₂₃N₂O₃.

Gen-eralMassMeth-ExStructureMWFoundod503 [Image Omitted]

389.4390.2N 504 [Image Omitted]

389.4390.2N 505 [Image Omitted]

420.8420.8N 506 [Image Omitted]

420.8420.8N 507 [Image Omitted]

389.4389.8N 508 [Image Omitted]

389.4389.8N 509 [Image Omitted]

419.4420.2N 510 [Image Omitted]

419.4420.2N 511 [Image Omitted]

405.5406.0N 512 [Image Omitted]

405.5406.0N 513 [Image Omitted]

407.4408.2N 514 [Image Omitted]

464.5465.2N 515 [Image Omitted]

464.5465.2N 516 [Image Omitted]

463.2464.2N 517 [Image Omitted]

463.2464.2N 518 [Image Omitted]

446.5447.2N 519 [Image Omitted]

446.5447.2N 520 [Image Omitted]

450.8450.8N 521 [Image Omitted]

450.8450.8N 522 [Image Omitted]

419.4419.8N 523 [Image Omitted]

419.4419.8N 524 [Image Omitted]

420.4420.8N 525 [Image Omitted]

420.4420.8N 526 [Image Omitted]

488.4488.8N 527 [Image Omitted]

470.2471.2N 528 [Image Omitted]

470.2471.2N 529 [Image Omitted]

390.1391.2O 530 [Image Omitted]

452.5453.0N 531 [Image Omitted]

452.5453.0N 532 [Image Omitted]

390.1391.2N 533 [Image Omitted]

445.2446.2N 534 [Image Omitted]

445.2446.2N

Ex-am-ple1H NMR Dataâ€‚â€‚4(400 MHz, DMSO-d₆) Î´ ppm 8.54 (d, J = 9.73 Hz, 1 H), 8.51 (d, J = 2.78 Hz, 1 H), 8.42 (d, J = 5.31 Hz, 1 H), 8.09 (s, 1 H), 7.94 (d, J = 9.73 Hz, 2 H), 7.58 (d, J = 2.78 Hz, 1 H), 6.83 (d, J = 5.31 Hz, 1 H), 5.15 (d, J = 6.19 Hz, 1 H), 3.94 (s, 1 H), 3.94 (s, 3 H), 2.52 (s, 3 H)â€‚14(400 MHz, DMSO-d₆) Î´ ppm 6.26 (s, 2 H), 7.57-7.64 (m, 3 H), 7.73 (d, J = 5.56 Hz, 1 H), 8.01 (d, J = 9.73 Hz, 1 H), 8.07-8.13 (m, 2 H), 8.35 (d, J = 5.56 Hz, 1 H), 8.47 (d, J = 9.73 Hz, 1 H), 8.64 (s, 1 H), 8.95 (s, 1 H)â€‚34(400 MHz, DMSO-d₆) Î´ ppm 2.39 (s, 3 H) 3.95 (s, 3 H) 5.16 (d, J = 5.94 Hz, 2 H) 6.82 (d, J = 5.43 Hz, 1 H) 7.38 (s, 1 H) 7.58 (d, J = 2.78 Hz, 1 H) 7.88 (d, J = 9.73 Hz, 1 H) 7.95 (t, J = 5.87 Hz, 1 H) 8.41 (d, J = 5.31 Hz, 1 H) 8.52 (d, J = 2.78 Hz, 1 H) 8.55 (d, J = 9.73 Hz, 1 H)â€‚38(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 6.00 (s, 2 H) 6.52 (d, J = 7.58 Hz, 1 H) 7.13 (dd, J = 2.46 Hz, 2 H) 7.27 (d, J = 5.31 Hz, 1 H) 7.34 (d, J = 2.40 Hz, 1 H) 7.64 (t, J = 7.64 Hz, 1 H) 7.80-8.11 (m, 3 H) 8.75 (d, J = 5.31 Hz, 1 H) 9.24 (s, 1 H) 11.42 (s, 1 H)â€‚39(400 MHz, DMSO-d₆) Î´ ppm 4.71 (s, 2 H), 7.49 (d, J = 9.54 Hz, 1 H), 7.51 (dd, J = 8.35, 3.51 Hz, 1 H), 7.75 (dd, J = 8.53, 1.51 Hz, 1 H), 7.87(s, 1 H), 7.98 (d, J = 8.53 Hz, 1 H), 8.31 (d, J = 8.53 Hz, 1 H), 8.46 (d, J = 10.04 Hz, 1 H), 8.87 (d, J = 5.52 Hz, 1 H)â€‚40(400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H), 4.79 (s, 2 H), 7.56-7.61 (m, 3 H), 7.64 (dd, J = 8.61, 1.96 Hz, 1 H), 7.72 (d, J = 2.74 Hz, 1 H) ,7.83 (d, J = 1.37 Hz, 1 H), 7.91 (d, J = 8.61 Hz, 1 H), 7.96 (d, J = 9.78 Hz, 1 H), 8.07-8.12 (m, 2 H), 8.45 (d, J = 9.78 Hz, 1 H), 8.58 (d, J = 2.93 Hz, 1 H)â€‚41(400 MHz, MeOH) Î´ ppm 8.73 (s, 1 H), 8.22 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 4.3 Hz, 2 H), 7.71-7.75 (m, 1 H), 7.66 (d, J = 9.0 Hz, 3 H), 7.45-7.53 (m, 3 H), 7.36-7.42 (m, 1 H), 7.01-7.03 (m, 1 H), 6.91 (d, J = 2.2 Hz, 1 H), 4.29 (s, 2 H), 3.90 (s, 3 H).â€‚42(400 MHz, DMSO-d₆) Î´ ppm 13.01 (s, 1 H), 8.44 (d, J = 9.73 Hz, 1 H), 8.18-8.30 (m, 2 H), 8.14 (s, 1 H), 7.94-8.06 (m, 3 H), 7.49- 7.59 (m, 3 H), 5.36 (s, 2 H).â€‚45(400 MHz, MeOH) Î´ ppm 9.27 (s, 1 H), 8.70 (d, J = 5.30 Hz, 1 H),8.41 (d, J = 9.85 Hz, 1 H), 8.06-8.10 (m, 2 H), 7.90-7.99 (m, 2 H), 7.62-7.67 (m, 2 H), 7.30-7.33 (m, 2 H), 7.10-7.14 (m, 1 H), 6.08 (s, 2 H), 3.92 (s, 3 H).â€‚51(400 MHz, DMSO-d₆) Î´ ppm 13.98 (s, 1 H), 9.82 (s, 1 H), 8.73 (d, J = 1.26 Hz, 1 H), 8.59 (s, 1 H), 8.51 (d, J = 9.85 Hz, 1 H), 8.16 (d, J = 12.00 Hz, 1 H), 8.07 (d, J = 9.73 Hz, 2 H), 7.62-7.73 (m, 2 H), 7.22 (d, J = 6.06 Hz, 1 H), 5.43 (d, J = 5.68 Hz, 2 H), 4.01 (s, 3 H), 3.86 (t, J = 6.95 Hz, 2 H), 2.50-2.47 (m, 2 H), 2.11-2.21 (m, 2 H).â€‚53(400 MHz, DMSO-d₆) Î´ ppm 8.59 (s, 1 H), 8.51 (d, J = 2.8 Hz, 1 H), 8.41 (d, J = 5.5 Hz, 1 H), 8.34 (d, J = 9.7 Hz, 1 H), 8.21-8.22 (m, 1 H), 7.95-7.98 (m, 1 H), 7.73 (d, J = 9.7 Hz, 1 H), 7.57 (d, J = 2.8 Hz, 1 H), 6.83 (d, J = 5.2 Hz, 1 H), 5.13 (d, J = 6.3 Hz, 2 H), 4.55-4.63 (m, 1 H), 3.93 (s, 3 H), 1.49 (s, 3 H), 1.47 (s, 3 H).â€‚56(400 MHz, DMSO-d₆) Î´ ppm 3.87 (s, 3 H), 5.84 (s, 2 H), 7.07-7.12 (m, 1 H), 7.27-7.33 (m, 2 H), 7.46-7.53 (m, 3 H), 7.88-7.96 (m, 2 H), 8.01-8.06 (m, 2 H), 8.12 (s, 1 H), 8.30 (d, J = 9.47 Hz, 1 H), 8.72 (d, J = 5.18 Hz, 1 H).â€‚58(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 5.86 (s, 2 H) 7.09 (dd, J = 9.09, 2.27 Hz, 1 H) 7.29 (d, J = 5.43 Hz, 1 H) 7.30-7.34 (m, 1 H) 7.55-7.63 (m, 1 H) 7.90-7.98 (m, 3 H) 8.07-8.15 (m, 2 H) 8.33 (d, J = 9.60 Hz, 1 H) 8.72 (d, J = 5.31 Hz, 1 H)â€‚60(400 MHz, DMSO-d₆) Î´ ppm 3.32 (s, 3 H) 6.09 (d, J = 0.88 Hz, 2 H) 7.07 (dd, J = 9.28, 2.46 Hz, 1 H) 7.37 (d, J = 2.53 Hz, 1 H) 7.47-7.54 (m, 2 H) 7.55-7.60 (m, 1 H) 7.86-7.92 (m, 3 H) 8.04 (d, J = 9.85 Hz, 1 H) 8.52 (d, J = 9.85 Hz, 1 H) 8.89 (d, J = 3.79 Hz, 1 H).â€‚61(400 MHz, DMSO-d₆) Î´ ppm 3.92 (s, 3 H) 5.07 (d, J = 6.19 Hz, 2 H) 6.82 (d, J = 5.43 Hz, 1 H) 7.54 (d, J = 2.78 Hz, 1 H) 7.88- 7.91 (m, 2 H) 8.00 (t, J = 6.20 Hz, 1 H) 8.19-8.28 (m, 3 H) 8.38 (d, J = 5.43 Hz, 1 H) 8.47 (d, J = 2.91 Hz, 1 H).â€‚65(400 MHz, DMSO-d₆) Î´ ppm 8.53 (s, 1 H), 8.40 (d, J = 5.05 Hz, 1 H), 8.13-8.19 (m, 2 H), 8.00 (t, J = 6.00 Hz, 1 H), 7.86 (s, 1 H), 7.56-7.61 (m, 4 H), 6.83 (d, J = 5.31 Hz, 1 H), 5.19 (d, J = 6.06 Hz, 2 H), 3.93 (s, 3 H), 2.67 (s, 3 H).â€‚66(400 MHz, DMSO-d₆) Î´ ppm 9.30 (s, 1 H), 8.58 (s, 1 H), 7.83 (d, J = 9.47 Hz, 1 H), 7.67-7.73 (m, 3 H), 7.51 (t, J = 7.58 Hz, 2 H), 7.43 (t, J = 7.26 Hz, 1 H), 7.14 (d, J = 8.34 Hz, 2 H), 6.69 (d, J = 8.34 Hz, 2 H), 4.51 (s, 2 H).â€‚69(400 MHz, DMSO-d₆) Î´ ppm 11.44 (s, 1 H), 9.31 (s, 1 H), 8.53 (s, 1 H), 7.65-7.76 (m, 2 H), 7.13 (d, J = 8.08 Hz, 2 H), 6.96 (s, 1 H), 6.69 (d, J = 8.34 Hz, 2 H), 6.62 (s, 1 H), 6.16 (s, 1 H), 4.38 (s, 2 H)â€‚70(300 MHz, DMSO-d₆) Î´ ppm 4.76 (s, 2 H) 7.54-7.68 (m, 4 H) 7.85 (dd, J = 8.33, 2.05 Hz, 1 H) 7.95 (d, J = 9.79 Hz, 1 H) 8.05 (s, 1 H) 8.09-8.17 (m, 2 H) 8.19 (d, J = 1.90 Hz, 1 H) 8.44 (d, J = 9.79 Hz, 1 H).â€‚77(400 MHz, DMSO-d₆) Î´ ppm 1.96 (d, J = 7.2 Hz, 3 H), 5.15 (d, J = 7.2 Hz, 1 H), 7.50 (dd, J = 8.4, 4.1 Hz, 1 H), 7.52-7.57 (m, 3 H), 7.83 (dd, J = 8.7, 1.9 Hz, 1 H), 7.92 (d, J = 9.8 Hz, 1 H), 7.97-8.03 (m, 4 H), 8.35 (d, J = 7.4 Hz, 1 H), 8.42 (d, J = 9.8 Hz, 1 H), 8.84 (dd, J = 4.1, 1.6 Hz, 1 H).â€‚89(400 MHz, DMSO-d₆) Î´ ppm 9.23 (s, 1 H), 8.74 (d, J = 5.05 Hz, 1 H), 8.19 (s, 1 H), 7.86-7.97 (m, 3 H), 7.70 (s, 1 H), 7.34 (s, 1 H), 7.24 (d, J = 5.05 Hz, 1 H), 7.14 (dd, J = 9.16, 1.83 Hz, 1 H), 5.98 (s, 2 H), 3.89 (s, 3 H).â€‚94(400 MHz, DMSO-d₆) Î´ ppm 9.16 (t, J = 1.26 Hz, 1 H), 8.68-8.75 (m, 2 H), 7.91-7.97 (m, 2 H), 7.85-7.88 (m, 1 H), 7.34 (d, J = 2.53 Hz, 1 H), 7.25 (d, J = 5.43 Hz, 1 H), 7.14 (dd, J = 9.16, 2.59 Hz, 1 H), 6.00 (s, 2 H), 3.89 (s, 3 H), 3.26-3.32 (m, 2 H), 1.11 (t, J = 7.20 Hz, 3 H).117(300 MHz, CHLOROFORM-d) Î´ ppm 2.09 (d, J = 7.31 Hz, 3 H) 3.92 (s, 3 H) 5.08 (q, J = 7.21 Hz, 1 H) 7.33 (d, J = 2.78 Hz, 1 H) 7.48-7.55 (m, 4 H) 7.72 (dd, J = 8.62, 2.05 Hz, 1 H) 7.77 (s, 1 H) 7.84 (dd, J = 7.45, 2.19 Hz, 2 H) 8.01 (d, J = 8.62 Hz, 1 H) 8.14 (d, J = 9.79 Hz, 1 H) 8.62 (d, J = 2.92 Hz, 1 H).118(300 MHz, CHLOROFORM-d) Î´ ppm 2.09 (d, J = 7.31 Hz, 3 H) 3.92 (s, 3 H) 5.08 (q, J = 7.31 Hz, 1 H) 7.33 (d, J = 2.78 Hz, 1 H) 7.47-7.56 (m, 4 H) 7.72 (dd, J = 8.55, 1.97 Hz, 1 H) 7.77 (s, 1 H) 7.84 (dd, J = 7.45, 2.19 Hz, 2 H) 8.01 (d, J = 8.62 Hz, 1 H) 8.14 (d, J = 9.65 Hz, 1 H) 8.62 (d, J = 2.92 Hz, 1 H).119(300 MHz, CHLOROFORM-d) Î´ ppm 2.09 (d, J = 7.31 Hz, 3 H) 3.92 (s, 3 H) 5.08 (q, J = 7.21 Hz, 1 H) 7.33 (d, J = 2.78 Hz, 1 H) 7.47-7.55 (m, 4 H) 7.72 (dd, J = 8.62, 2.05 Hz, 1 H) 7.77 (s, 1 H) 7.82-7.88 (m, 2 H) 8.01 (d, J = 8.62 Hz, 1 H) 8.14 (d, J = 9.65 Hz, 1 H) 8.62 (d, J = 2.92 Hz, 1 H).120(300 MHz, CHLOROFORM-d) Î´ ppm 3.48 (s, 3 H) 3.79-3.87 (m, 2 H) 4.18-4.27 (m, 2 H) 4.82 (s, 2 H) 7.33 (d, J = 2.78 Hz, 1 H) 7.50-7.59 (m, 4 H) 7.71 (d, J = 8.48 Hz, 1 H) 7.78 (s, 1 H) 7.90- 7.96 (m, 2 H) 8.00 (d, J = 8.48 Hz, 1 H) 8.15 (d, J = 9.65 Hz, 1 H) 8.68 (d, J = 2.92 Hz, 1 H).123(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H), 6.02 (s, 2 H), 7.12 (dd, J = 9.16, 2.46 Hz, 1 H), 7.30-7.36 (m, 2 H), 7.50-7.61 (m, 3 H), 7.97 (d, J = 9.22 Hz, 1 H), 8.03-8.10 (m, 3 H), 8.55 (d, J = 9.73 Hz, 1 H), 8.73 (d, J = 5.30 Hz, 1 H)125(400 MHz, DMSO-d₆) Î´ ppm 5.83 (s, 2 H), 7.21 (d, J = 5.94 Hz, 2 H), 7.55-7.63 (m, 3 H), 8.06 (d, J = 9.73 Hz, 1 H), 8.08-8.14 (m, 2 H), 8.45 (d, J = 5.81 Hz, 2 H), 8.53 (d, J = 9.60 Hz, 1 H)126(400 MHz, DMSO-d₆) Î´ ppm 5.66 (s, 2 H), 5.89 (s, 2 H), 6.18 (s, 1 H), 6.31 (d, J = 3.92 Hz, 1 H), 7.60 (s, 3 H), 7.76 (d, J = 5.68 Hz, 1 H), 8.05 (d, J = 9.73 Hz, 1 H), 8.08-8.16 (m, 2 H), 8.53 (d, J = 9.73 Hz, 1 H)131(400 MHz, DMSO-d₆) Î´ ppm 2.81 (s, 3 H), 3.88 (s, 3 H), 6.03 (s, 2 H), 7.11 (d, J = 8.72 Hz, 1 H), 7.28-7.38 (m, 2 H), 7.92-8.02 (m, 3 H), 8.10 (d, J = 9.60 Hz, 1 H), 8.15 (d, J = 7.58 Hz, 2 H), 8.52- 8.64 (m, 2 H), 8.73 (d, J = 4.42 Hz, 1 H)132(400 MHz, DMSO-d₆) Î´ ppm 2.79 (d, J = 4.42 Hz, 3 H), 3.89 (s, 3 H), 6.05 (s, 2 H), 7.12 (dd, J = 9.16, 2.46 Hz, 1 H), 7.31-7.35 (m, 2 H), 7.76 (t, J = 7.64 Hz, 1 H), 7.95-8.05 (m, 3 H), 8.12 (d, J = 9.85 Hz, 1 H), 8.39 (d, J = 4.80 Hz, 1 H), 8.60 (d, J = 9.85 Hz, 1 H), 8.73 (d, J = 5.18 Hz, 1 H)135(400 MHz, DMSO-d₆) Î´ ppm 2.77 (d, J = 4.55 Hz, 3 H), 3.88 (s, 3 H), 6.05 (s, 2 H), 7.12 (dd, J = 9.16, 2.34 Hz, 1 H), 7.32 (d, J = 5.31 Hz, 1 H), 7.34 (s, 1 H), 7.58 (d, J = 7.96 Hz, 1 H), 7.98 (d, J = 9.09 Hz, 1 H), 8.08 (d, J = 8.08 Hz, 1 H), 8.12 (d, J = 9.85 Hz, 1 H), 8.18 (s, 1 H), 8.42-8.50 (m, 1 H), 8.58 (d, J = 9.85 Hz, 1 H), 8.73 (d, J = 5.31 Hz, 1 H)155(400 MHz, DMSO-d₆) Î´ ppm 3.94 (s, 3 H) 5.25 (d, J = 6.19 Hz, 2 H) 6.89 (d, J = 5.68 Hz, 1 H) 7.57 (d, J = 2.65 Hz, 1 H) 7.88 (t, J = 1.83 Hz, 1 H) 8.07 (d, J = 9.73 Hz, 1 H) 8.27 (d, J = 1.77 Hz, 3 H) 8.43 (d, J = 5.56 Hz, 1 H) 8.50 (d, J = 9.85 Hz, 1 H) 8.55 (d, J = 2.78 Hz, 1 H)155(400 MHz, DMSO-d₆) Î´ ppm 3.94 (s, 3 H) 5.25 (d, J = 6.19 Hz, 2 H) 6.89 (d, J = 5.68 Hz, 1 H) 7.57 (d, J = 2.65 Hz, 1 H) 7.88 (t, J = 1.83 Hz, 1 H) 8.07 (d, J = 9.73 Hz, 1 H) 8.27 (d, J = 1.77 Hz, 3 H) 8.43 (d, J = 5.56 Hz, 1 H) 8.50 (d, J = 9.85 Hz, 1 H) 8.55 (d, J = 2.78 Hz, 1 H)157(400 MHz, DMSO-d₆) Î´ ppm 3.93 (s, 3 H) 5.23 (d, J = 6.19 Hz, 2 H) 6.85 (d, J = 5.18 Hz, 1 H) 7.57 (d, J = 2.65 Hz, 1 H) 7.85 (t, J = 7.83 Hz, 1 H) 7.93-8.04 (m, 2 H) 8.10 (d, J = 9.85 Hz, 1 H) 8.40 (d, J = 5.43 Hz, 1 H) 8.45-8.54 (m, 4 H)157(400 MHz, DMSO-d₆) Î´ ppm 3.93 (s, 3 H) 5.23 (d, J = 6.19 Hz, 2 H) 6.85 (d, J = 5.18 Hz, 1 H) 7.57 (d, J = 2.65 Hz, 1 H) 7.85 (t, J = 7.83 Hz, 1 H) 7.93-8.04 (m, 2 H) 8.10 (d, J = 9.85 Hz, 1 H) 8.40 (d, J = 5.43 Hz, 1 H) 8.45-8.54 (m, 4 H)158(400 MHz, DMSO-d₆) Î´ ppm 8.63 (d, J = 5.31 Hz, 1 H), 8.49 (d, J = 9.73 Hz, 1 H), 8.02 (t, J = 9.54 Hz, 2 H), 7.93 (d, J = 7.20 Hz, 2 H), 7.56 (t, J = 7.20 Hz, 1 H), 7.50 (t, J = 7.39 Hz, 2 H), 7.31 (d, J = 2.40 Hz, 1 H), 7.16 (d, J = 5.43 Hz, 1 H), 7.12 (dd, J = 9.22, 2.53 Hz, 1 H), 6.61 (q, J = 6.44 Hz, 1 H), 3.87 (s, 3 H), 2.07 (d, J = 6.57 Hz, 3 H)159(400 MHz, DMSO-d₆) Î´ ppm 8.46 (d, J = 9.73 Hz, 1 H), 8.32 (d, J = 5.31 Hz, 1 H), 8.19 (s, 1 H), 8.12-8.18 (m, 2 H), 7.99 (d, J = 9.85 Hz, 1 H), 7.85 (t, J = 5.49 Hz, 1 H), 7.53-7.63 (m, 3 H), 7.17 (d, J = 2.53 Hz, 1 H), 7.07 (dd, J = 9.16, 2.59 Hz, 1 H), 6.66 (d, J = 5.43 Hz, 1 H), 5.13 (d, J = 5.56 Hz, 2 H), 3.85 (s, 3 H)160(400 MHz, DMSO-d₆) Î´ ppm 8.69 (d, J = 4.67 Hz, 1 H), 8.46 (d, J = 9.85 Hz, 1 H), 8.08-8.16 (m, 2 H), 8.00 (d, J = 9.73 Hz, 1 H), 7.95 (d, J = 9.22 Hz, 1 H), 7.77 (d, J = 4.80 Hz, 1 H), 7.56-7.65 (m, 3 H), 7.36 (d, J = 2.40 Hz, 1 H), 7.23 (dd, J = 9.22, 2.40 Hz, 1 H), 5.12 (s, 2 H), 3.89 (s, 3 H)161(400 MHz, DMSO-d₆) Î´ ppm 8.52 (d, J = 2.78 Hz, 1 H), 8.45 (d, J = 9.85 Hz, 1 H), 8.41 (d, J = 5.30 Hz, 1 H), 8.14-8.21 (m, 2 H), 7.94-8.04 (m, 2 H), 7.54-7.63 (m, 4 H), 6.85 (d, J = 5.31 Hz, 1 H), 5.20 (d, J = 6.06 Hz, 2 H), 3.93 (s, 3 H)171(400 MHz, DMSO-d₆) Î´ ppm 8.52 (d, J = 2.78 Hz, 1 H), 8.48 (d, J = 9.73 Hz, 1 H), 8.40 (d, J = 5.31 Hz, 1 H), 8.34-8.40 (m, 1 H), 8.05-8.15 (m, 2 H), 8.02 (d, J = 9.85 Hz, 1 H), 7.63-7.77 (m, 1 H), 7.57 (d, J = 2.78 Hz, 1 H), 6.85 (d, J = 5.56 Hz, 1 H), 5.21 (d, J = 6.19 Hz, 2 H), 3.93 (s, 3 H)172(400 MHz, DMSO-d₆) Î´ ppm 8.51 (d, J = 6.19 Hz, 1 H), 8.50 (s, 1 H), 8.40 (d, J = 5.31 Hz, 1 H), 8.23-8.33 (m, 2 H), 8.12 (t, J = 5.68 Hz, 1 H), 8.03 (d, J = 9.85 Hz, 1 H), 7.56 (d, J = 2.53 Hz, 1 H), 6.86(d, J = 5.43 Hz, 1 H), 5.21 (d, J = 6.06 Hz, 2 H), 3.93 (s, 3 H)176(400 MHz, DMSO-d₆) Î´ ppm 8.51 (d, J = 2.91 Hz, 1 H), 8.36-8.43 (m, 2 H), 7.85-7.95 (m, 3 H), 7.57 (d, J = 2.78 Hz, 1 H), 7.47 (s, 1 H), 6.83 (d, J = 5.31 Hz, 1 H), 5.11 (d, J = 5.94 Hz, 2 H), 3.94 (s, 3 H), 2.29 (s, 3 H)182(300 MHz, DMSO-d₆) Î´ ppm 2.56 (s, 4 H), 2.59-2.68 (m, 1 H), 4.09 (s, 2 H), 6.87 (dd, J = 5.92, 2.27 Hz, 1 H), 7.21 (s, 1 H), 7.63 (s, 1 H), 7.65 (d, J = 1.75 Hz, 1 H), 8.08-8.16 (m, 2 H), 8.17 (d, J = 1.75 Hz, 2 H), 8.58 (d, J = 9.79 Hz, 1 H), 9.10 (s, 1 H)184(400 MHz, DMSO-d₆) Î´ ppm 8.73 (d, J = 5.18 Hz, 1 H), 8.48- 8.55 (m, 2 H), 8.03 (d, J = 9.85 Hz, 1 H), 7.96 (d, J = 9.09 Hz, 1 H), 7.70-7.75 (m, 2 H), 7.30-7.35 (m, 2 H), 7.12 (dd, J = 9.22, 2.40 Hz, 1 H), 5.98 (s, 2 H), 3.88 (s, 3 H).194(400 MHz, MeOH) Î´ ppm 8.69 (d, J = 4.93 Hz, 1 H), 8.35 (d, J = 9.85 Hz, 1 H), 8.08 (d, J = 9.22 Hz, 1 H), 8.00 (d, J = 9.85 Hz, 1 H), 7.85-7.93 (m, 2 H), 7.29-7.33 (m, 2 H), 7.10-7.20 (m, 2 H), 6.05 (s, 2 H), 3.93 (s, 3 H), 2.28 (s, 3 H).198(400 MHz, MeOH) Î´ ppm 8.68 (d, J = 5.43 Hz, 1 H), 8.42 (d, J = 9.73 Hz, 2 H), 8.26 (d, J = 6.82 Hz, 1 H), 8.06 (dd, J = 9.47, 2.78 Hz, 2 H), 7.78 (d, J = 8.72 Hz, 1 H), 7.28-7.31 (m, 2 H), 7.08-7.12 (m, 1 H), 6.07 (s, 2 H), 3.92 (s, 3 H).215(400 MHz, DMSO-d₆) Î´ ppm 2.33 (s, 3 H) 3.96 (s, 3 H) 6.00 (s, 2 H) 7.19 (dd, J = 9.16, 2.46 Hz, 1 H) 7.38 (d, J = 5.31 Hz, 1 H) 7.40 (d, J = 2.27 Hz, 1 H) 7.48 (s, 1 H) 7.99 (s, 1 H) 8.01-8.10 (m, 2 H) 8.54 (d, J = 9.73 Hz, 1 H) 8.80 (d, J = 5.31 Hz, 1 H)219(400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H) 6.06 (s, 2 H) 7.12 (d, J = 9.09 Hz, 1 H) 7.29-7.38 (m, 2 H) 7.51 (t, J = 9.03 Hz, 1 H) 7.86 (d, J = 6.44 Hz, 2 H) 7.98 (d, J = 9.09 Hz, 1 H) 8.12 (d, J = 9.98 Hz, 1 H) 8.62 (d, J = 9.35 Hz, 1 H) 8.74 (d, J = 4.80 Hz, 1 H)220(400 MHz, DMSO-d₆) Î´ ppm 3.90 (s, 3 H) 6.06 (s, 2 H) 7.13 (d, J = 8.59 Hz, 1 H) 7.32 (d, J = 5.05 Hz, 1 H) 7.35 (s, 1 H) 7.99 (d, J = 9.35 Hz, 1 H) 8.05-8.15 (m, 3 H) 8.62 (d, J = 9.73 Hz, 1 H) 8.74 (d, J = 5.05 Hz, 1 H)222(400 MHz, DMSO-d₆) Î´ ppm 2.50 (s, 3 H) 3.89 (s, 3 H) 5.98 (s, 2 H) 7.12 (d, J = 8.84 Hz, 1 H) 7.32 (d, J = 14.91 Hz, 2 H) 7.93-8.06 (m, 2 H) 8.09 (s, 1 H) 8.63 (d, J = 8.97 Hz, 1 H) 8.74 (s, 1 H)224(400 MHz, DMSO-d₆) Î´ ppm 4.31 (s, 3 H) 6.49 (s, 2 H) 7.55 (dd, J = 8.84, 2.02 Hz, 1 H) 7.74 (d, J = 5.18 Hz, 1 H) 7.76 (s, 1 H) 8.27 (s, 1 H) 8.41 (d, J = 9.22 Hz, 1 H) 8.54 (d, J = 1.14 Hz, 2 H) 8.58 (s, 1 H) 9.02 (d, J = 9.60 Hz, 1 H) 9.16 (d, J = 5.31 Hz, 1 H)233(400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H) 3.90 (s, 3 H) 5.93 (s, 2 H) 7.13 (dd, J = 9.16, 2.59 Hz, 1 H) 7.30 (d, J = 5.31 Hz, 1 H) 7.34 (d, J = 2.40 Hz, 1 H) 7.79 (d, J = 9.73 Hz, 1 H) 7.96 (d, J = 9.22 Hz, 1 H) 8.09 (s, 1 H) 8.44 (d, J = 9.73 Hz, 1 H) 8.46 (s, 1 H) 8.73 (d, J = 5.30 Hz, 1 H).234(400 MHz, DMSO-d₆) Î´ ppm 3.93 (s, 3 H) 3.94 (s, 3 H) 5.12 (d, J = 6.19 Hz, 2 H) 6.82 (d, J = 5.43 Hz, 1 H) 7.57 (d, J = 2.78 Hz, 1 H) 7.70 (d, J = 9.73 Hz, 1 H) 7.96 (t, J = 6.19 Hz, 1 H) 8.21 (s, 1 H) 8.34 (d, J = 9.73 Hz, 1 H) 8.41 (d, J = 5.43 Hz, 1 H) 8.51 (d, J = 2.78 Hz, 1 H) 8.52 (s, 1 H).238(400 MHz, DMSO-d₆) Î´ ppm 1.37 (t, J = 6.95 Hz, 3 H), 3.89 (s, 3 H), 4.19 (q, J = 6.95, 2 H), 6.01 (s, 2 H), 7.12 (dd, J = 8.91, 2.46 Hz, 1 H), 7.28-7.36 (m, 3 H), 7.92 (d, J = 7.71 Hz, 1 H), 7.97 (d, J = 9.09 Hz, 2 H), 8.06 (d, J = 9.85 Hz, 1 H), 8.51 (d, J = 9.85 Hz, 1 H), 8.73 (d, J = 5.18 Hz, 1 H)245(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H), 6.03 (s, 2 H), 7.12 (dd, J = 9.16, 2.46 Hz, 1 H), 7.25 (d, J = 5.31 Hz, 1 H), 7.27-7.31 (m, 1 H), 7.34 (d, J = 2.53 Hz, 1 H), 7.50-7.59 (m, 1 H), 7.63-7.74 (m, 2 H), 7.90-8.00 (m, 2 H), 8.74 (d, J = 5.31 Hz, 1 H), 9.02 (s, 1 H)245(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H), 6.04 (s, 2 H), 7.13 (d, J = 10.86 Hz, 1 H), 7.24 (d, J = 5.31 Hz, 1 H), 7.34 (s, 1 H), 7.45 (d, J = 6.44 Hz, 1 H), 7.50 (t, J = 6.63 Hz, 2 H), 7.78 (d, J = 7.45 Hz, 2 H), 7.89 (d, J = 12.25 Hz, 1 H), 7.97 (d, J = 9.22 Hz, 1 H), 8.74 (d, J = 6.19 Hz, 1 H), 8.94 (s, 1 H)247(400 MHz, DMSO-d₆) Î´ ppm 3.91 (s, 3 H), 5.16 (d, J = 5.94 Hz, 1 H), 6.91 (d, J = 5.31 Hz, 1 H), 7.32 (t, J = 8.34 Hz, 1 H), 7.55 (d, J = 2.53 Hz, 1 H), 7.57-7.63 (m, 1 H), 7.64-7.74 (m, 2 H), 7.83 (d, J = 12.51 Hz, 1 H), 8.34-8.45 (m, 2 H), 8.50 (d, J = 2.53 Hz, 1 H), 9.11 (s, 2 H)252(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 6.02 (s, 2 H) 7.12 (dd, J = 9.16 Hz, 1 H) 7.25 (d, J = 5.31 Hz, 1 H) 7.30-7.42 (m, 3 H) 7.73-7.89 (m, 3 H) 7.89-8.01 (m, 2 H) 8.73 (d, J = 5.31 Hz, 1 H) 9.01 (s, 1 H)252(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 6.02 (s, 2 H) 7.12 (dd, J = 9.16 Hz, 1 H) 7.25 (d, J = 5.31 Hz, 1 H) 7.30-7.42 (m, 3 H) 7.73-7.89 (m, 3 H) 7.89-8.01 (m, 2 H) 8.73 (d, J = 5.31 Hz, 1 H) 9.01 (s, 1 H)254(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 6.00 (s, 2 H) 7.12 (dd, J = 9.09 Hz, 1 H) 7.26 (d, J = 5.43 Hz, 1 H) 7.33 (d, J = 2.40 Hz, 1 H) 7.51-7.71 (m, 2 H) 7.81-8.02 (m, 4 H) 8.74 (d, J = 5.30 Hz, 1 H) 9.08 (s, 1 H)259(400 MHz, DMSO-d₆) Î´ ppm 2.76 (d, J = 4.29 Hz, 3 H) 3.88 (s, 3 H) 6.03 (s, 2 H) 7.13 (d, J = 8.84 Hz, 1 H) 7.26 (d, J = 5.05 Hz, 1 H) 7.33 (s, 1 H) 7.54 (d, J = 7.58 Hz, 1 H) 7.79 (d, J = 7.83 Hz, 1 H) 7.85-8.04 (m, 4 H) 8.39 (d, J = 3.66 Hz, 1 H) 8.74 (d, J = 5.31 Hz, 1 H) 9.12 (s, 1 H)263(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 6.00 (s, 2 H) 7.12 (dd, J = 9.09 Hz, 1 H) 7.26 (d, J = 5.18 Hz, 1 H) 7.33 (d, J = 2.27 Hz, 1 H) 7.65-7.69 (m, 1 H) 7.69-7.74 (m, 1 H) 7.92-7.97 (m, 3 H) 8.08 (d, J = 2.27 Hz, 1 H) 8.74 (d, J = 5.18 Hz, 1 H) 9.07 (s, 1 H)266(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 6.01 (s, 2 H) 7.11 (dd, J = 9.22 Hz, 1 H) 7.26 (d, J = 5.30 Hz, 1 H) 7.29-7.37 (m, 2 H) 7.60 (d, J = 6.95 Hz, 2 H) 7.89-8.01 (m, 3 H) 8.75 (d, J = 5.31 Hz, 1 H) 9.16 (s, 1 H)267(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 5.99 (s, 2 H) 7.11 (dd, J = 2.40 Hz, 1 H) 7.26 (d, J = 5.31 Hz, 1 H) 7.34 (d, J = 2.27 Hz, 1 H) 7.79-7.93 (m, 3 H) 7.93-8.04 (m, 2 H) 8.75 (d, J = 5.31 Hz, 1 H) 9.14 (s, 1 H)270(400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H) 6.01 (s, 2 H) 7.14 (dd, J = 9.16 Hz, 1 H) 7.22-7.26 (m, 2 H) 7.35 (d, J = 2.53 Hz, 1 H) 7.55 (d, J = 3.92 Hz, 1 H) 7.78 (dd, J = 9.60 Hz, 1 H) 7.93-8.00 (m, 2 H) 8.74 (d, J = 5.31 Hz, 1 H) 8.97 (t, 1 H)279(400 MHz, DMSO-d₆) Î´ ppm 2.50 (s, 3 H) 3.89 (s, 3 H) 6.06 (s, 2 H) 7.13 (d, J = 7.58 Hz, 1 H) 7.25 (d, J = 2.40 Hz, 1 H) 7.35 (s, 1 H) 7.66 (s, 1 H) 7.91-8.01 (m, 3 H) 8.74 (d, J = 5.68 Hz, 1 H) 9.18 (s, 1 H)283(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 5.92 (s, 2 H) 6.15 (s, 1 H) 6.69 (s, 1 H) 6.94 (s, 1 H) 7.12 (dd, J = 8.91, 1.96 Hz, 1 H) 7.29 (d, J = 5.18 Hz, 1 H) 7.34 (d, J = 1.77 Hz, 1 H) 7.81-7.90 (m, 2 H) 7.98 (d, J = 9.22 Hz, 1 H) 8.76 (d, J = 5.18 Hz, 1 H) 8.88 (s, 1 H) 11.49 (s, 1 H).284(400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 6.03 (s, 2 H) 7.13 (dd, J = 9.16, 2.34 Hz, 1 H) 7.25 (d, J = 5.30 Hz, 1 H) 7.33 (d, J = 2.15 Hz, 1 H) 7.43 (t, J = 7.14 Hz, 1 H) 7.50 (t, J = 7.45 Hz, 2 H) 7.75 (d, J = 7.45 Hz, 2 H) 7.85 (d, J = 8.72 Hz, 1 H) 7.96 (d, J = 9.22 Hz, 2 H) 8.74 (d, J = 5.31 Hz, 1 H) 9.00 (s, 1 H).285(400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H) 6.03 (s, 2 H) 7.11-7.21 (m, 2 H) 7.24 (d, J = 5.30 Hz, 1 H) 7.34 (d, J = 2.27 Hz, 1 H) 7.62- 7.67 (m, 2 H) 7.81 (dd, J = 9.60, 1.14 Hz, 1 H) 7.96 (dd, J = 16.55, 9.35 Hz, 2 H) 8.73 (d, J = 5.18 Hz, 1 H) 8.96 (s, 1 H).287(400 MHz, DMSO-d₆) Î´ ppm 2.23 (s, 3 H) 3.89 (s, 3 H) 6.02 (s, 2 H) 7.14 (dd, J = 9.16, 2.46 Hz, 1 H) 7.20-7.26 (m, 2 H) 7.34 (d, J = 2.53 Hz, 1 H) 7.47 (s, 1 H) 7.76 (dd, J = 9.66, 1.45 Hz, 1 H) 7.94 (dd, J = 18.88, 9.41 Hz, 2 H) 8.74 (d, J = 5.18 Hz, 1 H) 8.92 (s, 1 H).290(400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H) 6.02 (s, 2 H) 7.15 (dd, J = 9.28, 2.34 Hz, 1 H) 7.25 (d, J = 5.31 Hz, 1 H) 7.35 (d, J = 2.27 Hz, 1 H) 7.87 (d, J = 10.36 Hz, 1 H) 7.98 (d, J = 8.84 Hz, 2 H) 8.45 (s, 1 H) 8.74 (d, J = 5.43 Hz, 1 H) 9.06 (s, 1 H) 9.17 (s, 1 H)291(400 MHz, DMSO-d₆) Î´ ppm 2.46 (s, 3 H) 3.89 (s, 3 H) 6.01 (s, 2 H) 7.14 (dd, J = 9.22, 2.53 Hz, 1 H) 7.25 (d, J = 5.31 Hz, 1 H) 7.35 (d, J = 2.40 Hz, 1 H) 7.73 (s, 1 H) 7.77 (dd, J = 9.60, 1.52 Hz, 1 H) 7.97 (d, J = 9.22 Hz, 1 H) 8.00 (d, J = 9.60 Hz, 1 H) 8.75 (d, J = 5.31 Hz, 1 H) 9.19 (s, 1 H)295(400 MHz, DMSO-d₆) Î´ ppm 3.93 (s, 3 H) 5.14 (d, J = 5.94 Hz, 2 H) 6.91 (d, J = 5.18 Hz, 1 H) 7.57 (d, J = 2.02 Hz, 1 H) 7.73 (s, 1 H) 7.76 (d, J = 11.37 Hz, 1 H) 8.35 (t, J = 6.00 Hz, 1 H) 8.43 (d, J = 4.80 Hz, 1 H) 8.53 (d, J = 2.53 Hz, 1 H) 9.17 (s, 1 H)297(400 MHz, DMSO-d₆) Î´ ppm 2.30 (s, 3 H) 3.89 (s, 3 H) 6.03 (s, 2 H) 7.07 (s, 1 H) 7.13 (dd, J = 9.09, 2.53 Hz, 1 H) 7.25 (d, J = 5.43 Hz, 1 H) 7.35 (d, J = 2.40 Hz, 1 H) 7.88 (dd, J = 9.73, 1.39 Hz, 1 H) 7.96 (d, J = 9.22 Hz, 1 H) 8.04 (d, J = 9.60 Hz, 1 H) 8.75 (d, J = 5.31 Hz, 1 H) 9.29 (s, 1 H)298(400 MHz, DMSO-d₆) Î´ ppm 3.93 (s, 3 H) 5.16 (d, J = 5.94 Hz, 2 H) 6.91 (d, J = 5.43 Hz, 1 H) 7.56 (d, J = 2.27 Hz, 1 H) 7.83-7.94 (m, 3 H) 8.34 (t, J = 5.75 Hz, 1 H) 8.43 (d, J = 5.18 Hz, 1 H) 8.52 (d, J = 2.27 Hz, 1 H) 9.14 (s, 1 H)302(400 MHz, DMSO-d₆) Î´ ppm 2.22 (s, 3 H), 3.88 (s, 3 H), 6.03 (s, 2 H), 7.04-7.42 (m, 4 H), 7.50 (s, 1 H), 7.79 (d, J = 9.47 Hz, 1 H), 7.97 (d, J = 6.06, 1 H), 8.76 (d, J = 18.95, 2 H)306(400 MHz, CHLOROFORM-d) Î´ ppm 4.72 (s, 1 H) 7.27 (dd, J = 9.59, 1.56 Hz, 1 H) 7.41 (dd, J = 8.31, 4.21 Hz, 1 H) 7.62-7.66 (m, 2 H) 7.69 (dd, J = 9.68, 0.88 Hz, 1 H) 7.87-7.91 (m, 1 H) 8.05-8.12 (m, 2 H) 8.92 (dd, J = 4.21, 1.66 Hz, 1 H)307(400 MHz, DMSO-d₆) Î´ ppm 5.03 (s, 2 H) 7.49 (t, J = 7.34 Hz, 1 H) 7.57 (t, J = 7.43 Hz, 3 H) 7.84 (d, J = 7.43 Hz, 2 H) 7.93-8.02 (m, 1 H) 8.08 (d, J = 9.59 Hz, 1 H) 8.12-8.20 (m, 2 H) 8.27 (s, 1 H) 8.35 (d, J = 7.82 Hz, 1 H) 9.00 (d, J = 6.46 Hz, 1 H) 9.11 (d, J = 5.09 Hz, 1 H) 9.22 (d, J = 3.91 Hz, 1 H).308(400 MHz, DMSO-d₆) Î´ ppm 2.32 (s, 3 H) 5.00 (s, 2 H) 7.92 (d, J = 9.54 Hz, 1 H) 8.01 (t, J = 15.56, 6.53 Hz, 2 H) 8.16 (d, J = 8.53 Hz, 1 H) 8.25 (s, 1 H) 8.37 (d, J = 9.03 Hz, 1 H) 9.04 (d, J = 8.03 Hz, 1 H) 9.21 (s, 1 H) 9.23 (d, J = 4.52 Hz, 1 H)315(400 MHz, DMSO-d₆) Î´ ppm 5.06 (s, 2 H), 7.52-7.62 (m, 3 H), 7.62-7.71 (m, 1 H), 7.83 (d, J = 7.07 Hz, 1 H), 7.93 (d, J = 9.73 Hz, 1 H), 8.01-8.11 (m, 3 H), 8.21 (d, J = 6.06 Hz, 1 H), 8.41 (d, J = 9.85 Hz, 1 H), 8.55 (d, J = 5.94 Hz, 1 H), 9.32 (s, 1 H)323(400 MHz, CDCl₃) Î´ ppm 3.84 (t, J = 7.33 Hz, 2 H), 3.93-4.00 (m, 5 H), 7.33 (d, J = 4.42 Hz, 1 H), 7.48-7.56 (m, 4 H), 7.59 (s, 1 H), 7.85 (dd, J = 7.45, 1.77 Hz, 2 H), 8.11 (d, J = 9.73 Hz, 1 H), 8.69 (d, J = 4.42 Hz, 1 H), 8.72 (d, J = 2.90 Hz, 1 H)328(300 MHz, DMSO-d₆) Î´ ppm 4.48 (s, 2 H) 6.90 (d, J = 8.33 Hz, 1 H) 7.14 (dd, J = 8.11, 1.39 Hz, 1 H) 7.42 (d, J = 1.46 Hz, 1 H) 7.53-7.71 (m, 3 H) 7.94 (d, J = 9.79 Hz, 1 H) 8.05-8.22 (m, 2 H) 8.42 (d, J = 9.79 Hz, 1 H), 10.2 (br, 1 H).332(300 MHz, DMSO-d₆) Î´ ppm 2.01 (s, 3 H) 3.34 (s, 1 H) 4.53 (s, 2 H) 7.32 (d, J = 7.60 Hz, 2 H) 7.51 (d, J = 7.45 Hz, 2 H) 7.59 (s, 3 H) 7.94 (d, J = 9.50 Hz, 1 H) 8.11 (s, 2 H) 8.42 (d, J = 9.65 Hz, 1 H) 9.89 (s, 1 H).336(300 MHz, MeOH) Î´ ppm 2.31 (s, 3 H) 4.79 (s, 2 H) 7.29 (s, 1 H) 7.51 (dd, J = 8.33, 4.38 Hz, 1 H) 7.70 (s, 1 H) 7.82 (d, J = 9.79 Hz, 1 H) 7.85-7.90 (m, 1 H) 7.95-8.01 (m, 1 H) 8.03 (s, 1 H) 8.14 (d, J = 9.79 Hz, 1 H) 8.34 (d, J = 8.62 Hz, 1 H) 8.79 (dd, J = 4.31, 1.68 Hz, 1 H).337(300 MHz, CHLOROFORM-d) Î´ ppm 4.85 (s, 2 H) 7.35-7.48 (m, 2 H) 7.57 (dd, J = 8.18, 6.43 Hz, 2 H) 7.82 (d, J = 8.62 Hz, 1H) 7.91 (s, 1 H) 8.08 (d, J = 8.62 Hz, 1 H) 8.13 (d, J = 8.33 Hz, 1 H) 8.21 (d, J = 9.79 Hz, 1 H) 8.90 (d, J = 4.24 Hz, 1 H).338(300 MHz, CHLOROFORM-d) Î´ ppm 4.85 (s, 2 H) 6.97-7.06 (m, 1 H) 7.35-7.43 (m, 1 H) 7.43-7.51 (m, 3 H) 7.84 (d, J = 8.62 Hz, 1 H) 7.93 (t, J = 4.90 Hz, 1 H) 8.08 (d, J = 8.48 Hz, 1 H) 8.13 (d, J = 8.77 Hz, 1 H) 8.20 (d, J = 9.65 Hz, 1 H) 8.89 (dd, J = 4.17, 1.68 Hz, 1 H).339(300 MHz, CHLOROFORM-d) Î´ ppm 4.84 (s, 2 H) 7.17-7.26 (m, 2 H) 7.39 (dd, J = 8.18, 4.24 Hz, 1 H) 7.51 (d, J = 9.79 Hz, 1 H) 7.85 (dd, J = 8.70, 1.97 Hz, 1 H) 7.88-7.96 (m, 3 H) 8.01-8.13 (m, 2 H) 8.16 (d, J = 9.79 Hz, 1 H) 8.89 (dd, J = 4.24, 1.61 Hz, 1 H).340300 MHz, CHLOROFORM-d) Î´ ppm 4.84 (s, 2 H) 7.34 (d, J = 9.65 Hz, 1 H) 7.40 (dd, J = 8.18, 4.24 Hz, 1 H) 7.48 (d, J = 9.65 Hz, 1 H) 7.61-7.69 (m, 1 H) 7.74-7.80 (m, 1 H) 7.83 (dd, J = 8.62, 2.05 Hz, 1 H) 7.90 (s, 1 H) 8.08 (d, J = 8.62 Hz, 1 H) 8.12 (d, J = 9.06 Hz, 1 H) 8.18 (d, J = 9.79 Hz, 1 H) 8.89 (dd, J = 4.17, 1.68 Hz, 1 H).341300 MHz, CHLOROFORM-d) Î´ ppm 4.01 (s, 3 H) 4.79 (s, 2 H) 7.25 (s, 1 H) 7.38 (dd, J = 8.33, 4.24 Hz, 1 H) 7.81-7.89 (m, 2 H) 7.91 (s, 1 H) 8.00 (s, 1 H) 8.03-8.10 (m, 2 H) 8.11 (s, 1 H) 8.88 (dd, J = 4.24, 1.61 Hz, 1 H).342(300 MHz, DMSO-d₆) Î´ ppm 4.74 (s, 2 H) 7.45 (d, J = 2.63 Hz, 1 H) 7.53 (dd, J = 8.62, 1.90 Hz, 1 H) 7.56-7.61 (m, 3 H) 7.79 (s, 1 H) 7.84 (d, J = 8.62 Hz, 1 H) 7.94 (d, J = 9.79 Hz, 1 H) 8.10 (dd, J = 6.65, 3.00 Hz, 2 H) 8.42 (d, J = 9.79 Hz, 1 H) 8.51 (d, J = 2.78 Hz, 1 H) 10.29 (s, 1 H).343(400 MHz, DMSO-d₆) Î´ ppm 5.98 (d, J = 2.74 Hz, 1 H), 5.99 (s, 2 H), 6.05 (d, J = 9.39 Hz, 1 H), 7.40 (d, J = 2.74 Hz, 1 H), 7.58- 7.64 (m, 3 H), 7.93 (d, J = 9.59 Hz, 1 H), 8.00 (d, J = 9.78 Hz, 1 H), 8.10-8.16 (m, 2 H), 8.46 (d, J = 9.78 Hz, 1 H), 11.44 (br. s., 1 H)3481H NMR (400 MHz, DMSO-d₆) Î´ ppm 8.70 (d, J = 2.74 Hz, 1 H), 8.53 (s, 1 H), 8.50 (d, J = 5.28 Hz, 1 H), 8.35 (d, J = 9.68 Hz, 1 H), 8.21 (d, J = 0.78 Hz, 1 H), 8.17 (s, 1 H), 7.94 (d, J = 2.64 Hz, 1 H), 7.69-7.73 (m, 1 H), 6.94 (d, J = 5.38 Hz, 1 H), 5.15 (d, J = 6.16 Hz, 2 H), 3.94 (s, 3 H)3511H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 8.66 (d, J = 1.56 Hz, 1 H), 8.08 (d, J = 8.51 Hz, 1 H), 7.83-7.93 (m, 2 H), 7.61 (s, 1 H), 7.53 (d, J = 8.61 Hz, 1 H), 7.42 (d, J = 9.78 Hz, 1 H), 7.33 (s, 1 H), 6.80-6.95 (m, 3 H), 4.78 (s, 2 H), 3.93 (s, 3 H).3521H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 8.67 (d, J = 2.84 Hz, 1 H), 8.15 (d, J = 8.51 Hz, 1 H), 7.94-7.99 (m, 1 H), 7.86 (dd, J = 9.59 Hz, 1 H), 7.62 (s, 1 H), 7.56 (dd, J = 8.61 Hz, 1 H), 7.34- 7.43 (m, 2 H), 7.07 (s, 1 H), 4.77 (s, 2 H), 3.95 (s, 3 H), 2.51 (s, 3 H).3551H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.52 (s, 3 H) 5.19 (d, J = 6.26 Hz, 2 H) 6.95 (d, J = 5.38 Hz, 1 H) 7.71 (dd, J = 8.51, 4.11 Hz, 1 H) 7.94 (d, J = 9.78 Hz, 1 H) 8.04 (t, J = 6.21 Hz, 1 H) 8.09 (s, 1 H) 8.21 (dd, J = 8.51, 1.56 Hz, 1 H) 8.50 (d, J = 5.28 Hz, 1 H) 8.54 (d, J = 9.78 Hz, 1 H) 8.79 (dd, J = 4.11, 1.56 Hz, 1 H).3591H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.51 (s, 3 H) 5.19 (d, J = 6.06 Hz, 2 H) 6.96 (d, J = 5.48 Hz, 1 H) 7.94 (d, J = 9.68 Hz, 1 H) 8.05 (dd, J = 10.03, 2.49 Hz, 1 H) 8.09 (s, 1 H) 8.22 (s, 1 H) 8.48-8.59 (m, 2 H) 8.85 (d, J = 2.64 Hz, 1 H)3641H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.51 (s, 3 H) 5.17 (d, J = 6.16 Hz, 2 H) 6.94 (d, J = 5.38 Hz, 1 H) 7.53 (t, J = 73.21 Hz, 1 H) 7.89-7.99 (m, 2 H) 8.09 (s, 1 H) 8.12 (t, J = 6.26 Hz, 1 H) 8.51 (d, J = 5.28 Hz, 1 H) 8.54 (d, J = 9.68 Hz, 1 H) 8.70 (d, J = 2.74 Hz, 1 H).3651H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.52 (s, 3 H) 3.33 (s, 3 H) 3.71-3.76 (m, 2 H) 4.27-4.31 (m, 2 H) 5.14 (d, J = 6.16 Hz, 2 H) 6.82 (d, J = 5.38 Hz, 1 H) 7.59 (d, J = 2.74 Hz, 1 H) 7.94 (d, J = 9.78 Hz, 2 H) 8.09 (s, 1 H) 8.41 (d, J = 5.28 Hz, 1 H) 8.49-8.57 (m, 2 H)3701H NMR (400 MHz, MeOH) Î´ ppm 3.44 (s, 3 H) 3.82-3.87 (m, 2 H) 4.29-4.34 (m, 2 H) 5.40 (s, 2 H) 7.02 (d, J = 5.97 Hz, 1 H) 7.19-7.27 (m, 1 H) 7.51 (d, J = 2.64 Hz, 1 H) 7.75-7.86 (m, 2 H) 7.95 (d, J = 9.88 Hz, 1 H) 8.33 (d, J = 9.88 Hz, 1 H) 8.39 (d, J = 6.26 Hz, 1 H) 8.59 (s, 1 H)3711H NMR (400 MHz, DMSO-d₆) Î´ ppm 5.02 (q, J = 8.80 Hz, 2 H) 5.22 (d, J = 6.26 Hz, 2 H) 6.91 (d, J = 5.48 Hz, 1 H) 7.53 (t, J = 9.15 Hz, 1 H) 7.79 (d, J = 2.64 Hz, 1 H) 7.99-8.10 (m, 3 H) 8.21 (t, J = 5.97 Hz, 1 H) 8.44 (d, J = 5.28 Hz, 1 H) 8.51 (d, J = 9.78 Hz, 1 H) 8.61 (d, J = 2.64 Hz, 1 H)3721H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.52 (s, 3 H) 5.02 (q, J = 8.90 Hz, 2 H) 5.15 (d, J = 6.16 Hz, 2 H) 6.87 (d, J = 5.38 Hz, 1 H) 7.80 (d, J = 2.84 Hz, 1 H) 7.94 (d, J = 9.78 Hz, 1 H) 8.01 (t, J = 6.11 Hz, 1 H) 8.09 (s, 1 H) 8.45 (d, J = 5.28 Hz, 1 H) 8.54 (d, J = 9.78 Hz, 1 H) 8.62 (d, J = 2.84 Hz, 1 H).3831H NMR (400 MHz, DMSO-d₆) Î´ ppm 3.94 (s, 3 H) 4.50-4.62 (m, 2 H) 5.14 (d, J = 6.16 Hz, 2 H) 6.30-6.64 (m, 1 H) 6.87 (d, J = 5.48 Hz, 1 H) 7.66-7.74 (m, 2 H) 8.06 (t, J = 6.11 Hz, 1 H) 8.21 (d, J = 0.68 Hz, 1 H) 8.34 (d, J = 9.68 Hz, 1 H) 8.44 (d, J = 5.38 Hz, 1 H) 8.52 (s, 1 H) 8.59 (d, J = 2.84 Hz, 1 H).390(400 MHz, DMSO-d₆) Î´ ppm 8.64 (s, 1 H), 8.51 (d, J = 2.8 Hz, 1 H), 8.40 (d, J = 5.2 Hz, 1 H), 8.35 (d, J = 9.6 Hz, 1 Hz), 8.19 (s, 1 H), 7.99 (t, J = 6.0 Hz, 1 H), 7.72 (d, J = 10 Hz, 1 H), 7.57 (d J = 2.8 Hz, 1 H), 6.83 (d, J = 5.2 Hz, 1 H), 5.12 (d, J = 6.0 Hz, 2 H), 3.93 (s, 3 H), 3.80-3.86 (m, 1 H), 1.10-1015 (m, 2 H), 1.00-1.08 (m, 2 H).3991H NMR (400 MHz, DMSO-d₆) Î´ ppm 8.49-8.55 (m, 2 H), 8.41 (d, J = 5.38 Hz, 1 H), 8.24 (s, 1 H), 8.03 (d, J = 9.68 Hz, 1 H), 7.94 (t, J = 6.16 Hz, 1 H), 7.58 (d, J = 2.84 Hz, 1 H), 6.83 (d, J = 5.38 Hz, 1 H), 5.67 (t, J = 5.77 Hz, 1 H), 5.15 (d, J = 6.16 Hz, 2 H), 4.63 (d, J = 5.67 Hz, 2 H), 3.93 (s, 3 H).4001H NMR (400 MHz, DMSO-d₆) Î´ ppm 5.26 (d, J = 6.36 Hz, 2 H) 7.02 (d, J = 5.38 Hz, 1 H) 7.96-8.10 (m, 2 H) 8.22-8.32 (m, 2 H) 8.48-8.57 (m, 3 H) 8.85 (d, J = 2.84 Hz, 1 H)4051H NMR (400 MHz, DMSO-d₆) Î´ ppm 3.43-3.53 (m, 4 H) 3.70-3.80 (m, 4 H) 3.94 (s, 3 H) 5.16 (d, J = 6.16 Hz, 2 H) 6.85 (d, J = 5.28 Hz, 1 H) 7.57 (d, J = 2.74 Hz, 1 H) 7.87 (s, 1 H) 7.90 (d, J = 9.68 Hz, 1 H) 8.01-8.08 (m, 1 H) 8.35-8.45 (m, 2 H) 8.52 (d, J = 2.64 Hz, 1 H)4061H NMR (400 MHz, DMSO-d₆) Î´ ppm 3.94 (s, 3 H) 5.19 (d, J = 6.26 Hz, 2 H) 6.85 (d, J = 5.38 Hz, 1 H) 7.57 (d, J = 2.93 Hz, 1 H) 7.97-8.02 (m, 1 H) 8.05 (d, J = 9.78 Hz, 1 H) 8.42 (d, J = 5.28 Hz, 1 H) 8.45 (d, J = 9.68 Hz, 1 H) 8.52 (d, J = 2.84 Hz, 1 H) 8.71 (d, J = 1.96 Hz, 1 H) 9.36 (d, J = 1.96 Hz, 1 H)4081H NMR (400 MHz, DMSO-d₆) Î´ ppm 1.90 (d, J = 7.04 Hz, 3 H) 2.44 (s, 3 H) 5.24 (q, J = 7.01 Hz, 1 H) 7.51 (dd, J = 8.27, 4.16 Hz, 1 H) 7.64-7.73 (m, 2 H) 7.81 (dd, J = 8.75, 2.01 Hz, 1 H) 7.94 (d, J = 1.96 Hz, 1 H) 8.00 (d, J = 8.61 Hz, 1 H) 8.32 (d, J = 8.41 Hz, 1 H) 8.64 (d, J = 1.17 Hz, 1 H) 8.86 (dd, J = 4.16, 1.71 Hz, 1 H)4091H NMR (400 MHz, DMSO-d₆) Î´ ppm 1.92 (d, J = 7.14 Hz, 3 H) 5.26 (q, 1 H) 7.31 (t, J = 9.29 Hz, 1 H) 7.49 (dd, J = 8.36, 4.16 Hz, 2 H) 7.55 (d, J = 8.61 Hz, 1 H) 7.77-7.86 (m, J = 8.22 Hz, 2 H) 7.95 (s, 1 H) 7.99 (d, J = 8.71 Hz, 1 H) 8.31 (d, J = 7.24 Hz, 1 H) 8.68 (s, 1 H) 8.85 (dd, J = 4.11, 1.66 Hz, 1 H)4111H NMR (400 MHz, DMSO-d₆) Î´ ppm 1.89 (d, J = 7.04 Hz, 3 H) 2.27 (s, 3 H) 3.88 (s, 3 H) 5.22 (q, J = 6.98 Hz, 1 H) 6.99 (s, 1 H) 7.63 (dd, J = 8.71, 2.05 Hz, 1 H) 7.67-7.70 (m, 1 H) 7.72 (d, J = 1.86 Hz, 1 H) 7.76 (dd, J = 11.54, 1.17 Hz, 1 H) 7.93 (d, J = 8.61 Hz, 1 H) 8.58 (d, J = 2.93 Hz, 1 H) 8.64 (d, J = 1.08 Hz, 1 H)4131H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.40 (s, 3 H) 2.44 (d, J = 23.28 Hz, 3 H) 7.56-7.61 (m, 2 H) 7.75 (dd, J = 8.90, 2.15 Hz, 1 H) 7.80 (dd, J = 11.49, 1.22 Hz, 1 H) 8.02 (d, J = 0.88 Hz, 1 H) 8.09 (d, J = 8.90 Hz, 1 H) 8.12 (d, J = 2.05 Hz, 1 H) 8.43-8.47 (m, 1 H) 8.95 (dd, J = 4.21, 1.76 Hz, 1 H)4181H NMR (400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H) 4.88 (s, 2 H) 7.61 (dd, J = 8.56, 2.01 Hz, 1 H) 7.68 (d, J = 2.74 Hz, 1 H) 7.70-7.75 (m, 1 H) 7.83 (s, 1 H) 7.89 (dd, J = 11.44, 1.08 Hz, 1 H) 7.93 (d, J = 8.61 Hz, 1 H) 8.59 (d, J = 2.84 Hz, 1 H) 9.17 (d, J = 1.08 Hz, 1 H)4301H NMR (400 MHz, DMSO-d₆) Î´ ppm 8.84 (dd, J = 4.25, 1.71 Hz, 1 H), 8.42-8.46 (m, 1 H), 8.26 (d, J = 2.05 Hz, 1 H), 8.15 (d, J = 9.49 Hz, 1 H), 7.94 (s, 1 H), 7.90 (d, J = 8.80 Hz, 1 H), 7.67-7.76 (m, 4 H), 7.52 (dd, J = 8.26, 4.25 Hz, 1 H), 7.38-7.44 (m, 1 H), 7.32-7.37 (m, 2 H), 6.17 (s, 1 H), 2.17 (s, 3 H)4311H NMR (400 MHz, DMSO-d₆) Î´ ppm 8.85 (dd, J = 4.21, 1.76 Hz, 1 H), 8.31-8.35 (m, 1 H), 8.21 (d, J = 9.59 Hz, 1 H), 8.04-8.08 (m, 2 H), 7.95-7.99 (m, 2 H), 7.75-7.83 (m, 3 H), 7.49-7.58 (m, 4 H), 4.62 (s, 2 H)4331H NMR (400 MHz, DMSO-d₆) Î´ ppm 9.01 (dd, J = 4.21, 1.66 Hz, 1 H), 8.54-8.59 (m, 1 H), 8.47 (s, 1 H), 8.44 (d, J = 9.59 Hz, 1 H), 8.16 (d, J = 8.80 Hz, 1 H), 8.13 (s, 1 H), 8.00 (dd, J = 8.90, 2.05 Hz, 1 H), 7.88 (d, J = 9.59 Hz, 1 H), 7.64 (dd, J = 8.31, 4.21 Hz, 1 H), 7.11 (s, 1 H), 2.33 (s, 3 H)4361H NMR (400 MHz, DMSO-d₆) Î´ ppm 8.46 (d, J = 2.74 Hz, 1 H), 8.38 (d, J = 5.38 Hz, 1 H), 8.29 (d, J = 9.39 Hz, 1 H), 8.00 (s, 1 H), 7.76-7.82 (m, 3 H), 7.54 (d, J = 2.84 Hz, 1 H), 6.79 (d, J = 5.38 Hz, 1 H), 4.98 (d, J = 6.36 Hz, 2 H), 3.91 (s, 3 H)437¹H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 4.80 (s, 2 H) 7.19 (dd, J = 10.76, 1.17 Hz, 1 H) 7.31-7.35 (m, 2 H) 7.38-7.43 (m, 4 H) 7.65-7.71 (m, 3 H) 8.07 (dd, J = 8.31, 0.88 Hz, 1 H) 8.11 (d, J = 8.41 Hz, 1 H) 8.91 (dd, J = 4.21, 1.66 Hz, 1 H).438¹H NMR (400 MHz, DMSO-d₆) Î´ ppm 3.88 (s, 3 H) 4.76 (s, 2 H) 7.52-7.59 (m, 1 H) 7.61 (s, 1 H) 7.65 (d, J = 12.32 Hz, 1 H) 7.80 (s, 1 H) 7.91 (d, J = 8.80 Hz, 1 H) 8.01 (s, 1 H) 8.27 (s, 1 H) 8.57-8.66 (m, 2 H) 10.59 (br. s., 1 H)4391H NMR (400 MHz, DMF) Î´ ppm 7.69 (tt, J = 9.32, 2.27 Hz, 3 H) 7.99 (dd, J = 8.31, 4.21 Hz, 1 H)8.01-8.09 (m, 2 H) 8.43 (dd, J = 8.90, 2.15 Hz, 1 H) 8.54 (d, J = 8.8 Hz 1 H) 8.83-8.95 (m, 2 H) 9.19 (d, J = 2.25 Hz, 1 H) 9.37 (dd, J = 4.25, 1.71 Hz, 1 H) 9.53 (d, J = 2.25 Hz, 1 H). MS m/z = 410.0 [M + l]⁺ Calc'd for C₂₂H₁₁F₄N₃O: 409.3.4421H NMR (400 MHz, DMSO-d₆) Î´ ppm 4.00 (s, 3 H) 5.24 (d, J = 5.97 Hz, 2 H) 5.76 (d, J = 46.46 Hz, 2 H) 7.64 (d, J = 2.74 Hz, 1 H) 7.77 (s, 1 H) 8.01 (d, J = 9.68 Hz, 1 H) 8.10 (t, J = 6.26 Hz, 1 H) 8.48 (d, J = 5.28 Hz, 1 H) 8.59 (d, J = 2.74 Hz, 1 H) 8.64 (d, J = 9.68 Hz, 1 H).4431H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.40-2.40 (m, 1 H) 7.58(dd, J = 8.31, 4.21 Hz, 1 H) 7.81 (s, 1 H) 8.00 (dd, J = 8.90, 2.25 Hz, 1 H) 8.12 (d, J = 8.90 Hz, 1 H) 8.44 (d, J = 1.27 Hz, 1 H) 8.47 (dd, J = 8.46, 1.03 Hz, 1 H) 8.70 (d, J = 2.25 Hz, 1 H) 8.95 (dd, J = 4.26, 1.71 Hz, 1 H) 9.07 (d, J = 2.15 Hz, 1 H).4441H NMR (400 MHz, DMSO-d₆) Î´ ppm 7.44-7.53 (m, 1 H) 7.68 (dd, J = 8.31, 4.21 Hz, 1 H) 8.00 (td, J = 7.78, 1.76 Hz, 1 H) 8.11 (dd, J = 8.90, 2.05 Hz, 1 H) 8.25 (dd, J = 15.60, 8.36 Hz, 2 H) 8.55 (s, 1 H) 8.58 (dd, J = 8.41, 0.78 Hz, 1 H) 8.75 (dq, J = 4.77, 0.82 Hz, 1 H) 9.01-9.11 (m, 2 H) 9.53 (d, J = 2.15 Hz, 1 H).4501H NMR (400 MHz, DMSO-d₆) Î´ ppm 7.35-7.45 (m, 1 H) 7.67 (dd, J = 8.31, 4.21 Hz, 1 H) 7.73-7.85 (m, 2 H) 8.11 (dd, J = 8.9, 2.0 Hz, 1 H) 8.21 (d, J = 8.90 Hz, 1 H) 8.48 (d, J = 9.10 Hz, 1 H) 8.57 (s, 1 H) 8.60 (m, 2 H) 9.04 (dd, J = 4.11, 1.56 Hz, 1 H).4601H NMR (400 MHz, DMSO-d₆) Î´ ppm 3.89 (s, 3 H); 3.89 (s, 3 H); 4.01-4.02 (m, 1 H); 7.86 (dd, J = 8.8, 2.2 Hz, 1 H); 7.91 (dd, J = 12.0, 1.0 Hz, 1 H); 7.95 (d, J = 2.7 Hz, 1 H); 8.11 (d, J = 0.7 Hz, 1 H); 8.15 (d, J = 8.7 Hz, 1 H); 8.32 (d, J = 1.5 Hz, 1 H); 8.56(d, J = 0.7 Hz, 1 H); 8.78 (d, J = 2.9 Hz, 1 H)4621H NMR (400 MHz, DMSO-d₆) Î´ ppm 1.93-2.07 (m, 2 H) 2.30-2.42 (m, 4 H) 2.43-2.49 (m, 2 H) 3.50-3.65 (m, 4 H) 3.89 (s, 3 H) 4.20 (t, J = 6.41 Hz, 2 H) 7.86 (dd, J = 8.75, 1.91 Hz, 1 H) 7.96 (s, 1 H) 7.98 (d, J = 2.64 Hz, 1 H) 8.13 (s, 1 H) 8.15 (d, J = 8.90 Hz, 1 H) 8.32 (s, 1 H) 8.46 (s, 1 H) 8.57 (s, 1 H) 8.78 (d, J = 2.84 Hz, 1 H)4681H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 2.41 (s, 3 H); 3.97 (s, 3 H); 6.54 (s, 1 H); 7.39 (dd, J = 9.8, 1.2 Hz, 1 H); 7.47 (d, J = 2.8 Hz, 1 H); 7.83 (dd, J = 8.8, 2.1 Hz, 1 H); 8.17 (d, J = 1.1 Hz, 1 H); 8.21 (d, J = 8.7 Hz, 1 H) 8.75-8.84 (m, 2 H)4691H NMR (400 MHz, DMSO-d₆) ppm 3.95 (s, 3 H); 7.83-7.92 (m, 2 H); 7.93-8.03 (m, 2 H); 8.18 (d, J = 5.6 Hz, 1 H); 8.34 (s, 1 H); 8.69 (s, 1 H); 8.80 (d, J = 2.93 Hz, 1 H)4701H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.34 (s, 3 H); 7.26 (s, 1 H); 7.69 (dd, J = 8.3, 4.2 Hz, 1 H); 8.05 (dd, J = 8.8, 2.2 Hz, 1 H); 8.09 (dd, J = 11.3, 1.1 Hz, 1 H); 8.25 (d, J = 8.9 Hz, 1 H); 8.50 (d, J = 1.7 Hz, 1 H); 8.60 (s, 1 H); 8.80 (d, J = 1.0 Hz, 1 H); 9.08 (dd, J = 4.3, 1.7 Hz, 1 H)4711H NMR (400 MHz, DMSO-d₆) Î´ ppm 3.70 (s, 3 H); 7.57-7.67 (m, 1 H); 7.72 (s, 1 H); 7.87-8.16 (m, 3 H); 8.29 (s, 1 H); 8.55 (s, 1 H); 8.70 (s, 1 H)4731H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.32 (s, 3 H); 3.47 (s, 1 H); 3.55 (dd, J = 11.4, 2.01 Hz, 1 H); 3.67 (s, 2 H); 3.80 (s, 1 H); 3.89 (s, 1 H); 3.98 (s, 1 H); 4.16 (d, J = 5.0 Hz, 2 H); 7.22 (s, 1 H); 7.87 (dd ,J = 8.9, 2.0 Hz, 1 H); 7.98 (d, J = 2.8 Hz, 1 H); 8.05 (dd, J = 11.3, 0.6 Hz, 1 H); 8.16 (d, J = 8.8 Hz, 1 H); 8.31 (s, 1 H); 8.74 (s, 1 H); 8.81 (d, J = 2.9 Hz, 1 H)4741H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.35 (s, 3 H); 3.94 (s, 3 H); 4.79 (d, J = 5.97 Hz, 2 H); 6.76 (d, J = 5.4 Hz, 1 H); 7.01 (s, 1 H); 7.57 (d, J = 2.7 Hz, 1 H); 7.89-7.94 (m, 1 H); 7.93 (d, J = 8.6 Hz, 1 H); 8.21 (d, J = 8.6 Hz, 1 H); 8.34 (s, 1 H); 8.40 (d, J = 5.4 Hz, 1 H); 8.51 (d, J = 2.7 Hz, 1 H)475¹H NMR (400 MHz, DMSO-d₆) ppm 3.89 (s, 3 H) 7.68 (dd, J = 8.28, 4.27 Hz, 1 H) 7.93 (d, J = 12.05 Hz, 1 H) 8.04 (d, J = 8.53 Hz, 1 H) 8.13 (s, 1 H) 8.23 (d, J = 8.53 Hz, 1 H) 8.43-8.52 (m, 2 H) 8.55-8.63 (m, 2 H) 9.07 (d, J = 4.02 Hz, 1 H).476¹H NMR (400 MHz, DMSO-d₆) d ppm 7.56-7.74 (m, 2 H) 7.99 (d, J = 9.03 Hz, 1 H) 8.21 (d, J = 8.53 Hz, 1 H) 8.40 (s, 1 H) 8.57 (d, J = 8.03 Hz, 1 H) 8.63 (d, J = 10.04 Hz, 1 H) 9.05 (d, J = 4.02 Hz, 1 H)477¹H NMR (400 MHz, DMSO-d₆) d ppm 3.92 (s, 3 H) 3.94 (s, 3 H) 7.80-7.87 (m, 2 H) 8.01-8.07 (m, 1 H) 8.11 (d, J = 9.04 Hz, 1 H) 8.37 (s, 1 H) 8.46-8.51 (m, 2 H) 8.75 (d, J = 3.01 Hz, 1 H)478¹H NMR (400 MHz, DMSO-d₆) d ppm 7.67 (dd, J = 8.03, 4.02 Hz, 1 H) 7.80-7.89 (m, 2 H) 8.17 (dd, J = 13.05, 9.54 Hz, 2 H) 8.54 (s, 1 H) 8.60 (d, J = 8.53 Hz, 1 H) 8.69 (d, J = 10.04 Hz, 1 H) 9.04 (d, J = 3.51 Hz, 1 H)484¹H NMR (400 MHz, DMSO-d₆) d ppm 2.94 (t, J = 7.78 Hz, 2 H) 3.03-3.14 (m, 2 H) 7.44 (d, J = 8.03 Hz, 2 H) 7.68 (dd, J = 8.28, 4.27 Hz, 1 H) 7.85 (br. s., 2 H) 7.95 (d, J = 8.03 Hz, 2 H) 8.05 (d, J = 8.53 Hz, 1 H) 8.12 (d, J = 9.54 Hz, 1 H) 8.21 (d, J = 8.53 Hz, 1 H) 8.49 (s, 1 H) 8.57-8.66 (m, 2 H) 9.05 (d, J = 4.02 Hz, 1 H).490¹H NMR (300 MHz, CHLOROFORM-d) d ppm 2.10 (d, J = 7.16 Hz, 3 H) 2.55 (s, 3 H) 5.04 (q, J = 6.87 Hz, 1 H) 7.27-7.52 (m, 3 H) 7.82 (d, J = 8.62 Hz, 1 H) 7.93 (s, 1 H) 8.05 (d, J = 8.62 Hz, 1 H) 8.15 (d, J = 9.21 Hz, 2 H) 8.85 (d, J = 2.63 Hz, 1 H).496¹H NMR (300 MHz, CHLOROFORM-d)ppm 3.58 (s, 3 H) 4.78 (s, 2 H) 7.48-7.63 (m, 4 H) 7.66 (d, J = 8.48 Hz, 1 H) 7.87 (d, J = 7.16 Hz, 1 H) 7.91-8.06 (m, 3 H) 8.14 (d, J = 9.65 Hz, 1 H) 8.47 (s, 1 H).499¹H NMR (300 MHz, CHLOROFORM-d) Î´ ppm 3.94 (s, 3 H) 4.73 (s, 2 H) 7.10 (d, J = 9.65 Hz, 1 H) 7.33 (d, J = 2.78 Hz, 1 H) 7.63 (d, J = 10.67 Hz, 1 H) 7.76 (s, 1 H) 8.00 (d, J = 8.48 Hz, 1 H) 8.07 (d, J = 9.65 Hz, 1 H) 8.64 (d, J = 2.92 Hz, 1 H).501¹H NMR (300 MHz, MeOH) d ppm 4.05 (s, 11 H) 4.82 (s, 7 H) 7.40 (dd, J = 10.08, 1.46 Hz, 4 H) 7.81 (dd, J = 8.77, 1.90 Hz, 4 H) 7.96 (d, J = 0.88 Hz, 4 H) 8.05 (d, J = 8.77 Hz, 4 H) 8.21 (d, J = 2.78 Hz, 4 H) 8.50 (d, J = 0.73 Hz, 3 H) 8.85 (d, J = 2.92 Hz, 4 H).502¹H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 2.59 (s, 3 H) 3.93 (s, 3 H) 4.77 (s, 2 H) 7.34 (d, J = 2.74 Hz, 1 H) 7.38 (d, J = 9.68 Hz, 1 H) 7.46 (s, 1 H) 7.66 (dd, J = 8.61, 2.05 Hz, 1 H) 7.84 (d, J = 1.96 Hz, 1 H) 7.98 (d, J = 8.61 Hz, 1 H) 8.16 (d, J = 9.59 Hz, 1 H) 8.61 (d, J = 2.93 Hz, 1 H).

Example¹H NMR Data503¹H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 2.16 (d, J = 5.18 Hz, 3 H)3.97 (s, 3 H) 6.82 (d, J = 6.55 Hz, 1 H) 7.01-7.13 (m, 2 H) 7.41-7.49(m, 1 H) 7.54 (d, J = 6.26 Hz, 1 H) 7.61 (s, 1 H) 7.71 (s, 1 H) 8.33 (s, 1 H)8.78 (d, J = 7.73 Hz, 1 H) 8.93 (s, 1 H).5051H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.01 (d, J = 7.04 Hz, 3 H) 6.78 (d,J = 7.82 Hz, 1 H) 7.03 (d, J = 6.94 Hz, 1 H) 7.54 (dd, J = 8.07, 4.55 Hz, 1 H)7.78 (d, J = 7.82 Hz, 1 H) 7.97-8.09 (m, 2 H) 8.16 (dd, J = 8.56, 2.49 Hz,1 H) 8.61 (dd, J = 7.97, 1.71 Hz, 1 H) 8.70-8.78 (m, 1 H) 8.92 (dd,J = 4.55, 1.81 Hz, 1 H) 9.03 (d, 1 H).5071H NMR (400 MHz, DMSO-d₆) Î´ ppm 1.97 (d, J = 6.94 Hz, 3 H) 3.68 (s,3 H) 6.75 (d, J = 7.73 Hz, 1 H) 6.94 (d, J = 6.85 Hz, 1 H) 7.52-7.59 (m, 1H) 7.64 (dd, J = 7.78, 0.54 Hz, 1 H) 7.69-7.75 (m, 3 H) 8.46 (s, 1 H) 8.63(dt, J = 8.12, 0.88 Hz, 1 H) 8.90-8.94 (m, 1 H)509¹H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 2.17 (d, J = 7.14 Hz, 3 H)4.00-4.09 (m, 2 H) 4.29-4.33 (m, 2 H) 6.91 (d, J = 7.92 Hz, 1 H) 7.04(dd, 1 H) 7.10 (dd, J = 10.56, 1.17 Hz, 1 H) 7.51 (dd, J = 8.17, 4.74 Hz, 1H) 7.59 (d, J = 7.82 Hz, 1 H) 7.72 (d, J = 0.68 Hz, 1 H) 7.76 (d, J = 0.78 Hz,1 H) 8.34 (d, J = 1.17 Hz, 1 H) 8.84 (dd, J = 8.07, 1.22 Hz, 1 H) 8.92 (dd,J = 4.74, 1.81 Hz, 1 H)514¹H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 2.17 (d, J = 7.14 Hz, 3 H)2.39 (s, 3 H) 3.49 (s, 3 H) 3.78-3.94 (m, 2 H) 4.23-4.43 (m, 2 H) 6.43(s, 1 H) 6.85 (d, J = 7.82 Hz, 1 H) 7.08 (q, J = 7.11 Hz, 1 H) 7.29 (dd,J = 10.07, 1.17 Hz, 1 H) 7.43 (d, J = 7.82 Hz, 1 H) 8.17 (d, J = 2.93 Hz, 1 H)8.58-8.81 (m, 2 H).516¹H NMR (400 MHz, CHLOROFORM-d) Î´ ppm 2.15 (d, J = 7.14 Hz, 3 H)3.49 (s, 3 H) 3.80-3.90 (m, 2 H) 3.97 (s, 3 H) 4.27-4.39 (m, 2 H) 6.83(d, J = 7.73 Hz, 1 H) 7.00-7.13 (m, 2 H) 7.42 (d, J = 7.82 Hz, 1 H) 7.61 (s,1 H) 7.72 (s, 1 H) 8.15 (d, J = 2.84 Hz, 1 H) 8.31 (s, 1 H) 8.72 (d, J = 3.03Hz, 1 H).5181H NMR (400 MHz, DMSO-d₆) Î´ ppm 8.89 (t, 1 H), 8.68 (d, J = 3.03 Hz,1 H), 8.01-8.02 (m, 1 H), 7.96 (dd, J = 9.59, 1.08 Hz, 1 H), 7.79 (dd,J = 9.54, 1.61 Hz, 1 H), 7.60 (d, J = 7.82 Hz, 1 H), 7.01-7.05 (m, 1 H),6.99 (s, 1 H), 6.75 (d, J = 7.63 Hz, 1 H), 4.29-4.32 (m, 2 H), 3.70-3.73(m, 2 H), 3.32 (s, 3 H), 2.31 (s, 3 H), 1.99 (d, J = 7.04 Hz, 3 H).5241H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.00 (d, J = 7.04 Hz, 3 H) 2.31 (s,3 H) 3.94 (s, 3 H) 6.77 (dd, J = 7.78, 0.54 Hz, 1 H) 6.94-7.05 (m, 2 H)7.64 (d, J = 7.82 Hz, 1 H) 7.76-7.89 (m, 1 H) 7.98 (dd, J = 3.08, 0.54 Hz,1 H) 8.68 (d, J = 3.03 Hz, 1 H) 8.80 (d, J = 1.08 Hz, 1 H).5261H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.01 (d, J = 7.04 Hz, 3 H) 2.25-2.38 (m, 3 H) 5.05 (q, J = 8.77 Hz, 2 H) 6.74-6.83 (m, 1 H) 6.96-7.07(m, 2 H) 7.71 (d, J = 7.82 Hz, 1 H) 7.86 (dd, J = 11.49, 1.12 Hz, 1 H) 8.20(d, J = 2.74 Hz, 1 H) 8.78 (d, J = 3.03 Hz, 1 H) 8.83 (d, J = 1.08 Hz, 1 H)527¹H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.01 (d, J = 7.04 Hz, 3 H) 2.31 (s,3 H) 3.89 (s, 3 H) 6.78 (d, J = 8.41 Hz, 1 H) 6.95-7.09 (m, 2 H) 7.72 (d,J = 7.82 Hz, 1 H) 7.85 (d, J = 12.62 Hz, 1 H) 8.12 (s, 1 H) 8.46 (s, 1 H)8.67 (dd, J = 2.35, 0.68 Hz, 1 H) 8.83 (d, J = 1.08 Hz, 1 H) 9.20 (d, J = 2.45Hz, 1 H)529¹H NMR (400 MHz, DMSO-d₆) Î´ ppm 2.00 (d, J = 7.04 Hz, 3 H) 2.31 (s,3 H) 6.78 (d, J = 7.92 Hz, 1 H) 6.95-7.12 (m, 2 H) 7.54 (dd, J = 8.22, 4.50Hz, 1 H) 7.77 (d, J = 7 .7 3 Hz, 1 H) 7.85 (d, J = 11.54 Hz, 1 H) 8.62 (d,J = 9.59 Hz, 1 H) 8.82 (s, 1 H) 8.92 (dd, J = 4.55, 1.71 Hz, 1 H)

Although the pharmacological properties of the compounds of the current invention vary with structural change, in general, activity possessed by these compounds may be demonstrated in vivo. The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological in vitro assays. The exemplified pharmacological assays, which follow, have been carried out with the compounds according to the invention. The exemplified compounds of the present invention demonstrated a K_ibetween 20 Î¼M and 0.1 nM.

Illustrative activity values are provided in the following table.

Ex.cMet K_i(Î¼M)10.007030.400440.00321220136.6667146.6667170.0093180.0066191.9075200.5562210.8054230.1329240.017433 0.0732340.0159380.0370390.0505400.0075414.2537450.0121500.0238520.0050530.0067550.0009582.0618590.0845610.3994620.0017661.2312670.7584680.5563690.3749700.0229730.0128750.0022790.0834820.2617840.0261850.0020860.00248720880.1516890.0079910.01921121.57651180.00261210.00541220.02721340.11611400.00521410.00291440.16881480.00921520.48371540.05021640.14101670.07331700.05081720.00271760.00121860.00621870.00491990.03452020.00242030.00752080.02372090.00892140.01762220.00162260.00472290.04022310.00672320.00262790.01972810.06312820.00952830.00482890.05262940.00282950.02692960.00892970.00323020.00033060.04903090.00203110.00703143.28553150.21993170.84653190.85323210.24083241.6093325203260.39363330.10713340.41603360.00073410.00913430.72033730.00014300.34804370.03644390.25314400.17164410.02864470.01214500.18234660.63515030.00155050.00155081.34385090.00325110.00055140.00075160.00615180.00155200.00115220.00115240.00095250.02575270.00035290.0021

Biological Testing

The efficacy of the compounds of the invention as inhibitors of HGF related activity is demonstrated as follows.

c-Met Receptor Assay

Cloning, Expression and Purification of c-Met Kinase Domain

A PCR product covering residues 1058-1365 of c-Met (c-Met kinase domain) is generated from Human Liver QuickCloneâ„¢ cDNA (Invitrogen) using forward primer 5â€²-ATTGACGGATCCATGCTAAATCCAGAGCTGGTCCAGGCA-3â€² (SEQ ID NO. 1) and reverse primer 5â€²-ACAACAGAATTCAATACGGAGCGACACATTTTACGTT-3â€² (SEQ ID NO. 2). The PCR product is cloned into a modified pFastBac1 expression vector (harboring the gene for S. japonicum glutathione S-transferase immediately upstream of the multiple cloning site) using standard molecular biological techniques. The GST-c-Met kinase domain fusion (GST-Met) gene is transposed into full-length baculovirus DNA using the BacToBacâ„¢ system (Invitrogen). High5 cells are infected with the recombinant baculovirus for 72 h at 27Â° C. The infected cells are harvested by centrifugation and the pellet is stored at âˆ’80Â° C. The pellet is resuspended in buffer A (50 mM HEPES, pH 8.0, 0.25 M NaCl, 10 mM 2-mercaptoethanol, 10% (w/v) glycerol, 0.5% (v/v) protease inhibitor cocktail (Sigma P8340), stirred at 4Â° C. to homogeneity, and the cells are disrupted by microfluidization (Microfluidics) at 10,000 psi. The resulting lysate is centrifuged at 50,000Ã—g for 90 min at 4Â° C., and the supernatant is adsorbed onto 10 mL of glutathione Sepharoseâ„¢ 4B (Amersham) by batch method. The slurry is rocked gently overnight at 4Â° C. The glutathione resin is harvested by centrifugation and washed three times with 40 mL buffer A by batch method. The resin is washed three times with buffer B (buffer A adjusted to 0.1 M NaCl, less protease inhibitors). The protein is eluted with buffer B containing 25 mM reduced glutathione. Eluted fractions are analyzed by SDS-PAGE and concentrated to <10 mL (Ëœ10 mg/mL total protein). The concentrated protein is separated by Superdexâ„¢ 200 (Amersham) size exclusion chromatography in buffer C (25 mM Tris, pH 7.5, 0.1 M NaCl, 10 mM 2-mercaptoethanol, 10% glycerol). The fractions are analyzed by SDS-PAGE and the appropriate fractions are pooled and concentrated to Ëœ1 mg/mL. The protein is aliquotted and stored at âˆ’80Â° C.

Alternative Purification of Human GST-cMET from Baculovirus Cells

Baculovirus cells are broken in 5Ã— (volume/weight) of Lysis Buffer (50 mM HEPES, pH 8.0, 0.25 M NaCl, 5 mM mercaptoethanol, 10% glycerol plus Complete Protease Inhibitors (Roche (#10019600), 1 tablet per 50 mL buffer). The lysed cell suspension is centrifuged at 100,000Ã—g (29,300 rpm) in a Beckman ultracentrifuge Ti45 rotor for 1 h. The supernatant is incubated with 10 ml of Glutathione Sepharose 4B from Amersham Biosciences (#27-4574-01). Incubation is carried out overnight in a cold room (approximately 8Â° C.). The resin and supernatant is poured into an appropriately sized disposable column and the flow through supernatant was collected. The resin is washed with 10 column volumes (100 mL) of Lysis Buffer. The GST-cMET is eluted with 45 mL of 10 mM Glutathione (Sigma #G-4251) in Lysis Buffer. The elution is collected as 15 mL fractions. Aliquots of the elution fractions are run on SDS PAGE (12% Tris Glycine gel, Invitrogen, #EC6005BOX). The gel is stained with 0.25% Coomassie Blue stain. Fractions with GST-cMET are concentrated with a Vivaspin 20 mL Concentrator (#VS2002; 10,00 MW cutoff) to a final volume less than 2.0 ml. The concentrated GST-cMET solution is applied to a Superdex 75 16/60 column (Amersham Biosciences #17-1068-01) equilibrated with 25 mM Tris, pH 7.5, 100 mM NaCl, 10 mM mercaptoethanol, 10% glycerol. The GST-cMET is eluted with an isocratic run of the above buffer, with the eluent collected in 1.0 mL fractions. Fractions with significant OD₂₈₀readings are run on another 12% Tris Glycine gel. The peak tubes with GST-cMET are pooled and the OD₂₈₀is read with the column buffer listed above as the blank buffer.

Phosphorylation of the purified GST-cMET is performed by incubating the protein for 3 h at RT with the following:

Final concentrationa) 100 mM ATP (Sigma #A7699)25 mMb) 1.0M MgCl₂(Sigma #M-0250)100 mMc) 200 mM Sodium Orthovanadate (Sigma15mM#S-6508)d) 1.0M Tris-HCl, pH 7.00 (in house)50 mMe) H₂0f) GST-cMET0.2-0.5mg/mL

After incubation, the solution is concentrated in a Vivaspin 20 ml Concentrator to a volume less than 2.00 ml. The solution is applied to the same Superdex 75 16/60 column used above after re-equilibration. The GST-cMET is eluted as described above. The elution fractions corresponding to the first eluted peak on the chromatogram are run on a 12% Tris Glycine gel, as above, to identify the fractions with GST-cMET. Fractions are pooled and the OD₂₈₀is read with the column buffer used as the blank.

A Kinase reaction Buffer is prepared as follows:

Per 1 L60 mM HEPES _pH 7.41M stock16.7X60 mL50 mM NaCl5M stock100 X10 mL20 mM MgCl₂1M stock50X20 mL5 mM MnCl₂1M stock200X5 mL

When the assay is carried out, freshly add:

2 mM DTT1Mstock500X0.05% BSA5% stock100X0.1 mM Na₃OV₄0.1Mstock1000X

The HTRF buffer contains:

50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 0.1% BSA, 0.05% Tween 20.5 mM EDTA

Fresh add SA-APC (PJ25S Phycolink Streptavidin-Allophycocyanin Conjugate, Prozyme Inc.) and Eu-PT66 (Eu-W1024 labeled anti-phosphorotyrosine antibody PT66, AD0069, Lot 168465, Perkin-Elmer Inc.) to reach the final concentration:

- 0.1 nM final Eu-PT66
- 11 nM final SA-APC

Methods:

1. Dilute GST-cMet (P) enzyme in kinase buffer as follows:
Prepare 8 nM GST-cMet (P) working solution (7.32 Î¼M to 8 nM, 915Ã—, 10 Î¼L to 9.15 mL). In a 96 well clear plate [Costar #3365] add 100 Î¼L in eleven columns, in one column add 100 Î¼L kinase reaction buffer alone.
2. Assay plate preparation:
Use Biomek FX to transfer 10 Î¼L 8 nM GST-cMet (P) enzyme, 48.4 Î¼L kinase reaction buffer, 1.6 Î¼L compound (in DMSO) (Start concentration at 10 mM, 1 mM and 0.1 mM, sequential dilution 1:3 to reach 10 test points) in a 96 well costar clear plate [Costar #3365], mix several times. Then incubate the plate at RT for 30 min.
3. Prepare Gastrin and ATP working solution in kinase reaction buffer as follows:
Prepare 4 Î¼M Gastrin and 16 Î¼M ATP working solution

Per 10 mLGastrin 4 Î¼M stock(500 Î¼M to 4 Î¼M, 125 X)80 Î¼LATP 16 Î¼M stock(1000 Î¼M to 16 Î¼M, 62.5 X)160 Î¼L

Use Biomek FX to add 20 Î¼l ATP and Gastrin working solution to the assay plate to start reaction, incubate the plate at RT for 1 h.
4. Transfer 5 Î¼L reaction product at the end of 1 h into 80 Î¼L HTRF buffer in black plate [Costar #3356], read on Discover after 30 min incubation.

Assay Condition Summary:

K_MATP*6Î¼M[ATP]4Î¼MK_MGastrin/p(EY)3.8Î¼M[gastrin]1Î¼M[enzyme]1Î¼M

K_MATP, K_Mgastrin for various enzymes were determined by HTRF/³³P labeling and HTRF methods.

Examples 1-28, 30, 33-34, 36-37, and 39-48 exhibited activity with IC₅₀values less than 0.5 Î¼M.

c-Met Cell-Based Autophosphorylation Assay

Human PC3 and mouse CT26 cells are available obtained from ATCC. The cells were cultured in a growth medium containing RPMI 1640, penicillin/streptomycin/glutamine (1Ã—) and 5% FBS. 2Ã—10⁴cells in medium were plated per well in a 96 well plate and incubated at 37Â° C. overnight. The cells were serum-starved by replacing the growth media with basic medium (DMEM low glucose+0.1 BSA, 120 Î¼L per well) at 37Â° C. for 16 h. Compounds (either 1 mM and 0.2 mM) in 100% DMSO were serially diluted (1:3) 3333 fold on a 96 well plate, diluting 1:3 with DMSO from column 1 to 11 (columns 6 and 12 receive no compound). Compound samples (2.4 Î¼L per well) were diluted with basic medium (240 Î¼L) in a 96 well plate. The cells were washed once with basic medium (GIBCO, DMEM 11885-076) then compound solution was added (100 Î¼L). The cells were incubated at 37Â° C. for 1 h. A (2 mg/mL) solution of CHO-HGF (7.5 Î¼L) was diluted with 30 mL basic medium to provide a final concentration of 500 ng/mL. This HGF-containing media (120 Î¼L) was transferred to a 96 well plate. Compounds (1.2 Î¼L) was added to the HGF-containing media and mixed well. The mixture of media/HGF/compound (100 Î¼L) was added to the cells (final HGF concentrationâ€”250 ng/mL) then incubated at 37Â° C. for 10 min. A cell lysate buffer (20 mL) was prepared containing 1% Triton X-100, 50 mM Tris pH 8.0, 100 mM NaCl, Protease inhibitor (Sigma, #P-8340) 200 Î¼L, Roche Protease inhibitor (Complete, #1-697-498)2 tablets, Phosphatase Inhibitor II (Sigma, #P-5726) 200 Î¼L, and a sodium vanadate solution (containing 900 Î¼L PBS, 100 Î¼L 300 mM NaVO₃, 6 Î¼L H₂O₂(30% stock) and stirred at RT for 15 min) (90 Î¼L). The cells were washed once with ice cold 1Ã—PBS (GIBCO, #14190-136), then lysis buffer (60 Î¼L) was added and the cells were incubated on ice for 20 min.

The IGEN assay was performed as follows: Dynabeads M-280 streptavidin beads were pre-incubated with biotinylated anti-human HGFR (240 Î¼L anti-human-HGFR (R&D system, BAF527 or BAF328) @ 100 Î¼g/mL+360 Î¼L Beads (IGEN #10029+5.4 Î¼L buffer-PBS/1%

BSA/0.1% Tween20) by rotating for 30 min at RT. Antibody beads (25 Î¼L) were transferred to a 96 well plate. Cell lysate solution (25 Î¼L) was transferred added and the plate was shaken at RT for 1 h. Anti-phosphotyrosine 4G10 (Upstate 05-321) (19.7 Î¼L antibody+6 mL 1Ã— PBS) (12.5 Î¼L) was added to each well, then incubated for 1 h at RT. Anti-mouse IgG ORI-Tag (ORIGEN #110087) (24 Î¼L Antibody+6 mL buffer) (12.5 Î¼L) was added to each well, then incubated at RT for 30 min. 1Ã—PBS (175 Î¼L) was added to each well and the electrochemiluminescence was read by an IGEN M8. Raw data was analyzed using a 4-parameter fit equation in XLFit. IC₅₀values are then determined using Grafit software. Examples 2, 4, 6-8, 11, 13, 15-21, 23-26, 36-37, 39, 41, and 43-44 exhibited activity in PC3 cells with IC₅₀values less than 1.0 Î¼M. Examples 2, 4, 6-8, 11-13, 15-21, 23-26, 36-37, 41, and 43-44 exhibited activity in CT26 cells with IC₅₀values less than 1.0 Î¼M.

rHu-bFGF: Stock concentration of 180 ng/Î¼L: R&D rHu-bFGF: Added 139 Î¼L of the appropriate vehicle above to the 25 Î¼g vial lyophilized vial. 13.3 Î¼L of the [180 ng/Î¼L] stock vial and added 26.6 Î¼L of vehicle to yield a final concentration of 3.75 Î¼M concentration.

Nitro-cellulose disk preparation: The tip of a 20-gauge needle was cut off square and beveled with emery paper to create a punch. This tip was then used to cut out â‰…0.5 mm diameter disks from a nitrocellulose filter paper sheet (Gelman Sciences). Prepared disks were then placed into Eppendorf microfuge tubes containing solutions of either 0.1% BSA in PBS vehicle, 10 Î¼M rHu-VEGF (R&D Systems, Minneapolis, Minn.), or 3.75 Î¼M rHu-bFGF (R&D Systems, Minneapolis, Minn.) and allowed to soak for 45-60 min before use. Each nitrocellulose filter disk absorbs approximately 0.1 Î¼L of solution.

In the rat micropocket assay, compounds of the present invention will inhibit angiogenesis at a dose of less than 50 mg/kg/day.

Tumor Model

A431 cells (ATCC) are expanded in culture, harvested and injected subcutaneously into 5-8 week old female nude mice (CD1 nu/nu, Charles River Labs) (n=5-15). Subsequent administration of compound by oral gavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumor cell challenge and generally continues either once or twice a day for the duration of the experiment. Progression of tumor growth is followed by three dimensional caliper measurements and recorded as a function of time. Initial statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe post hoc testing for multiple comparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control. Compounds of the present invention will be active at doses less than 150 mpk.

Tumor Models

Human glioma tumor cells (U87MG cells, ATCC) are expanded in culture, harvested and injected subcutaneously into 5-8 week old female nude mice (CD1 nu/nu, Charles River Labs) (n=10). Subsequent administration of compound by oral gavage or by IP (10-100 mpk/dose) begins anywhere from day 0 to day 29 post tumor cell challenge and generally continues either once or twice a day for the duration of the experiment. Progression of tumor growth is followed by three dimensional caliper measurements and recorded as a function of time. Initial statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe post hoc testing for multiple comparisons. Vehicle alone (captisol, or the like) is the negative control. Compounds of the present invention will be active at 150 mpk.

Human gastric adenocarcinoma tumor cells (MKN45 cells, ATCC) are expanded in culture, harvested and injected subcutaneously into 5-8 week old female nude mice (CD1 nu/nu, Charles River Labs) (n=10). Subsequent administration of compound by oral gavage or by IP (10-100 mpk/dose) begins anywhere from day 0 to day 29 post tumor cell challenge and generally continues either once or twice a day for the duration of the experiment. Progression of tumor growth is followed by three dimensional caliper measurements and recorded as a function of time. Initial statistical analysis is done by repeated measures analysis of variance (RMANOVA), followed by Scheffe post hoc testing for multiple comparisons. Vehicle alone (captisol, or the like) is the negative control. Compounds of the present invention will be active at 150 mpk.

Formulations

Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of the current invention in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as â€œcarrierâ€ materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.

The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.

The amount of compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.01 to 500 mg/kg, preferably between about 0.01 and about 50 mg/kg, and more preferably about 0.01 and about 30 mg/kg body weight may be appropriate. The daily dose can be administered in one to four doses per day.

For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.

In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound, which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by a transdermal device. Preferably transdermal administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes, which are obvious to one skilled in the art are intended to be within the scope and nature of the invention, which are defined, in the appended claims.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.

All mentioned references, patents, applications and publications, are hereby incorporated by reference in their entirety, as if here written.