CROSS-REFERENCE TO RELATED APPLICATIONS

The application claims the benefit of priority to U.S. application No. 63/376,791, filed on 23rd September 2022, U.S. application No. 63/483,797 filed on 8th February 2023, and U.S. application No. 63/580,500 filed on 5 Sep. 2023, which are incorporated herein by reference in their entirety.

The present disclosure relates to compounds which inhibit PCSK9 and their use in methods of treatment.

Reference To Sequence Listing Submitted Electronically The content of the electronically submitted sequence listing (201319.xml; Size: 2,564 bytes; and Date of Creation: Sep. 13, 2023) submitted in this application is incorporated herein by reference in its entirety.

BACKGROUND

PCSK9, also referred to as “proprotein convertase subtilisin/kexin 9”, is a member of the secretory proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases the levels of circulating LDL cholesterol (LDL-C) via the enhanced degradation of the LDLRs independently of its catalytic activity. Secreted PCSK9 binds to the Epidermal Growth Factor domain A (EGFA) of the LDL receptor (LDLR) at the cell surface and the PCSK9/LDLR complex is internalized into endosomal/lysosomal compartments. The enhanced binding affinity of PCSK9 to the LDLR at the acidic pH of late endosomes/lysosomes reduces LDLR recycling and instead targets LDLR for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events.

For cardiovascular disease, few options exist for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and in human primary hepatocytes through the increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since an elevated level of PCSK9 decreases the abundance of LDLR on the cell surface, increasing doses of statins have failed to achieve proportional LDL-C lowering effects.

Two monoclonal antibodies (mAbs) that bind selectively to extracellular PCSK9 and prevent its interaction with the LDLR, alirocumab and evolocumab, have recently received FDA approval for lowering LDL-C levels. In clinical trials, alirocumab showed an about 50% decrease in LDL levels compared to placebo (Elbitar 2016). Patients taking evolocumab showed an about 60-75% decrease in LDL levels. The potency of these drugs demonstrates the potential for inhibitors of PCSK9 to be effective treatments for those with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and can cause allergic reactions or other deleterious immune responses in the body.

Cardiovascular diseases often require management over a person's lifetime, unlike an infection that could be episodic. Thus, ease of dosing and administration become important factors for patient compliance with maintenance drug treatments. There is a need for PCSK9 inhibitors with increased efficacy and greater ease of administration, which can be achieved with small molecule PCSK9 inhibitors.

WO 2020/150473 A2 relates to heteroaryl compounds and pharmaceutical preparations thereof. It also relates to methods of treating or preventing cardiovascular diseases, and methods of treating sepsis or septic shock, using the described novel heterocyclic compounds.

WO 2020/150474 A1 relates to an inhibitor pharmacophore of PCSK9 and heteroaryl compounds that bind the PCSK9 protein.

SUMMARY

A first aspect provides a compound with the Formula (I):

A-B-C (I)

- or a pharmaceutically acceptable salt and tautomeric forms or stereoisomers thereof, wherein A is of the following formula:

[Image Omitted]

- wherein the wavy line indicates the point of attachment to B;
- X¹is N;
- R^A2is selected from the group consisting of:
- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) C_1-6alkoxy, optionally substituted by OH, C_1-6alkyl amido, or one or more halo groups;
- (vi) C_1-6acyl amido (wherein the acyl is optionally substituted by H or methyl);
- (vii) C_1-6thioalkyl;
- (viii) C_1-6alkyl ester;
- (ix) C_1-6alkyl acyl;
- (x) C_4-5heterocyclyl;
- (xi) C₅heteroaryl;
- (xii) C_1-6alkyl amido, optionally substituted by C_1-3alkyl amido, CN, OH, C_2-3alkynyl, C_4-6heterocyclyl, C_1-3alkyl wherein the C_1-3alkyl is optionally substituted with one or more halo or OH groups;
- (xiii) OH; and
- (xiv) C_1-6alkylamino; R^A3is selected from the group consisting of:
- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon which is optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl, C_1-6acyloxy, carboxy, C_1-6alkyl ester, C_1-6alkylamino, —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkyl acylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups; (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups; (vii) C_1-6acyloxy;
- (viii) C₄heterocycyl;
- (ix) NH₂;
- (x) C_1-6alkylamino, optionally substituted by CN, OH, C₄heterocyclyl;
- (xi) C_1-6dialkylamino, optionally substituted by —NH₂;
- (xii) C_1-6acylamido (where acyl substituent is H or Me);
- (xiii) carbaimidoyl or methyl-carbaimidoyl;
- (xiv) carboxyamino;
- (xv) C_1-6thioalkyl, optionally substituted by OH or NH₂;
- (xvi) C_1-6alkyl sulfinyl;
- (xvii) C_1-6alkyl sulfonyl, optionally substituted by one or more halo groups;
- (xviii) C_1-6sulfonimodyl;
- (xix) C_1-6alkyl phosphinyl;
- (xx) carboxy;
- (xxi) C(═O)NH₂;
- (xxii) C_1-6alkyl ester;
- (xxiii) C_1-6alkyl acyl, optionally substituted by one or more halo groups;
- (xxiv) C_1-6alkyl amido;
- or wherein R^A3and R^A2together with the carbon atoms to which they are bound form:
- (i) an optionally substituted C_5-7heterocycle ring;
- (ii) an optionally substituted C_5-7heteroaromatic ring;
- (iii) an optionally substituted C₆carboaromatic ring;
- (iv) an optionally substituted C_5-7carbocyclic ring
  - wherein the optional substituents are selected from C_1-6alkyl, halo, C_1-6alkoxy, NH₂, C_1-6alkylamino, OH, and CN;
- wherein B is of formula (B-1) or (B-2)

[Image Omitted]

- wherein the wavy line indicates the point of attachment to A and C;
- R^B1is H, OH, ═CHCH₂—OH, O—C_1-4alkyl, C_1-4alkyl which C_1-4alkyl is optionally substituted by OH or OMe;

[Image Omitted]

- wherein the wavy line indicates the point of attachment to A and C;
- R^B2is C_1-2alkyl-OH, CH₂CONHMe or C_1-3alkyl;
- wherein C is selected from the group consisting of C_6-10carboaryl, C_5-6heteroaryl and C_5-10heterocyclyl, which groups are optionally substituted by:
  - (i) a group selected from C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl C_4-10heterocyclyl, or C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups:
  - a) one or two ═O groups;
  - b) one or more halo groups;
  - c) CN, NH₂, OH;
  - d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
  - e) C_1-6alkoxy with optional substituents of one or more halo groups;
  - f) C_1-6alkylester;
  - g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
  - h) C_5-6heteroaryl;
  - i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
  - j) C_6-10carboaryl with optional substituents of one or more halo groups;
  - l) P(═O)Me₂;
  - m) carboxy or CH₂-carboxy;
  - n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;
  - and/or
  - (ii) one or more groups selected from carboxy, CN, halo, nitro, C_1-6alkyl, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6alkyl amido, di-C_1-6alkyl amido, C_1-6alkyl sulfonamido, and di-C_1-6alkyl sulfonamido.

A second aspect provides a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable diluent, carrier or excipient.

The third aspect provides the compound of the first aspect for use in a method of therapy. The third aspect also provides the use of a compound of the first aspect in the manufacture of a medicament for treating a cardiovascular disease. The third aspect also provides a compound of the first aspect for use in the treatment of a cardiovascular disease. The third aspect also provides a method of treating a cardiovascular disease comprising administering a therapeutically effective amount of a compound of the first aspect or a composition according to the second aspect to a patient in need thereof.

The disclosure includes the combination of the aspects and features described except where such a combination is clearly impermissible or expressly avoided.

DETAILED DESCRIPTION

Aspects and embodiments will now be discussed. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

Compounds of Formula (I) and its use in the treatment of cardiovascular diseases are described herein. The compounds disclosed herein are PCSK9 inhibitors. The compounds may have higher inhibition of PCSK9, lower hERG activity, improved secondary pharmacology profile including GSK3β and/or other kinases, good stability, and/or improved activity in the treatment of cardiovascular diseases. The compounds may have an improved secondary pharmacology profile or an improved off-target profile.

Definitions
Substituents

The phrase “optionally substituted” as used herein, pertains to a parent group which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term “substituted” as used herein, pertains to a parent group which bears one or more substituents. The term “substituent” is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known.

Examples of substituents are described in more detail below.

Unless otherwise stated, halo is selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), such as fluoro.

Cyano (nitrile, carbonitrile): —CN.

Hydroxy: —OH.

Oxo: ═O (oxygen double bonded to the rest of the molecule).

C_1-6hydrocarbon: The term “C_1-6hydrocarbon” as used herein pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 6 carbon atoms, which may be aliphatic or alicyclic, which may be saturated or unsaturated (e.g. partially unsaturated, fully unsaturated) and may also be branched. Thus, the term “hydrocarbon” includes the terms alkyl, alkenyl, alkynyl, cycloalkyl, etc., discussed below.

C_1-6alkyl: The term “C_1-6alkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 6 carbon atoms, which are saturated and may also be branched. The term “C_1-4alkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 4 carbon atoms, which are saturated.

Examples of saturated alkyl groups include, but are not limited to, methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl (C₅) and hexyl (C₆).

Examples of saturated linear alkyl groups include, but are not limited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl (C₄), n-pentyl (amyl) (C₅) and n-hexyl (C₆).

Examples of saturated branched alkyl groups include iso-propyl (C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄), iso-pentyl (C₅), and neo-pentyl (C₅).

C_2-6Alkenyl: The term “C_2-6alkenyl” as used herein, pertains to a hydrocarbon group having one or more carbon-carbon double bonds.

Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, —CH═CH₂), 1-propenyl (—CH═CH—CH₃), 2-propenyl (allyl, —CH—CH═CH₂), isopropenyl (1-methylvinyl, —C(CH₃)═CH₂), butenyl (C₄), pentenyl (C₅), and hexenyl (C₆).

C_2-6alkynyl: The term “C_2-6alkynyl” as used herein, pertains to a hydrocarbon group having one or more carbon-carbon triple bonds.

Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (—C═CH) and 2-propynyl (propargyl, —CH₂C═CH).

C_1-6alkoxy: The term C_1-6alkoxy as used herein, pertains to an OR group, wherein R is an C_1-6hydrocarbon group. Examples of C_1-6alkoxy groups include, but are not limited to, OMe, OEt (ethoxy), —O(nPr) (n-propoxy), —O(iPr) (isopropoxy), O(nBu) (n-butoxy), O(sBu) (sec-butoxy), O(iBu) (isobutoxy), and O(tBu) (tert-butoxy).

C_1-6acyloxy: The term C_1-6acyloxy (reverse ester) as used herein, pertains to an —OC(═O)R, wherein R is a C_1-6hydrocarbon group. Examples of acyloxy groups include, but are not limited to, —OC(═O)CH₃(acetoxy), —OC(═O)CH₂CH₃, or —OC(═O)C(CH₃)₃.

Amino: —NR¹R², wherein R¹and R²are independently amino substituents, for example, hydrogen, a C_1-6hydrocarbon group (also referred to as C_1-6alkylamino or C_1-6dialkylamino), or, in the case of a “cyclic” amino group, R¹and R², taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 6 ring atoms. Amino groups may be primary (—NH₂), secondary (—NHR¹), or tertiary (—NHR¹R²), and in cationic form, may be quaternary (—⁺NR¹R²R³). Examples of amino groups include, but are not limited to —NH₂, —NHCH₃, —NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.

C_1-6acylamido: Acylamido (acylamino): NR¹C(═O)R², wherein R¹is an amide substituent, for example, hydrogen or a C_1-6hydrocarbon group, and R²is an acyl substituent, for example, a C_1-6hydrocarbon group. Examples of acylamide groups include, but are not limited to, NHC(═O)CH₃and NHC(═O)CH₂CH₃. In some embodiments R¹and R²may together form a cyclic or bicyclic structure and form a cyclic acylamido groups. Examples of such groups include succinimidyl, maleimidyl, phthalimidyl, 2-oxo-3H-benzimidazol-1-yl, 3-methyl-2-oxo-benzimidazol-1-yl, 1-methyl-2-oxoimidazo[4,5-b]pyridin-3-yl, 2,5-dioxoimidazolidin-1-yl and 2,4-dioxoimidazolidin-1-yl:

[Image Omitted]

Carbaimidoyl: —C(═NH)(NH₂).

Methyl-carbaimidoyl: —C(═N—CH₃)NH₂.

Carboxyamino: —N(H)(C(═O)OH).

C_1-6thioalkyl: The term C_1-6thioalkyl as used herein, pertains to an —SR, wherein R is a C_1-6hydrocarbon group. Examples of C_1-6alkylthio groups include, but are not limited to, —SCH₃and —SCH₂CH₃.

C_1-6alkyl sulfinyl: The term C_1-6alkyl sulfinyl pertains to a sulfine (sulfinyl, sulfoxide) which has the structure —S(═O)R, wherein R is a C_1-6hydrocarbon group. Examples of C_1-6alkyl sulfinyl groups include, but are not limited to, —S(═O)CH₃and —S(═O)CH₂CH₃.

C_1-6alkyl sulfonyl: The term C_1-6alkyl sulfonyl as used herein pertains to an —S(═O)₂R, group wherein R is a C_1-6hydrocarbon group, including, for example, a fluorinated or perfluorinated C_1-6alkyl group. Examples of C_1-6alkyl sulfonyl groups include, but are not limited to, —S(═O)₂CH₃(methanesulfonyl, mesyl), —S(═O)₂CF₃(triflyl), —S(═O)₂CH₂CH₃(esyl), —S(═O)₂C₄F₉(nonaflyl) and —S(═O)₂CH₂CF₃(tresyl).

C_1-6sulfonimodyl: The term C_1-6sulfonimodyl is also referred to as Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide) and has the structure —S(═O)₂NR¹R², wherein R¹and R²are independently amino substituents, as defined for amino groups. Examples of sulfonamido groups include, but are not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂, —S(═O)₂NH(CH₂CH₃) and —S(═O)₂N(CH₂CH₃)₂.

C_1-6alkyl phosphinyl: The term C_1-6alkyl phosphinyl (phosphine oxide) has the structure —P(═O)R₂, wherein each R is independently a C_1-6hydrocarbon group. Examples of C_1-6alkyl phosphinyl groups include, but are not limited to, P(═O)(CH₃)₂, P(═O)(CH₂CH₃)₂and P(═O)(tBu)₂. Wherein each R group can be the same or different groups.

Carboxy (carboxylic acid): —C(═O)OH.

C_1-6alkyl ester: The term C_1-6alkyl ester (carboxylate, carboxylic acid ester, oxycarbonyl) has the structure —C(═O)OR, wherein R is a C_1-6hydrocarbon group. Examples of ester groups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃and —C(═O)OC(CH₃)₃.

C_1-6alkyl acyl: The term C_1-6alkyl acyl also known as Acyl (keto) has the structure —C(═O)R, wherein R is a C_1-6hydrocarbon group. Examples of C_1-6alkyl acyl groups include, but are not limited to, —C(═O)CH₃(acetyl), —C(═O)CH₂CH₃(propionyl) or —C(═O)C(CH₃)₃(t-butyryl). C_1-6alkyl amido: The term C_1-6alkyl amido (also referred to as carbamoyl, carbamyl, aminocarbonyl, carboxamide) has the structure C(═O)NR¹R², wherein R¹and R²are independently amino substituents, as defined for amino groups for example, hydrogen, a C_1-6hydrocarbon group (also referred to as C_1-6alkylamido or C_1-6dialkylamido), or, in the case of a “cyclic” amido group, R¹and R², taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 6 ring atoms. Examples of amido groups include, but are not limited to, C(═O)NH₂, C(═O)NHCH₃, C(═O)N(CH₃)₂, C(═O)NHCH₂CH₃, and C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹and R², together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

C_3-12cycloalkyl: The term “C_3-12cycloalkyl” as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 carbon atoms, including from 3 to 7 ring atoms. The carbocyclic ring may be saturated or unsaturated and may be bridged or unbridged. The ring may be a fused ring or a single ring.

Examples of cycloalkyl groups include, but are not limited to, those derived from:

- saturated monocyclic hydrocarbon compounds:
  
  cyclopropane (C₃), cyclobutane (C₄), cyclopentane (C₅), cyclohexane (C₆), cycloheptane (C₇), methylcyclopropane (C₄), dimethylcyclopropane (C₅), methylcyclobutane (C₅), dimethylcyclobutane (C₆), methylcyclopentane (C₆), dimethylcyclopentane (C₇) and methylcyclohexane (C₇);
- unsaturated monocyclic hydrocarbon compounds:
  
  cyclopropene (C₃), cyclobutene (C₄), cyclopentene (C₅), cyclohexene (C₆), methylcyclopropene (C₄), dimethylcyclopropene (C₅), methylcyclobutene (C₅), dimethylcyclobutene (C₆), methylcyclopentene (C₆), dimethylcyclopentene (C₇) and methylcyclohexene (C₇); and
- saturated polycyclic hydrocarbon compounds:
  
  norcarane (C₇), norpinane (C₇), norbornane (C₇).

C_3-10heterocyclyl: The term “C_3-10heterocyclyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 10 ring atoms, of which from 1 to 5 are ring heteroatoms. In certain embodiments, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. The ring may be saturated or unsaturated, and may be bridged or unbridged. The ring may be a fused ring or a single ring. For the avoidance of doubt, substituents on the heterocycloalkyl ring may be linked via either a carbon atom or a heteroatom.

In this context the term ‘heteroatom’ means O, S, N, Si or B (Boron).

In this context, the prefixes (e.g. C_3-10C_3-7, C_5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C_5-6heterocyclyl”, as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from:

- N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole) (C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆), dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);
- O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole (dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆), pyran (C₆), oxepin (C₇);
- S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene) (C₅), thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);
- O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);
- O₃: trioxane (C₆);
- N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline (C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);
- N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆);
- N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);
- N₂O₁: oxadiazine (C₆);
- O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,
- N₁O₁S₁: oxathiazine (C₆).

Examples of bicyclic heterocyclyl groups include, but are not limited to those derived from:

Compound
Structure

7-azabicyclo[4.2.0]octane (N₁)C₈

[Image Omitted]

3-azabicyclo[3.1.0]hexane (N₁)C₆

[Image Omitted]

6-azabicyclo[3.2.0]heptane (N₁)C₇

[Image Omitted]

2,3,3a,4,5,6,7,7a- octahydrofuro[2,3- c]pyridine(N₁O₁)C₉

[Image Omitted]

C_6-10carboaryl: The term “C_6-10carboaryl”, as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 6 to 10 ring atoms and the ring atoms are all carbon atoms, as in “carboaryl groups”. The ring may be a fused ring or a single ring. Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C₆), naphthalene (C₁₀) and azulene (C₁₀).

In this context, the prefixes (e.g. C_5-7, C_5-6, C_5-10, etc.) denote the number of ring atoms, or range of number of ring atoms. For example, the term “C_5-6aryl” as used herein, pertains to an aryl group having 5 or 6 ring atoms.

Examples of carboaryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g. 2,3-dihydro-1H-indene) (C₉), indene (C₉), isoindene (C₉) and tetraline (1,2,3,4-tetrahydronaphthalene) (C₁₀).

C_5-10heteroaryl: The term “C_5-10heteroaryl”, as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 5 to 10 ring atoms of which from 1 to 5 are ring heteroatoms. In certain embodiments, each ring has from 5 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.

For the avoidance of doubt, substituents on the heteroaryl ring may be linked via either a carbon atom or a heteroatom. The ring may be a fused ring or a single ring.

In this context the term ‘heteroatom’ means O, S, N, Si or B (Boron).

Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:

- N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);
- O₁: furan (oxole) (C₅);
- S₁: thiophene (thiole) (C₅);
- N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);
- N₂O₁: oxadiazole (furazan) (C₅);
- N₃O₁: oxatriazole (C₅);
- N₁S₁: thiazole (O₅), isothiazole (C₅);
- N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅), pyridazine (1,2-diazine) (O₆), pyrimidine (1,3-diazine) (O₆) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (O₆);
- N₃: triazole (C₅), triazine (O₆); and,
- N₄: tetrazole (C₅).

Examples of heteroaryl which comprise fused rings, include, but are not limited to O₉(with 2 fused rings) derived from:

Compound
Structure

benzofuran (O₁)

[Image Omitted]

isobenzofuran (O₁)

[Image Omitted]

indole (N₁)

[Image Omitted]

isoindole (N₁)

[Image Omitted]

indolizine (N₁)

[Image Omitted]

indoline (N₁)

[Image Omitted]

isoindoline (N₁)

[Image Omitted]

purine (N₄)(e.g., adenine, guanine)

[Image Omitted]

benzimidazole (N₂),

[Image Omitted]

indazole (N₂)

[Image Omitted]

benzoxazole (N₁O₁)

[Image Omitted]

benzisoxazole (N₁O₁)

[Image Omitted]

benzodioxole (O₂)

[Image Omitted]

benzofurazan (N₂O₁)

[Image Omitted]

benzotriazole (N₃)

[Image Omitted]

benzothiofuran (S₁)

[Image Omitted]

benzothiazole (N₁S₁)

[Image Omitted]

benzothiadiazole (N₂S)

[Image Omitted]

3H-imidazo[4,5- b]pyridine (N₃)

[Image Omitted]

5H-pyrrolo[2,3- b]pyrazine (N₃)

[Image Omitted]

1H-pyrazolo[3,4- b]pyrazine (N₄)

[Image Omitted]

Examples of heteroaryl which comprise fused rings, include, but are not limited to C₁₀(with 2 fused rings) derived from:

Compound
Structure

2H-chromene (O₁)

[Image Omitted]

1H- isochromene (O₁)

[Image Omitted]

chroman (O₁)

[Image Omitted]

isochroman (O₁)

[Image Omitted]

3,4-dihydro- benzo[d][1,2]dioxine (O₂)

[Image Omitted]

quinoline (N₁)

[Image Omitted]

isoquinoline (N₁)

[Image Omitted]

quinolizine (N₁)

[Image Omitted]

benzoxazine (N₁O₁)

[Image Omitted]

And isomers thereof

benzodiazine (N₂)

[Image Omitted]

pteridine (N₄)

[Image Omitted]

quinoxaline (N₂)

[Image Omitted]

quinazoline (N₂)

[Image Omitted]

cinnoline (N₂)

[Image Omitted]

phthalazine (N₂)

[Image Omitted]

naphthyridine (N₂)

[Image Omitted]

and isomer thereof

Spiro C_6-12carbocyclyl: The term Spiro C_6-12carbocyclyl as used herein pertains to a moiety that has at least two molecular rings with only one common atom. The simplest spiro compounds are bicyclic (having just two rings), or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common atom. Spiro C_6-12carbocyclyl pertains to a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 6 to 12 carbon atoms, including from 3 to 7 ring atoms wherein the rings share a common atom.

Spiro C_6-12heterocyclyl: The term Spiro C_6-12heterocyclyl as used herein pertains to a moiety that has at least two molecular rings with only one common atom. The simplest spiro compounds are bicyclic (having just two rings), or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common atom. The spiro C_6-12heterocyclyl moiety pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 8 to 12 ring atoms of which from 1 to 3 are ring heteroatoms wherein the rings share a common atom. In certain embodiments, each ring has from 9 to 11 ring atoms, of which from 1 to 2 are ring heteroatoms. For the avoidance of doubt, substituents on the heteroaryl ring may be linked via either a carbon atom or a heteroatom.

For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may comprise the same substituents or different substituents from within the given group.

Pharmaceutically Acceptable Salt

The term “pharmaceutically acceptable” is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zürich: Wiley-VCH/VHCA, 2002. A suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid-addition salt. An acid addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. An acid addition salt may for example be formed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.

Therefore, in one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid salt. In one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a methanesulfonic acid salt. In one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a mono-methanesulfonic acid salt, i.e. the stoichiometry of the compound of the compound of Formula (I) to methanesulfonic acid is 1:1.

Other Forms

Compounds and salts described in this specification may exist in solvated forms and unsolvated forms. For example, a solvated form may be a hydrated form, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or an alternative quantity thereof. The compounds of Formula (I) encompass all such solvated and unsolvated forms of compounds of Formula (I), particularly to the extent that such forms possess PCSK9 kinase inhibitory activity, as for example measured using the tests described herein.

Compounds and salts described in this specification include one or more chiral (i.e. asymmetric) centres. To the extent a structure or chemical name in this specification does not indicate the chirality, the structure or name is intended to encompass any single stereoisomer (i.e. any single chiral isomer) corresponding to that structure or name, as well as any mixture of stereoisomers (e.g. a racemate). In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g. a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained through direct synthesis from, for example, a chiral starting material.

A particular enantiomer of a compound described herein may be more active than other enantiomers of the same compound.

According to one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is a single enantiomer being in an enantiomeric excess (% ee) of ≥95, ≥98% or ≥99%. Conveniently, the single enantiomer is present in an enantiomeric excess (% ee) of ≥99%.

According to another embodiment there is provided a pharmaceutical composition, which comprises a compound of Formula (I), which is a single enantiomer being in an enantiomeric excess (% ee) of ≥95, ≥98% or ≥99% or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients. Conveniently, the single enantiomer is present in an enantiomeric excess (% ee) of ≥99%.

Isotopes

Atoms of the compounds and salts described in this specification may exist as their isotopes. The compound of Formula (I) encompasses all compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is an ¹¹C or ¹³C carbon isotope, or where one or more hydrogen atoms is a ²H or ³H isotope).

Tautomers

Compounds and salts described in this specification may exist as a mixture of tautomers. “Tautomers” are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. The compound of Formula (I) includes all tautomers of compounds of Formula (I) particularly to the extent that such tautomers possess PCSK9 inhibitory activity.

For example, tautomeric forms of some of the exemplified compounds where R^A3is OH can be shown as follows.

[Image Omitted]

Crystalline Forms

Compounds and salts described in this specification may be crystalline and may exhibit one or more crystalline forms. The compound of Formula (I) encompasses any crystalline or amorphous form of a compound of Formula (I), or mixture of such forms, which possesses PCSK9 inhibitory activity.

It is generally known that crystalline materials may be characterised using conventional techniques such as X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of crystalline materials may be determined by Karl Fischer analysis.

Therapy, Prophylaxis and Related Terms

The term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

The term “treatment” is used synonymously with “therapy”. Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

The term “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a paediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. Preferred subjects are humans.

An “effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A “therapeutically effective amount”, as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of the disease to be treated.

Pharmaceutical Compositions

The compounds of Formula (I), and pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients.

Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

The pharmaceutical compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures well known in the art. Compositions intended for oral use may contain additional components, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable daily doses of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, in therapeutic treatment of humans are about 0.0001-100 mg/kg body weight. Pharmaceutical formulations as described herein may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.1 mg to 1000 mg. The daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co-administered, and the severity of the illness being treated. Accordingly, the practitioner who is treating any particular patient may determine the optimum dosage.

The pharmaceutical compositions described herein comprise compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.

As such, in one embodiment there is provided a pharmaceutical composition for use in therapy, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment there is provided a pharmaceutical composition for use in the treatment of a disease in which inhibition of PCSK9 is beneficial, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In one embodiment there is provided a pharmaceutical composition for use in the treatment of a cardiovascular disease, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In one embodiment there is provided a pharmaceutical composition for use in the treatment of a cardiovascular disease in which inhibition of PCSK9 is beneficial, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Methods of Use

The compounds described herein may be used in a method of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I. The term “therapeutically effective amount” is an amount sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.

A compound may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) for use in therapy. In one embodiment there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I) for the manufacture of a medicament. In another embodiment there is provided a method of treatment comprising administering to a subject the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula (I).

The compounds described herein are PCSK9 inhibitors. The PCSK9 gene was identified using genetic mapping techniques on DNA from subjects with autosomal dominant hypercholesterolemia (Abifadel 2003). The encoded protein is a serine protease that is mostly expressed in the liver, gut, kidney, and nervous system and circulates in plasma. While not wishing to be bound by any particular theory, studies on mutations in the gene indicated that its putative role was in reducing LDLRs at the cell surface independently of its catalytic activity. (Abifadel 2010). Binding of PCSK9 to the LDLR results in their lysosomal degradation. This enhanced LDLR degradation results in increases in the amount of circulating low-density lipoprotein (LDL). PCSK9 is upregulated by statins, SREBP-1a and SREBP-2, LXR agonist, and insulin, but downregulated by dietary cholesterol, glucagon, ethinylestradiol, chenodeoxycholic acid and the bile acid-activated farnesoid X receptor (FXR) (Maxwell 2003; Persson 2009; Langhi 2008). Since an elevated level of PCSK9 decreases the abundance of LDLR on the cell surface, increasing doses of statins fail to achieve proportional LDL-C lowering results. Thus, disclosed herein are methods for treating a wide range of cardiovascular diseases and conditions that benefit from inhibiting PCSK9 thereby lowering LDL-C.

In certain embodiments, the method of inhibiting PCSK9 occurs in a subject in need thereof, thereby treating a disease or disorder mediated by PCSK9. Also, disclosed herein are methods of treating or preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein are methods of treating a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein are methods of preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The prevention of cardiovascular events through the inhibition of PCSK9 has been described, e.g., in Robinson 2015.

In some embodiments there is provided a method of treating a cardiovascular disease comprising administering to a subject a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I). In some embodiments there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) for use in the treatment of a cardiovascular disease. In some embodiments there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) for the manufacture of a medicament for the treatment of a cardiovascular disease.

Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure or congestive heart failure. In certain embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease. In certain embodiments, the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In certain embodiments, the disease is hyperlipidemia. In certain embodiments, the disease is coronary artery disease.

In certain embodiments, the disclosed methods of treatment can decrease high levels of circulating serum cholesterol, such as LDL-C and VLDL-Cholesterol. In addition, the disclosed methods are useful for decreasing circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL-C and atherogenic lipoproteins. In certain embodiments, the diseases or conditions treated with the disclosed compounds and compositions include atherosclerosis and atherosclerotic plaque formation. Subjects having a gain-of-function mutation in the PCSK9 gene also benefit with treatment with the disclosed compounds and compositions counteracting the mutation through their inhibition of PCSK9.

Combination Treatments

Disclosed compounds and compositions may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of high levels of LDL-C and triglycerides. In certain embodiments, conjointly administering one or more additional therapeutic agents with a compound described herein provides a synergistic effect. In certain embodiments, conjointly administering one or more additional therapeutic agents provides an additive effect.

In some embodiments in which a combination therapy is used, the amount of the compound or salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the animal patient. In this context, the combined amounts are “therapeutically effective amounts” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound or salt and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).

A pharmaceutical composition of the specification may comprise one or more further active ingredients, as appropriate, examples of combinations of a compound of the specification (or a pharmaceutically acceptable salt thereof) and one or more additional active ingredients are described herein.

The specification further relates to a combination therapy wherein a compound of the specification, or a pharmaceutically acceptable salt thereof, and a second active ingredient are administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above. Such a combination may be used in combination with one or more further active ingredients.

In one aspect there is provided a combination (for example, for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as a cardiovascular disease) comprising a compound of the specification, or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from:

- i) a statin;
- ii) a cholesterol absorption inhibitor;
- iii) a SGLT2 inhibitor;
- iv) a P2Y12 inhibitor;
- v) a citrate lyase inhibitor; and
- vi) anti-hypertensive drugs.

In a further aspect of the present specification there is provided a pharmaceutical composition (for example, for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as a cardiovascular disease) comprising a compound of the specification, or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from:

- i) a statin;
- ii) a cholesterol absorption inhibitor;
- iii) a SGLT2 inhibitor;
- iv) a P2Y12 inhibitor;
- v) citrate lyase inhibitor;
- vi) anti-hypertensive drugs.

In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a statin, wherein the statin is selected from atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin or Simvastatin. In another aspect the statin is Rosuvastatin (Crestor).

In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a cholesterol absorption inhibitor, wherein the cholesterol absorption inhibitor is selected from Ezetimibe (Ezetrol).

In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a SGLT2 inhibitor, wherein the SGLT2 inhibitor is selected from Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin etabonate, Sergliflozin etabonate, Sotagliflozin or Tofogliflozin. In some aspects the SGLT2 inhibitor is selected from Dapagliflozin (Farxiga or Forxiga).

In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a P2Y12 inhibitor, wherein the P2Y12 inhibitor is selected from Ticagrelor and Clopidogrel (Plavix).

In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a citrate lyase inhibitor, wherein the citrate lyase inhibitor is Bempedoic acid (Nexletol).

In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor. In one embodiment there is one additional active ingredient. In another embodiment there are two additional active ingredients. In one embodiment the additional active ingredient is Ezetimibe, Rosuvastatin, Dapagliflozin or Ticagrelor. In another embodiment the additional two active ingredients are Ezetimibe and Rosuvastatin or Dapagliflozin and Rosuvastatin.

In another embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from anti-hypertensive drugs. In some aspects, the antihypertensive drug is selected from Valsartan (Diovan), Metoprolol (Lopressor), HCTZ (Hydrochlorothiazide), Olmesartan (Benicar), Lisinopril (Prinivil, Zestril), Amlodipine besylate (Norvasc), Candesartan, or a calcium channel blocker or a combination thereof. In another aspect there is provided the compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with:

- i) Valsartan;
- ii) Metoprolol;
- iii) Valsartan and HCTZ;
- iv) Olmesartan;
- v) Olmesartan and HCTZ;
- vi) Lisinopril;
- vii) Amlodipine;
- viii) Candesartan;
- ix) a calcium channel blocker; or
- x) HCTZ.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient for use in the simultaneous, separate or sequential treatment of a cardiovascular disease. In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular disease, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one an additional active substance selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor.

In another embodiment there is provided a method of treating a cardiovascular disease in a subject, which comprises administering to said subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional active substance, wherein the at least one additional active substance is selected from Ezetimibe, Rosuvastatin, Dapagliflozin and Ticagrelor.

Further Embodiments

The following embodiments may apply to all aspects as described above or may relate to a single aspect. The embodiments may be combined together in any combination.

- X¹

In some embodiments, X¹is N.

- R^A2

In some embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) C_1-6alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups;
- (vi) C_1-6acyl amido (where acyl substituent is H or Me);
- (vii) C_1-6thioalkyl,
- (viii) C_1-6alkyl ester;
- (ix) C_1-6alkyl acyl,
- (x) C_4-5heterocyclyl;
- (xi) C₅heteroaryl;
- (xii) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, OH, C_2-3alkynyl, C_4-6heterocyclyl, C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups;
- (xiii) OH; and
- (xiv) C_1-6alkylamino.

In some embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) C_1-6alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups;
- (vi) C_1-6acyl amido (where acyl substituent is H or Me);
- (vii) C_1-6thioalkyl,
- (viii) C_1-6alkyl ester;
- (ix) C_1-6alkyl acyl,
- (x) C_4-5heterocyclyl;
- (xi) C₅heteroaryl;
- (xii) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups; and
- (xiii) OH.

In some embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, C_1-6alkyl amido, or one or more halo groups;
- (vii) C_1-6alkyl ester;
- (viii) C_1-6alkyl acyl;
- (ix) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups; and
- (x) C_1-6alkylamino

In further embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, C_1-6alkyl amido, or one or more halo groups;
- (vii) C_1-6alkyl ester;
- (viii) C_1-6alkyl acyl; and
- (ix) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups.

In further embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) C_1-6alkoxy, optionally substituted by OH, C_1-6alkyl amido, or one or more halo groups;
- (vi) C_1-6thioalkyl;
- (viii) C_1-6alkyl ester; and
- (ix) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups.

In further embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) C_1-6alkyl ester;
- (iv) C_1-6hydrocarbon;
- (v) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups;
- (vi) C_1-6thioalkyl;
- (vii) C_1-6alkyl acyl;
- (viii) C₅heteroaryl; or
- (ix) C_1-6alkylamino.

When R^A2is halo, in some embodiments it is Br or Cl. In further embodiments it is Cl.

In some embodiments R^A2is selected from CN, Cl, OMe, methyl, cyclopropyl, —OCHF₂, —OCF₃and optionally substituted C_1-6alkylamido.

In some embodiments R^A2is selected from C_1-6alkyl ester,

In some embodiments R^A2is CN.

In some embodiments R^A2is H.

In some embodiments R^A2is OH.

In some embodiments R^A2is —C(═O)CH₃.

In some embodiments R^A2is —OCHF₂.

In some embodiments R^A2is cyclopropyl.

In some embodiments R^A2is Cl.

In some embodiments R^A2is methyl.

In some embodiments R^A2is S-ethyl.

In some embodiments R^A2is a pyrazole.

In some embodiments R^A2is N(CH₃)₂.

In some embodiments R^A2is C(═O)NH(CH₂C(═O)NH₂, C(═O)NHCH₂C≡CH, C(═O)NH(oxetane), C(═O)NH(CH₂CHF₂), C(═O)NH(CH₂CH₃), C(═O)NH₂, C(═O)NH(CH₂), C(═O)N(CH₃)₂, C(═O)N(CH₃)(CH₂CH₂OH), C(═O)N(CH₃)(CH₂C═CH or C(═O)NH(CH₂CH₂OH).

When R^A2is a C_1-6hydrocarbon it is an optionally substituted C_1-6alkyl. In some embodiments it is optionally substituted methyl, optionally substituted ethyl or optionally substituted cyclopropyl.

In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl. In other embodiments it is unsubstituted cyclopropyl.

When R^A2is optionally substituted C_1-6alkyl, in some embodiments the optional substituents are selected from OH, CN, or one or more halo groups. In further embodiments the optional substituents are selected from OH, F and Br.

When R^A2is optionally substituted C_1-6alkoxy, in some embodiments it is optionally substituted OMe or ethoxy.

When R^A2is optionally substituted C_1-6alkoxy, in some embodiments the optional substituents are selected from alkyl amido or one or more halo groups. In another embodiment the optional substituents are selected from one or more F. In another embodiment where R^A2is optionally substituted C_1-6alkoxy it is difluoromethoxy (OCHF₂).

When R^A2is C_1-6alkyl ester, in some embodiments it is —C(═O)OCH₂CH₃.

When R^A2is C_1-6alkyl amido, in some embodiments the optional substituents are selected from one or more methyl groups, an oxetane ring, a C₂alkylamido, ethyl which ethyl is optionally substituted by OH or one or more halo groups. In other embodiments when R^A2is C_1-6alkyl amido it is C(═O)NHCH₂C(═O)NH₂, C(═O)NHCH₂CHCH, —C(═O)NH-oxetane, C(═O)NHCH₂CHF₂, C(═O)NHCH₂CH₂OH, C(═O)NHCH₂CH₃, C(═O)NH₂, C(═O)NHCH₃, C(═O)N(CH₃)₂. When R^A2is C_1-6alkyl amido, in some embodiments the optional substituent is OH.

When R^A2is C_1-6alkylamino in some embodiments it is NHCH₃, NHC(CH₃)₂, N(CH₂CH₃)₂, or N(CH₃)₂. In some embodiments when R^Ais C_1-6alkylamino it is N(CH₃)₂.

In other embodiments R^A2is selected from —OCHF₂, Cl, —OMe, methyl, C(═O)CH₃, CN, —CH₂OH, H and cyclopropyl. In further embodiments R^A2is selected from methyl, —OCHF₂, Cl, —CH₂OH, H, CN, —C(═O)CH₃or —OMe.

In further embodiments R^A2is selected from methyl, —OCHF₂, Cl and cyclopropyl.

In further embodiments R^A2is selected from H, —COOH, —CH₂OH, methyl, CN, cyclopropyl, —C(═O)CH₃, —OCHF₂, Cl, —C(═O)OCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CHCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₂OH, —C(═O)NHCH₂CH₃.

In some embodiments R^A2is selected from the group consisting of —CN, methyl, Cl, —C(═O)CH₃, —C(═O)OCH₂CH₃, cyclopropyl, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CHCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₂OH, —C(═O)NHCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OCHF₂, H, —OMe, and —OCF₃.

In some embodiments R^A2is selected from C(═O)OCH₂CH₃, cyclopropyl, methyl, C(═O)NH(CH₂C(═O)NH₂, C(═O)NHCH₂C≡CH, C(═O)NH(oxetane), C(═O)NH(CH₂CHF₂), C(═O)NH(CH₂CH₃), C(═O)NH₂, C(═O)NH(CH₃), C(═O)N(CH₃)₂, H, C(═O)N(CH₃)(CH₂CH₂OH), C(═O)N(CH₃)(CH₂C═CH, Cl, N(CH₃)₂, pyrazole, S-ethyl, C(═O)CH₃, or C(═O)NH(CH₂CH₂OH). In some embodiments R¹²is selected from ON, methyl, Cl, —C(═O)CH₃, —C(C═O)OCH₂CH₃, cyclopropyl, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CHCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₂OH, —C(═O)NHCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OCHF₂, H, —OMe, —OCF₃. These groups are as shown in the table below:

In some embodiments R^A2is selected from the following groups:

In some embodiments R^A2is selected from the following groups:

[Image Omitted]

- R^A3

In some embodiments R^A3is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl, C_1-6acyloxy, carboxy, C_1-6alkyl ester, C_1-6alkylamino, —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkyl acylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups;
- (vii) C_1-6acyloxy;
- (viii) C₄heterocycyl;
- (ix) —NH₂;
- (x) C_1-6alkylamino, optionally substituted by CN, OH or C₄heterocyclyl;
- (xi) C_1-6dialkylamino, optionally substituted by —NH₂;
- (xii) C_1-6acylamido (where acyl substituent is H or Me);
- (xiii) carbaimidoyl or methyl-carbaimidoyl;
- (xiv) carboxyamino;
- (xv) C_1-6thioalkyl, optionally substituted by OH or NH₂;
- (xvi) C_1-6alkyl sulfinyl;
- (xvi) C_1-6alkyl sulfonyl, optionally substituted by one or more halo groups;
- (xvii) C_1-6sulfonimodyl;
- (xviii) C_1-6alkyl phosphinyl;
- (xix) carboxy;
- (xx) C(═O)NH₂
- (xxi) C_1-6alkyl ester;
- (xxii) C_1-6alkyl acyl, optionally substituted by one or more halo groups; and
- (xxiii) C_1-6alkyl amido.

In some embodiments R^A3is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl C_1-6acyloxy, carboxy, C_1-6alkylester, C_1-6alkylamino; —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkylacylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH; and
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups.

In some embodiments R^A3is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6acyloxy, carboxy, C_1-6alkylester, C_1-6alkylamino; —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkylacylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups.

Where R^A3is halo, in some embodiments it is Br or Cl. In some embodiments it is Cl. In further embodiments R^A3is Br.

Where R^A3is a C_1-6hydrocarbon it is an optionally substituted C_1-6alkyl. In some embodiments it is optionally substituted methyl or optionally substituted ethyl. In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl.

When R^A3is optionally substituted C_1-6alkyl, in some embodiments the optionally substituents are selected from OH, CN, or one or more halo groups. In further embodiments the optional substituents are selected from OH, F and Br.

In some embodiments R^A3is OH.

When R^A3is optionally substituted C₁-alkoxy, in some embodiments it is optionally substituted OMe or ethoxy. In further embodiments it is OMe.

When R^A3is optionally substituted C₁-alkoxy, in some embodiments the optional substituents are selected from alkyl amido or one or more halo groups. In another embodiment the optional substituents are selected from one or more F.

In some embodiments R^A3is selected from H, CF₃, CN, C_1-2alkyl, NH₂and halo. In other embodiments R^A3is selected from H, methyl, CN and Cl.

In some embodiments R^A3is selected from H, OMe, CF₃, CN, C_1-2alkyl, NH₂and halo.

In some embodiments R^A3is CN.

In some embodiments R^A3is H.

In some embodiments R^A3is methyl.

In some embodiments R^A3is OMe. In some embodiments R^A3is selected from methyl, H and CN.

In some embodiments R^A3is selected from H, methyl or OH.

R^A2and R^A3

When R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C carboaromatic ring or C_5-7heteroaromatic ring they form an optionally substituted benzene ring or an optionally substituted pyridine ring.

When R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C carboaromatic ring or C_5-7heteroaromatic ring the optional substituents are selected from NH₂, C_1-6alkyl, C_1-6alkoxy and halo. In other embodiments the optional substituents are selected from methyl, ethyl, OMe, NH₂, F, Cl and Br. In other embodiments the optional substituents are selected from methyl, NH₂, Cl, F and OMe. In other embodiments the optional substituent is methyl.

In one embodiment when R^A2and R^A3together with the carbon atoms to which they are bound form an optionally substituted C_5-7heteroaromatic ring, they form an optionally substituted pyridine. In some embodiments the optional substituent is NH₂. In another embodiment R^A2and R^A3together with the carbon atoms to which they are bound form an unsubstituted pyridine. In another embodiment R^A2and R^A3together form an optionally substituted pyrazole, an optionally substituted pyrrole or an optionally substituted thiazole. In some embodiments the optional substituent is methyl.

When R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C_5-7heteroaromatic ring, the optional substituents are selected from C_1-6alkyl, C_1-6alkoxy, NH₂and halo. In other embodiments the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH₂and halo. In other embodiments the optional substituents are selected from NH₂and methyl.

When R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C_5-7heterocycle ring, they form a 5 membered ring which comprises one or two atoms selected from N, O and S. In some embodiments the 5 membered ring contains one N and one S. In other embodiments the 5 membered ring contains one N. In other embodiments the 5 membered ring contains one N and one O. In other embodiments the 5 membered ring contains two Ns. In some embodiments R^A3and R^Atogether with the carbon atoms to which they are bound form an optionally substituted pyrrole or pyrazole.

When R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C_5-7heterocycle ring, the optional substituents are selected from NH₂, C_1-6alkyl, C_1-6alkoxy and halo. In other embodiments the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH₂, F, Cl and Br. In other embodiments the optional substituent is methyl.

In other embodiments R^A2and R^A3together with the carbon atoms to which they are bound form:

- (i) optionally substituted C₆heteroaromatic ring; wherein the optional substituent is NH₂;
- (ii) optionally substituted C₆carboaromatic ring; wherein the optional substituent is F, OMe, Cl;
- (iii) optionally substituted C₅heteroaromatic or C₅heterocycle ring wherein the optional substituent is methyl.

In some embodiments R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C carboaromatic ring or C_5-7heteroaromatic ring wherein the optional substituents are selected from C_1-6alkyl, and halo.

In some embodiments R^A2and R^A3together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, pyridine optionally substituted by NH₂, or a phenyl optionally substituted by Cl, F or OMe.

In some embodiments R^A2and R^A3together form a ring selected from:

[Image Omitted]

B

In some embodiments B is of formula (B-1):

[Image Omitted]

wherein the wavy lines indicate the point of attachment to A and C; wherein R^B1is H, OH, —OMe, —O-Ethyl, —CH₂OH, —CH₂CH₂OH or ═CHCH₂—OH.

In other embodiments R^B1is H, —CH₂OH, —CH₂CH₂OH or ═CHCH₂—OH.

In other embodiments R^B1is —CH₂OH, —CH₂CH₂OH or ═CHCH₂—OH.

In other embodiments R^B1is H.

In another embodiment B is of the formula (B-1a):

[Image Omitted]

In further embodiments B is of the formula (B-1b):

[Image Omitted]

Therefore in some embodiments the compounds of Formula (I) is the S,S-enantiomer.

In some embodiments B is of formula (B-2):

[Image Omitted]

wherein the wavy line indicates the point of attachment to A and C; R^B2 is C_1-2alkyl-OH, CH₂CONHMe or C_1-3alkyl.

In some of these embodiments, R^B2is C_1-2alkyl-OH, or C_1-3alkyl In some embodiments when B is of the formula (B-2) it is of the following formula (B-2a) wherein the wavy line indicates the point of attachment to A and C; and R^B2is C_1-2alkyl-OH, CH₂CONHMe or C_1-2alkyl;

[Image Omitted]

In some embodiments B is of the following formula:

[Image Omitted]

In further embodiments B is of the following formula:

[Image Omitted]

C

C is selected from the group consisting of C₆10 carboaryl, C_5-6heteroaryl and C_5-10heterocyclyl, which groups are optionally substituted by:

- (i) C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl C_4-10heterocyclyl, or C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups:
- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂, OH;
- d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- l) P(═O)Me₂;
- m) carboxy or CH₂-carboxy;
- n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;
- (ii) one or more groups selected from carboxy, CN, halo, nitro, C_1-6alkyl, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6alkyl amido, di-C_1-6alkyl amido, C_1-6alkyl sulfonamido, and di-C_1-6alkyl sulfonamido.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_5-10heterocyclyl, C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups:

- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂or OH;
- d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- l) P(═O)Me₂;
- m) carboxy or CH₂-carboxy; and/or
- n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

When C is an optionally substituted C_5-6heteroaryl in some embodiments it is an optionally substituted C₆heteroaryl. In other embodiments it is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl. In other embodiments it is an optionally substituted pyridinyl.

When C is an optionally substituted C_5-6heteroaryl it can be optionally substituted by:

- (i) C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_5-10heterocyclyl, or C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl,
  
  which are themselves optionally substituted by one or more of the groups selected from:
- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂, OH;
- d) C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- l) P(═O)Me₂;
- m) carboxy or CH₂-carboxy; and/or
- n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;
- (ii) one or more groups selected from carboxy, CN, halo, nitro, C_1-6alkyl, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6alkyl amido, di-C_1-6alkyl amido, C_1-6alkyl sulfonamido and di-C_1-6alkyl sulfonamido.

Where C is substituted by C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, it may bear a number of substituent groups. The substituents are selected from:

- a) one or two ═O groups;
- b) one or more halo groups, CN, NH₂;
- c) one or more C_1-6alkyl including (CH₃)₂, C_1-6alkoxy, or C₁-alkylester, wherein each is optionally substituted by one or more halo groups;
- d) C_5-6heterocyclyl or C_5-6heteroaryl with an optional methyl substituent;
- e) C_6-10carboaryl optionally substituted by one or more halo atoms;
- f) P(═O)Me₂; or
- g) carboxy or CH₂-carboxy.

In some embodiments one substituent of C is at the para position.

In some embodiments when C is an optionally substituted C_5-6heteroaryl, the optional substituents are selected from C_1-6alkyl and halo. In further embodiments the optional substituent is methyl. In further embodiments C is substituted by methyl at the meta position.

In other embodiments where C is substituted by an optionally substituted C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, it may be substituted by an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted imidazolidinyl, an optionally substituted dihydroquinolinyl, an optionally substituted benzimidazolyl or an optionally substituted imidazopyridinyl. These group themselves may be optionally substituted by one or two ═O groups, halo, CN, one or more C_1-6alkyl, C_1-6alkoxy, C_1-6alkylester, C_5-6heterocyclyl (with an optional methyl substituent), phenyl substituted by F at the para position, carboxy, CH₂-carboxy, tetrazolyl, pyrazolyl, triazolyl or P(═O)Me₂.

In other embodiments when C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl it may bear a number of substituent groups. The substituents are selected from an optionally substituted C_5-10heteroaryl and C_5-10heterocyclyl, which are themselves optionally substituted by one or two ═O groups, one or more halo groups, CN, one or more C_1-6alkyl, C_1-6alkoxy, C₁6alkylester, O_5-6heterocyclyl (with an optional methyl substituent), phenyl optionally substituted with one or two halo groups, carboxy, CH₂-carboxy, tetrazolyl, pyrazolyl, triazolyl, a pyridine ring, NH₂or OH. In some embodiments the substituents are an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted imidazolidine, an optionally substituted dihydroquinoline, an optionally substituted benzimidazolyl or an optionally substituted imidazopyridinyl.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from:

- i) C_6-10carboaryl, C_5-10heteroaryl C_5-10heterocyclyl, which are themselves optionally substituted by one or more of the following groups:
  - a) one or two ═O groups;
  - b) one or more halo groups;
  - c) CN, NH₂, OH;
  - d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
  - e) C_1-6alkoxy with optional substituents of one or more halo groups;
  - f) C_1-6alkylester;
  - g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
  - h) C_5-6heteroaryl;
  - i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
  - j) C_6-10carboaryl with optional substituents of one or more halo groups;
  - l) P(═O)Me₂;
  - m) carboxy, CH₂-carboxy; and/or
  - n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;
- ii) one or more groups selected from carboxy, CN, halo, nitro, C_1-6alkyl, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6alkyl amido, di-C_1-6alkyl amido, C_1-6alkyl sulfonamido and di-C_1-6alkyl sulfonamido.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from C_6-10carboaryl, C_5-10heteroaryl C_5-10heterocyclyl, which are themselves optionally substituted by one or more groups selected from the following:

- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂, OH;
- d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- l) P(═O)Me₂;
- m) carboxy, CH₂-carboxy; and/or
- n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_5-10heterocyclyl, C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups:

- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂or OH;
- d) one or more C_1-6alkyl groups including branched and cyclic and with a substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- l) P(═O)Me₂;
- m) carboxy or CH₂-carboxy; and/or
- n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C₆₁0 carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_5-10heterocyclyl, C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups:

- a) one or more halo groups;
- b) CN, NH₂or OH;
- c) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- d) C_1-6alkoxy with optional substituents of one or more halo groups;
- e) C_1-6alkylester;
- f) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- g) C_5-6heteroaryl;
- h) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- i) C_6-10carboaryl with optional substituents of one or more halo groups;
- j) P(═O)Me₂;
- k) carboxy or CH₂-carboxy; and/or
- l) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_5-10heterocyclyl, C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or two ═O groups and substituted with one or more of the following groups:

- a) one or more halo groups;
- b) CN, NH₂or OH;
- c) one or more C_1-6alkyl groups including branched and cyclic and with a substituent selected from OH or one or more halo groups;
- d) C_1-6alkoxy with optional substituents of one or more halo groups;
- e) C_1-6alkylester;
- f) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- g) C_5-6heteroaryl;
- h) C_4-10ocarbocyclyl with an optional methyl or ═O substituent;
- i) C_6-10carboaryl with optional substituents of one or more halo groups;
- j) P(═O)Me₂;
- k) carboxy or CH₂-carboxy; and/or
- l) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from C₆heteroaryl or C₆heterocyclyl, which are themselves optionally substituted by one or more groups selected from the following:

- i) one or two ═O groups;
- ii) methyl;
- iii) OMe;
- iv) Cl;
- v) CN;
- vi) CF₃;
- vii) F;
- viii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl;
- ix) O—CF₃;
- x) O—CHF₂.

In some embodiments C is a substituted pyridyl which is substituted by a C₆heterocyclyl or C₆heteroaryl, each of which contain either one or two N atoms and are substituted by ═O and another group selected from methyl, Cl, OMe, CN, and OCHF₂.

In some embodiments C is a substituted pyridyl which is substituted by a pyridyl which is itself substituted by at least one ═O group and another group selected from CF₃, OCF₃, Cl, CN, OMe, pyrazole optionally substituted by methyl, tetrazole, F, OCHF₂or triazole.

In further embodiments C is an optionally substituted pyridinyl wherein the optional substituents are selected from phenyl and pyridyl which are themselves optionally substituted by methyl or CN.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from pyridine, pyridazine and pyrimidine which are themselves optionally substituted by one or more groups selected from the following:

- a) one or two ═O groups;
- b) one or more halo groups;
- c) methyl;
- d) OMe;
- e) CN; or
- f) OCHF₂.

In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is phenyl or pyridyl which are themselves optionally substituted by one or more groups selected from the following:

- a) one or more OMe groups;
- b) one or more F groups;
- c) CN;
- d) tetrazole; or
- e) carboxy.

In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is a C₅heteroaryl or C₅heterocyclyl which are themselves optionally substituted by one or more substituents selected from methyl and CN. In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is a pyrazole, triazole, imidazole or an oxazole which are themselves optionally substituted by one or more substituents selected from methyl and CN.

In further embodiments the pyrazole, triazole, imidazole or oxazole are substituted by two methyl groups and optionally one CN group.

In some embodiments C is an optionally substituted pyridinyl wherein the optional substituent is an unsubstituted C₉membered heterocyclyl containing 2 or 3 nitrogen atoms.

In another embodiment C is of the formula (C-1):

[Image Omitted]

wherein D is C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, which are themselves optionally substituted by ═O, halo, CN, NH₂, OH, one or more C_1-6alkyl groups, which alkyl is optionally substituted by halo, C_1-6alkoxy which is optionally substituted by halo, C_1-6alkylester, C_5-6heterocyclyl (with an optional methyl substituent), carboxy, CH₂-carboxy, P(═O)Me₂, tetrazolyl, pyrazolyl or triazolyl. In some embodiments the optional substituents are selected from ═O, CN, F, Cl, Br, CN, methyl, ethyl, OMe, ethoxy, O—CF₃, OMe, CF₃, P(═O)Me₂and C_1-2alkyl ester.

When C is (C-1) in some embodiments D is an optionally substituted pyridin-2-one. In some embodiments the optional substituents are selected from OMe, C, F, methyl, trifluoromethyl, OCF₃, —C(═O)OH (carboxy), CN, pyrazolyl, triazolyl, tetrazolyl, phenyl with an optional F substituent at the para position or piperazinyl with a methyl substituent. In some embodiments the pyridine-2-one is unsubstituted. In some embodiments the pyridin-2-one is pyridin-2(1H-one.

When C is (C-1), in some embodiments D is an optionally substituted 6 membered heteroaryl which contains one or two N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position and the other optional substituents are selected from methyl, OMe, piperazine substituted by methyl, C(═O)OH (carboxy), Cl, phenyl substituted by fluoro, CN, CF₃, F, pyrazolyl, triazolyl, tetrazolyl, or O—CF₃.

In some embodiments C is of the formula (C-1):

[Image Omitted]

wherein D is C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, each of which are themselves optionally substituted by:

- i) one or two ═O groups;
- ii) one or two C_1-4alkyl groups which can be branched;
- iii) OMe;
- iv) piperazinyl, optionally substituted by methyl;
- v) C(═O)OH (carboxy);
- vi) Cl;
- vii) F;
- viii) phenyl, optionally substituted by one or more fluoro;
- ix) CN;
- x) CF₃;
- xi) O—CF₃;
- xii) tetrazolyl, pyrazolyl, triazolyl each of which is optionally substituted by methyl;
- xiii) NH₂;
- xiv) pyridinyl;
- xv) CH₂OH;
- xvi) OH;
- xvii) P(═O)Me₂; or
- xviii) OCHF₂.

In some embodiments C is of the formula (C-1):

[Image Omitted]

wherein D is C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, each of which are themselves optionally substituted by:

- i) one or two ═O groups;
- ii) one or two C_1-4alkyl groups which can be branched;
- i) OMe;
- ii) piperazinyl, optionally substituted by methyl;
- iii) C(═O)OH (carboxy);
- iv) Cl;
- v) F;
- vi) phenyl, optionally substituted by one or more fluoro;
- vii) CN;
- viii) CF₃;
- ix) O—CF₃;
- x) OMe;
- xi) tetrazolyl, pyrazolyl, triazolyl;
- xii) NH₂;
- xiii) (CH₃)₂;
- xiv) pyridinyl;
- xv) CH₂OH;
- xvi) OH; or
- xvii) P(═O)Me₂.

In some embodiments D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position, wherein the optional substituents are selected from:

- i) methyl;
- ii) OMe;
- iii) piperazinyl substituted by methyl;
- iv) C(═O)OH (carboxy);
- v) C;
- vi) phenyl substituted by fluoro;
- vii) CN;
- viii) CF₃;
- ix) O—CF₃;
- x) F; or
- xi) pyrazolyl, triazolyl or tetrazolyl.

In some embodiments when C is (C-1), D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position wherein the optional substituents are selected from:

- i) methyl;
- ii) OMe;
- iii) piperazinyl substituted by methyl;
- iv) C(═O)OH (carboxy);
- v) Cl;
- vi) F;
- vii) phenyl substituted by fluoro;
- viii) CN;
- ix) CF₃;
- x) O—CF₃;
- xi) O—CHF₂;
- xii) pyrazole, triazole, tetrazole each of which is optionally substituted by methyl.

In some embodiments D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position, wherein the optional substituents are selected from:

- i) methyl;
- ii) OMe;
- iii) Cl;
- iv) F;
- v) CN;
- vi) CF₃;
- vii) O—CF₃;
- viii) O—CHF₂; or
- ix) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl.

In some embodiments D is a substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position, wherein the substituents are selected from:

- i) OMe;
- ii) Cl;
- iii) F;
- iv) CN;
- v) CF₃;
- vi) O—CF₃;
- vii) O—CHF₂; or
- viii) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl.

In some embodiments C is of the formula (C-1) wherein D is C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, each of which are themselves optionally substituted by:

- i) one or two ═O groups;
- ii) one or two C_1-4alkyl groups which can be branched and optionally substituted by one or more halo groups;
- iii) one or more OMe groups;
- iv) C(═O)OH (carboxy);
- v) halo;
- vi) CN;
- vii) C_1-4alkoxy optionally substituted by one or more halo groups;
- viii) tetrazolyl, pyrazolyl, triazolyl wherein each is optionally substituted by methyl;
- ix) P(═O)Me₂.

In some embodiments C is of the formula (C-1) and D is C_6-10carboaryl, C_5-10heteroaryl or CO_5-10heterocyclyl, each of which are themselves optionally substituted by: one or two ═O groups; methyl, CF₃; OCF₃; Cl, CN, OMe, pyrazole optionally substituted by methyl, tetrazole, F, OCHF₂, triazole, C(═O)OH, P(═O)Me₂.

In some embodiments D is optionally substituted by 1, 2 or 3 substituents,

In some embodiments D is optionally substituted by 1 substituent,

In some embodiments D is optionally substituted by 2 or 3 substituents,

In some embodiments when C is (C-1), D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position wherein the optional substituents are selected from:

- i) methyl;
- ii) OMe;
- iii) piperazinyl substituted by methyl;
- iv) C(═O)OH (carboxy);
- v) Cl;
- vi) F;
- vii) phenyl substituted by fluoro;
- viii) CN;
- ix) CF₃;
- x) O—CF₃;
- xi) pyrazole optionally substituted by methyl, triazole, tetrazole.

In some embodiments C is of the formula (C-1) and D is an optionally substituted phenyl or piperidyl wherein there are one or two optional substituents selected from F, OMe and CN. In some embodiments C is of the formula (C-1) and D is an optionally substituted phenyl or pyridyl wherein there are one or two optional substituents selected from F, OMe and CN.

In some embodiments D is an optionally substituted C₅heterocyclyl or C₅heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl and CN. In further embodiments D is a triazole substituted with two methyl groups. In further embodiments D is a pyrazole substituted by two methyl groups. In further embodiments D is an imidazole substituted by two methyl groups and CN. In further embodiments D is an oxazole substituted by two methyl groups.

In some embodiments D is a C₉heterocyclyl or C₉heteroaryl comprising 2 or 3 nitrogen atoms.

In further embodiments D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl.

In some embodiments D is optionally substituted by 1, 2 or 3 substituents.

In another embodiment D is of the formula (D-1):

[Image Omitted]

wherein one or two of R^D1, R^D2, R^D3and R^D4are selected from a C_1-6alkyl optionally substituted by one or more halo groups; C_1-6alkoxy optionally substituted by one or more halo groups, C_5-6heterocyclyl or C_5-6heteroaryl with an optional methyl substituent, carboxy, ═O, halo, NH₂, CN, or phenyl optionally substituted by one or more halo atoms; or wherein R^D3and R^D4form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(═O)Me₂and C(═O)OH;

or wherein R^D1, R^D2, R^D3and R^D4are all H.

In another embodiment one or two of R^D1, R^D2, R^D3and R^D4are selected from C_1-6alkyl optionally substituted by one or more halo groups, C_1-6alkoxy optionally substituted by one or more halo groups, C_5-6heterocyclyl or C_5-6heteroaryl with an optional methyl substituent, carboxy halo, CN, or phenyl optionally substituted by one or more halo atoms, and the rest are H.

In some embodiments D is of the formula (D-1) and one or two of R^D1, R^D2, R^D3and R^D4are selected from:

- i) methyl;
- ii) OMe;
- iii) piperazine substituted by methyl;
- iv) C(═O)OH (carboxy);
- v) Cl;
- vi) phenyl substituted by fluoro;
- vii) CN;
- viii) CF₃;
- ix) F;
- x) pyrazolyl, triazolyl, tetrazolyl;
- xi) O—CF₃
- and the rest of R^D1, R^D2, R^D3and R^D4are H.

In some embodiments D is of the formula (D-1) and one or two of R^D1, R^D2, R^D3and R^D4are selected from:

- i) methyl;
- ii) OMe;
- iii) C;
- iv) CN;
- v) CF₃;
- vi) F;
- vii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl;
- viii) O—CF₃
- ix) O—CHF₂
- and the rest of R^D1, R^D2, R^D3and R^D4are H.

In another embodiment one or two of R^D1, R^D2, R^D3and R^D4are selected from methyl, —OMe, halo, —C(═O)OH, CN, CF₃, —OCF₃, —OCHF₂and the rest of R^D1, R^D2, R^D3and R^D4are H.

In one embodiment all of R^D1, R^D2, R^D3and R^D4are H.

In another embodiment R^D3is selected from H, optionally substituted phenyl (wherein the optional substituent is halo), methyl, OMe, —C(═O)OH, —OCHF₂, Cl, CN and piperazinyl optionally substituted by methyl wherein R^D1, R^D2and R^D4are all H. In some embodiments R^D3is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF₂, or triazole and wherein R^D1, R^D2and R^D4are all H. In some embodiments R^D3is selected from H, CN, OMe, Cl, pyrazole, tetrazole, methyl, OCHF₂, or triazole and wherein R^D1, R^D2and R^D4are all H.

In some embodiments R^D2is selected from H, OMe, C and CN and wherein R^D1, R^D3and R^D4are all H.

In other embodiments R^D1is selected from H, methyl, OMe, C, CF₃, OCF₃, OCHF₂and CN and R^D2, R^D3and R^D4are all H. In some embodiments R^D1is selected from H, OMe, C, CF₃, OCF₃, OCHF₂, CN, F, triazole and pyrazole optionally substituted by methyl, and R^D2, R^D3and R^D4are all H.

In another embodiment R^D3and R^D4form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, CN, P(═O)Me₂, methyl, OMe, halo and C(═O)OH.

In some embodiments R^D3and R^D4form an optionally substituted benzene ring or an optionally substituted pyridine ring.

In some embodiments R^D3and R^D4form an unsubstituted benzene ring or an unsubstituted pyridine ring.

In another embodiment D is of the formula (D-2):

[Image Omitted]

- Wherein X^Dis NR^D5aor CR^D5aR^D5b;
- R^D5ais selected from H or methyl;
- either R^D5band R^D6bare both H or together they are —CH₂—;
- R^D6ais selected from H, ═O, methyl, —CH₂OH or —C(═O)OH, wherein when R^D6ais ═O, R^D6bis absent;
- R^D7ais selected from H, ═O, methyl, —CH₂OH or —C(═O)OH;
- R^D7bis H, wherein when R^D7ais ═O, R^D7bis absent;
- or wherein R^D6aand R^D7atogether form a benzene ring or a C₆heteroaromatic ring which is optionally substituted by CN, P(═O)Me₂or carboxy and R^D6band R^D7bare absent.

In some embodiments C is of the formula (C-1) and D is of the formula (D-2) and X^Dis N and R^D5ais methyl.

In some embodiments C is of the formula (C-1) and D is of the formula (D-2) and R^D6aand R^D6bboth H and R^D7ais selected from ═O, —CH₂OH or —C(═O)OH and R^D7bis H or when R^D7ais —O, R^D7bis absent.

In some embodiments C is of the formula (C-1) and D is of the formula (D-2) and X^Dis N and R^D5ais methyl wherein R^D7ais selected from H and ═O and R^D6ais H and ═O, wherein when R^D7ais ═O, R^D6aand R^D6bare H and R^D7bis absent and wherein R^D6ais ═O, R^D7aand R^D7bare H and R^D6bis absent.

In some embodiments C is of the formula (C-1) and D is of the formula (D-2), R^D7ais ═O, and R^D7bis absent, XD is C and R^D5band R^D6btogether are —CH₂— and R^D6aand R^D5aare methyl.

In another embodiment R^D6aand R^D7atogether form a benzene ring or a C₆heteroaromatic ring which is optionally substituted by CN, P(═O)Me₂or —C(═O)OH, and R^D6band R^D7bare absent.

In some embodiments R^D6aand R^D7atogether form a benzene ring or a pyridine ring which is optionally substituted by CN, P(═O)Me₂, or C(═O)OH and R^D6band R^D7bare absent.

In some embodiments R^D6aand R^D7aform an unsubstituted benzene ring and R^D6band R^D7bare absent. In some embodiments R^D6aand R^D7aform an unsubstituted pyridine ring and R^D6band R^D7bare absent.

In some embodiments X^Dis N and R^D5ais H or methyl.

In some embodiments X^Dis C and R^D5ais H or methyl and R^D5bis H. In further embodiments both R^D5aand R^D5bare H.

In some embodiments R^D7ais carboxy, —CH₂OH or ═O. In some embodiments R^D7ais ═O. R^D7bis H, or when R^D7ais ═O, R^D7bis absent.

In some embodiments R^D6ais H or ═O. In some embodiments R^D6ais ═O and R^D6bis absent.

In some embodiments where R^D7ais ═O, R^D6aand R^D6bare H and R^D7bis absent and where R^D6ais ═O, R^D7aand R^D7bare H and R^D6ais absent.

In some embodiments X^Dis N and R^D5ais H or methyl, R^D6bis H and R^D6aand R^D7atogether form a pyridine ring or a benzene ring which is optionally substituted by —C(═O)OH or CN or P(═O)Me₂and R^D6band R^D7bare absent.

In some embodiments D is selected from the following table:

Name
Structure

2-oxo-1-pyridyl

[Image Omitted]

3-methyl-2-oxo-1- pyridyl

[Image Omitted]

3-methoxy-2- oxo-1-pyridyl

[Image Omitted]

5-methoxy-2-oxo- 1-pyridyl

[Image Omitted]

/

5-chloro-2-oxo- 1-pyridyl

[Image Omitted]

/

2-oxo-1,8- naphthyridin-1-yl

[Image Omitted]

2-oxo-1-quinolyl

[Image Omitted]

3-methyl-2-oxo- benzimidazol-1-yl

[Image Omitted]

3-methyl-2,4- dioxo- imidazolidin-1-yl

[Image Omitted]

3-methyl-2,5- dioxo-imidazolidin- 1-yl

[Image Omitted]

3-chloro-2-oxo- 1-pyridyl

[Image Omitted]

3-cyano-2-oxo-1- pyridyl

[Image Omitted]

5-cyano-2-oxo- 1-pyridyl

[Image Omitted]

3-fluoro-2- oxopyridin-1(2H)- yl

[Image Omitted]

5-methyl-2-oxo- 1-pyridyl

[Image Omitted]

5-carboxy-2-oxo- 1-pyridyl

[Image Omitted]

2-oxo-5-(1H- pyrazol-4-yl)-1- pyridyl

[Image Omitted]

2-oxo-5-(1H- triazol-4-yl)-1- pyridyl

[Image Omitted]

5-cyano-3- methyl-2-oxo- benzimidazol-1- yl

[Image Omitted]

5-carboxy-3- methyl-2-oxo- benzimidazol-1-yl

[Image Omitted]

6-carboxy-3- methyl-2-oxo- benzimidazol-1- yl

[Image Omitted]

(6-dimethylphosphor- yl-3-methyl-2-oxo- benzimidazol-1-yl)

[Image Omitted]

2-oxo-3H- benzimidazol-1- yl

[Image Omitted]

2-oxo-1H- imidazo[4,5- b]pyridin-3-yl

[Image Omitted]

6-oxopyridazin- 1-yl

[Image Omitted]

6-oxopyrimidin-1- yl

[Image Omitted]

1-methyl-2-oxo- 3-pyridyl

[Image Omitted]

2-oxo-3- (trifluoromethyl)-1- pyridyl

[Image Omitted]

2-oxo-3- (trifluoromethoxy)- 1-pyridyl

[Image Omitted]

2-oxo-5-(1H- tetrazol-5-yl)-1- pyridyl

[Image Omitted]

In some embodiments D is selected from the following table:

[3- (difluoromethoxy)- 2-oxo-1-pyridyl]

[Image Omitted]

[5- (difluoromethoxy)- 2-oxo-1-pyridyl]

[Image Omitted]

(3-carboxy-6- fluoro-2-methoxy- phenyl)

[Image Omitted]

(3-cyano-6-fluoro- 2-methoxy-phenyl)

[Image Omitted]

[6-fluoro-2- methoxy-3-(1H- tetrazol-5- yl)phenyl]

[Image Omitted]

(4-methoxy-2-oxo- 1-pyridyl)

[Image Omitted]

(4-chloro-2-oxo-1- pyridyl)

[Image Omitted]

(4-cyano-2-oxo-1- pyridyl)

[Image Omitted]

[3-(1- methylpyrazol-4- yl)-2-oxo-1- pyridyl]

[Image Omitted]

[2-oxo-3-(1H- pyrazol-4-yl)-1- pyridyl]

[Image Omitted]

[2-oxo-3-(1H- triazol-4-yl)-1- pyridyl]

[Image Omitted]

[5-(1- methylpyrazol-4- yl)-2-oxo-1-pyridyl]

[Image Omitted]

(5-cyano-1- methyl-2-oxo- imidazo[4,5- b]pyridin-3-yl)

[Image Omitted]

(6-cyano-1-methyl- 2-oxo-imidazo[4,5- b]pyridin-3-yl)

[Image Omitted]

(5-methoxy-6- oxo-pyridazin-1- yl)

[Image Omitted]

(3-chloro-6-oxo- pyridazin-1-yl)

[Image Omitted]

(2-cyanophenyl)

[Image Omitted]

(3-methyl-2-pyridyl)

[Image Omitted]

(3,5- dimethylpyrazol- 1-yl)

[Image Omitted]

(5-cyano-2,4- dimethyl-imidazol- 1-yl)

[Image Omitted]

(5-cyano-6-oxo- pyridazin-1-yl)

[Image Omitted]

[5- (difluoromethoxy)- 6-oxo-pyridazin-1- yl]

[Image Omitted]

(3-methoxy-2- pyridyl)

[Image Omitted]

(6-methoxy-2- pyridyl)

[Image Omitted]

(2,6- dimethoxyphenyl)

[Image Omitted]

(2-fluoro-6- methoxy-phenyl)

[Image Omitted]

2-pyridyl

pryazolo[3,4- b]pyridin-1-yl

[Image Omitted]

indazol-1-yl

[Image Omitted]

indazol-2-yl

[Image Omitted]

(3,5-dimethyl- 1,2,4-triazol-1-yl)

[Image Omitted]

(2,5- dimethyloxazol-4- yl)

[Image Omitted]

(6-cyano-3- methyl-2-oxo- benzimidazol-1- yl)

[Image Omitted]

(1-methyl-2-oxo- imidazo[4,5- b]pyridin-3-yl)

[Image Omitted]

(5-chloro-6-oxo- pyridazin-1-yl)

[Image Omitted]

In some embodiments D is selected from the following table:

In another embodiment C has the formula (C-2):

[Image Omitted]

- wherein one or two of R^C7, R^C8, R^C9and R^C10are selected from methyl, OMe, halo, C(═O)OH, piperazine optionally substituted by methyl, optionally substituted phenyl (wherein the optional substituent is methyl or halo), CN, CF₃, —O—CF₃, O—CHF₂, tetrazolyl, pyrazolyl optionally substituted by methyl, or triazolyl and the rest of R^C7, R^C8, R^C9and R^C10are H; or R^C9and R^C10form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(═O)Me₂or —C(═O)OH; or
- wherein R^C7, R^C8, R^C9and R^C10are all H.

In some embodiments one or two of R^C7, R^C8, R^C9and R^C10are selected from methyl, OMe, halo, C(═O)OH, piperazine optionally substituted by methyl, optionally substituted phenyl (wherein the optional substituent is methyl or halo), CN, CF₃, —O—CF₃, tetrazolyl, pyrazolyl, or triazolyl and the rest of R^C7, R^C8, R^C9and R^C10are H; or R^C9and R^C10form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(═O)Me₂or —C(═O)OH; or wherein R^C7, R^C8, R^C9and R^C10are all H.

In one embodiment C has the formula (C-1) and all of R^C7, R^C8, R^C9and R^C10are H.

In another embodiment one or two of R^C7, R^C8, R^C9and R^C10are selected from methyl, Cl, OMe, phenyl substituted with F at para position, —C(═O)OH, CN, OCF₃, CF₃, F, pyrazolyl, triazolyl, tetrazolyl, piperazinyl substituted by methyl and the rest of R^C7, R^C8, R^C9and R^C1Oare H. In another embodiment one or two of R^C7, R^C8, R^C9and R^C10are selected from methyl, OMe, Cl, CN, CF₃, F; pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl; O—CF₃, O—CHF₂and the rest of R^D1, R^D2, R^D3and R^D4are H.

In another embodiment one of R^C7and R^C9are independently selected from methyl, —OMe, Cl, —C(═O)OH, piperazinyl optionally substituted by methyl, optionally substituted phenyl (wherein the optional substituent is F), CN, CF₃, —O—CF₃, F, pyrazolyl, triazolyl or tetrazolyl and the other is H and R^C10and R^C8are H. In another embodiment one of R^C7and R^C9are independently selected from methyl, —OMe, Cl, —C(═O)OH, CN, CF₃, O—CHF₂, —O—CF₃, F, pyrazolyl, triazolyl or tetrazolyl and the other is H and R^C10and R^C8are H.

In another embodiment R^C9is selected from H, optionally substituted phenyl (wherein the optional substituent is halo), methyl, OMe, C(═O)OH, Cl, CN, pyrazolyl, triazolyl, tetrazolyl, and piperazinyl optionally substituted with methyl and R^C7, R^C8and R^C10are all H. In some embodiments R^C9is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF₂, or triazole and R^C7, R^C8and R^C10are all H.

In other embodiments R^C7is selected from H, methyl, OMe, C, F, CF₃, —OCF₃and CN and R^C8, R^C9and R^C10are all H. In some embodiments R^C7is selected from H, OMe, C, CF₃, OCF₃, OCHF₂, CN, F, triazole and pyrazole optionally substituted by methyl, and R^C7, R^C8and R^C10are all H.

In some embodiments R^C8is selected from H, OMe, C and CN and wherein R^C7, R^C9and R^C10are all H.

In another embodiment C is selected from the group consisting of the groups 1-48 listed in the following table:

No.
Structure

1

[Image Omitted]

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

In another embodiment C is selected from the group consisting of the 49-80 listed in the following table:

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

In another embodiment C is selected from the group consisting of the groups listed in the following table:

A-B-C

In other embodiments the compound of formula A-B-C is of the Formula (I-A):

[Image Omitted]

- wherein X¹is N.

In some embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) C_1-6alkyl ester;
- (iv) C_1-6hydrocarbon;
- (v) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups;
- (vi) C_1-6thioalkyl;
- (vii) C_1-6alkyl acyl;
- (viii) C₅heteroaryl; or
- (ix) alkylamino.

In some embodiments R^A2is selected from the group consisting of: Br, Cl, CN, H, —C(═O)CH₃, C_1-6alkyl amido which alkyl amido is optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups, optionally substituted methoxy, methyl, ethyl or cyclopropyl wherein the optional substituents are selected from OH, CN, or one or more halo groups, an optionally substituted methoxy or ethoxy wherein the optional substituents are selected from alkyl amido or one or more halo groups. In further embodiments R^A2is selected from CN, methyl, Cl, —C(═O)CH₃, —C(═O)OCH₂CH₃, cyclopropyl, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CHCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₂OH, —C(═O)NHCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OCHF₂, H, —OMe, —OCF₃. In some embodiments R^A2is selected from —C(═O)OCH₂CH₃, cyclopropyl, methyl, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, C(═O)N(CH₃)₂, H, —C(═O)N(CH₃)CH₂CH₂OH, —C(═O)N(CH₃)CH₂CCH, Cl, N(CH₃)₂, pyrazole, —SCH₂CH₃, —C(═O)CH₃, and —C(═O)NHCH₂CH₂OH.

In some embodiments R^A3is selected from the group consisting of CN, Br, Cl, OH, H, CF₃, C_1-2alkyl, C_1-2alkoxy, NH₂. In further embodiments R^A3is selected from H, methyl and CN. In some embodiments R^A3is selected from H, methyl or OH.

In other embodiments R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C₆carboaromatic ring or C_5-7heteroaromatic ring, the optional substituents are selected from NH₂, C_1-6alkyl, C_1-6alkoxy and halo. In other embodiments the optional substituents are selected from NH₂, methyl, ethyl, OMe, F, Cl and Br.

In some embodiments R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted pyridine, an optionally substituted benzene, a pyrrole or a pyrazole. In some embodiments R^A2and R^A1together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, pyridine optionally substituted by NH₂or benzene optionally substituted by Cl, F or OMe.

In some embodiments C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl. In some embodiments the optional substituents are selected from:

- (i) C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_5-10heterocyclyl, or C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the groups selected from:
- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂, OH;
- d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent; h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- k) carboxy, CH₂-carboxy;
- l) P(═O)Me₂;
- (ii) one or more of the groups selected from carboxy, CN, halo, nitro, C_1-6alkyl, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6alkyl amido, di-C_1-6alkyl amido, C_1-6alkyl sulfonamido di-C_1-6alkyl sulfonamido.

In other embodiments the compound of formula A-B-C is of the Formula (I-B):

[Image Omitted]

- wherein X¹, R^A2and R^A3are as defined (I-A).

In some embodiments Formula (I-B) can be Formula (I-Ba) or (I-Bb) as shown below:

[Image Omitted]

In some embodiments D is C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl or C_5-10heterocyclyl which are themselves optionally substituted by one or more groups selected from the following:

- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂, OH;
- d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- l) carboxy, CH₂-carboxy
- m) P(═O)Me₂.

In some embodiments D is an optionally substituted pyridine-2-one. In some embodiments the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF₃), OCF₃, carboxy (C(═O)OH), CN, phenyl with an optional F substituent at the para position or a piperazine with a methyl substituent. In some embodiments the pyridine-2-one is unsubstituted. In some embodiments the pyridine-2-one is pyridin-2(1H-one.

In some embodiments D is an optionally substituted 6 membered heteroaryl which contains one or two N atoms, one of which is bonded to C, which is substituted by ═O at the ortho position and the other optional substituents are selected from methyl, OMe, piperazinyl substituted by methyl, C(═O)OH (carboxy), Cl, F, pyrazolyl, triazolyl, tetrazolyl, phenyl substituted by fluoro, CN, CF₃or O—CF₃. In some embodiments D is an optionally substituted 6 membered heteroaryl which contains one or two N atoms, one of which is bonded to C, which is substituted by ═O at the ortho position and the other optional substituents are selected from methyl, OMe, piperazinyl substituted by methyl, C(═O)OH (carboxy), Cl, F, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, phenyl substituted by fluoro, CN, CF₃, OCHF₂or O—CF₃.

In some embodiments D is an optionally substituted C₅heterocycle or C₅heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl. In further embodiments D is a triazole substituted with two methyl groups. In further embodiments D is a pyrazole substituted by two methyl groups. In further embodiments D is an imidazole substituted by two methyl groups and CN. In further embodiments D is an oxazole substituted by two methyl groups.

In some embodiments D is a C₉heterocyclyl or C₉heteroaryl comprising 2 or 3 nitrogen atoms.

In further embodiments D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl.

In other embodiments the compound of formula A-B-C is of the Formula (I-C):

[Image Omitted]

- wherein X¹, R^A2and R^A3are as defined (I-A).

In some embodiments one or two of R^D1, R^D2, R^D3and R^D4are selected from a C_1-6alkyl optionally substituted by one or more halo groups; C_1-6alkoxy optionally substituted by one or more halo groups, C_5-6heterocyclyl or C_5-6heteroaryl with an optional methyl substituent, carboxy, ═O, halo, NH₂, CN, or phenyl optionally substituted by one or more halo atoms; or

- wherein R^D3and R^D4form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring wherein the optional substituents are selected from OH, methyl, OMe, halo, C(═O)OH.

In another embodiment one or two of R^D1, R^D2, R^D3and R^D4are selected from methyl, OMe, halo, C(═O)OH, CN, CF₃, OCF₃, OCHF₂, pyrazolyl, triazolyl, tetrazolyl and the rest are H. In another embodiment one or two of R^D1, R^D2, R^D3and R^D4are selected from methyl, OMe, halo, C(═O)OH, CN, CF₃, OCF₃, OCHF₂, pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl and the rest are H.

In one embodiment all of R^D1, R^D2, R^D3and R^D4are H.

In some embodiments R^D3and R^D4form an unsubstituted benzene ring or an unsubstituted pyridine ring.

In other embodiments the compound of formula A-B-C is of Formula (I-D):

[Image Omitted]

In some embodiments X¹, R^A2and R^A3are as defined (I-A).

In some embodiments X^Dis NR^D5aor CR^D5aR^D5b

- R^D5ais selected from H or methyl;
- either R^D5band R^D6bare both H or together they are —CH₂—;
- R^D6ais selected from H, ═O, methyl, CH₂OH or C(═O)OH;
- R^D7ais selected from H, ═O, methyl, CH₂OH or C(═O)OH;
- R^D7bis H, wherein when R^D7ais ═O, R^D7bis absent;
- or wherein R^D6aand R^D7atogether form a benzene ring or a C₆heteroaromatic ring which is optionally substituted by CN, P(═O)Me₂or carboxy and R^D6band R^D7bare absent.

In some embodiments R^D6aand R^D7atogether form a benzene ring or a pyridine ring which is optionally substituted by CN, P(═O)Me₂, or carboxy and R^D6band R^D7aare absent.

In other embodiments the compound of formula A-B-C is of the Formula (I-E):

[Image Omitted]

In some embodiments R^A2is selected from:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) OH
- (vi) C_1-6alkoxy, optionally substituted by OH, C_1-6alkyl amido, or one or more halo groups;
- (vii) carboxy;
- (viii) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups.

In some embodiments R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) C_1-6alkyl ester;
- (iv) C_1-6hydrocarbon;
- (v) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups;
- (vi) C_1-6thioalkyl;
- (vii) C_1-6alkyl acyl;
- (viii) C₅heteroaryl; or
- (ix) alkylamino.

In some embodiments R^A2is selected from CN, methyl, Cl, —C(═O)CH₃, —C(═O)OCH₂CH₃, cyclopropyl, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CHCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₂OH, —C(═O)NHCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OCHF₂, H, —OMe, —OCF₃, or

- R^A2and R^A3together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, pyridine optionally substituted by NH₂, or benzene optionally substituted by Cl, F or OMe.

In some embodiments R^A2is selected from —C(═O)OCH₂CH₃, cyclopropyl, methyl, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, H, —C(═O)N(CH₃)CH₂CH₂OH, —C(═O)N(CH₃)CH₂CCH, Cl, —N(CH₃)₂, pyrazole, —SCH₂CH₃, —C(═O)CH₃, and —C(═O)NHCH₂CH₂OH.

In some embodiments R^A3is selected from:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl C_1-6acyloxy, carboxy, C_1-6alkylester, C_1-6alkylamino; —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkylacylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups.

In some embodiments R^A3is selected from:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl C_1-6acyloxy, carboxy, C_1-6alkylester, C_1-6alkylamino; —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkylacylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups.

In some embodiments the compound is of the Formula (I-E) and R^A3is H, methyl or OH. In further embodiments the compound is of the Formula (I-E) and R^A3is H.

In some embodiments the compound is of the Formula (I-E) and D is a C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl or C_5-10heterocyclyl, which are themselves optionally substituted by ═O; halo; CN; NH₂; OH; one or more C_1-6alkyl groups, which alkyl is optionally substituted by halo; C_1-6alkoxy which is optionally substituted by halo; C_1-6alkylester; C_5-6heterocyclyl with an optional methyl substituent; carboxy; CH₂-carboxy; tetrazolyl; pyrazolyl or triazolyl. In some embodiments the optional substituents are selected from ═O, CN, F, Cl, Br, CN, methyl, ethyl, OMe, ethoxy, O—CF₃, CF₃, C_1-2alkyl ester. In some embodiments the compound is of the Formula (I-E) and D is a C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl or C_5-10heterocyclyl, which are themselves optionally substituted by ═O; methyl; OMe; piperazinyl substituted by methyl; C(═O)OH (carboxy); Cl; F; phenyl substituted by fluoro; CN; CF₃; OCHF₂, O—CF₃; pyrazole optionally substituted by methyl, triazole, tetrazole.

In some embodiments the compound is of the Formula (I-E) and D is an optionally substituted pyridin-2-one. In some embodiments the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF₃), OCF₃, carboxy (C(═O)OH), CN, phenyl with an optional F substituent at the para position or a piperazinyl with a methyl substituent. In some embodiments the compound is of the Formula (I-E) and D is an optionally substituted pyridin-2-one or pyridin-2(1H-one. In some embodiments the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF₃), OCHF₂, OCF₃, carboxy (C(═O)OH), CN, phenyl with an optional F substituent at the para position or a piperazinyl with a methyl substituent. In some embodiments the pyridine-2-one is unsubstituted. In some embodiments the pyridine-2-one is pyridin-2(1H)-one.

In some embodiments the compound is of the Formula (I-E) and D is an optionally substituted C₅heterocycle or C₅heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments D is an optionally substituted pyrazole, imidazole, triazole or oxazole wherein the optional substituents are selected from methyl. In further embodiments D is a triazole substituted with two methyl groups. In further embodiments D is a pyrazole substituted by two methyl groups. In further embodiments D is an imidazole substituted by two methyl groups and CN. In further embodiments D is an oxazole substituted by two methyl groups. In some embodiments D is a C₉heterocyclyl or C₉heteroaryl comprising 2 or 3 nitrogen atoms. In further embodiments D is 1H-pyrazolo[3,4-b]pyridiyl, indazol-1-yl or indazol-2-yl.

In some embodiments D is optionally substituted by 1, 2 or 3 substituents.

In another embodiment the compound is of Formula (I-Ea):

[Image Omitted]

- wherein D and R^A3are a defined above for Formula (I-E).

In another embodiment the compound is of Formula (I-Eb):

[Image Omitted]

Wherein D and R^A3are a defined above for Formula (I-E).

In one embodiment the compound is of Formula (I)

A-B-C (I)

- or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following:

[Image Omitted]

- wherein the wavy line indicates the point of attachment to B;
- X¹is N;
- R^A2is selected from the group consisting of:
- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) C_1-6alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups;
- (vi) C_1-6acyl amido (wherein the acyl is optionally substituted by H or methyl);
- (vii) C_1-6thioalkyl;
- (viii) C_1-6alkyl ester;
- (ix) C_1-6alkyl acyl;
- (x) C_4-5heterocyclyl;
- (xi) C₅heteroaryl;
- (xii) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl or C_1-3alkyl wherein the C_1-3alkyl is optionally substituted with one or more halo or OH groups; and
- (xiii) OH;
- R^A3is selected from the group consisting of:
- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl, C_1-6acyloxy, carboxy, C_1-6alkyl ester, C_1-6alkylamino, —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkyl acylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups;
- (vii) C_1-6acyloxy;
- (viii) C₄heterocycyl;
- (ix) —NH₂;
- (x) C_1-6alkylamino, optionally substituted by CN, OH or C₄heterocyclyl;
- (xi) C_1-6dialkylamino, optionally substituted by —NH₂;
- (xii) C_1-6acylamido (where acyl substituent is H or Me);
- (xiii) carbaimidoyl or methyl-carbaimidoyl;
- (xiv) carboxyamino;
- (xv) C_1-6thioalkyl, optionally substituted by OH or NH₂;
- (xvi) C_1-6alkyl sulfinyl;
- (xvi) C_1-6alkyl sulfonyl, optionally substituted by one or more halo groups;
- (xvii) C_1-6sulfonimodyl;
- (xviii) C_1-6alkyl phosphinyl;
- (xix) carboxy;
- (xx) C(═O)NH₂
- (xxi) C_1-6alkyl ester;
- (xxii) C_1-6alkyl acyl, optionally substituted by one or more halo groups; and
- (xxiiv) C_1-6alkyl amido;
- or wherein R^A3and R^A2together with the carbon atoms to which they are bound form:
- (i) an optionally substituted C_5-7heterocycle ring;
- (ii) an optionally substituted C₅-heteroaromatic ring;
- (iii) an optionally substituted C₆carboaromatic ring;
- (iv) an optionally substituted C_5-7carbocyclic ring
  - wherein the optional substituents are selected from C_1-6alkyl, halo, C_1-6alkoxy, NH₂, C_1-6alkylamino, OH, and CN;
- wherein B is of formula (B-1) or (B-2)

[Image Omitted]

- wherein the wavy line indicates the point of attachment to A and C;
- R^B1is H, OH, ═CHCH₂—OH, —O—C_1-4alkyl or C_1-4alkyl, wherein the C_1-4alkyl is optionally substituted by OH or OMe;

[Image Omitted]

- wherein the wavy line indicates the point of attachment to A and C;
- R^B2is C_1-2alkyl-OH, CH₂CONHMe or C_1-3alkyl;
- wherein C is selected from the group consisting of C_6-10carboaryl, C_5-6heteroaryl and C_5-10heterocyclyl, which groups are optionally substituted by:
  - (i) C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_4-10heterocyclyl, or C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups:
  - a) one or two ═O groups;
  - b) one or more halo groups;
  - c) CN, NH₂, OH;
  - d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
  - e) C_1-6alkoxy with optional substituents of one or more halo groups;
  - f) C_1-6alkylester;
  - g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
  - h) C_5-6heteroaryl;
  - i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
  - j) C_6-10carboaryl with optional substituents of one or more halo groups;
  - l) P(═O)Me₂;
  - m) carboxy or CH₂-carboxy; and/or
  - n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;
  - (ii) one or more groups selected from carboxy, CN, halo, nitro, C_1-6alkyl, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6alkyl amido, di-C_1-6alkyl amido, C_1-6alkyl sulfonamido, and di-C_1-6alkyl sulfonamido.

In some embodiments the compound is of Formula (I)

A-B-C (I)

- or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof,
- wherein A is of the following:

[Image Omitted]

- wherein the wavy line indicates the point of attachment to B;
- R^A2is C_1-6alkylamino;
- X¹, R^A3, B and C are as defined above.

In some embodiments the compound of Formula (I) is selected from the following in Table 1.

TABLE 1

Ex
Structure
Name

10

[Image Omitted]

Ethyl 3-(((1S,3S)-3-((2-oxo-2H-[1,3′- bipyridin]-6′-yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxylate

50

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′- bipyriidn]-2-one

51

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3- (trifluoromethyl)-2H-[1,3′-bipyridin]-2-one

52

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3- (trifluoromethoxy)-2H-[1,3′-bipyridin]-2-one

53

[Image Omitted]

(1S,3S)-N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)- N³-(5-(2,6-difluorophenyl)pyridin-2- yl)cyclopentane-1,3-diamine

54

[Image Omitted]

(1S,3S)-N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)- N³-(5-(2-fluoro-6-methoxyphenyl)pyridin-2- yl)cyclopentane-1,3-diamine

55

[Image Omitted]

3-Chloro-6′-(((1S,3S)-3-((6-cyclopropyl-1,2,4- triazin-3-yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

56

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′- bipyridine]-5-carbonitrile

57

[Image Omitted]

3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin- 3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1- methylimidazolidine-2,4-dione

58

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′- bipyridine]-3-carbonitrile

59

[Image Omitted]

2-(5-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin- 3-yl)amino)cyclopentyl)amino)pyrazin-2- yl)pyridazin-3(2H)-one

60

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-1-methyl-[3,3′- bipyridin]-2(1H)-one

61

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3-fluoro-[2,3′- bipyridine]-6-carbonitrile

62

[Image Omitted]

1-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin- 3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3- methylimidazolidine-2,4-dione

63

[Image Omitted]

3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin- 3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1- methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one

64

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3-methoxy-2H- [1,3′-bipyridin]-2-one

65

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-5-methoxy-2H- [1,3′-bipyridin]-2-one

66

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3-methyl-2H- [1,3′-bipyridin]-2-one

67

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′- bipyridin]-2-one

68

[Image Omitted]

N-(2-Amino-2-oxoethyl)-3-(((1S,3S)-3-((2- oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6- carboxamide

69

[Image Omitted]

3-(((1S,3S)-3-((2-Oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N-(prop-2-yn-1- yl)-1,2,4-triazine-6-carboxamide

70

[Image Omitted]

N-(Oxetan-3-yl)-3-(((1S,3S)-3-((2-oxo-2H- [1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6- carboxamide

71

[Image Omitted]

N-(2,2-Difluoroethyl)-3-(((1S,3S)-3-((2-oxo- 2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6- carboxamide

72

[Image Omitted]

N-(2-Hydroxyethyl)-3-(((1S,3S)-3-((2-oxo-2H- [1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6- carboxamide

73

[Image Omitted]

N-Ethyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3′- bipyridin]-6′-yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide

74

[Image Omitted]

3-(((1S,3S)-3-((2-Oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6- carboxamide

75

[Image Omitted]

N-Methyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3′- bipyridin]-6′-yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide

76

[Image Omitted]

N,N-Dimethyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3′- bipyridin]-6′-yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide

Further compounds are shown in Table 2:

TABLE 2

Ex
Structure
Name

112

[Image Omitted]

5-Chloro-6′-(((1S,3S)-3-((6-cyclopropyl-1,2,4- triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′- bipyridin]-2-one

113

[Image Omitted]

3-(5-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyrazin-2-yl)-1- methylpyridin-2(1H)-one

114

[Image Omitted]

3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin- 4(3H)-one

115

[Image Omitted]

3-(2-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyrimidin-5-yl)-1- methylpyridin-2(1H)-one

116

[Image Omitted]

3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- carbonitrile

117

[Image Omitted]

1-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- carbonitrile

118

[Image Omitted]

2-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin- 3(2H)-one

119

[Image Omitted]

2-(2-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyrimidin-5- yl)pyridazin-3(2H)-one

120

[Image Omitted]

2′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-6H-[1,5′-bipyrimidin]- 6-one

121

[Image Omitted]

1-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- carboxylic acid

122

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-5-(1H-1,2,3-triazin-4- yl)-2H-[1,3′-bipyridin]-2-one

123

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-5-(1H-pyrazol-4-yl)- 2H-[1,3′-bipyridin]-2-one

124

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-5-(1H-tetrazol-5-yl)- 2H-[1,3′-bipyridin]-2-one

125

[Image Omitted]

3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin-3-yl)-5- (dimethylphosphoryl)-1-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one

126

[Image Omitted]

6′-(((1S,3S)-3-((5-Methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2- one

127

[Image Omitted]

6′-(((1S,3S)-3-((5,6-Dimethyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2- one

128

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′- bipyridine]-5-carbonitrile

129

[Image Omitted]

3-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2- one

130

[Image Omitted]

5-Methyl-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2- one

131

[Image Omitted]

3-Methyl-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2- one

132

[Image Omitted]

3-Methoxy-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin- 3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]- 2-one

133

[Image Omitted]

5-Methoxy-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin- 3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]- 2-one

134

[Image Omitted]

5-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2- one

135

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3-(trifluoromethyl)- 2H-[1,3′-bipyridin]-2-one

136

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′- bipyridine]-3-carbonitrile

137

[Image Omitted]

3-Fluoro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2- one

138

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3-(trifluoromethoxy)- 2H-[1,3′-bipyridin]-2-one

Further compounds are shown in Table 3:

TABLE 3

Ex
Structure
Name

151

[Image Omitted]

N-(2-Hydroxyethyl)-N-methyl-3- (((1S,3S)-3-((2-oxo-2H-[1,3′- bipyridin]-6′- yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide

152

[Image Omitted]

N-Methyl-3-(((1S,3S)-3-((2-oxo- 2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (prop-2-yn-1-yl)-1,2,4-triazine-6- carboxamide

153

[Image Omitted]

3-(((1S,3S)-3-((3-Methoxy-2- oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (oxetan-3-yl)-1,2,4-triazine-6- carboxamide

154

[Image Omitted]

3-(((1S,3S)-3-((5-Methoxy-2- oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (oxetan-3-yl)-1,2,4-triazine-6- carboxamide

155

[Image Omitted]

3-(((1S,3S)-3-((3-Methyl-2-oxo- 2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (oxetan-3-yl)-1,2,4-triazine-6- carboxamide

156

[Image Omitted]

3-(((1S,3S)-3-((5-Methyl-2-oxo- 2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (oxetan-3-yl)-1,2,4-triazine-6- carboxamide

157

[Image Omitted]

3-(((1S,3S)-3-((3-Chloro-2-oxo- 2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (oxetan-3-yl)-1,2,4-triazine-6- carboxamide

158

[Image Omitted]

3-(((1S,3S)-3-((5-Chloro-2-oxo- 2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (oxetan-3-yl)-1,2,4-triazine-6- carboxamide

159

[Image Omitted]

3-(((1S,3S)-3-((3-Cyano-2-oxo- 2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-N- (oxetan-3-yl)-1,2,4-triazine-6- carboxamide

160

[Image Omitted]

N-(Oxetan-3-yl)-3-(((1S,3S)-3- ((2-oxo-3-(trifluoromethoxy)-2H- [1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide

161

[Image Omitted]

N-(Oxetan-3-yl)-3-(((1S,3S)-3- ((2-oxo-3-(trifluoromethyl)-2H- [1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide

165

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-3- (difluoromethoxy)-2H-[1,3′- bipyridin]-2-one

166

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-5- (difluoromethoxy)-2H-[1,3′- bipyridin]-2-one

167

[Image Omitted]

3-(6-(((1S,3S)-3-((6-Cyclopropyl- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-4-fluoro-2- methoxybenzoic acid

168

[Image Omitted]

3-(6-(((1S,3S)-3-((6-Cyclopropyl- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-4-fluoro-2- methoxybenzonitrile

169

[Image Omitted]

(1S,3S)-N1-(6-Cyclopropyl- 1,2,4-triazin-3-yl)-N3-(5-(6- fluoro-2-methoxy-3-(1H-tetrazol- 5-yl)phenyl)pyridin-2- yl)cyclopentane-1,3-diamine

173

[Image Omitted]

rel-3-Methyl-6′-(((1R,3R)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

180

[Image Omitted]

4-Methoxy-6′-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

182

[Image Omitted]

4-Chloro-6′-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

183

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-2- oxo-2H-[1,3′-bipyridine]-4- carbonitrile

185

[Image Omitted]

5-(Difluoromethoxy)-6′-(((1S,3S)- 3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

187

[Image Omitted]

3-(Difluoromethoxy)-6′-(((1S,3S)- 3-((6-methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

197

[Image Omitted]

1-(6-(((1S,3S)-3-((6-Methyl- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-1,8-naphthyridin-2(1H)- one

198

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-3- (1-methyl-1H-pyrazol-4-yl)-2H- [1,3′-bipyridin]-2-one

199

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-3- (1H-pyrazol-4-yl)-2H-[1,3′- bipyridin]-2-one

200

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-3- (1H-1,2,3-triazol-4-yl)-2H-[1,3′- bipyridin]-2-one

201

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-5- (1-methyl-1H-pyrazol-4-yl)-2H- [1,3′-bipyridin]-2-one

202

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-5- (1H-pyrazol-4-yl)-2H-[1,3′- bipyridin]-2-one

208

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-5- (1H-1,2,3-triazol-4-yl)-2H-[1,3′- bipyridin]-2-one

210

[Image Omitted]

1-Methyl-3-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carbonitrile

211

[Image Omitted]

3-Methyl-1-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carbonitrile

212

[Image Omitted]

1-Methyl-3-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-1,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one

213

[Image Omitted]

1-Methyl-3-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridine-5- carbonitrile

214

[Image Omitted]

1-Methyl-3-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridine-6- carbonitrile

220

[Image Omitted]

4-Methoxy-2-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)pyridazin-3(2H)-one

221

[Image Omitted]

4-Chloro-2-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)pyridazin-3(2H)-one

222

[Image Omitted]

6-Chloro-2-(6-(((1S,3S)-3-((6- methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)pyridazin-3(2H)-one

247

[Image Omitted]

2-(6-(((1S,3S)-3-((6-Methyl- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)benzonitrile

248

[Image Omitted]

(1S,3S)-N1-(6-Methyl-1,2,4- triazin-3-yl)-N3-(3-methyl-[2,3′- bipyridin]-6′-yl)cyclopentane-1,3- diamine

249

[Image Omitted]

(1S,3S)-N1-(5-(3,5-Dimethyl-1H- pyrazol-1-yl)pyridin-2-yl)-N3-(6- methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

250

[Image Omitted]

2,4-Dimethyl-1-(6-(((1S,3S)-3- ((6-Methyl-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-1H-imidazole-5- carbonitrile

254

[Image Omitted]

6′-(((1S,3S)-3-((6-Methyl-5-oxo- 4,5-dihydro-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

255

[Image Omitted]

6′-(((1S,3S)-3-((6-Chloro-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

256

[Image Omitted]

6′-(((1S,3S)-3-((6- (Dimethylamino)-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

257

[Image Omitted]

6′-(((1S,3S)-3-((6-(1H-Pyrazol-5- yl)-1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

258

[Image Omitted]

6′-(((1S,3S)-3-((6-(Ethylthio)- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

260

[Image Omitted]

6′-(((1S,3S)-3-((6-Acetyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)-2H- [1,3′-bipyridin]-2-one

277

[Image Omitted]

2-(6-(((1S,3S)-3-((6-Methyl- 1,2,4-triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)-3-oxo-2,3- dihydropyridazine-4-carbonitrile

281

[Image Omitted]

4-(Difluoromethoxy)-2-(6- (((1S,3S)-3-((6-methyl-1,2,4- triazin-3- yl)amino)cyclopentyl)amino)pyridin- 3-yl)pyridazin-3(2H)-one

304

[Image Omitted]

(1S,3S)-N1-(3-Methoxy-[2,3′- bipyridin]-6′-yl)-N3-(6-methyl- 1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine

305

[Image Omitted]

(1S,3S)-N1-(6-Methoxy-[2,3′- bipyridin]-6′-yl)-N3-(6-methyl- 1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine

306

[Image Omitted]

(1S,3S)-N1-(5-(2- Methoxyphenyl)pyridin-2-yl)-N3- (6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

307

[Image Omitted]

(1S,3S)-N1-(5-(2,6- Dimethoxyphenyl)pyridin-2-yl)- N3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

308

[Image Omitted]

(1S,3S)-N1-(5-(2-Fluoro-6- methoxyphenyl)pyridin-2-yl)-N3- (6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

309

[Image Omitted]

(1S,3S)-N1-([2,3′-Bipyridin]-6′- yl)-N3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

310

[Image Omitted]

(1S,3S)-N1-(5-(1H-Pyrazolo[3,4- b]pyridin-1-yl)pyridin-2-yl)-N3-(6- methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

311

[Image Omitted]

(1S,3S)-N1-(5-(1H-Indazol-1- yl)pyridin-2-yl)-N3-(6-methyl- 1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine

312

[Image Omitted]

(1S,3S)-N1-(5-(2H-Indazol-2- yl)pyridin-2-yl)-N3-(6-methyl- 1,2,4-triazin-3-yl)cyclopentane- 1,3-diamine

313

[Image Omitted]

(1S,3S)-N1-(5-(3,5-Dimethyl-1H- 1,2,4-triazol-1-yl)pyridin-2-yl)- N3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

314

[Image Omitted]

(1S,3S)-N1-(5-(2,5- Dimethyloxazol-4-yl)pyridin-2-yl)- N3-(6-methyl-1,2,4-triazin-3- yl)cyclopentane-1,3-diamine

315

[Image Omitted]

rac-(R)-6′-((4-Hydroxy-2-(((6- methyl-1,2,4-triazin-3- yl)amino)methyl)butyl)amino)-3- methyl-2H-[1,3′-bipyridin]-2-one

316

[Image Omitted]

rac-(R)-6′-((4-Hydroxy-2-(((6- methyl-1,2,4-triazin-3- yl)amino)methyl)butyl)amino)-5- methyl-2H-[1,3′-bipyridin]-2-one

317

[Image Omitted]

rac-(R)-6′-((4-Hydroxy-2-(((6- methyl-1,2,4-triazin-3- yl)amino)methyl)butyl)amino)-5- methoxy-2H-[1,3′-bipyridin]-2- one

318

[Image Omitted]

rac-(R)-1-(6-((4-Hydroxy-2-(((6- methyl-1,2,4-triazin-3- yl)amino)methyl)butyl)amino)pyri- din-3-yl)quinolin-2(1H)-one

319

[Image Omitted]

rac-(R)-3-(6-((4-Hydroxy-2-(((6- methyl-1,2,4-triazin-3- yl)amino)methyl)butyl)amino)pyri- din-3-yl)-1-methyl-1,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one

320

[Image Omitted]

rac-(R)-1-(6-((4-Hydroxy-2-(((6- methyl-1,2,4-triazin-3- yl)amino)methyl)butyl)amino)pyri- din-3-yl)-1,8-naphthyridin-2(1H)- one

321

[Image Omitted]

rac-(R)-1-(6-((4-Hydroxy-2-(((6- methyl-1,2,4-triazin-3- yl)amino)methyl)butyl)amino)pyri- din-3-yl)-3-methyl-1,3-dihydro- 2H-benzo[d]imidazol-2-one

In some embodiments the compound is selected from 50, 57, 129, 132 and 136. In some embodiments the compound is 132.

General Synthesis

The compounds according to general formula (I-B) can be prepared according to the following schemes 1, 2, 3, 4 and 5. The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I-B) and are not intended to be limiting. It is clear that the order of transformations as exemplified in schemes 1, 2, 3, 4 and 5 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting.

Routes for the preparation of compounds of general formula (I-B) and corresponding intermediates are described in schemes 1, 2, 3, 4 and 5.

[Image Omitted]

Monoarylated diamines of general formula (A3) can be obtained via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A2a) with X being a leaving group like halogen or —S(O)Me as depicted in Scheme 1. For S_NAr approaches with X being groups like for example fluorine or —S(O)Me, diamines (A1) may be reacted with (A2a) in the presence of inorganic bases like K₂CO₃or Na₂CO₃or in the presence of organic bases like triethylamine or DIPEA or without any additional base in polar solvents such as for example DMSO, NMP or nBuOH at temperatures between 100-130° C. The reaction times may vary between 1 hour and 24 hours. In certain instances, it can be beneficial to apply microwave heating.

For palladium catalyzed Buchwald-Hartwig aminations all methods that are known in the art may be applied. For example, diamines (A1) may be reacted with (A2a) in the presence of a palladium catalyst like Pd PEPPSI-IpentCl [CAS 1612891-29-8], Pd₂(dba)₃or tBuXPhos Pd G3 [1447963-75-8] and a base like Cs₂CO₃or NaOtBu in aprotic solvents like 1,4-dioxane, DMF, toluene or DMA at temperatures between room temperature and 130° C., preferably at 65-100° C., for 15-24 h.

Diamines of general formula (A1) and heteroaryls of general formula (A2a) are either commercially available or can be prepared according to procedures available from the public domain. For the synthesis of diamines (A1) see for example WO2004004726 and references therein.

Arylated diamines of general formula (A6) can be obtained from (A3) via copper catalyzed Ullmann couplings with heterocycles (A4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (A5). For Ullmann couplings all methods that are known in the art may be applied. For example, (A3) may be reacted with (A4) in the presence of a copper catalyst like Cu(I)I, Cu(Otf)₂or Cu(Oac)₂and a base like Cs₂CO₃or K₂CO₃in polar, aprotic solvents like 1,4-dioxane, DMF or pyridine at temperatures between room temperature and 120° C., preferably at 100° C. for 15-20 h. In some instances a ligand like N¹,N²-dimethylcyclohexane-1,2-diamine, TMEDA, N¹,N²-dimethylethane-1,2-diamine or N,N-dimethylglycine might be added to the reaction mixture.

For Suzuki couplings towards (A6) all methods that are known in the art may be applied. For example, (A3) may be reacted with boronic acid derivatives (A5) in the presence of a palladium catalyst like 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride [CAS 72287-26-4] and a base like Cs₂CO₃, K₂CO₃or K₃PO₄in polar solvents such as 1,4-dioxane, THF and water or mixtures thereof at temperatures between room temperature and 120° C. for 2-15 hours.

Heterocycles of general formula (A4) and boronic acid derivatives of general formula (A5) are either commercially available or can be prepared according to procedures available from the public domain.

Primary amines of general formula (A7) can be obtained from monoprotected diamines of general formula (A6) via deprotection methods. Depending on the protective group applied these can be for example acidic, basic, oxidative or hydrogenation methods. Appropriate protective moieties for amino groups and their introduction and cleavage are well-known in the art. For an overview of protective group chemistry see for example Wuts 2014.

Final compounds of general formula (I-B) can be synthesized from primary amines of general formula (A7) via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination. Primary amines of general formula (A7) can be reacted with heteroaryls of general formula (A8) with X being a leaving group like halogen such as chlorine or —S(O)Me applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A8) are either commercially available or can be prepared according to procedures available from the public domain.

An alternative route to compounds of general formula (I-B) starts with deprotection of diamines of general formula (A3) to give primary amines of general formula (A9) as depicted in Scheme 1. For deprotection the same procedures apply as described for the synthesis of (A7) from (A6).

Primary amines of general formula (A9) in turn can be reacted with heteroaryls of general formula (A8) via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination to give aryl iodides of general formula (A10) applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

Final compounds of general formula (I-B) can be synthesized from aryl iodides of general formula (10) via copper catalyzed Ullmann couplings with heterocycles H-D (A4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (A5) applying procedures in analogy to those described for the synthesis of compounds (A6) from (A3) in Scheme 1.

Yet another approach to compounds of general formula (I-B) starts from monoprotected diamines (1) or their corresponding salts and preassembled heteroaryls (A11a) with X being a leaving group like halogen or —S(O)Me via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination to give arylated diamines of general formula (A6). The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A11a) are either commercially available or can be prepared according to procedures available from the public domain (for example via Chan-Lam coupling). Specific examples of (A11a) are described in the subsequent paragraphs.

An alternative route for the preparation of compounds of general formula (I-B) and intermediates of general formula (A10) is depicted in Scheme 2.

[Image Omitted]

Monoarylated diamines of general formula (A12) can be obtained via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A8) with X being a leaving group such as halogen or —S(O)Me. The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

Deprotection of diamines of general formula (A12) can give primary amines of general formula (A13). For deprotection the same procedures apply as described for the synthesis of (A7) from (A6) in Scheme 1.

Final compounds of general formula (I-B) in turn can be synthesized from primary amines (A13) or their corresponding salts and preassembled heteroaryls (A11a) with X being a leaving group like halogen or —S(O)Me via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination. The procedures that can be applied are in analogy to those described for the synthesis of (A6) from (A1) and (A11a) in Scheme 1.

For the synthesis of intermediates of general formula (A10) primary amines (A13) or their corresponding salts may be reacted with heteroaryls (A2a) with X being a leaving group like halogen or —S(O)Me in a nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination. The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

Carboxylic acid derivatives of general formula (A21) may be synthesized according to the route depicted in Scheme 3. Nitro compounds of general formula (A15) can be obtained from reacting monoprotected diamines (A1) or their corresponding salts and nitroaryls (A14) with X being a leaving group like chlorine in a nucleophilic aromatic substitution (S_NAr). The reaction can be carried out in the presence of inorganic bases like K₂CO₃in polar solvents such as for example DMSO at temperatures between room temperature and the boiling point of the solvent for 2-12 h. Nitroaryls of general formula (A14) are either commercially available or can be prepared according to procedures available from the public domain.

Anilines of general formula (A16) may be obtained from nitro compounds of general formula (A15) by reduction. For reduction all methods that are known in the art may be applied. For example, nitro compounds of general formula (A15) can be reacted in the presence of a metal catalyst like palladium on charcoal under an atmosphere of hydrogen gas (1-5 bar) in polar, protic solvents like methanol or ethanol at temperatures between 0° C. and the boiling point of the solvent for 15-24 h.

[Image Omitted]

Pyridones of general formula (A18) may be obtained from anilines (A16) by condensation with oxo-pyranes of general formula (A17) with Alk being methyl or ethyl in polar, protic solvents like ethanol at temperatures between room temperature and the boiling point of the solvent for 2-12 h. Oxo-pyranes of general formula (A17) are either commercially available or can be prepared according to procedures available from the public domain.

Primary amines of general formula (A19) may be synthesized from (A18) via removal of the protective group. For deprotection the same procedures apply as described for the synthesis of (A7) from (A6) in Scheme 1.

Carboxylic esters of general formula (A20) can be obtained from primary amines (A19) and heteroaryls (A8) via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

Carboxylic acid derivatives of general formula (A21) may be synthesized from carboxylic esters of general formula (A20) by ester hydrolysis. For saponification all methods that are known in the art may be applied. For example, esters (A20) may be reacted with bases like sodium hydroxide in polar, protic solvents like methanol, water or mixtures thereof at temperatures between 0° C. and the boiling point of the solvent for 0.5-2 h. 1,2,4-Triazines of general formula (A29) may be synthesized according to the routes depicted in Scheme 4. The methyl-thioether moiety of 3-(methylthio)-1,2,4-triazine (A22) [CAS 28735-21-9] might be activated for nucleophilic displacement by oxidation for which all methods that are known in the art may be applied. For example, (A22) can be reacted with mCPBA or Oxone® in inert solvents like dichloromethane at temperatures between 0° C. and the boiling point of the solvent for 0.5-2 h. The crude oxidation product may be directly converted to monoarylated diamines of general formula (A23) in a nucleophilic aromatic substitution (S_NAr) by reacting it with primary amines of general formula (A1) in polar solvents such as for example nBuOH at temperatures between room temperature and the boiling point of the solvent for 2-18 hours.

Aryl bromides of general formula (A24) can be obtained from triazines of general formula (A23) by bromination. For bromination all methods that are known in the art may be applied. For example, triazines (A23) can be reacted with bromine or N-bromosuccinimide (NBS) in solvents like methanol, water, DMF or mixtures thereof at temperatures between 0° C. and the boiling point of the solvent for 4-15 h.

3,6-Disubstituted triazines of general formula (A27) may be synthesized from aryl bromides (A24) via Suzuki coupling for which all methods that are known in the art may be applied. For example, (A24) may be reacted with potassium trifluoroborates (A25) or trioxatriborinanes (A26) in the presence of a palladium catalyst like CataCXium A Pd G3 [CAS 1651823-59-4] or 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] and a base like Cs₂CO₃, K₂CO₃or K₃PO₄in polar solvents such as 1,4-dioxane, THF and water or mixtures thereof at temperatures between room temperature and 120° C. for 8-15 hours. Trifluoroborates of general formula (A25) or trioxatriborinanes (A26) are either commercially available or can be prepared according to procedures available from the public domain.

[Image Omitted]

Primary amines of general formula (A28) may be obtained from (A27) via removal of the protective group. For deprotection the same procedures apply as described for the synthesis of (A7) from (A6) in Scheme 1.

Final compounds of general formula (A29) can be synthesized from primary amines (A28) or their corresponding salts and preassembled heteroaryls (All) with X being a leaving group like halogen via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination. The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

Heteroaryls of general formula (A11) are either commercially available or can be prepared according to procedures available from the public domain. Specific examples of (All) are described in the subsequent paragraphs.

In an alternative route to triazines of general formula (A29), primary amines (A28) or their corresponding salts may be first reacted with heteroaryls (A2) with X being a leaving group like halogen via nucleophilic aromatic substitution (S_NAr) or palladium catalyzed Buchwald-Hartwig amination to give aryl iodides of general formula (A30). The procedures that can be applied are in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

Heteroaryls of general formula (A2) are either commercially available or can be prepared according to procedures available from the public domain.

Final compounds of general formula (A29) can be synthesized from aryl iodides of general formula (A30) via copper catalyzed Ullmann couplings with heterocycles H-D (A4) or via palladium catalyzed Suzuki couplings with boronic acid derivatives (A5) applying procedures in analogy to those described for the synthesis of compounds (A6) from (A3) in Scheme 1.

In an alternative approach to 3,6-disubstituted triazines of general formula (A27), ketoacetals of general formula (A31) may be reacted with methyl hydrazinecarbimidothioate (A32) or its corresponding salts in polar solvents such as for example methanol at temperatures between room temperature and the boiling point of the solvent for 5-12 h to give triazine thioethers of general formula (A33) [for a similar approach to triazine thioethers see Duan 2012]. Ketoacetals of general formula (A31) and methyl hydrazinecarbimidothioate (A32) are either commercially available or can be prepared according to procedures available from the public domain.

Triazine thioethers of general formula (A33) in turn could be transferred to 3,6-disubstituted triazines of general formula (A27) by a two-step approach including oxidation of (A33) followed by nucleophilic aromatic substitution (S_NAr) with primary amines of general formula (A1) applying procedures in analogy to those described for the synthesis of compounds (A23) from (A22) in Scheme 4.

Carboxylic ester or amide derivatives of general formulae (A35) and (A37) may be synthesized according to the routes depicted in Scheme 5. Carboxylic esters of general formula (A35) may be obtained from primary amines (A7) [see Scheme 1] and triazines of general formula (A34) via nucleophilic aromatic substitution (S_NAr) applying procedures in analogy to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. For example, (A7) and (A34) can be reacted in the presence of an organic base like DIPEA in polar solvents such as NMP at temperatures between room temperature and the boiling point of the solvent for 0.5-2 h applying microwave heating. Triazines of general formula (A34) are either commercially available or can be prepared according to procedures available from the public domain.

Carboxamides of general formula (A37) can be obtained from carboxylic esters (A35) via direct amidation. For amidation reactions all methods that are known in the art may be applied. For example, esters (A35) can be reacted with amines (A36) in polar solvents such as methanol, ethanol or THE at temperatures between room temperature and the boiling point of the solvent for 1-5 hours. If an amine (A36) of limited nucleophilicity is used it is possible to increase the temperature and prolong the reaction time and/or to add Lewis acids like AIMe₃.

[Image Omitted]

Alternatively, esters (A35) may first be hydrolyzed to carboxylic acids of general formula (A38).

For saponification all methods that are known in the art may be applied. For example, esters (A35) may be reacted with bases like sodium hydroxide, lithium hydroxide or potassium hydroxide in polar, protic solvents like water or methanol or mixtures thereof at temperatures between 0 00 and the boiling point of the solvent for 0.5-24 hours. In certain cases it might be beneficial to add ethers like THE or 1,4-dioxane to the reaction mixture.

Carboxamides of general formula (A37) in turn can be obtained from carboxylic acids (A38) via amide coupling with appropriate amines (A36). For amide coupling all methods that are known from peptide chemistry in the art may be applied. For example, acids (A38) may be reacted with amines (A36) in polar, aprotic solvents like DMF, acetonitrile or NMP via an activated acid derivative. These activated derivatives can be obtained from acids (A38) with reagents such as HOBt, HOAt or N-hydroxysuccinimide and a carbodiimide such as DCC or EDC or else with preformed reagents like HATU, PyBOP or T3P®. In order to increase reactivity a suitable base such as DIPEA or triethylamine can be used. In certain cases, the activated acid derivative might be isolated prior to the reaction with the amine (A36). Amide formation might also be accomplished via the acid halide (which can be formed from a carboxylic acid by reaction with e.g. oxalyl chloride, thionyl chloride or sulfuryl chloride), mixed anhydride (which can be formed from a carboxylic acid by reaction with e.g. isobutylchloroformate), imidazolide (which can be formed from a carboxylic acid by reaction with e.g. CDI) or azide (which can be formed from a carboxylic acid by reaction with DPPA).

For the synthesis of final compounds of general formula (B-2) routes and methods comparable to the ones described in Schemes 1-5 may be applied. Without being intended to be limiting the routes to compounds of general formula (A43) in Schemes 6-7 are given for further illustration. Diamines of general formula (A39) are either commercially available or can be prepared according to procedures available from the public domain.

[Image Omitted]

[Image Omitted]

Further compounds with different formulae as described above can be prepared by similar methods.

EXPERIMENTAL SECTION

NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.

The following table lists the abbreviations used in this paragraph and in the examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

Abbreviations

- Aq Aqueous
- BINAP 2,2′-Bis(diphenylphosphaneyl)-1,1′-binaphthalene
- Boc tert-Butoxycarbonyl
- Brine Saturated aqueous sodium chloride solution
- nBuOH Butan-1-ol
- CataCXium A Di(adamantan-1-yl)(butyl)phosphane (CAS Registry Number 321921-71-5)
- CataCXium A Pd G3 Methanesulfonato(diadamantyl-n-butylphosphino)-2′-amino-1,1′ biphenyl-2-yl)palladium(II) precatalyst generation 3
- CDI 1,1′-Carbonyldiimidazole
- CHAPS 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate
- m-CPBA 3-Chlorobenzoperoxoic acid
- DavePhos 2′-(Dicyclohexylphosphaneyl)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (CAS Registry Number 213697-53-1)
- dba (all-trans)-Dibenzylideneacetone
- DCC Dicyclohexylcarbodiimide
- DCM Dichloromethane
- DEA Diethylamine
- DIPEA N-ethyl-N-isopropyl-propan-2-amine
- DMA N,N-Dimethylacetamide
- DME Dimethoxyethane
- DMF N,N-Dimethylformamide
- DMSO Dimethyl sulfoxide
- DPPA Diphenyl phosphorazidate
- dppf 1,1′-Bis(diphenylphosphino)ferrocene
- EDC 2-(((Ethylimino)methylene)amino)-N,N-dimethylethan-1-amine hydrochloride
- ESI Electrospray ionization
- EtOAc Ethyl acetate
- EtOH Ethanol
- FA Formic acid
- G3 Generation 3
- Gmean Geometric mean
- HATU (1-(Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxo hexafluorophosphate
- HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)
- HOAt 3H-[1,2,3]Triazolo[4,5-b]pyridin-3-ol
- HOBt 1H-Benzo[d][1,2,3]triazol-1-ol
- HPLC High performance liquid chromatography
- HRMS High resolution mass spectrometry
- i-PrOH Propan-2-ol
- IC₅₀Half maximal inhibitory concentration
- K_DDissociation constant
- MeCN Acetonitrile
- MeOH Methanol
- MS Mass spectrometry
- MTBD 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene
- MTBE Methyl tert-butyl ether
- MW Microwave
- NBS N-Bromosuccinimide
- NCS 1-Chloropyrrolidine-2,5-dione
- NIS 1-lodopyrrolidine-2,5-dione
- NMP 1-Methylpyrrolidin-2-one
- NMR Nuclear magnetic resonance
- O.n Overnight
- Otf Trifluoromethanesulfonate
- Pd-118/PdCl₂(dtbpf) [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)
- Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium (0)
- Pd₂(dba)₃-CHCl₃Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct
- Pd(dppf)Cl₂-DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
- CH₂Cl₂(1:1)
- PdCl₂(dppf) [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
- Pd-PEPPSI-IpentCl
- 2-methylpyridine (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (CAS Registry Number 1612891-29-8)
- PE Petroleum ether
- PG Protective group
- prep. Preparative
- PyBOP ((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate
- qToF Quadrupole time-of-flight
- RockPhos Di-tert-butyl(2′,4′,6′-triisopropyl-3-methoxy-6-methyl-[1,1′-biphenyl]-2-yl)phosphine
- rt Room temperature
- sat. Saturated
- SFC Supercritical fluid chromatography
- S_NAr Nucleophilic aromatic substitution
- T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
- TEA Triethylamine
- TFA Trifluoroacetic acid
- TFAA 2,2,2-Trifluoroacetic anhydride
- THE Tetrahydrofurane
- TLC Thin layer chromatography
- TMEDA N¹N¹,N²,N²-Tetramethylethane-1,2-diamine
- t_RRetention time
- UPLC Ultra high performance liquid chromatography
- XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)
- XPhos Dicyclohexyl(2 4′,6′-triisopropyl-[1,1′-biphenyl]-2-yi)phosphane

Units

- atm atmosphere
- C Celcius
- g gram
- h hour(s)
- Hz hertz
- L liter
- M mole per liter
- mg milligram
- MHz megahertz
- min minute(s)
- mL milliliter
- mm millimeter
- mM millimole per liter
- mol mole
- mmol millimole(s)
- nA nanoampere
- nL nanolitre
- μm micrometer
- μL microliter
- N equivalents per liter
- nm nanometer
- ppm parts per million
- Å Angstrom

The various embodiments described in this application are illustrated by the following examples which are not meant to limit the compound of Formula (I) in any way.

The example testing experiments described herein serve to illustrate the present embodiments and is not limited to the examples given.

Experimental Section—General Part
General Conditions

- (i) operations were carried out at room temperature (rt), i.e. in the range 17 to 28° C. and were needed under an atmosphere of an inert gas such as N₂;
- (ii) where reactions refer to being degassed or purged, this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g));
- (iii) where reactions refer to the use of a microwave reactor, one of the following microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator or CEM Explorer;
- (iv) in general, the course of reactions was followed by thin layer chromatography (TLC) and/or analytical high performance liquid chromatography (HPLC or UPLC) which was usually coupled to a mass spectrometer (LCMS);
- (v) to remove excess water, organic solutions were dried over anhydrous MgSO₄or Na₂SO₄, or by using ISOLUTE® Phase Separator, and work-up procedures were carried out using traditional phase separating techniques;
- (vi) evaporations were carried out either by rotary evaporation in vacuo or in a Genevac™ HT-4/EZ-2 or Biotage® V10;
- (vii) unless otherwise stated, flash column chromatography was performed on normal phase silica, using either Merck Silica Gel (Art. 9385) or pre-packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica, 4-330 g), Biotage® Sfar Silica HC D cartridges (20 μm, 10-100 g), Interchim puriFlash™ cartridges (25 μm, 4-120 g), Interchim puriFlash™ cartridges (50 μm, 25-330 g), Grace™ GraceResolv™ Silica Flash Cartridges (4-120 g) or Agela Flash Colum Silica-CS cartridges (80-330 g), or on reverse phase silica using Agela Technologies C-18, spherical cartridges (20-35 μm, 100 A, 80-330 g), manually or automated using a Grace Reveleris® X2 Flash system or similar system;
- (viii) preparative reversed phase HPLC and preparative reversed phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either a MS and/or UV triggered fraction collecting instrument, using either isocratic or a gradient of the mobile phase as described in the experimental section;
- relevant fractions were collected, combined and freeze-dried or evaporated to give the purified compound or relevant fractions were collected, combined and concentrated at reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried either over Na₂SO₄or by using a phase-separator, and then concentrated at reduced pressure to give the purified compound;
- (ix) chiral preparative chromatography was carried out using HPLC or SFC on a standard HPLC or SFC instrument, respectively, and using either isocratic or gradient run with mobile phase as described in the experimental section;
- (x) preparative thin layer chromatography (TLC) was performed using TLC glass plates and applying a suitable solvent or mixture of solvents;
- (xi) yields, where present, are not necessarily the maximum attainable, and some, reactions were repeated if a larger amount of the reaction product was required;
- (xii) where certain compounds were obtained as an acid-addition salt, for example a mono-hydrochloride salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data. Where stated the salts were treated according to literature-known processes to generate the corresponding free base prior to being used;
- (xiii) in general, the structures of the end-products of the Formula (I) were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at ¹H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25° C. Chemical shifts are given in ppm with the solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. In certain instances, protons can be masked or partially masked by solvent peaks and will therefore either be missing and not reported or reported as multiplets overlapping with solvent. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; high resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported;
- (xiv) intermediates were in certain cases not fully purified but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis and/or mass spectrometry;
- (xv) certain intermediates were isolated as TFA salts and can contain excess TFA. The excess can be calculated from the weight of the crude sample. Where stated the salts were treated according to literature-known processes to generate the corresponding free base prior to being used;
- (xvi) unless stated otherwise compounds containing an asymmetric carbon and/or sulfur atom were not resolved;
- (xvii) in general Examples and Intermediate compounds are named using ChemDraw Professional version 21.0.0.28 from PerkinElmer. ChemDraw Professional version 21.0.0.28 generates the names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules.

Where applicable ChemDraw is using labels in the graphical representation of stereocenters such as ‘&’ and ‘or’ to describe the configuration of the stereochemical centers present in the structure. A number following the ‘&’ and ‘or’ flag is assigned to each stereocenter present.

In some cases, the purification methods as described above can provide those compounds of Formula (I) which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of Formula (I) which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of Formula (I) which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known in the art or be used as salt in subsequent biological assays. It is to be understood the specific form (e.g. salt, free base etc.) of a compound of Formula (I) as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

Purification Methods
Preparative HPLC Methods:

- PrepMethod A: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeOH in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod B: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod C: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod D: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod E: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/FA (0.1%) buffer system as mobile phase;
- PrepMethod F: The compound was purified by preparative HPLC on a Xbridge™ C18 column (10 μm, 250×50 mm ID) using a gradient of MeCN in H₂O/MeCN/NH₃(95/5/0.2) buffer system as mobile phase;
- PrepMethod G: The compound was purified by preparative HPLC on a Kromasil C₈column (10 μm, 250×20 mm ID) using a gradient of MeCN in H₂O/MeCN/FA (95/5/0.2) buffer system as mobile phase;
- PrepMethod H: The compound was purified by preparative HPLC on a Xbridge™ C18 column (10 μm, 250×19 mm ID) using a gradient of MeCN in H₂O/MeCN/NH₃(95/5/0.2) buffer system as mobile phase;
- PrepMethod I: The compound was purified by preparative HPLC on a Xbridge™ C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM, pH 9) buffer system as mobile phase;
- PrepMethod J: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/FA (0.1%) as mobile phase;
- PrepMethod K: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod L: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod M: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod N: The compound was purified by preparative HPLC on a Xbridge™ OBD Phenyl column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod 0: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod P: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O as mobile phase;
- PrepMethod Q: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod R: The compound was purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/FA (10 mM) as mobile phase;
- PrepMethod S: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM) buffer system as mobile phase;
- PrepMethod T: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 150×30 mm ID) using a gradient of 20 mM NaOH+10% MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod U: The compound was purified by preparative HPLC on a Xbridge™ OBD Phenyl column (5 μm, 250×19 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod V: The compound was purified by preparative HPLC on a Xbridge™ OBD Phenyl column (5 μm, 250×19 mm ID) using a gradient of MeCN in a H₂O/TFA (0.05%) buffer system as mobile phase;
- PrepMethod X: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod Y: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod Z: The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H₂O/FA (0.1%) buffer system as mobile phase;
- PrepMethod Z1: The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod Z2: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod Z3: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod Z4: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN in a H₂O/TFA (0.005%) buffer system as mobile phase;
- PrepMethod Z5: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeOH in a H₂O/NH₄HCO₃(10 mM)/NH₃(0.05%, aq) buffer system as mobile phase;
- PrepMethod Z6: The compound was purified by preparative HPLC on a Xbridge™ Shield RP18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod Z7: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 100×50 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase;
- PrepMethod Z8: The compound was purified by preparative HPLC on a Xbridge™ RP18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in H₂O/NH₄HCO₃(10 mM)/NH₃(0.1%, aq) buffer system as mobile phase.

PrepMethod Z9: The compound was purified by preparative HPLC on a Xbridge™ 08 column (5 μm, 250×20 mm ID) using a gradient of MeCN in H₂O/MeCN/NH₃(95/5/0.2) buffer system as mobile phase;

- PrepMethod Z10: The compound was purified by preparative HPLC on a Xbridge™ 08 column (5 μm, 250×50 mm ID) using a gradient of MeCN in H₂O/MeCN/NH₃(95/5/0.2) buffer system as mobile phase.

Preparative SFC Methods:

- PrepMethod SFC-A: The compound was purified by preparative SFC on a Waters™ BEH (5 μm, 250×30 mm ID) using MeOH/H₂O (NH₃, 50 mM) (97/3) in CO₂as mobile phase;
- PrepMethod SFC-B: The compound was purified by preparative SFC on a Phenomenex Luna Hilic (3.5 μm, 100×3 mm ID) using MeOH/NH₃20 mM in CO₂as mobile phase;
- PrepMethod SFC-C: The compound was purified by preparative SFC on a Waters™ Acquity UPC2 BEH (3.5 μm, 100×3 mm ID) using MeOH/H₂O (NH₃, 50 mM) (97/3) in CO₂as mobile phase;
- PrepMethod SFC-D: The compound was purified by preparative SFC on a Waters™ BEH (5 μm, 250×30 mm ID) using MeOH/NH₃(20 mM) in CO₂as mobile phase;
- PrepMethod SFC-E: The compound was purified by preparative SFC on a Phenomenex Luna Hilic (5 μm, 250×30 mm ID) using MeOH/NH₃20 mM in CO₂as mobile phase.

Preparative HPLC Methods for Parallel Experiment Set-Up:

- PrepMethod Parallel A: The compound was purified by preparative HPLC on a Waters™ Xbridge™ C18 column (5 μm, 100×10 mm ID) using a gradient (2-94%) of MeCN in H₂O/NH₃(pH 10) buffer system as mobile phase;
- PrepMethod Parallel B: The compound was purified by preparative HPLC on a Waters™ Xselect™ CSH Fluoro Phenyl column (5 μm, 100×10 mm ID) using a gradient (2-94%) of MeCN in H₂O/FA (pH 3) buffer system as mobile phase;
- PrepMethod Parallel C: The compound was purified by preparative HPLC on a Waters™ Xbridge™ C18 OBD column (5 μm, 150×19 mm ID) using a gradient (5-95%) of MeCN in H₂O/MeCN/NH₃(95/5/0.2) (pH 10) buffer system as mobile phase;
- PrepMethod Parallel D: The compound was purified by preparative HPLC on a Xbridge™ C18 OBD column (5 μm, 150×19 mm ID) using a gradient (5-95%) of MeCN in a H₂O/NH₄HCO₃(10 mM) (pH 9) buffer system as mobile phase.

Synthesis Methods
General Method 1 (GM1): Nucleophilic Aromatic Substitution (S_NAr)
Condition a (GM1A): Conventional Heating

To a solution of the respective amine nucleophile or its salt (1 eq.) in DMSO (alternatively NMP or n-BuOH or 1,4-dioxane) is added base (1-7 eq.) and the respective heteroaryl electrophile (0.9-2 eq.) at rt and the resulting mixture stirred under heating (100-130° C.) until TLC and/or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is either concentrated under reduced pressure and the obtained crude material subjected to chromatography or prep. TLC and/or prep. HPLC to give the desired aniline product.

In an alternative aqueous work-up, the reaction mixture is poured into sat. brine or water and extracted with EtOAc. The combined organic layers are washed with water or brine, dried over Na₂SO₄, filtered and evaporated and the obtained crude material subjected to chromatography on silica to give the desired aniline product.

Condition B (GM1B): Microwave Heating

To a mixture of the respective amine nucleophile or its salt (1 eq.) and the respective heteroaryl electrophile (1-1.5 eq.) in a microwave vial is added NMP and base (1-3 eq.), the vial capped and heated under microwave radiation until TLC and/or LCMS indicate consumption of the starting material (typically 0.5-2 h). The reaction mixture is concentrated under reduced pressure and the obtained crude material subjected to prep. HPLC to give the desired aniline product.

General Method 2 (GM2): Buchwald-Hartwiq Amination

A solution of the respective amine nucleophile or its salt (1 eq.) in 1,4-dioxane under nitrogen at rt is treated with the respective heteroaryl electrophile (0.5-4 eq.), Cs₂CO₃(1.2-5 eq.) and Pd PEPPSI-IpentCl [CAS 1612891-29-8] (3-7 mol %) and the reaction mixture stirred under heating (100° C.) until TLC and/or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is either filtered through a pad of Celite or silica, the filter cake washed with EtOAc and the combined filtrates concentrated under reduced pressure. The obtained crude material is either triturated with PE/EtOAc or subjected to prep. TLC and/or prep. HPLC to give the desired aniline product.

In an alternative aqueous work-up, the reaction mixture is concentrated under reduced pressure and the residue partitioned between EtOAc and water. The phases are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with water and/or brine, dried over Na₂SO₄, filtered and evaporated and the obtained crude material subjected to prep. TLC and/or prep. HPLC to give the desired aniline product.

General Method 3 (GM3): Ullmann Coupling

A solution of the respective aryl halide (1 eq.) in 1,4-dioxane under nitrogen at rt is treated with the respective heteroatom nucleophile H-D (A4) (1-10 eq.), Cs₂CO₃(3-6 eq.), Cu(I)I (0.2-2 eq.) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine [CAS 67579-81-1] (0.2-2 eq.) and the reaction mixture stirred under heating (80-100° C.) until TLC and/or LCMS indicate complete consumption of the starting material (typically 15-18). The reaction mixture is diluted with EtOAc and washed sequentially with water and brine. Alternatively, the reaction mixture is diluted with water or brine and the aqueous layer extracted with EtOAc. The organic layer is dried over Na₂SO₄, filtered and evaporated. The obtained crude material is either triturated with PE/EtOAc or subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.

In an alternative non-aqueous work-up, the reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and the combined filtrates concentrated under reduced pressure. The obtained crude material is subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.

General Method 4 (GM4): Suzuki Coupling

Condition a (GM4A): Coupling with Boronic Acid Derivatives

A solution of the respective aryl halide (1 eq.) in a mixture of 1,4-dioxane and water under nitrogen at rt is treated with the respective boronic acid derivative (A5) (1.5-2 eq.) or (A26) (10 eq.), Cs₂CO₃(3 eq.) or K₂CO₃(3 eq.) or K₃PO₄(2-3 eq.) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS 95408-45-0] (5-10 mol %) or 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride [CAS 72287-26-4] (10 mol %) and the reaction mixture stirred under heating (80-100° C.) until TLC and/or LCMS indicate complete consumption of the starting material (2-18). The reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and the combined filtrates concentrated under reduced pressure. The obtained crude material is subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.

In an alternative aqueous work-up, the reaction mixture is diluted with water, the phases separated and the aqueous phase extracted with EtOAc. The combined organic layers are dried over Na₂SO₄, filtered and evaporated and the obtained crude material subjected to prep. TLC and/or C18-flash chromatography or prep. HPLC to give the desired coupling product.

Condition B (GM4B): Coupling with Trifluoroborates

A solution of the respective aryl halide (1 eq.) in 1,4-dioxane under nitrogen at rt is treated with the respective potassium trifluoroborate (A25) (4 eq.), Cs₂CO₃(4 eq.) and CataCXium A Pd G3 [CAS 1651823-59-4] (20 mol %) and the reaction mixture stirred under heating (100° C.) until TLC and/or LCMS indicate complete consumption of the starting material (typically 15). The reaction mixture is filtered through a pad of Celite, the filter cake washed with DCM and the combined filtrates concentrated under reduced pressure. The obtained crude material is subjected to prep. TLC and/or prep. HPLC to give the desired coupling product.

General Method 5 (GM5): Chan-Lam Coupling

A mixture of the respective heteroatom nucleophile H-D (A4) (1 eq.) in 1,4-dioxane at rt is treated with the respective boronic acid (2-3 eq.), TMEDA (3 eq.) and Cu(Otf)₂(1.2-2 eq.) and the reaction mixture stirred under heating (100° C.) until TLC and/or LCMS indicate complete consumption of the starting material (typically 16). The reaction mixture is filtered through a pad of Celite, the filtrate concentrated under reduced pressure and the residue partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc, the combined organic layers washed with water, dried over Na₂SO₄, filtered and evaporated. The obtained crude material is subjected to C18-flash chromatography to give the desired coupling product.

General Method 6 (GM6): Boc Deprotection

Condition A (GM6A): Deprotection with HCl

A solution of the respective Boc protected amine (1 eq.) in MeOH at rt is treated with 4 M HCl in MeOH (13-77 eq.) and the reaction mixture stirred under heating (60-80° C.) until TLC and/or LCMS indicate complete consumption of the starting material (typically 2-3). The reaction mixture is concentrated under reduced pressure to give the desired amine as (an unspecified) HCl salt.

Condition B (GM6B): Deprotection with TFA

A solution of the respective Boc protected amine (1 eq.) in DCM at rt is treated with TFA (11-190 eq.) and the reaction mixture stirred at rt until TLC and/or LCMS indicate complete consumption of the starting material (3-16). The reaction mixture is concentrated under reduced pressure to give the desired amine as (an unspecified) TFA salt.

General Method 7 (GM7): Amide Formation

In a microwave vial a solution of the respective ester (A35) in MeOH is treated with the respective amine or its salt (A36) (4-100 eq., neat or as a solution in THF) and where applicable additionally with DIPEA (4-8 eq.) at rt. The vial is capped, and the reaction mixture stirred at rt or heating (60-70° C.) until TLC and/or LCMS indicate complete consumption of the starting material (3). The reaction mixture is concentrated under reduced pressure and the obtained crude material subjected to preparative HPLC to give the desired amide.

General Method 8 (GM8): Methyl-thioether Oxidation

A solution of the methyl-thioether (1 eq.) in DCM is cooled to 0° C. and treated slowly with 3-chlorobenzoperoxoic acid (m-CPBA) [CAS 937-14-41 (0.9-1.2 eq.) and the resulting mixture stirred at rt until TLC and/or LCMS indicate complete consumption of the starting material (0.5-2). The reaction mixture is directly used in the next step.

Alternatively, the reaction mixture is concentrated under reduced pressure and the obtained crude material is subjected to flash chromatography on silica to give the desired oxidation product.

INTERMEDIATES
Intermediate 1
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one
Step A. i-1a
tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate

[Image Omitted]

According to GM1A 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (2.23 g, 9.99 mmol) was added to tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (2.00 g, 9.99 mmol) and K₂CO₃(2.76 g, 20 mmol) in DMSO (30 mL). The resulting solution was stirred at 125° C. for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-50% EtOAc in PE) to give the title compound (2.70 g, 67%) as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 403.9.

Step B. i-1b
tert-Butyl ((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate

[Image Omitted]

In a slight modification of GM3 rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (CAS Reg. No. 67579-81-1) (0.212 g, 1.49 mmol) and Cu(I)I (0.283 g, 1.49 mmol) were added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (3.0 g, 7.44 mmol), K₂CO₃(3.08 g, 22.3 mmol) and pyridin-2(1H)-one (CAS Reg. No. 142-08-5) (1.42 g, 14.9 mmol) in 1,4-dioxane (20 mL). The resulting solution was stirred at 110° C. for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with water (3×25 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated. The crude material was triturated with EtOAc:PE (5:1) to give a solid which was collected by filtration and dried under vacuum to give the title compound (2.70 g, 98%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 371.2.

Step C. i-1c
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

In a modification of GM6A HCl (2 M in diethyl ether, 27 mL, 54 mmol) was added slowly to tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-1b (1.0 g, 2.70 mmol) in DCM (10 mL) at 25° C. The resulting mixture was stirred at 25° C. for 3 h. This synthesis procedure was repeated for a second batch of tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-1b (1.7 g, 4.6 mmol). The two batches were combined and concentrated. The crude product was recrystallised with EtOAc:PE (5:1) to give a solid which was collected by filtration and dried under vacuum to give an unspecified HCl salt of the title compound (2.5 g, 100%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 270.9.

Intermediate 3
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methoxy-2H-[1,3′-bipyridin]-2-one×2 HCl
Step A. i-3a
tert-Butyl ((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate

[Image Omitted]

According to GM3 tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (500 mg, 1.24 mmol), 3-methoxypyridin-2(1H)-one (CAS Reg. No. 20928-63-6) (776 mg, 6.20 mmol), rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (176 mg, 1.24 mmol), Cs₂CO₃(2020 mg, 6.20 mmol) and Cu(I)I (236 mg, 1.24 mmol) were reacted in 1,4-dioxane (5 mL) at 100° C. for 15 h to give after aqueous work-up and preparative TLC (MeOH:DCM=1:20) the title compound (387 mg, 78%) as a brown solid. MS (ESI): m/z [M+H]⁺ 401.3.

Step B. i-3b
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methoxy-2H-[1,3′-bipyridin]-2-one×2 HCl

[Image Omitted]

According to GM6A3 tert-butyl ((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-3a (370 mg, 0.92 mmol) was reacted with 4 M HCl in MeOH (10 mL, 40 mmol) in MeOH (15 mL) at 60° C. for 2 h to give the crude title compound (340 mg, 99%) as a brown solid. MS (ESI): m/z [M+H]⁺ 301.1.

Intermediate 6
i-6a
1-(6-Chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[Image Omitted]

According to GM5 (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (1.29 g, 8.21 mmol), 1,8-naphthyridin-2(1H)-one (CAS Reg. No. 15936-09-1) (600 mg, 4.11 mmol), N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (1431 mg, 12.32 mmol) and Cu(Otf)₂(1782 mg, 4.93 mmol) were reacted in 1,4-dioxane (10 mL) at 100° C. for 16 h to give upon purification by C18-flash chromatography (gradient: 5-43% MeCN in water+0.1% NH₃(aq)) the title compound (252 mg, 23%) as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 257.9.

Intermediate 7
3-(6-Chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione
Step A. i-7a
4-Nitrophenyl (6-chloropyridin-3-yl)carbamate

[Image Omitted]

4-Nitrophenyl carbonochloridate (CAS Reg. No. 7693-46-1) (1.73 g, 8.56 mmol) was added to 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (1.0 g, 7.8 mmol) in MeCN (20 mL) at 20° C. and the resulting solution stirred at this temperature for 30 min. The reaction mixture was diluted with MeCN (200 mL), filtered through an organic phase filter and evaporated to give the crude title compound (2.18 g, 96%) as a purple solid. MS (ESI): m/z [M+H]⁺ 293.9.

Step B. i-7b
3-(6-Chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione

[Image Omitted]

DIPEA (3.90 mL, 22.3 mmol) was added to methyl methylglycinate HCl (CAS Reg. No. 13515-93-0) (1.04 g, 7.44 mmol) in MeCN (20 mL) at 20° C. The resulting suspension was stirred at 20° C. for 15 min upon which 4-nitrophenyl (6-chloropyridin-3-yl)carbamate compound i-7a (2.18 g, 7.44 mmol) was added and stirring at 20° C. continued for 10 min. The mixture was concentrated under reduced pressure and the obtained crude material purified by flash chromatography on silica (gradient: 65-70% EtOAc in PE) to give the title compound (1.55 g, 92%) as a white solid. MS (ESI): m/z [M+H]⁺ 225.8.

Intermediate 8
6′-Chloro-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile
Step A. i-8a
Methyl 6′-chloro-2-oxo-2H-[1,3′-bipyridine]-5-carboxylate

[Image Omitted]

6-Chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (1.0 g, 7.8 mmol) was added to a solution of methyl 2-oxo-2H-pyran-5-carboxylate (CAS Reg. No. 6018-41-3) (1.2 g, 7.8 mmol) in EtOH (20 mL) at 15° C. and it was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOH (20 mL), filtered through an organic phase filter and evaporated to give the crude title compound (1.53 g, 74%) as a purple solid. MS (ESI): m/z [M+H]⁺ 265.2.

Step B. i-8b
6′-Chloro-2-oxo-2H-[1,3′-bipyridine]-5-carboxylic acid

[Image Omitted]

Methyl 6′-chloro-2-oxo-2H-[1,3′-bipyridine]-5-carboxylate compound i-8a (300 mg, 1.13 mmol) was added to NaOH (91 mg, 2.3 mmol) in a mixture of THE (8 mL) and water (2 mL) at 20° C. and the resulting solution stirred at 20° C. for 15 h. The reaction mixture was concentrated und reduced pressure, the residue diluted with water (5 mL) and the pH adjusted to pH<7 with 1 M HCl. The mixture was further diluted with water (100 mL) and extracted with EtOAc (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated to give crude title compound (230 mg, 81%) as a white solid. MS (ESI): m/z [M+H]⁺ 251.

Step C. i-8c
6′-Chloro-2-oxo-2H-[1,3′-bipyridine]-5-carboxamide

[Image Omitted]

6′-Chloro-2-oxo-2H-[1,3′-bipyridine]-5-carboxylic acid compound i-8b (160 mg, 0.64 mmol) was added to HATU (485 mg, 1.28 mmol), TEA (0.712 mL, 5.11 mmol) and NH₄Cl (137 mg, 2.55 mmol) in DMF (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. for 3 h, subsequently cooled to rt, quenched with sat brine (100 mL) and extracted with EtOAc (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the obtained residue purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (130 mg, 82%) as a white solid. MS (ESI): m/z [M+H]⁺ 250.

Step D. i-8d
6′-Chloro-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile

[Image Omitted]

6′-Chloro-2-oxo-2H-[1,3′-bipyridine]-5-carboxamide compound i-8c (700 mg, 2.80 mmol) was added to a solution of pyridine (0.68 mL, 8.4 mmol) in DCM (10 mL). TFAA (1.19 mL, 8.41 mmol) was slowly added to the mixture at 0° C. and it was stirred at 20° C. for 1 h. The synthesis procedure was repeated with a second batch of 6′-chloro-2-oxo-2H-[1,3′-bipyridine]-5-carboxamide compound i-8c (100 mg, 0.40 mmol). The two batches were combined, concentrated under reduced pressure and purified by preparative TLC (EtOAc:PE=3:1) to give the title compound (540 mg, 72%) as a white solid. MS (ESI): m/z [M+H]⁺ 232.1.

Intermediate 9
3-(Trifluoromethoxy)pyridin-2-ol
Step A. i-9a
2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine

[Image Omitted]

KotBu (682 mg, 6.07 mmol) was added to (4-methoxyphenyl)methanol (CAS Reg. No. 105-13-5) (629 mg, 4.56 mmol) in 1,4-dioxane (2 mL) at 20° C. and it was stirred at 20° C. for 2 h. 2-Chloro-3-(trifluoromethoxy)pyridine (CAS Reg. No. 1206980-39-3) (600 mg, 3.04 mmol) was added to the reaction mixture and the resulting suspension was stirred at 100° C. for 15 h. The reaction mixture was poured into sat. brine (125 mL) and extracted with EtOAc (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the obtained residue was purified by preparative TLC (EtOAc:PE=1:5) to give the title compound (600 mg, 66%) as a pale yellow liquid. MS (ESI): m/z [M+H]⁺ 300.0.

Step B. i-9b
3-(Trifluoromethoxy)pyridin-2-ol

[Image Omitted]

2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine compound i-9a (500 mg, 1.67 mmol) was added to TFA (10 mL) at 25° C., it was warmed to 60° C. and the resulting solution stirred at this temperature for 15 h. The solvent was removed under reduced pressure and the obtained residue purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (150 mg, 50%) as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 180.0.

Intermediate 10
i-10a
6′-Chloro-2-oxo-2H-[1,3′-bipyridine]-3-carbonitrile

[Image Omitted]

In a variation of GM5 pyridine (0.81 mL, 10 mmol) was added to a mixture of 2-oxo-1,2-dihydropyridine-3-carbonitrile (CAS Reg. No. 20577-27-9) (600 mg, 5.00 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (1.57 g, 10 mmol), Cu(Oac)₂(1.82 g, 10 mmol) and 5A molecular sieves (500 mg, dried 24 h at 200° C.) in DCM (100 mL) and DMF (15 mL) at 25° C. Air was allowed to diffuse into the reaction mixture via a CaCl₂tube. The resulting mixture was stirred at 25° C. for 15 h and subsequently filtered through Celite. The filter cake was washed with DCM (3×10 mL), the combined filtrates concentrated under reduced pressure and the residue partitioned between EtOAc (400 mL) and water (150 mL). The aqueous layer was extracted with EtOAc (5×200 mL), the combined organic layers were washed with sat. brine (5×100 mL), dried over Na₂SO₄, filtered and evaporated. The dry solid was triturated with DMF (3×5 mL), the solid filtered off and the filter cake washed with MTBE (3×5 mL). The solid was dried under vacuum to give the title compound (105 mg, 9%) as a grey solid. MS (ESI): m/z [M+H]⁺ 232.1.

Intermediate 11
i-11a
2-(5-Bromopyrazin-2-yl)pyridazin-3(2H)-one

[Image Omitted]

In a slight variation of GM3 2-bromo-5-iodopyrazine (CAS Reg. No. 622392-04-5) (1.00 g, 3.51 mmol), pyridazin-3(2H)-one (CAS Reg. No. 504-30-3) (0.337 g, 3.51 mmol), Cs₂CO₃(2.287 g, 7.02 mmol), Cu(I)I (0.669 g, 3.51 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (0.499 g, 3.51 mmol) were reacted in 1,4-dioxane (25 mL) at 60° C. for 1 h to give upon non-aqueous work-up followed by preparative TLC (EtOAc:PE=1:1) the title compound (300 mg, 33%) as a white solid. The product contained the corresponding iodo compound as well. MS (ESI): m/z [M+H]⁺ 252.9.

Intermediate 12
i-12a
6′-Chloro-1-methyl-[3,3′-bipyridin]-2 (1H)-one

[Image Omitted]

According to GM4A (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (301 mg, 1.91 mmol), 3-bromo-1-methylpyridin-2(1H)-one (81971-38-2) (200 mg, 1.06 mmol), Cs₂CO₃(1.04 g, 3.19 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (34.7 mg, 0.05 mmol) were reacted in a mixture of 1,4-dioxane (12 mL) and water (3 mL) at 80° C. for 15 h to give upon non-aqueous work-up followed by preparative TLC (100% EtOAc) the title compound (230 mg, 98%) as a light yellow solid. MS (ESI): m/z [M+H]⁺ 221.0.

Intermediate 13
i-13a
3-Chloro-6′-fluoro-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

In a slight variation of GM3 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (560 mg, 2.51 mmol), 3-chloropyridin-2(1H-one (CAS Reg. No. 13466-35-8) (651 mg, 5.02 mmol), potassium phosphate, tribasic (1.60 g, 7.53 mmol), Cu(I)I (478 mg, 2.51 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (357 mg, 2.51 mmol) were reacted in 1,4-dioxane (60 mL) at 100° C. for 18 h. The reaction mixture was poured into sat. brine (350 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3×250 mL), the organic layer dried over Na₂SO₄, filtered and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-30% EtOAc in PE) to give the title compound (258 mg, 45%) as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 224.9.

Intermediate 14
i-14a
6′-Chloro-3-fluoro-[2,3′-bipyridine]-6-carbonitrile

[Image Omitted]

According to GM4A, 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (49 mg, 0.07 mmol) was added to 6-bromo-5-fluoropicolinonitrile (CAS Reg. No. 1416713-45-5) (300 mg, 1.49 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (352 mg, 2.24 mmol) and K₃PO₄(950 mg, 4.48 mmol) in water (2 mL) and 1,4-dioxane (8 mL). The resulting solution was stirred at 100° C. for 2 h. Aqueous work-up and purification by preparative TLC (EtOAc:PE=2:1) gave the title compound (214 mg, 61%) as a white solid; MS (ESI) m/z [M+H]⁺=234.0.

Intermediate 17
(1S,3S)—N¹-(5-Chloropyrazin-2-yl)-N¹-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine
Step A. i-17a
(1S,3S)—N¹-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine×3 HCl

[Image Omitted]

According to GM6A tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (Intermediate 1, Step A) (1.29 g, 3.19 mmol) was reacted with HCl in MeOH (4 M, 10 mL, 40 mmol) in MeOH (20 mL) at 80° C. for 2 h to afford the title compound (1.27 g, 96%) as a beige solid. MS (ESI): m/z [M+H]⁺ 303.90.

Step B. i-17b
(1S,3S)—N¹-(5-Chloropyrazin-2-yl)-N¹-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[Image Omitted]

According to GM1A (1S,3S)—N-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-17a (1.26 g, 3.05 mmol), 2,5-dichloropyrazine (CAS Reg. No. 19745-07-4) (0.910 g, 6.11 mmol) and Na₂CO₃(1.62 g, 15.3 mmol) were reacted in DMSO (25 mL) at 120° C. for 15 h. The mixture was filtered through a Celite pad and the filtrate purified by flash C18-flash chromatography (gradient: 10-61% MeCN in water, containing 0.1% NH₃, aq) to give the title compound (0.78 g, 61%) as a beige solid. MS (ESI): m/z [M+H]⁺ 415.90.

Intermediate 21
1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one
Step A. i-21a
1-(6-Chloropyridin-3-yl)quinolin-2(1H)-one

[Image Omitted]

According to GM5 quinolin-2(1H-one (CAS Reg. No. (59-31-4) (500 mg, 3.44 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. (444120-91-6) (1.63 g, 10.3 mmol), Cu(Otf)₂(2.49 g, 6.89 mmol) and N,N,N′,N′tetramethylethylenediamine (1.20 g, 10.3 mmol) were reacted in 1,4-dioxane (20 mL) at 100° C. for 16 h to give upon purification by C18-flash chromatography (gradient: 5-46% MeCN in water, containing 0.1% NH₃, aq) 1-(6-chloropyridin-3-yl)quinolin-2(1H-one (211 mg, 24%) as a green solid. MS (ESI): m/z [M+H]⁺ 256.95.

Step B. i-21b
tert-Butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[Image Omitted]

According to GM2 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one compound i-21a (90 mg, 0.35 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (211 mg, 1.05 mmol), Cs₂CO₃(571 mg, 1.75 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (29.5 mg, 0.04 mmol) were reacted in 1,4-dioxane (10 mL) at 100° C. for 15 h to give upon aqueous work-up and purification by preparative TLC (MeOH:DCM=1:40) tert-butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate (122 mg, 83%) as a white solid. MS (ESI): m/z [M+H]⁺ 421.00.

Step C. i-21c
1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[Image Omitted]

According to GM6A tert-butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate compound i-21b (110 mg, 0.26 mmol) was reacted with HCl in methanol (4 M, 5.0 mL, 20 mmol) in MeOH (10 mL) at 80° C. for 2 h to afford an unspecified HCl salt of 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H-one (90 mg, 96%) as a brown gum. MS (ESI): m/z [M+H]⁺ 321.00.

Intermediate 22
(1S,3S)—N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)-NM-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine
Step A. i-22a
tert-Butyl ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

m-CPBA (5.60 g, 25.95 mmol) was added in small portions to a solution of 3-(methylthio)-1,2,4-triazine (CAS Reg. No. 28735-21-9) (3.0 g, 23.6 mmol) in DCM (80 mL) at 0° C. and the resulting suspension was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure without heating, the residue dissolved in n-butanol (40 mL) and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (5.20 g, 26.0 mmol) was added and the resulting solution was stirred at 120° C. for 18 h. The reaction mixture was poured into 1 M NaOH (250 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford the crude product as a brown solid which was purified by flash chromatography on silica (gradient: 5-60% EtOAc in PE) to give (3.7 g, 56%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 280.

Step B. i-22b
tert-Butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

A solution of Br₂in DCM (1 M, 15.9 mL, 15.9 mmol) was added dropwise to a solution of tert-butyl ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22a (3.7 g, 13.2 mmol) in a mixture of MeOH (60 mL) and water (30 mL) and the mixture was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was poured into sat. Na₂SO₃(aq) (150 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford the crude product as brown solid which was purified by flash chromatography on silica (gradient: 5-30% EtOAc in PE) to give (3.5 g, 74%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 358.

Step C. i-22c
tert-Butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

According to GM4B tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (1.5 g, 4.2 mmol), potassium cyclopropyltrifluoroborate (2.48 g, 16.8 mmol), Cs₂CO₃(5.46 g, 16.8 mmol) and CataCXium A Pd G3 (CAS Reg. No. 1651823-59-4) (0.61 g, 0.84 mmol) were reacted in dioxane (70 mL) at 100° C. for 15 h. Upon combination with a second batch (prepared in the same manner, 1.12 mmol scale) the material was purified by preparative TLC (EtOAc:PE=1:3) to afford (1.12 g, 66%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 320.

Step D. i-22d
(1S,3S)—N′-(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine×4 TFA

[Image Omitted]

According to GM6B tert-butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22c (500 mg, 1.57 mmol) was reacted with TFA (5.0 mL, 65 mmol) in DCM (20 mL) at rt for 15 h to give (940 mg, 89%) of the title compound as a yellow gum (contains 4 mol eq of residual TFA). MS (ESI): m/z [M+H]⁺ 220.

Step E. i-22e
(1S,3S)—N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)-NM-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[Image Omitted]

According to GM1A (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4TFA compound i-22d (880 mg, 1.30 mmol), 2-fluoro-5-iodopyridine (436 mg, 1.95 mmol) and K₂CO₃(900 mg, 6.51 mmol) were reacted in DMSO (10 mL) at 120° C. for 15 h to give upon aqueous work-up and purification by preparative TLC (EtOAc:PE=3:1) the title compound (369 mg, 67%) as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 423.

Intermediate 23
i-23a
1-(6-Chloropyridin-3-yl)-3-methylimidazolidine-2,4-dione

[Image Omitted]

CuI (0.230 g, 1.57 mmol) was added to a mixture of 2-chloro-5-iodopyridine (CAS Reg. No. 69045-79-0) (0.50 g, 2.09 mmol), 3-methylimidazolidine-2,4-dione (CAS Reg. No. 6843-45-4) (0.48 g, 4.18 mmol), N,N-dimethylglycine hydrochloride (0.22 g, 1.57 mmol) and Cs₂CO₃(1.36 g, 4.18 mmol) in dioxane (20 mL) and the resulting suspension was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was poured into brine (125 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford the crude product as yellow gum which was purified by preparative TLC (EtOAc:PE=1:1) to give (0.25 g, 53%) of the title compound as a pale yellow oil which solidified on standing. MS (ESI): m/z [M+H]⁺ 226.

Intermediate 24
i-24a
3-(6-Chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[Image Omitted]

According to GM5 (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (2.93 g, 18.6 mmol), 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (CAS Reg. No. 50339-06-5) (1.11 g, 7.44 mmol), Cu(Otf)₂(4.04 g, 11.2 mmol) and TMEDA (2.59 g, 22.3 mmol) were reacted in dioxane (100 mL) at 100° C. for 16 h to give upon work-up and purification by C18-flash chromatography (gradient: 5-40% MeCN in water, containing 0.1% NH₃, aq) (0.235 g, 12%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 261.

Intermediate 25
i-25a
6′-Chloro-3-methoxy-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

3-Methoxypyridin-2(1H)-one (CAS Reg. No. 20928-63-6) (1.35 g, 10.8 mol) and 2-chloro-5-iodopyridine (CAS Reg. No. 69045-72-0) (1.03 g, 4.32 mmol) were added to dimethylglycine hydrochloride (301 mg, 2.16 mmol), CuI (411 mg, 2.16 mmol) and Cs₂CO₃(4.22 g, 13.0 mmol) in dioxane (20 mL) and the resulting solution was stirred at 100° C. for 15 h. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (PE:EtOAc=1:2) to afford (250 mg, 55%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 237.

Intermediate 26
i-26a
6′-Chloro-5-methoxy-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

CuI (159 mg, 0.84 mmol) and N,N-dimethylglycine hydrochloride (117 mg, 0.84 mmol) were added to a mixture of 2-chloro-5-iodopyridine (400 mg, 1.67 mmol), 5-methoxypyridin-2(1H-one (CAS Reg. No. 61941-79-5) (523 mg, 4.18 mmol) and Cs₂CO₃(1.63 mg, 5.01 mmol) in dioxane (8 mL) and the resulting suspension was stirred at 100° C. for 15 h under nitrogen. The mixture was filtered through a Celite pad, the solvent removed under reduced pressure and the crude product purified by preparative TLC (EtOAc:PE=3:1) to afford (179 mg, 45%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 237.

Intermediate 27
i-27a
6′-Chloro-3-methyl-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

In a slight variation of GM3 2-chloro-5-iodopyridine (600 mg, 2.51 mmol), 3-methylpyridin-2(1H)-one (CAS Reg. No. 1003-56-1) (273 mg, 2.51 mmol), K₃PO₄(1.60 g, 7.52 mmol), Cu(I)I (239 mg, 1.25 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (178 mg, 1.25 mmol) were reacted in dioxane (20 mL) at 100° C. for 1 h to give upon aqueous work-up and purification by preparative TLC (DCM:MeOH=20:1) the title compound (261 mg, 47%) as a brown solid. MS (ESI): m/z [M+H]⁺ 221.

Intermediate 28
(1S,3S)—N¹-(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine×2 TFA
Step A. i-28a
tert-Butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

According to GM4A tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (300 mg, 0.84 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane in THE (2.10 g, 8.37 mmol), K₃PO₄(356 mg, 1.67 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (55 mg, 0.08 mmol) were reacted in a mixture of dioxane (4 mL) and water (1 mL) at 100° C. for 15 h to give upon aqueous work-up and purification by preparative TLC (MeOH:DCM=1:20) followed by C18-flash chromatography (gradient: 0-49% MeOH in water) the title compound (103 mg, 42%) as a brown solid. MS (ESI): m/z [M+H]⁺ 294.

Step B. i-28b
(1S,3S)—N¹-(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine×2 TFA

[Image Omitted]

According to GM6B tert-butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-28a (100 mg, 0.34 mmol) was reacted with TFA (5 mL) in DCM (5 mL) at rt for 15 h to afford (100 mg, 95%) of title compound as a white solid. MS (ESI): m/z [M+H]⁺ 194.

Intermediate 29
i-29a
6′-Chloro-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

According to GM3 2-chloro-5-iodopyridine (3.0 g, 12.5 mmol), pyridin-2(1H-one (CAS Reg. No. 142-08-5) (3.57 g, 37.6 mmol), Cu(I)I (1.19 g, 6.26 mmol), Cs₂CO₃(8.16 g, 25.1 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (0.891 g, 6.26 mmol) were reacted in dioxane (80 mL) at 100° C. for 15 h to give upon aqueous work-up and trituration with PE:EtOAc (1:1, 30 mL) a solid which was collected by filtration and dried under vacuum to yield (0.60 g, 23%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 207.

Intermediate 30
i-30a
3-(((1S,3S)-3-((2-Oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxylic acid

[Image Omitted]

Ethyl 3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxylate compound 10 (22 mg, 0.05 mmol), finely-ground NaOH (10 mg, 0.26 mmol) and water (0.5 mL) was added to a vial and the mixture was stirred at room temperature for 0.5 h. The compound was purified by preparative HPLC (PrepMethod G, gradient: 5-45%) to give (17 mg, 86%) of the title compound as an off-white solid. MS (ESI): m/z [M+H]⁺ 394.

Intermediate 31
(1S,3S)—N¹-(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine
Step A. i-31a
tert-Butyl ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate

[Image Omitted]

The reaction was run in 3 parallel batches.

According to GM2 tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (420 mg, 2.10 mmol), 2-bromo-5-methylpyrazine (CAS Reg. No. 98006-90-7) (363 mg, 2.10 mmol), Cs₂CO₃(1.03 g, 3.15 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (62 mg, 0.07 mmol) were reacted in 1,4-dioxane (20 mL) at 100° C. for 15 h. Upon combination of batches, non-aqueous work-up and trituration (PE:EtOAc=2:1, 20 mL) a solid was collected by filtration which was dried under vacuum to yield the title compound (1.2 g, 63%) as a grey solid. MS (ESI): m/z [M+H]⁺ 293.3. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.46 (11H, s), 1.93 (2H, td), 2.25 (2H, ddt), 2.39 (3H, d), 4.15 (1H, d), 4.23 (1H, p), 4.47 (1H, d), 4.57 (1H, s), 7.80 (1H, d), 7.85-7.90 (1H, m).

Step B. i-31b
(1S,3S)—N¹-(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine

[Image Omitted]

According to GM6B tert-butyl ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate compound i-31a (350 mg, 1.20 mmol) was reacted with TFA (2 mL, 26 mmol) in DCM (10 mL) at 20° C. for 15 h to afford an unspecified TFA salt of the title compound (704 mg, 91%) as a brown gum. MS (ESI): m/z [M+H]⁺ 193.0. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.64 (2H, m), 1.91 (2H, m), 2.06-2.19 (2H, m), 2.26 (3H, s), 3.60-3.73 (1H, m), 4.21-4.32 (1H, m), 7.74-7.94 (5H, m).

Intermediate 35
Step A. i-35a
tert-Butyl ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate

[Image Omitted]

In a slight variation of GM2 6′-chloro-2-oxo-2H-[1,3′-bipyridine]-3-carbonitrile compound i-10a (560 mg, 1.89 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (1.13 g, 5.66 mmol), Cs₂CO₃(1.84 g, 5.66 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (79 mg, 0.09 mmol) were reacted in DMF (30 mL) at 100° C. for 15 h. The reaction mixture was filtered through a pad of Celite, the filter cake washed with DCM (3×10 mL) and the combined filtrates concentrated under reduced pressure. The obtained material was purified by C18-flash chromatography (gradient: 10-100% MeCN in water+0.1% NH₃(aq), 910 mg material isolated) followed by preparative TLC (EtOAc:PE=3:1) to give the title compound (174 mg, 23%) as a grey solid. MS (ESI): m/z [M+H]⁺ 396.20.

Step B. i-35b
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-3-carbonitrile×4 HCl

[Image Omitted]

According to GM6A tert-butyl ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-35a (865 mg, 2.19 mmol) was reacted with HCl in methanol (4 M 8.0 mL, 32 mmol) in MeOH (20 mL) at 80° C. for 2 h to give the title compound (966 mg, 100%) as a brown gum. MS (ESI): m/z [M+H]⁺ 296.00.

Intermediate 36
Step A. i-36a
6-Methyl-3-(methylthio)-1,2,4-triazine

[Image Omitted]

Methyl hydrazinecarbimidothioate HI (CAS Reg. No. 35600-34-1) (9.87 g, 42.4 mmol) was added to a stirred solution of 1,1-dimethoxypropan-2-one (CAS Reg. No. 6342-56-9) (5.00 g, 42.3 mmol) in ethanol (250 mL) at rt and the resulting solution stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the obtained residue purified by flash chromatography on silica (gradient: 40-50% EtOAc in PE) to give the title compound (2.77 g, 46%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 141.9. H NMR (300 MHz, DMSO-d₆) δ ppm 2.56 (3H, s), 2.59 (3H, s), 8.56 (1H, s).

Step B. i-36b
6-Methyl-3-(methylsulfinyl)-1,2,4-triazine

[Image Omitted]

According to GM8 6-methyl-3-(methylthio)-1,2,4-triazine compound i-36a (1.99 g, 14.1 mmol) was treated with 3-chlorobenzoperoxoic acid (3.65 g, 16.9 mmol) in DCM (25 mL) at rt for 2 h to give upon purification by flash chromatography on silica (gradient: 10-20% MeOH in DCM) the title compound (1.36 g, 61%) as a yellow oil. MS (ESI): m/z [M+H]⁺ 157.8. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.71 (3H, s), 2.96 (3H, s), 8.95 (1H, s).

Intermediate 37
i-37a
6′-Fluoro-5-methyl-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

According to GM3 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (150 mg, 0.67 mmol), 2-hydroxy-5-methylpyridine (CAS Reg. No. 1003-68-5) (367 mg, 3.36 mmol), Cs₂CO₃(658 mg, 2.02 mmol), Cu(I)I (128 mg, 0.67 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (96 mg, 0.67 mmol) were reacted in 1,4-dioxane (15 mL) at 100° C. for 15 h. The reaction mixture was filtered through a pad of Celite, the filter cake washed with EtOAc (3×5 mL) and the combined filtrates diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (4×100 mL). The combined organic layers were were washed with water (2×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) to give the title compound (116 mg, 84%) as a white solid. MS (ESI): m/z [M+H]⁺ 204.9. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.06 (3H, s), 6.47 (1H, d), 7.36 (1H, dd), 7.43 (1H, dd), 7.53-7.54 (1H, m), 8.12 (1H, ddd), 8.33 (1H, dd).

Intermediate 38
i-38a
6′-Fluoro-3-methyl-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

According to GM3 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (105 mg, 0.47 mmol), 2-hydroxy-3-methylpyridine (CAS Reg. No. 1003-56-1) (257 mg, 2.35 mmol), Cs₂CO₃(460 mg, 1.41 mmol), Cu(I)I (90 mg, 0.47 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (67 mg, 0.47 mmol) were reacted in 1,4-dioxane (10 mL) at 100° C. for 15 h. The reaction mixture was filtered through a pad of Celite, the filter cake washed with EtOAc (3×5 mL) and the combined filtrates diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (4×75 mL). The combined organic layers were washed with water (2×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) to give the title compound (85 mg, 88%) as a white solid. MS (ESI): m/z [M+H]⁺ 205.0. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.05 (3H, s), 6.29 (1H, t), 7.36 (1H, dd), 7.42-7.45 (1H, m), 7.58 (1H, dd), 8.13 (1H, ddd), 8.32-8.34 (1H, m).

Intermediate 39
i-39a
(1S,3S)—N′-(5-Iodopyridin-2-yl)-NM-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[Image Omitted]

According to GM1A 2-fluoro-5-iodopyridine (203 mg, 0.91 mmol) was added to a mixture of the 2HCl salt of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (220 mg, 0.83 mmol) and Na₂CO₃(263 mg, 2.48 mmol) in DMSO (15 mL). The resulting mixture was stirred at 100° C. for 15 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the obtained material was taken up with EtOAc (300 mL). The organic layer was washed with saturated brine (4×125 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (140 mg, 43%) as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 396.7. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.39-1.59 (2H, m), 1.79-1.95 (2H, m), 2.06-2.16 (2H, m), 2.37 (3H, s), 4.17-4.39 (2H, m), 6.37 (1H, dd), 6.83 (1H, d), 7.53-7.59 (2H, m), 8.10 (1H, d), 8.16 (1H, s).

Intermediate 42
Step A. i-42a
tert-Butyl ((1S,3S)-3-((5-methoxy-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate

[Image Omitted]

rel-(1R,2R)—N¹,N²-Dimethylcyclohexane-1,2-diamine (53 mg, 0.37 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (300 mg, 0.74 mmol), 5-methoxypyridin-2-ol (233 mg, 1.86 mmol), Cs₂CO₃(727 mg, 2.23 mmol) and Cu(I)I (70.8 mg, 0.37 mmol) in 1,4-dioxane (15 mL) at 25° C. The resulting suspension was stirred at 100° C. for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was purified by preparative TLC (EtOAc) to give the title compound (263 mg, 88%) as a brown solid. MS (ESI) m/z [M+H]⁺ 401.0.

Step B. i-42b
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-5-methoxy-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

TFA (5 ml, 64.90 mmol) was added to tert-butyl ((1S,3S)-3-((5-methoxy-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-42a (400 mg, 1.00 mmol) in DCM (15 mL) at 25° C. The resulting suspension was stirred at 25° C. for 18 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound (1.1 g, 100%) as a black gum. MS (ESI) m/z [M+H]⁺ 301.0.

Intermediate 44
Step A. i-44a
tert-Butyl ((1S,3S)-3-((5-chloro-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate

[Image Omitted]

rel-(1R,2R)—N¹/N²-Dimethylcyclohexane-1,2-diamine (106 mg, 0.74 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (300 mg, 0.74 mmol), 5-chloropyridin-2(1H)-one (193 mg, 1.49 mmol), Cu(I)I (142 mg, 0.74 mmol) and Cs₂CO₃(727 mg, 2.23 mmol) in 1,4-dioxane (25 mL) at 26° C. The resulting solution was stirred at 100° C. for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (3×25 mL) and sat brine (3×20 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was purified by preparative TLC (EtOAc:PE=2:1) to give the title compound (298 mg, 99%) as a green solid. MS (ESI) m/z [M+H]⁺ 405.0.

Step B. i-44b
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-5-chloro-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

TFA (5 mL, 64.90 mmol) was added to tert-butyl ((1S,3S)-3-((5-chloro-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-44a (220 mg, 0.54 mmol) in DCM (20 mL) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound (432 mg, 91%) as a brown gum. MS (ESI) m/z [M+H]⁺ 304.9.

Intermediate 47 i-47a (1S,3S)—N′-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyrimidin-2-yl)cyclopentane-1,3-diamine

[Image Omitted]

K₂CO₃(126 mg, 0.91 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (200 mg, 0.91 mmol), 2-chloro-5-iodopyrimidine (CAS Reg. No. 32779-38-7) (329 mg, 1.37 mmol) in DMSO (5 mL) at rt and the resulting suspension was stirred at 120° C. for 15 h. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (2×25 mL) and brine (25 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford crude product which was purified by flash C18-flash chromatography (elution gradient: 0-60% MeCN in water) to afford (150 mg, 39%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 424.0.

Intermediate 48
Step A. i-48a
Methyl 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzoate

[Image Omitted]

The reaction was run in 3 parallel batches (2×500 mg and 1×600 mg 6-chloropyridin-3-amine). Methyl 4-fluoro-3-nitrobenzoate (CAS Reg. No. 329-59-9) (929 mg, 4.67 mmol) was added to 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (500 mg, 3.89 mmol), XantPhos (338 mg, 0.58 mmol), Pd(OAc)₂(66 mg, 0.29 mmol) and K₂CO₃(1.61 g, 11.7 mmol) in 1,4-dioxane (25 mL) at rt and the resulting mixture was stirred at 80° C. for 18 h under nitrogen. The three reaction mixtures were combined, taken up with EtOAc (200 mL), loaded onto silica gel and subjected to flash chromatography on silica (gradient: 10-20% EtOAc in n-heptane) to afford (851 mg, 71% combined yield) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 307.9.

Step B. i-48b
Methyl 3-amino-4-((6-chloropyridin-3-yl)amino)benzoate

[Image Omitted]

Methyl 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzoate compound i-48a (420 mg, 1.37 mmol) was added to zinc (535 mg, 8.19 mmol) and NH₄Cl (730 mg, 13.65 mmol) in EtOAc (10 mL) and EtOH (10 mL) at rt and the resulting mixture was stirred at 60° C. for 18 h. The reaction mixture was filtered through celite. The celite was washed with EtOAc (3×25 mL). The filtrate was concentrated under reduced pressure to afford (761 mg) of the crude title compound (containing salts) as a light pink solid which was used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 277.9.

Step C. i-48c
Methyl 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

[Image Omitted]

Methyl 3-amino-4-((6-chloropyridin-3-yl)amino)benzoate compound i-48b (300 mg, 1.08 mmol) was added to CDI (771 mg, 4.75 mmol) in DMF (20 mL) at rt and the resulting solution was stirred at 80° C. for 18 h. The reaction mixture was concentrated, diluted with EtOAc (200 mL) and washed sequentially with brine (3×100 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford crude product. The crude solid was triturated with MeCN to give a solid which was collected by filtration and dried under vacuum to give (226 mg, 69%) of the title compound as a pink solid. MS (ESI): m/z [M+H]⁺ 303.8.

Step D. i-48d
Methyl 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

[Image Omitted]

CH₃I (246 mg, 1.73 mmol) was added to methyl 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate compound i-48c (351 mg, 1.16 mmol) and Na₂CO₃(367 mg, 3.47 mmol) in DMF (20 mL) at rt and the resulting mixture was stirred at 100° C. for 18 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with brine (3×100 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford (92 mg, 25%) of the crude product as a pale yellow solid which was used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 317.9.

Step E. i-48e
Methyl 1-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

[Image Omitted]

Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Reg. No. 1612891-29-8) (29 mg, 0.03 mmol) was added to methyl 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate compound i-48d (110 mg, 0.35 mmol), Cs₂CO₃(338 mg, 1.04 mmol) and (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (76 mg, 0.35 mmol) in 1,4-dioxane (20 mL) at rt and the resulting mixture was stirred at 100° C. for 18 h under nitrogen. The reaction mixture was concentrated, diluted with EtOAc (200 mL) and washed sequentially with brine (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the obtained residue purified by preparative TLC (EtOAc:PE=1:1) to afford (90 mg, 52%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 510.1.

Intermediate 49
Step A. i-49a
6′-Chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Cu(I)I (103 mg, 1.04 mmol) was added to 6′-chloro-5-ethynyl-2H-[1,3′-bipyridin]-2-one compound i-63b (240 mg, 1.04 mmol) and 1-(azidomethyl)-4-methoxybenzene (255 mg, 1.56 mmol) in 1,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 100° C. for 16 h under nitrogen. The mixture was filtered through a Celite pad and the filter cake washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the residue purified by preparative TLC (MeOH:DCM=1:20) to afford (410 mg, 100%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 394.0.

Step B. i-49b
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Reg. No. 1612891-29-8) (21 mg, 0.03 mmol) was added to 6′-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-49a (200 mg, 0.51 mmol), (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (167 mg, 0.76 mmol) and Cs₂CO₃(331 mg, 1.02 mmol) in 1,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (50 mL) and brine (25 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated and the obtained residue purified by preparative TLC (MeOH:DCM=1:10) to afford (166 mg, 57%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 577.2.

Step C. i-49c
5-(1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Prepared in a similar way as described for compound i-49b from 6′-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-49a (109 mg, 0.28 mmol), the 4×TFA salt of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (340 mg, 0.55 mmol), Cs₂CO₃(451 mg, 1.38 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (23 mg, 0.03 mmol) in 1,4-dioxane (5 mL) and purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) to give the title compound (22 mg, 14%) as a brown solid.

MS (ESI): m/z [M+H]⁺ 551.0.

Intermediate 50
Step A. i-50a
5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol

[Image Omitted]

XPhos (0.431 g, 0.90 mmol), XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (0.383 g, 0.45 mmol), 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Reg. No. 110539-88-0) (2.13 g, 6.79 mmol), 5-iodopyridin-2-ol (CAS Reg. No. 13472-79-2) (1.0 g, 4.5 mmol) and Cs₂CO₃(4.42 g, 13.6 mmol) in dioxane (10 mL) and water (2 mL) were stirred under an atmosphere of nitrogen at 80° C. for 15 h. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to give the crude product which was purified by flash C18-flash chromatography (elution gradient: 0-50% MeCN in water) to afford (160 mg, 13%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 282.0.

Step B. i-50b
6′-Chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Cu(I)I (102 mg, 0.53 mmol) was added to 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol compound i-50a (150 mg, 0.53 mmol), 2-chloro-5-iodopyridine (CAS Reg. No. 69045-79-0) (128 mg, 0.53 mmol), rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (114 mg, 0.80 mmol) and Cs₂CO₃(347 mg, 1.07 mmol) in 1,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 60° C. for 5 h under nitrogen. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the filtrate concentrated under reduced pressure. The obtained residue was first purified by preparative TLC (MeOH:DCM=1:10) and then by flash C18-flash chromatography (elution gradient: 0-30% MeCN in water) to afford (150 mg, 72%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 393.0.

Step C. i-50c
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Reg. No. 1612891-29-8) (14 mg, 0.02 mmol) was added to 6′-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-50b (130 mg, 0.33 mmol), (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (109 mg, 0.50 mmol) and Cs₂CO₃(216 mg, 0.66 mmol) in 1,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (50 mL) and brine (25 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to give the crude product which was purified by preparative TLC (MeOH:DCM=1:10) to afford (117 mg, 61%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 576.3.

Step D. i-50d
5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Prepared in a similar way as described for compound i-50c from 6′-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-50b and (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b and purified by preparative TLC (MeOH:DCM=1:15), to give the title compound (82 mg, 73%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 550.0.

Step E. i-50e
5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-6′-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Prepared in a similar way as described for compound i-50c from 6′-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-50b and (1S,3S)—N¹-(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine compound i-31b and purified by preparative TLC (MeOH:DCM=1:15) to give the title compound (150 mg, 43%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 549.0.

Intermediate 51
Step A. i-51a
5-Bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[Image Omitted]

TMEDA (1.33 mL, 8.81 mmol) was added to 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CAS Reg. No. 84712-08-3) (1.0 g, 4.4 mmol), (6-fluoropyridin-3-yl)boronic acid (CAS Reg. No. 351019-18-6) (1.55 g, 11.0 mmol) and Cu(OTf)₂(3.19 g, 8.81 mmol) in DCM (30 mL) at rt. Air was allowed to diffuse into the reaction mixture via a CaCl₂-tube on top of the flask and the resulting mixture was stirred at rt for 15 h. The reaction mixture was diluted with water (150 mL) and extracted with DCM (4×300 mL). The combined organic layers were washed with water (2×200 mL), dried (Na₂SO₄), filtered and evaporated. The obtained material was purified by purified by flash chromatography on silica (gradient: 0-60% EtOAc in n-heptane) to afford (0.38 g, 27%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 321.8/323.8 (Br isotope pattern).

Step B. i-51b
5-Bromo-3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[Image Omitted]

K₂CO₃(219 mg, 1.59 mmol) was added to 5-bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one compound i-51a (358 mg, 1.11 mmol) and (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (116 mg, 0.53 mmol) in DMSO (5 mL) at rt and the resulting mixture was stirred at 120° C. for 15 h. The mixture was filtered through a Celite pad and the filter cake washed with DCM (4×5 mL). The filtrate was concentrated under reduced pressure and purified by flash C18-flash chromatography (elution gradient: 0-100% MeOH in water) to afford (95 mg, 34%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 521/523 (Br isotope pattern).

Intermediate 52
Step A. i-52a
tert-Butyl ((1S,3S)-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

m-CPBA (733 mg, 3.40 mmol) was added portion-wise to a stirred solution of 5-methyl-3-(methylthio)-1,2,4-triazine (CAS Reg. No. 28735-24-2) (400 mg, 2.83 mmol) in DCM (8 mL) at rt and the resulting solution was stirred at this temperature for 2 h. The solvent was removed under reduced pressure to afford a pale-yellow solid which was dissolved in n-BuOH (8 mL). tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (567 mg, 2.83 mmol) was added and the resulting solution was stirred at 120° C. for 15 h. The reaction mixture was quenched with 1 M NaOH (aq) (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated and the residue purified by preparative TLC (EtOAc:PE=3:1) to afford (220 mg, 26%) of the title compound as an orange solid. MS (ESI): m/z [M+H]⁺ 294.2.

Step B i-52b
(1S,3S)—N¹-(5-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[Image Omitted]

tert-Butyl ((1S,3S)-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-52a (210 mg, 0.72 mmol) was treated with DCM (6 mL) and TFA (2 mL) and the resulting mixture stirred at rt for 3 h. The reaction mixture was quenched with sat. NaHCO₃(100 mL) and extracted with (7 M NH₃in MeOH:DCM=1:20) (3×75 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford (120 mg, 87%) of the title compound as an orange solid which was used without further purification. MS (ESI): m/z [M+H]⁺ 194.1.

Intermediate 53
Step A. i-53a
tert-Butyl ((1S,3S)-3-((5,6-dimethyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

5,6-Dimethyl-3-(methylthio)-1,2,4-triazine (CAS Reg. No. 7275-70-9) (400 mg, 2.58 mmol) was added portion-wise to a stirred solution of 3-chlorobenzoperoxoic acid (667 mg, 3.09 mmol) in DCM (10 mL) at rt and the resulting solution was stirred at this temperature for 2 h. The solvent was removed under reduced pressure to afford a pale-yellow solid which was dissolved in n-BuOH (10 mL). tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Reg. No. 645400-44-8) (567 mg, 2.83 mmol) was added and the resulting solution was stirred at 120° C. for 15 h. The reaction mixture was quenched with 1 M NaOH aq (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated and the obtained material purified by preparative TLC (EtOAc:PE=2:1) to afford (115 mg, 14%) of the title compound as an orange solid. MS (ESI): m/z [M+H]⁺ 308.2.

Step B. i-53b
(1S,3S)—N¹-(5,6-Dimethyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine×3 TFA

[Image Omitted]

tert-Butyl ((1S,3S)-3-((5,6-dimethyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-53a (100 mg, 0.33 mmol) was treated with TFA (2 mL) and DCM (6 mL).The resulting mixture was stirred at rt for 3 h and the organic solvents were removed by evaporation to afford (112 mg, 63%) of the crude title compound as a brown oil which was used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 208.0.

Intermediate 54
Step A. i-54a
tert-Butyl ((1S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate

[Image Omitted]

3-(Trifluoromethyl)pyridin-2(1H-one (CAS Reg. No. 22245-83-6) (324 mg, 1.98 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (400 mg, 0.99 mmol), Cu(I)I (94 mg, 0.50 mmol), Cs₂CO₃(970 mg, 2.98 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (70 mg, 0.50 mmol) in 1,4-dioxane (20 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was poured into water (150 mL), extracted with EtOAc (5×100 mL) and the combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (MeOH:EtOAc=1:1) and then by flash C18-flash chromatography (gradient: 0-100% MeCN in water) to afford (235 mg, 54%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 439.2.

Step B. i-54b
6′-(((1S,3S)-3-Aminocyclopentyl)amino)-3-(trifluoromethyl)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

tert-Butyl ((1S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-54a (220 mg, 0.50 mmol) was added to a mixture of 4M HCl in MeOH (2 mL, 8 mmol) and MeOH (8 mL) at rt and the resulting mixture was stirred at 60° C. for 2 h. The solvent was removed under reduced pressure and the material purified by flash C18-flash chromatography (gradient: 0-100% MeCN in water) to give (148 mg, 87%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 339.0.

Intermediate 57
i-57a
3-(5-Bromopyrazin-2-yl)-1-methylpyridin-2(1H)-one

[Image Omitted]

2-Bromo-5-iodopyrazine (CAS Reg. No. 622392-04-5) (1.68 g, 5.88 mmol) was added to (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (CAS Reg. No. 1454558-46-3) (300 mg, 1.96 mmol), KOAc (578 mg, 5.88 mmol) and PdCl₂(dppf)×DCM (160 mg, 0.20 mmol) in 1,4-dioxane (16 mL) and water (4 mL) at rt and the resulting mixture was stirred at 100° C. for 2 h under nitrogen. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (4×100 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated and the obtained material was purified by flash chromatography on silica (gradient: 0-100% EtOAc in n-heptane) to afford (360 mg, 69%) of the title compound as a brown solid. MS (ESI): m/z [M+H]⁺ 265.8/267.8.

Intermediate 58
i-58a
3-(6-Chloropyridin-3-yl)pyrimidin-4(3H)-one

[Image Omitted]

TMEDA (0.942 mL, 6.24 mmol) was added to (6-chloropyridin-3-yl)boronic acid (CAS Reg. No. 444120-91-6) (983 mg, 6.24 mmol), pyrimidin-4(3H)-one (CAS Reg. No. 4562-27-0) (300 mg, 3.12 mmol) and Cu(OTf)₂(2.26 g, 6.24 mmol) in DCM (35 mL) at rt. Air was allowed to diffuse into the reaction mixture via a CaCl₂-tube on top of the flask. The resulting suspension was stirred at rt for 18 h. The reaction mixture was diluted with DCM (150 mL), and washed sequentially with water (2×50 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated and the residue was purified by preparative TLC (EtOAc:PE=2:1) to afford (243 mg, 37%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 207.9.

Intermediate 59
i-59a
3-(2-Chloropyrimidin-5-yl)-1-methylpyridin-2(1H)-one

[Image Omitted]

3-Bromo-1-methylpyridin-2(1H-one (CAS Reg. No. 81971-38-2) (300 mg, 1.60 mmol) was added to (2-chloropyrimidin-5-yl)boronic acid (CAS Reg. No. 1003845-06-4) (505 mg, 3.19 mmol), K₂CO₃(662 mg, 4.79 mmol) and Pd-118/PdCl₂(dtbpf) (104 mg, 0.16 mmol) in 1,4-dioxane (8 mL) and water (2 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was poured into water (150 mL) and the aqueous layer was extracted with EtOAc (5×150 mL).The combined organic layers were dried (Na₂SO₄), filtered and evaporated and the residue was purified by preparative TLC (MeOH:DCM=1:20) to afford (105 mg, 30%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 221.9.

Intermediate 60
Step A. i-60a
3-((6-Chloropyridin-3-yl)amino-4-nitrobenzonitrile

[Image Omitted]

K₂CO₃(6.45 g, 46.7 mmol) was added to 3-fluoro-4-nitrobenzonitrile (CAS Reg. No 218632-01-0) (3.10 g, 18.7 mmol), 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (2.0 g, 15.6 mmol) and Pd(OAc)₂(0.262 g, 1.17 mmol) and XantPhos (1.35 g, 2.33 mmol) in MeCN (40 mL) at rt and the resulting mixture was stirred at 80° C. for 15 h under nitrogen. The reaction mixture was filtered through celite and the filter cake washed with DCM (3×50 mL). The combined filtrates were concentrated under reduced pressure and taken up with EtOAc (250 mL). The organic layer was washed sequentially with sat. NaHCO₃(3×250 mL), dried (Na₂SO₄), filtered and evaporated. The obtained residue was purified by preparative TLC (DCM) to afford (0.63 g, 15%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 275.1.

Step B. i-60b
4-Amino-3-((6-chloropyridin-3-yl)amino)benzonitrile

[Image Omitted]

Zinc (971 mg, 14.9 mmol) was added to 3-((6-chloropyridin-3-yl)amino)-4-nitrobenzonitrile compound i-60a (510 mg, 1.86 mmol) and NH₄Cl (795 mg, 14.8 mmol) in EtOH (15 mL) at rt and the resulting mixture was stirred at 60° C. for 5 h. The reaction mixture was filtered through celite and the filter cake washed with EtOH (3×50 mL). The combined filtrates were concentrated under reduced pressure to afford (363 mg, 80%) of the title compound as a brown solid which was used in the next step directly without further purification. MS (ESI): m/z [M+H]⁺ 245.1.

Step C. i-60c
3-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[Image Omitted]

CDI (795 mg, 4.90 mmol) was added to 4-amino-3-((6-chloropyridin-3-yl)amino)benzonitrile compound i-60b (300 mg, 1.23 mmol) in DMF (2 mL) at rt and the resulting mixture was stirred at 80° C. for 24 h. The solid was filtered off to afford the crude product which was triturated with MeCN and dried under vacuum to give (242 mg, 73%) of the title compound as a pink solid. MS (ESI): m/z [M+H]⁺ 271.0.

Step D. i-60d
3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[Image Omitted]

Cs₂CO₃(542 mg, 1.66 mmol) was added to a mixture of 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-60c (150 mg, 0.55 mmol) and CH₃I (118 mg, 0.83 mmol) in DMF (5 mL) at rt and it was stirred at 100° C. for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with brine (3×50 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated and the obtained material was triturated with MeCN. The formed solid was collected by filtration and dried under vacuum to give (110 mg, 70%) of the title compound as a pink solid. MS (ESI): m/z [M+H]⁺ 285.1.

Intermediate 61
Step A. i-61a
4-((6-Chloropyridin-3-yl)amino)-3-nitrobenzonitrile

[Image Omitted]

Pd(OAc)₂(0.262 g, 1.17 mmol) was added to a mixture of K₂CO₃(6.45 g, 46.7 mmol), 4-fluoro-3-nitrobenzonitrile (CAS Reg. No. 1009-35-4) (2.84 g, 17.1 mmol), 6-chloropyridin-3-amine CAS Reg. No. 5350-93-6 (2.0 g, 15.6 mmol) and XantPhos (1.35 g, 2.33 mmol) in MeCN (40 mL) at rt and it was stirred at 80° C. for 15 h under nitrogen. The reaction mixture was filtered through Celite and the filter cake washed with DCM (3×200 mL). The combined filtrates were concentrated under reduced pressure and taken up with EtOAc (300 mL). The organic layer was washed sequentially with sat. NaHCO₃(3×400 mL), dried over (Na₂SO₄), filtered and evaporated. The obtained material was purified by preparative TLC (DCM) to afford (0.70 g, 16%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 275.0

Step B. i-61b
3-Amino-4-((6-chloropyridin-3-yl)amino)benzonitrile

[Image Omitted]

Zinc (1.33 g, 20.4 mmol) was added to NH₄Cl (1.09 g, 20.4 mmol), 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzonitrile compound i-61a (0.70 g, 2.54 mmol) in EtOH (15 mL) at rt and the resulting mixture was stirred at 60° C. for 5 h. The reaction mixture was filtered through Celite and the filter cake washed with EtOH (3×50 mL). The combined filtrates were concentrated under reduced pressure to afford (0.51 g, 81%) of the title compound as a brown solid which was used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 245.1.

Step C. i-61c
1-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[Image Omitted]

CDI (1.19 g, 7.36 mmol) was added to 3-amino-4-((6-chloropyridin-3-yl)amino)benzonitrile compound i-61b (450 mg, 1.84 mmol) in DMF (10 mL) at rt and the resulting mixture was stirred at 80° C. for 24 h. The solid was filtered off to afford the crude product which was triturated with MeCN and dried under vacuum to give (342 mg, 69%) of the title compound as a pink solid. MS (ESI): m/z [M+H]⁺ 270.9.

Step D. i-61d
1-(6-Chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[Image Omitted]

CH₃I (157 mg, 1.11 mmol) was added to a mixture of 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-61c (200 mg, 0.74 mmol) and Cs₂CO₃(722 mg, 2.22 mmol) in DMF (8 mL) at rt and it was stirred at 100° C. for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (3×100 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford (119 mg, 57%) of the title compound as a yellow solid which was used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 285.0.

Intermediate 62
i-62a
2-(6-Fluoropyridin-3-yl)pyridazin-3(2H)-one

[Image Omitted]

2-Fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (300 mg, 1.35 mmol) was added to a mixture of pyridazin-3(2H)-one (CAS Reg. No. 504-30-3) (259 mg, 2.69 mmol), Cu(I)l (128 mg, 0.67 mmol), Cs₂CO₃(1315 mg, 4.04 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (96 mg, 0.67 mmol) in 1,4-dioxane (20 mL) at rt and it was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was diluted with water (50 mL) and the aqueous layer extracted with EtOAc (8×30 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated and the residue purified by preparative TLC (EtOAc) to afford (242 mg, 94%) of the title compound as a brown solid. MS (ESI): m/z [M+H]⁺ 191.9.

Intermediate 63
Step A. i-63a
5-((tert-Butyldimethylsilyl)ethynyl)-6′-chloro-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

Cs₂CO₃(2.23 g, 6.86 mmol) was added to 5-((tert-butyldimethylsilyl)ethynyl)pyridin-2(1H)-one (CAS Reg. No. 2448766-74-1) (800 mg, 3.43 mmol), 2-chloro-5-iodopyridine (CAS Reg. No. 69045-79-0) (821 mg, 3.43 mmol), Cu(I)l (653 mg, 3.43 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (731 mg, 5.14 mmol) in 1,4-dioxane (20 mL) at rt and the resulting suspension was stirred at 60° C. for 5 h under nitrogen. The mixture was combined with a second batch made in the same way and filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL) and the combined filtrates were concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (gradient: 0-50% EtOAc in n-heptane) to afford (590 mg, 25%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 345.0.

Step B. i-63b
6′-Chloro-5-ethynyl-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

A solution of TBAF in THE (1 M, 8.55 mL, 8.55 mmol) was added to 5-((tert-butyldimethylsilyl)ethynyl)-6′-chloro-2H-[1,3′-bipyridin]-2-one compound i-63a (590 mg, 1.71 mmol) in THE (15 mL) at rt and the resulting solution was stirred at for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc:PE=2:1) followed by flash C18-flash chromatography (elution gradient: 0-30% MeCN in water) to afford (290 mg, 74%) of the title compound as a beige solid. MS (ESI): m/z [M+H]⁺ 231.0.

Intermediate 67
Step A. i-67a
5-(1-Methyl-1H-pyrazol-4-yl)pyridin-2-ol

[Image Omitted]

A mixture of 5-iodo-2(1H)-pyridinone (CAS Reg. No. 13472-79-2) (500 mg, 2.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Reg. No. 761446-44-0) (565 mg, 2.71 mmol) and XPhos (CAS Reg. No. 564483-18-7) (108 mg, 0.23 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was treated with XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (192 mg, 0.23 mmol) under nitrogen and stirred at 100° C. for 18 h. The reaction mixture was cooled to rt and filtered through a pad of Celite. The filter cake was washed with EtOAc (100 mL) and the combined filtrates concentrated under reduced pressure. The obtained material was purified by flash chromatography on silica (gradient: 10-20% MeOH in DCM) to afford the title compound (250 mg, 63%) as a green solid. MS (ESI): m/z [M+H]⁺ 175.9.

Step B. i-67b
6′-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

According to GM3 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ol compound i-67a (250 mg, 1.43 mmol), 2-chloro-5-iodopyridine (342 mg, 1.43 mmol), rel-(1R,2R)—N¹,N²-dimethylcyclo-hexane-1,2-diamine (203 mg, 1.43 mmol), Cs₂CO₃(1.4 g, 4.3 mmol) and Cu(I)I (272 mg, 1.43 mmol) were reacted in 1,4-dioxane (8 mL) at 100° C. for 18 h to give upon non-aqueous work-up (EtOAc) and flash chromatography on silica (gradient: 0-10% MeOH in DCM) the title compound (250 mg, 61%) as a green solid. m/z [M+H]⁺ 287.1/289 (Cl isotope pattern).

Intermediate 68a
i-68a
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

3-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one Example 129 (280 mg, 0.70 mmol) was added to a mixture of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2doxaborolan-2-yl)-1H-1,2,3-triazole (CAS Reg. No. 2710298-24-9) (393 mg, 1.41 mmol), Cs₂CO₃(688 mg, 2.11 mmol), XPhos (CAS Reg. No. 564483-18-7) (34 mg, 0.07 mmol) and XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (59 mg, 0.07 mmol) in 1,4-dioxane (16 mL) and water (4 mL) under nitrogen. The resulting reaction mixture was stirred at 100° C. for 15 h and subsequently poured into saturated brine (150 mL). It was extracted with EtOAc (4×150 mL) and the combined organic layers were dried over Na₂SO₄, filtered and evaporated. The crude material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) to give the title compound (335 mg, 93%) as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 515.1.

Intermediate 76
i-76a
(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid

[Image Omitted]

tert-Butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-28a (1.32 g, 4.50 mmol) was dissolved in DCM (15 mL) and TFA (5 mL). After stirring for 1 h toluene was added, and the resulting mixture was concentrated. The residue was dissolved in DMSO (10 mL) and treated with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS Reg. No. 444120-95-0) (1.81 g, 8.11 mmol) and K₂CO₃(2.25 g, 16.3 mmol), and the resulting mixture was stirred at 80° C. for 20 h. The mixture was cooled to rt, solids were filtered off and the filtrate purified by preparative HPLC (PrepMethod G, gradient 0-50%) to afford (1.07 g, 66%) of the title compound as a red solid MS (ESI) m/z [M+H]⁺ 315.

Intermediate 77
Step. A i-77a
(1S,3S)—N¹-(5-(2,4-Dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[Image Omitted]

A mixture of (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (0.126 g, 0.40 mmol), 2,4-dimethyl-1H-imidazole (CAS Reg. No. 930-62-1), Cu(OAc)₂(0.175 g, 0.96 mmol) and pyridine (0.178 mL, 2.21 mmol) in DCM (4 mL) and DMF (0.8 mL) was stirred at rt for 24 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated and purified by preparative HPLC (PrepMethod F, gradient 20-60%) to afford (52 mg, 36%) of the title compound as a beige solid. MS (ESI) m/z [M+H]⁺ 365.

Step. B i-77b
(1S,3S)—N¹-(5-(5-lodo-2,4-dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-AP-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[Image Omitted]

A mixture of compound i-77a (0.051 g, 0.14 mmol) and NIS (0.063 g, 0.28 mmol) in MeCN (2 mL) was stirred at rt for 2 h. The mixture was concentrated, the residue dissolved in DCM and washed with water. The organic layer was concentrated and purified by preparative HPLC (PrepMethod H, gradient 20-60%) to afford (55 mg, 80%) of the title compound as a beige solid. MS (ESI) m/z [M+H]⁺ 491.

Intermediate 80
i-80a
6-Methyl-3-(methylsulfinyl)-1,2,4-triazin-5(4H)-one

[Image Omitted]

According to GM8 6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (CAS Reg. No. 1566-32-1) (300 mg, 1.91 mmol) was treated portionwise with 3-chlorobenzoperoxoic acid (494 mg, 2.29 mmol) in DCM (25 mL) at rt for 2 h to give upon purification by preparative TLC (DCM:MeOH=10:1) the title compound (200 mg, 61%) as a white solid. MS (ESI): m/z [M+H]⁺ 174. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15 (3H, s), 2.71 (3H, s).

Intermediate 81
Step A. i-81a
N-(6-Chloropyridin-3-yl)-6-methyl-3-nitropyridin-2-amine

[Image Omitted]

XantPhos (CAS Reg. No. 161265-03-8) (34 mg, 0.06 mmol) was added to a mixture of 2-chloro-6-methyl-3-nitropyridine (CAS Reg. No. 56057-19-3) (1.00 g, 8.69 mmol), 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (1.12 g, 7.8 mmol), Na₂CO₃(1.84 g, 17.4 mmol) and Pd(OAc)₂(13 mg, 0.06 mmol) in THF (15 mL) at rt under nitrogen and it was stirred at 80° C. for 15 h. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (250 mL). The organic layer was washed with sat. brine (4×125 mL), dried over Na₂SO₄, filtered and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-10% EtOAc in PE) to give the title compound (1.43 g, 93%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 265.0/267 (Cl isotope pattern).

Step B. i-81b
N²-(6-chloropyridin-3-yl)-6-methylpyridine-2,3-diamine

[Image Omitted]

N-(6-Chloropyridin-3-yl)-6-methyl-3-nitropyridin-2-amine compound I-81a (1.4 g. 5.3 mmol) was added to a mixture of zinc (2.08 g, 31.7 mmol) and NH₄Cl (2.83 g, 52.9 mmol) in a mixture of EtOH (8 mL) and EtOAc (8 mL) at rt and it was stirred at 60° C. for 15 h. The reaction mixture was filtered through a pad of Celite, the filtrate concentrated under reduced pressure and the crude material purified by preparative TLC (EtOAc) to give the title compound (1.2 g, 97%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 235.0/237 (Cl isotope pattern).

Step C. i-81c
3-(6-Chloropyridin-3-yl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[Image Omitted]

N²-(6-chloropyridin-3-yl)-6-methylpyridine-2,3-diamine compound i-81b (65 mg, 0.28 mmol) in DMF (5 nL) was treated with CDI (CAS Reg. No. 530-62-1) (225 mg, 1.38 mmol) at rt under nitrogen and it was stirred at 80° C. for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×50 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the crude material purified by preparative HPLC to give the title compound (42 mg, 58%) as a pale-yellow powder. MS (ESI): m/z [M+H]⁺ 260.9/263 (Cl isotope pattern).

Step D. i-81d
3-(6-Chloropyridin-3-yl)-1,5-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[Image Omitted]

In a vial a mixture of 3-(6-chloropyridin-3-yl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-81c (340 mg, 1.30 mmol) and K₂CO₃(541 mg, 3.01 mmol) in DMF (25 nL) was treated with iodomethane (1.85 g, 13.0 mmol) at rt under nitrogen and it was stirred at 80° C. for 1 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (3×50 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the crude material purified by flash chromatography on silica (gradient: 0-50% EtOAc in PE) to give the title compound (305 mg, 85%) as a pink film. MS (ESI): m/z [M+H]⁺ 275.0/277 (Cl isotope pattern).

Step E. i-81e
3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonitrile

[Image Omitted]

The reaction was run in 3 parallel batches (2× starting from 100 mg and 1×starting from 150 mg of compound i-81d). In a vial a mixture of 3-(6-chloropyridin-3-yl)-1,5-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-81d (150 mg, 0.55 mmol), 2-hydroxyisoindoline-1,3-dione (CAS Reg. No. 524-38-9) (45 mg, 0.27 mmol) and tert-butyl nitrite (CAS Reg. No. 540-80-7) (169 mg, 1.64 mmol) in MeCN (4 mL) was treated with Pd(OAc)₂(12 mg, 0.05 mmol) at rt under nitrogen and it was stirred at 80° C. for 24 h. The reaction mixtures of the three parallel batches were combined, poured into water (200 mL) and the mixture extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the crude material purified by preparative TLC (EtOAc:PE=1:3) to give the title compound (180 mg, 44% average yield) as a brown solid. MS (ESI): m/z [M+H]⁺ 286.2/288 (Cl isotope pattern).

Intermediate 82
Step A. i-82a
6-((6-Chloropyridin-3-yl)amino)-5-nitronicotinonitrile

[Image Omitted]

Na₂CO₃(1.73 g, 16.3 mmol) was added to a mixture of 6-chloro-5-nitronicotinonitrile (CAS Reg. No. 160906-98-9) (1.00 g, 5.45 mmol), 6-chloropyridin-3-amine (CAS Reg. No. 5350-93-6) (1.40 g, 10.9 mmol), XantPhos (CAS Reg. No. 161265-03-8) (315 mg, 0.54 mmol) and Pd(OAc)₂(61 mg, 0.27 mmol) in 1,4-dioxane (15 mL) at rt under nitrogen and it was stirred at 80° C. for 3 h. The reaction mixture was filtered through a filter membrane, concentrated under reduced pressure and the crude material was purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (1.28 g, 85%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 275.8/278 (Cl isotope pattern).

Step B. i-82b
5-Amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile

[Image Omitted]

6-((6-Chloropyridin-3-yl)amino)-5-nitronicotinonitrile compound i-82a (1.28 g, 4.64 mmol) was added to a mixture of zinc (1.52 g, 23.2 mmol) and acetic acid (2.79 g, 46.4 mmol) in EtOH (15 mL) at rt and it was stirred at 60° C. for 2 h. The reaction mixture was filtered through a filter membrane, the filtrate concentrated under reduced pressure and the crude material purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (1.26 g, 100%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 246.0/248 (Cl isotope pattern).

Step C. i-82c
3-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[Image Omitted]

5-Amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile compound i-82b (1.26 g, 5.13 mmol) in DMF (15 mL) was treated with CDI (CAS Reg. No. 530-62-1) (4.16 g, 25.6 mmol) at rt under nitrogen and it was stirred at 80° C. for 2 h. The reaction mixture was poured into water (100 mL) and the mixture extracted with EtOAc (3×75 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the crude material purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (590 mg, 38%) as a yellow oil. MS (ESI): m/z [M+H]⁺ 271.9/274 (Cl isotope pattern).

Step D. i-82d
3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[Image Omitted]

In a vial a mixture of 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile compound i-82c (580 mg, 2.13 mmol) and K₂CO₃(885 mg, 6.40 mmol) in DMF (2 nL) was treated with iodomethane (3.03 g, 21.4 mmol) at rt under nitrogen and it was stirred at 60° C. for 1 h. The reaction mixture was poured into water (100 mL) and the mixture extracted with EtOAc (3×75 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the crude material purified by preparative TLC (DCM:PE=10:1) to give the title compound (401 mg, 66%) as a brown oil. MS (ESI): m/z [M+H]⁺ 285.9/288 (Cl isotope pattern).

Intermediate 83
Step A. i-83a
(1S,3S)—N¹-(1,2,4-Triazin-3-yl)cyclopentane-1,3-diamine

[Image Omitted]

HCl (4 M in MeOH, 4 mL, 16 mmol) was added slowly to tert-butyl ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22a (200 mg, 0.72 mmol) in MeOH (10 mL) at 20° C. and the resulting solution was stirred at 60° C. for 1 h. The solvent was removed under reduced pressure to give an unspecified HCl salt of the crude title compound (265 mg, 100%) as a brown gum that was directly used in the next step. MS (ESI): m/z [M+H]⁺ 179.8.

Step B. i-83b
6′-(((1S,3S)-3-((1,2,4-Triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

(1S,3S)—N¹-(1,2,4-Triazin-3-yl)cyclopentane-1,3-diamine compound i-83a (255 mg, 0.69 mmol) was added to 6′-fluoro-2H-[1,3′-bipyridin]-2-one compound i-100a (197 mg, 1.04 mmol) and K₂CO₃(477 mg, 3.45 mmol) in DMSO (5 mL) at 25° C. The resulting mixture was stirred at 120° C. for 15 h under a nitrogen atmosphere. The crude product was purified by C18 flash chromatography (gradient: 40-55% MeCN in water) to give the title compound (175 mg, 72%) as a brown gum. MS (ESI): m/z [M+H]⁺ 349.9.

Intermediate 84
Step A. i-84a

(1S,3S)—N¹-(6-Bromo-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[Image Omitted]

TFA (2.2 mL, 29 mmol) was added to tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (1.2 g, 3.4 mmol) in DCM (20 mL) at 30° C. and the resulting mixture stirred at this temperature for 5 h. The reaction mixture was concentrated, diluted with MeOH:DCM=1:10 (300 mL) and washed sequentially with sat. NaHCO₃(3×125 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated to give the crude title compound (0.563 g, 65%) as a black gum that was directly used in the next step. MS (ESI): m/z [M+H]⁺ 259.8.

Step B. i-84b
6′-(((1S,3S)-3-((6-Bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

(1S,3S)—N¹-(6-bromo-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-84a (530 mg, 2.05 mmol) was added to 6′-fluoro-2H-[1,3′-bipyridin]-2-one compound i-100a (781 mg, 4.11 mmol) and Na₂CO₃(653 mg, 6.16 mmol) in DMSO (20 mL) at 30° C. and the resulting mixture was stirred at 120° C. for 15 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with sat. brine (3×100 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the obtained residue was purified by preparative TLC (EtOAc) to give the title compound (117 mg, 13%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 427.8.

Intermediate 85
Step A. i-85a
tert-Butyl ((1S,3S)-3-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

Cs₂CO₃(819 mg, 2.51 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (300 mg, 0.84 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Reg. No. 903550-26-5) (466 mg, 1.67 mmol) and PdCl₂(dtbpf) (55 mg, 0.08 mmol) in 1,4-dioxane (5 mL) at 20° C. and the resulting suspension was stirred at 100° C. for 2 h under a nitrogen atmosphere. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the residue was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) to give the title compound (273 mg, 76%) as a brown solid. MS (ESI): m/z [M+H]⁺ 430.1.

Step B. i-85b
(1S,3S)—N¹-(6-(1H-Pyrazol-5-yl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[Image Omitted]

tert-Butyl ((1S,3S)-3-((6-(1-(tetrahydro-2-pyran-2-yl)-1H-pyrazol-5-yl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-85a (263 mg, 0.61 mmol) was added to TFA (2 mL) and DCM (2 mL) at 20° C. and the resulting solution stirred at 60° C. for 2 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) to give the title compound (431 mg, 100%) as a brown gum. MS (ESI): m/z [M+H]⁺ 245.9.

Intermediate 86
Step A. i-86a
tert-Butyl ((1S,3S)-3-((6-(ethylthio)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

Sodium ethanethiolate (141 mg, 1.67 mmol) was added to tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (200 mg, 0.56 mmol) in EtOH (5 mL) at 20° C. and the resulting solution was stirred at 60° C. for 16 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) to give the title compound (84 mg, 44%) as an orange solid. MS (ESI): m/z [M+H]⁺ 339.9.

Step B. i-86b
(1S,3S)—N¹-(6-(Ethylthio)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine×3.3TFA

[Image Omitted]

TFA (2 mL, 26 mmol) was added to tert-butyl ((1S,3S)-3-((6-(ethylthio)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-86a (73.8 mg, 0.22 mmol) in DCM (2 mL) at 20° C. and the resulting solution was stirred at this temperature for 16 h. The solvent was removed under reduced pressure to give the title compound (133 mg, 99%) as a brown gum.

The compound was used directly in the next step. MS (ESI): m/z [M+H]⁺ 239.9.

Intermediate 87
Step A. i-87a
rel-tert-Butyl ((1R,3R)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

DIPEA (0.94 mL, 5.4 mmol) and rel-tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (CAS Reg. No. 947732-58-3) (0.446 g, 2.23 mmol) were added to a solution of crude 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (0.283 g, 1.8 mmol) in MeCN (6 mL) and the resulting mixture was stirred at 50° C. for 5 days. The reaction solution was cooled to rt, concentrated under reduced pressure and the residue was dissolved in DCM and washed with 1 M NaOH (aq). The phases were separated and the aqueous phase was re-extracted with DCM (3×). The organic phases were combined, passed through a phase separator and concentrated. The obtained brown solid was further purified by flash chromatography on silica (gradient: 0-100% EtOAc:MeOH=95:5 in n-heptane) to give the title compound (0.280 g, 53%) as an yellow solid. MS (ESI): m/z [M+H]⁺ 294.1.

Step B. i-87b
rel-(1 R,3R)—N¹-(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3HCl

[Image Omitted]

A solution of rel-tert-butyl ((1 R,3R)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-87a (280 mg, 0.95 mmol) in dioxane (4 mL) was treated with HCl (4 M in dioxane, 5 mL, 20 mmol) at rt and the formed slurry was stirred at rt for 20 h. The mixture was concentrated to dryness to give the crude title compound (312 mg) as a light-yellow solid. MS (ESI): m/z [M+H]⁺ 194.1.

Intermediate 90
Step A. i-90a
6-Bromo-3-(methylthio)-1,2,4-triazine

[Image Omitted]

tert-Butyl nitrite (10.6 g, 103 mmol) was added dropwise to a mixture of 6-bromo-1,2,4-triazin-3-amine (CAS Reg. No. 58-4-028-01) (3.0 g, 17 mmol) and 1,2-dimethyldisulfane (16.2 g, 171 mmol) in MeCN (60 mL) at rt over a period of 10 minutes under air and the resulting solution was stirred at this temperature for 16 h. The solvent was removed under reduced pressure. The crude product was combined with three other equal batches prepared in the same way and purified by flash chromatography on silica (gradient: 0-20% EtOAc in n-heptane) to afford (8.60 g, 60%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 205.8/207.8 (Br isotope pattern).

Step B. i-90b
Ethyl 3-(methylthio)-1,2,4-triazine-6-carboxylate

[Image Omitted]

Pd(OAc)₂(0.142 g, 0.63 mmol) and XantPhos (0.584 g, 1.01 mmol) were added to a mixture of 6-bromo-3-(methylthio)-1,2,4-triazine compound i-90a (2.6 g, 12.6 mmol) and TEA (5.3 mL, 38 mmol) in EtOH (26 mL) at rt under air. The resulting suspension was put under an atmosphere of carbon monoxide (20 atm) and stirred at 85° C. for 16 h. The mixture was combined with three other equal batches prepared in the same way and filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL) and the combined filtrates were concentrated under reduced pressure. The obtained material was purified by flash chromatography on silica (gradient: 0-20% EtOAc in n-heptane) to afford (6.10 g, 73%) of the title compound as a yellow oil. MS (ESI): m/z [M+H]⁺ 200.

Step C. i-90c
3-(Methylthio)-1,2,4-triazine-6-carboxylic acid

[Image Omitted]

NaOH (1 M aq) (18 mL, 18 mmol) was added dropwise to ethyl 3-(methylthio)-1,2,4-triazine-6-carboxylate compound i-90b (3.0 g, 15 mmol) in THE (20 mL) and water (10 mL) at 0° C. and the resulting solution was stirred at rt for 1 h. The reaction mixture was diluted with water/ice (150 mL), the aqueous layer was adjusted to pH 2 with 2 M HCl (aq) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford (2.5 g, 97%) of the title compound as a brown gum which was used without further purification. MS (ESI): m/z [M+H]⁺ 172.

Step D. i-90d
3-(Methylthio)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide

[Image Omitted]

T3P in EtOAc (50% w/w) (18.6 g, 29.2 mmol) was added to a mixture of crude 3-(methylthio)-1,2,4-triazine-6-carboxylic acid compound i-90c (2.5 g, 14.6 mmol), oxetan-3-amine (2.14 g, 29.2 mmol) and DIPEA (7.65 mL, 43.8 mmol) in EtOAc (75 mL) at rt and the resulting solution was stirred at 60° C. for 15 h. The reaction mixture was poured into sat. NaHCO₃(aq) (150 mL) and extracted with EtOAc (3×125 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford yellow gum. Th is material was triturated with EtOAc:PE=1:3 (10 mL) to afford (1.0 g, 30%) of the title compound as a pale yellow solid. MS (ESI): m/z [M+H]⁺ 227.1.

Step E. i-90e
3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide

[Image Omitted]

m-CPBA (1.05 g, 4.86 mmol) was added dropwise to 3-(methylthio)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90d (1.0 g, 4.42 mmol) in DCM (10 mL) at rt and the resulting solution was stirred at rt for 30 min. (1S,3S)—N¹-(5-Iodopyridin-2-yl)cyclopentane-1,3-diamine×2HCl compound i-17a (1.08 g, 2.87 mmol) and TEA (3.1 mL, 22 mmol) were added to the reaction mixture and it was stirred at rt for another 8 h. The reaction mixture was poured into 1 M NaOH aq (150 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford yellow oil which solidified on standing. This material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) to afford (0.50 g, 23%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 481.7.

Intermediate 91
Step A. i-91a
Methyl 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzoate

[Image Omitted]

CataCXium A Pd G3 (55 mg, 0.08 mmol) was added to a mixture of methyl 3-bromo-4-fluoro-2-methoxybenzoate (CAS Reg. No. 1935415-04-05) (200 mg, 0.76 mmol), 2-chloropyridine-5-boronic acid (CAS Reg. No. 444120-91-6) (179 mg, 1.14 mmol), K₂CO₃(210 mg, 1.52 mmol) and water (2 mL) in 1,4-dioxane (8 mL) at rt under nitrogen and it was stirred at 80° C. for 8 h. The reaction mixture was poured into water (50 mL) and filtered through a Celite pad. The filtrate was extracted with EtOAc (3×25 mL) and the combined organic layers were dried over Na₂SO₄, filtered and evaporated. The obtained material was purified by preparative TLC (PE:EtOAc=3:1) to afford (160 mg, 71%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 296.0.

Step B. i-91b
Methyl 3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzoate

[Image Omitted]

(1S,3S)—N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (133 mg, 0.61 mmol) was added to a mixture of methyl 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzoate compound i-91a (150 mg, 0.51 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (43 mg, 0.05 mmol) and Cs₂CO₃(496 mg, 1.52 mmol) in 1,4-dioxane (10 mL) at rt under nitrogen and it was stirred at 100° C. for 8 h. The reaction mixture was poured into water (20 mL) and filtered through a Celite pad. The filtrate was extracted with EtOAc (3×10 mL) and the combined organic layers were dried (Na₂SO₄), filtered and evaporated. The obtained material was purified by preparative TLC (EtOAc:PE=1:1) to afford (90 mg, 37%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 479.2.

Intermediate 92
Step A. i-92a
3-Bromo-4-fluoro-2-methoxybenzamide

[Image Omitted]

Sodium methoxide (30% w/w in MeOH, 458 mg, 2.54 mmol) was added dropwise to 3-bromo-2,4-difluorobenzamide (CAS Reg. No. 1518200-63-9) (500 mg, 2.12 mmol) in DMSO (30 mL) at rt and the resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with sat. NH₄Cl aq (3×50 mL), dried (Na₂SO₄), filtered and evaporated and the residue was purified by preparative TLC (DCM:MeOH=30:1) to afford (400 mg, 76%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 249.8.

Step B. i-92b
3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide

[Image Omitted]

3-Bromo-4-fluoro-2-methoxybenzamide compound i-92a (320 mg, 1.29 mmol) was added to a mixture of PdCl₂(dppf) DCM adduct (105 mg, 0.13 mmol), Na₂CO₃(273 mg, 2.58 mmol) and 2-chloropyridine-5-boronic acid (CAS Reg. No. 444120-91-6) (305 mg, 1.94 mmol) in 1,4-dioxane (15 mL) and water (2.5 mL) at rt and it was stirred at 80° C. for 8 h. The reaction mixture was poured into water (50 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3×) and the combined organic layers were dried (Na₂SO₄), filtered and evaporated. The obtained material was purified by preparative TLC (EtOAc:PE=1:2) to afford (130 mg, 36%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 281.

Step C. i-92c
3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzonitrile

[Image Omitted]

TFAA (0.13 mL, 0.93 mmol) was added to a mixture of TEA (0.258 mL, 1.85 mmol) and 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide compound i-92b (130 mg, 0.46 mmol) in DCM (10 mL) at 0° C. The reaction was allowed to reach rt and stirred at rt for 4 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated and the obtained material was purified by preparative TLC (PE:EtOAc=3:1) to afford (100 mg, 82%) of the title compound as a yellow solid. MS (ESI): m/z [M+H]⁺ 263.

Intermediate 100
i-100a
6′-Fluoro-2H-[1,3′-bipyridin]-2-one

[Image Omitted]

rel-(1R,2R)—N¹,N²-Dimethylcyclohexane-1,2-diamine (1.50 g, 10.5 mmol) was added to a mixture of pyridin-2(1H-one (CAS Reg. No. 142-08-5) (5.0 g, 52.6 mmol), 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (17.6 g, 78.9 mmol), Cu(I)I (4.01 g, 21.0 mmol) and K₂CO₃(14.53 g, 105.2 mmol) in 1,4-dioxane (50 mL) and it was stirred at 90° C. for 18 h under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica (gradient: 0-50% EtOAc in PE) to give the title compound (11.6 g, 116%) as a brown solid. MS (ESI): m/z [M+H]⁺ 191.1. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 6.36 (1H, dt), 6.52 (1H, d), 7.36 (1H, dd), 7.54 (1H, ddd), 7.73 (1H, dd), 8.14 (1H, ddd), 8.35 (1H, dd).

Intermediate 104
Step A. i-104a
tert-Butyl ((1S,3S)-3-((6-(1-ethoxyvinyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[Image Omitted]

Bis(triphenylphosphine)palladium (II) dichloride (CAS Reg. No. 13965-03-2) (59 mg, 0.08 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclo-pentyl)carbamate compound i-22b (300 mg, 0.84 mmol), tributyl(1-ethoxyvinyl)tin (CAS Reg. No. 97674) (605 mg, 1.67 mmol) and lithium chloride (177 mg, 4.19 mmol) in 1,4-dioxane (20 mL) at 20° C. under a nitrogen atmosphere and it was stirred at 100° C. for 6 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica (gradient: 2-25% EtOAc in PE) to give the title compound along with tin impurities (500 mg) as a yellow solid. MS (ESI): m/z [M+H]⁺ 350.1.

Step B. i-104b
1-(3-(((1S,3S)-3-Aminocyclopentyl)amino)-1,2,4-triazin-6-yl)ethan-1-one

[Image Omitted]

4 M HCl in dioxane (4.0 mL, 16 mmol) was added to tert-butyl ((1S,3S)-3-((6-(1-ethoxyvinyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-104a (250 mg, 1.05 mmol) in EtOAc (3 mL) at 20° C. and the resulting suspension was stirred at 20° C. for 18 h. The solvent was removed under reduced pressure to give an unspecified HCl salt of the title compound (200 mg) as a yellow gum which was used without further purification. MS (ESI) m/z [M+H]⁺ 222.

Intermediate 107
Step A. i-107a
4-Bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H-one

[Image Omitted]

1-(Chloromethyl)-4-methoxybenzene (7.48 g, 47.8 mmol) was added to a mixture of 4-bromo-6-chloro-3(2H-pyridazinone (CAS Reg. No. 933041-13-5) (5.0 g, 24 mmol) and Cs₂CO₃(15.6 g, 47.8 mmol) in MeCN (80 mL) at 15° C. and it was stirred at 60° C. for 3 h. The mixture was filtered through a pad of Celite, the filter cake washed with DCM (3×20 mL) and the combined filtrates were concentrated under reduced pressure. The obtained material was triturated with EtOAc:PE=1:5 (25 mL), the formed solid collected by filtration and dried under vacuum to give the title compound (7.8 g, 98%) as a yellow solid. MS (ESI): m/z [M+H]⁺ 329/331 (Br/Cl isotope pattern).

Step B. i-107b
6-Chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[Image Omitted]

RockPhos Pd G3 (CAS Reg. No. 2009020-38-4) (1.97 g, 2.35 mmol) was added to a mixture of 4-bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107a (7.75 g, 23.5 mmol), (E)-benzaldehyde oxime (3.70 g, 30.6 mmol) and Cs₂CO₃(15.6 g, 47.8 mmol) in DMF (40 mL) and water (10 mL) at 15° C. and it was stirred at 80° C. for 15 h. The reaction mixture was poured into sat. brine (100 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with sat. brine (3×100 mL), dried over Na₂SO₄, filtered and evaporated and the residue was purified by flash chromatography on silica (gradient: 0-100% EtOAc in PE) to give the title compound (4.0 g, 64%) as a tan solid. MS (ESI): m/z [M+H]⁺ 267/269 (Cl isotope pattern).

Step C. i-107c
6-Chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[Image Omitted]

Cs₂CO₃(293 mg, 0.90 mmol) was added to a mixture of 6-chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107b (200 mg, 0.75 mmol) and it was stirred at 20° C. for 1.5 h. Sodium chlorodifluoroacetate (CAS Reg. No. 1895-39-2) (343 mg, 2.25 mmol) was added and the resulting mixture was stirred at 100° C. for 3.5 h. The reaction mixture was poured into sat. brine (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with sat. brine (3×50 mL), dried over Na₂SO₄, filtered and evaporated and the residue was purified by reparative TLC (EtOAc:PE=1:3) to give the title compound (175 mg, 74%) as a yellow gum. MS (ESI): m/z [M+H]⁺ 317/319 (Cl isotope pattern).

Step D. i-107d
4-(Difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[Image Omitted]

Pd—C (11 mg, 0.11 mmol) was added to a mixture of 6-chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107c (680 mg, 2.15 mmol) in MeOH (30 mL) at 20° C. and the resulting suspension was stirred at this temperature for 2 h under a hydrogen atmosphere. The reaction mixture was concentrated under reduced pressure to afford the title compound (576 mg, 95%) as a white solid which was directly used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 283.0.

Step E. i-107e
4-(Difluoromethoxy)pyridazin-3(2H)-one

[Image Omitted]

TFA (20 mL) was added to 4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107d (546 mg, 1.93 mmol) at 20° C. and the mixture was stirred at 80° C. for 15 h.

The reaction mixture was concentrated under reduced pressure to give an unspecified TFA salt of the title compound (483 mg, 90%) as a black gum which was used without further purification. MS (ESI): m/z [M+H]⁺ 162.9.

Intermediate 108
Step A. i-108a
2-Bromo-1-(6-fluoropyridin-3-yl)propan-1-one

[Image Omitted]

A solution of 1-(6-fluoropyridin-3-yl)propan-1-one (CAS Reg. No. 949154-27-2) (201 mg, 1.31 mmol) in HOAc (2 mL) was treated with HBr (CAS Reg. No. 10035-10-6) (33 wt % in HOAc, 238 μL, 1.31 mmol) and bromine (67 μL, 1.3 mmol) and the mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude title compound (410 mg) which was used in the next step without further purification.

Step B. i-108b
4-(6-Fluoropyridin-3-yl)-2,5-dimethyloxazole

[Image Omitted]

A mixture of crude 2-bromo-1-(6-fluoropyridin-3-yl)propan-1-one compound i-108a (270 mg, 1.2 mmol) in xylenes (4 mL) was treated with acetamide (593 mg, 11.6 mmol) and stirred at 135° C. for 20 h. The reaction mixture was concentrated under reduced pressure and the obtained residue purified by preparative HPLC (PrepMethod Z9, gradient: 20-60%) to give the title compound (83 mg, 37%) as a brown solid. MS (ESI): m/z [M+H]⁺ 193.0. ¹H NMR (500 MHz, CDCl₃) δ ppm 2.44 (3H, s), 2.47 (3H, s), 6.96 (1H, dd), 8.04 (1H, dt), 8.42 (1H, d).

Intermediate 109
Step A. i-109a
2-(2-(Benzyloxy)ethyl)malonamide

[Image Omitted]

The reaction was run in 10 parallel batches of identical size.

Diethyl 2-(2-(benzyloxy)ethyl)malonate (CAS Reg. No. 41478-45-9) (2.0 g, 6.8 mmol) was treated with NH₃(7 M in MeOH, 25 mL, 140 mmol) at rt and the mixture was stirred at 60° C. for 16 h. The 10 reaction mixtures were combined and concentrated under reduced pressure. The obtained material was triturated with EtOAc (50 mL), the solid isolated by filtration and dried under reduced pressure to give the title compound (14.7 g, 92%) as a white solid. MS (ESI): m/z [M+H]⁺ 237.3.

Step B. i-109b
Di-tert-butyl (2-(2-(benzyloxy)ethyl)propane-1,3-diyl)dicarbamate

[Image Omitted]

A solution of 2-(2-(benzyloxy)ethyl)malonamide compound i-109a (13.5 g, 57.1 mmol) in THE (250 mL) was treated with BH3xSMe₂(10 M in SMe₂, 45.7 mL, 457 mmol) at 20° C. and the reaction mixture stirred at 60° C. for 16 h. The mixture was quenched with MeOH (400 mL) and concentrated under reduced pressure to give a pale-yellow gum. This material was dissolved in 1,4-dioxane (250 mL) at 20° C. and treated with Na₂CO₃(18.2 g, 171 mmol) in water (250 mL) followed by Boc₂O (39.8 mL, 171 mmol) and the resulting suspension stirred at 20° C. for 15 h. The reaction mixture was poured into sat. brine (500 mL) and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the obtained material purified by flash chromatography on silica (gradient: 2-20% EtOAc in PE) to give the title compound (9.0 g, 39%) as a colourless gum. MS (ESI): m/z [M+H]⁺ 409.3.

Step C. i-109c
Di-tert-butyl (2-(2-hydroxyethyl)propane-1,3-diyl)dicarbamate

[Image Omitted]

Pd(OH)₂—C (15%, 928 mg, 0.99 mmol) was added to a mixture of di-tert-butyl (2-(2-(benzyloxy)ethyl)propane-1,3-diyl)dicarbamate compound i-109b (9.0 g, 22 mmol) and TFA (3.0 mL, 39 mmol) in MeOH (50 mL) at 20° C. The resulting suspension was evacuated and backfilled with hydrogen gas 3 times and stirred at 20° C. for 16 h under a hydrogen atmosphere. The mixture was concentrated under reduced pressure to afford the title compound (7.0 g, quant.) as a colourless gum which was directly used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 319.2.

Step D. i-109d
rac-tert-Butyl (2-(aminomethyl)-4-hydroxybutyl)carbamate

[Image Omitted]

A solution of crude di-tert-butyl (2-(2-hydroxyethyl)propane-1,3-diyl)dicarbamate compound i-109c (7.0 g, 22 mmol) in MeOH (20 mL) was treated with HCl in MeOH (4 M, 20 mL, 80 mmol) at 20° C. and the reaction mixture was stirred at 60° C. for 5 h. The mixture was concentrated under reduced pressure and the obtained material was triturated with EtOAc (20 mL). The formed solid (fully deprotected title compound) was filtered off and the filtrate concentrated under reduced pressure to give an unspecified HCl salt of the title compound (1.4 g, purity 70%) as a pale-yellow gum which was directly used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 219.2.

Step E. i-109e
rac-tert-Butyl (4-hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)carbamate

[Image Omitted]

A suspension of crude rac-tert-butyl (2-(aminomethyl)-4-hydroxybutyl)carbamate compound i-109d (1.4 g) and K₂CO₃(1.55 g, 11.2 mmol) in i-PrOH (40 mL) was treated with 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (0.283 g, 1.8 mmol) at 20° C. and the reaction mixture was stirred at 100° C. for 15 h. The mixture was cooled to rt and concentrated under reduced pressure and the obtained material was purified by flash chromatography on silica (gradient: 0-5% 7 M NH₃in MeOH:DCM) to give the title compound (700 mg, 10% over three steps) as a pale-yellow gum. MS (ESI): m/z [M+H]⁺ 312.

Step F. i-109f
rac-4-Amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl butan-1-ol

[Image Omitted]

A solution of rac-tert-butyl (4-hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)carbamate compound i-109e (700 mg, 2.25 mmol) in MeOH (15 mL) was treated with HCl in MeOH (4 M, 3.0 mL, 12 mmol) at 20° C. and the reaction mixture was stirred at 60° C. for 15 h. The mixture was concentrated under reduced pressure to give an unspecified HCl salt of the title compound (530 mg) as a yellow gum which was directly used in the next step without further purification. MS (ESI): m/z [M+H]⁺ 212.1.

Step G. i-109g
rac-4-((5-Iodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol

[Image Omitted]

According to GM1A 2-fluoro-5-iodopyridine (CAS Reg. No. 171197-80-1) (499 mg, 2.24 mmol) was added to crude rac-4-amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109f (530 mg, 1.86 mmol) and K₂CO₃(515 mg, 3.73 mmol) in DMSO (10 mL) at 20° C. The resulting mixture was stirred at 120° C. for 15 h, cooled to rt and poured into sat. brine (250 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na₂SO₄, filtered and evaporated to afford a brown gum. The obtained material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) to give the title compound (230 mg, 25% over two steps) as a yellow gum. MS (ESI): m/z [M+H]⁺ 415.1. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49 (2H, q), 1.99 (1H, quint), 2.38 (3H, s), 3.23-3.39 (4H, m), 3.49 (2H, t), 5.75 (1H, s), 6.41 (1H, d), 6.78 (1H, brs), 7.44 (1H, brs), 7.56 (1H, dd), 8.06 (1H, d), 8.14 (1H, s).

EXAMPLES
Example 10
Ethyl 3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxylate—compound 10

[Image Omitted]

According to GM1B 6′-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one compound i-1c (226 mg, 0.84 mmol), ethyl 3-bromo-1,2,4-triazine-6-carboxylate (CAS Reg. No. 2091717-09-6) (194 mg, 0.84 mmol) and DIPEA (0.437 mL, 2.51 mmol) were reacted in NMP (2 mL) under microwave irradiation at 100° C. for 1 h to give upon purification by preparative HPLC (PrepMethod F, gradient: 15-55%) the title compound (182 mg, 52%) as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₄N₇O₃: 422.1936, found: 422.1924. ¹H NMR (500 MHz, DMSO-d₆, mixture of two rotamers ca 1.4/1) δ ppm 1.32 (3H, t), 1.5-1.58 (1H, m), 1.58-1.67 (1H, m), 1.87-2.04 (2H, m), 2.11-2.24 (2H, m), 4.29-4.44 (4H, m), 6.27 (1H, td), 6.44 (1H, dt), 6.53 (1H, d), 6.94-7.02 (1H, m), 7.40 (1H, dd), 7.44-7.51 (1H, m), 7.57-7.63 (1H, m), 7.93 (1H, d), 8.58 (d, minor rotamer), 8.63-8.71 (1H, m), 9.09 (1H, d, major rotamer).

Example 50
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 50

[Image Omitted]

K₃PO₄(60 mg, 0.28 mmol) was added to a mixture of (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (40 mg, 0.09 mmol), pyridin-2(1H)-one (CAS Reg. No. 142-08-5) (27 mg, 0.28 mmol), Cu(I)I (9.0 mg, 0.05 mmol) and N¹,N²-dimethylethane-1,2-diamine (4.2 mg, 0.05 mmol) in dioxane (2 mL) and the resulting suspension was heated at 100° C. for 16 h under nitrogen. The solvent was removed under reduced pressure and the residue was poured into water (50 mL), extracted with EtOAc (2×100 mL), dried (Na₂SO₄), filtered and evaporated to afford a crude product which was purified by preparative TLC (MeOH:DCM=1:40) followed by preparative HPLC (PrepMethod A, gradient: 33-58%) to give (12.4 mg, 34%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₄N₇O: 390.2036, found: 390.2042. ¹H NMR (300 MHz, DMSO-d₆) b ppm 0.82-1.01 (4H, m), 1.42-1.63 (2H, m,), 1.90 (2H, m), 1.99-2.22 (3H, m), 4.21-4.42 (2H, m), 6.25 (1H, td), 6.43 (1H, ddd), 6.51 (1H, dd), 6.91 (1H, d), 7.38 (1H, dd), 7.42-7.63 (3H, m), 7.91 (1H, d), 8.17 (1H, s).

Example 51
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(trifluoromethyl)-2H-[1,3′-bipyridin]-2-one—compound 51

[Image Omitted]

According to GM3 (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (90 mg, 0.21 mmol), 3-(trifluoromethyl)pyridin-2(1H-one (CAS Reg. No. 22245-83-6) (695 mg, 4.26 mmol), Cs₂CO₃(417 mg, 1.28 mmol), Cu(I)I (162 mg, 0.85 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (121 mg, 0.85 mmol) were reacted in 1,4-dioxane (10 mL) at 100° C. for 15 h to give upon aqueous work-up and purification by preparative TLC (7 M NH₃in MeOH:DCM=1:20) followed by preparative HPLC (PrepMethod B, 34-54%) the title compound (33 mg, 33%) as a pale yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₃F₃N₇O: 458.1910, found: 458.1928. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.87-1.00 (4H, m), 1.45-1.65 (2H, m), 1.85-2.24 (5H, m), 4.29-4.42 (2H, m), 6.43 (1H, t), 6.55 (1H, d), 7.03 (1H, d), 7.46 (1H, dd), 7.55 (1H, br d), 7.97-8.04 (3H, m), 8.19 (1H, s).

Example 52
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(trifluoromethoxy)-2H-[1,3′-bipyridin]-2-one—compound 52

[Image Omitted]

Prepared in analogy to Example 51 from (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (90 mg, 0.21 mmol) and 3-(trifluoromethoxy)pyridin-2-ol compound i-9b (382 mg, 2.13 mmol) and purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) followed by preparative HPLC (PrepMethod B, gradient: 38-58%) to give a white solid (20 mg, 19%). HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₃F₃N₇O₂: 474.1860, found: 474.1816. ¹H NMR (300 MHz, DMSO-de) b ppm 0.87-1.00 (4H, m), 1.45-1.61 (2H, m), 1.88-2.21 (5H, m), 4.28-4.39 (2H, m), 6.33 (1H, t), 6.55 (1H, d), 7.02 (1H, d), 7.45 (1H, dd), 7.50-7.60 (1H, m), 7.69-7.74 (2H, m), 7.98 (1H, d), 8.19 (1H, s).

Example 53
(1S,3S)—N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)-N¹-(5-(2,6-difluorophenyl)pyridin-2-yl)cyclopentane-1,3-diamine—compound 53

[Image Omitted]

According to GM4A (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N¹-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (95 mg, 0.22 mmol), (2,6-difluorophenyl)boronic acid (CAS Reg. No. 162101-25-9) (71 mg, 0.45 mmol), PdCl₂(dppf) (CAS Reg. No 72287-26-4) (16 mg, 0.02 mmol) and K₂CO₃(93 mg, 0.67 mmol) were reacted in a mixture of 1,4-dioxane (8 mL) and water (2 mL) at 100° C. for 15 h. Aqueous work-up of the reaction mixture and purification by preparative TLC (EtOAc:PE=1:1) followed by preparative HPLC (PrepMethod D, gradient: 44-59%) gave the title compound (18 mg, 19%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₃F₂N₆: 409.1946, found: 409.1960. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.94 (m, 4H), 1.45-1.66 (m, 2H), 1.92 (m, 2H), 1.99-2.24 (m, 3H), 4.37 (d, 2H), 6.53-6.61 (m, 1H), 6.93 (d, 1H), 7.12-7.24 (m, 2H), 7.34-7.49 (m, 2H), 7.55 (s, 1H), 8.04 (d, 1H), 8.19 (s, 1H).

Example 54
(1S,3S)—N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)-N¹-(5-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)cyclopentane-1,3-diamine—compound 54

[Image Omitted]

Prepared in analogy to Example 53 from (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N¹-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (95 mg, 0.22 mmol) and (2-fluoro-6-methoxyphenyl)boronic acid (CAS Reg. No. 78495-63-3) (76 mg, 0.45 mmol) applying 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (15 mg, 0.02 mmol) and purified by preparative TLC (EtOAc:PE=2:1) followed by preparative HPLC (PrepMethod C, gradient: 40-65%) to give a white solid (46 mg, 48%). HRMS (ESI) m/z [M+H]+ calcd for C₂₃H₂₆FN₆O: 421.2146, found: 421.2166. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.7-1.08 (4H, m), 1.42-1.77 (2H, m), 1.81-1.99 (2H, m), 1.99-2.32 (3H, m), 3.75 (3H, s), 4.19-4.57 (2H, m), 6.51 (1H, d), 6.73 (1H, d), 6.8-7.07 (2H, m), 7.2-7.45 (2H, m), 7.55 (1H, d), 7.83-8.03 (1H, m), 8.19 (1H, s).

Example 55
3-Chloro-6′-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 55

[Image Omitted]

According to GM1A (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4TFA compound i-22d (80 mg, 0.36 mmol), 3-chloro-6′-fluoro-2H-[1,3′-bipyridin]-2-one compound i-13a (164 mg, 0.73 mmol) and K₂CO₃(151 mg, 1.09 mmol) were reacted in DMSO (15 mL) at 120° C. for 15 h to give upon non-aqueous work-up and purification by preparative TLC (EtOAc:PE=2:1) followed by preparative HPLC (PrepMethod D, gradient: 24-44%) the title compound (45 mg, 29%) as a pale yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₃ClN₇O: 424.1648, found: 424.1650. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.87-1.00 (4H, m), 1.42-1.66 (2H, m), 1.87-2.21 (5H, m), 4.28-4.39 (2H, m), 6.31 (1H, t), 6.54 (1H, d), 7.01 (1H, d), 7.44 (1H, dd), 7.50-7.61 (1H, m), 7.67 (1H, dd), 7.82 (1H, dd), 7.96 (1H, d), 8.19 (1H, s).

Example 56
Example
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile—compound 56

[Image Omitted]

According to GM2 (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4TFA compound i-22d (292 mg, 0.43 mmol), 6′-chloro-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile compound i-8d (100 mg, 0.43 mmol), Cs₂CO₃(563 mg, 1.73 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (18 mg, 0.02 mmol) were reacted in 1,4-dioxane (12 mL) at 100° C. for 15 h to give upon non-aqueous work-up and purification by preparative HPLC (PrepMethod D, gradient: 23-43%) the title compound (71 mg, 39%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₃N₈O: 415.1990, found: 415.1970. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.77-1.04 (4H, m), 1.38-1.68 (2H, m), 1.8-1.97 (2H, m), 1.97-2.23 (3H, m), 4.2-4.45 (2H, m), 6.53 (2H, t), 7.02 (1H, d), 7.42 (1H, dd), 7.53 (1H, d), 7.72 (1H, dd), 7.97 (1H, d), 8.17 (1H, s), 8.55 (1H, d).

Example 57
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methylimidazolidine-2,4-dione—compound 57

[Image Omitted]

According to GM2 Cs₂CO₃(238 mg, 0.73 mmol) was added to a mixture of (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (128 mg, 0.59 mmol), 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione compound i-7b (110 mg, 0.49 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (20.50 mg, 0.02 mmol) in 1,4-dioxane (3 mL) at 25° C.

The resulting suspension was stirred at 100° C. for 16 h under a nitrogen atmosphere. The solvent was removed under reduced pressure, the residue taken up with water (50 mL) and extracted with DCM (2×100 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the obtained residue was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) followed by preparative HPLC (PrepMethod D, gradient: 20-35%) to give the title compound (10 mg, 5%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₅N₈O₂: 409.2094, found: 409.2104. ¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (m, 4H), 1.44-1.63 (m, 2H), 1.92 (m, 2H), 2.01-2.08 (m, 1H), 2.08-2.20 (m, 2H), 2.91 (s, 3H), 4.08 (s, 2H), 4.32 (m, 2H), 6.52 (m, 1H), 6.89 (d, 1H), 7.27 (m, 1H), 7.55 (d, 1H), 7.80-7.88 (m, 1H), 8.18 (s, 1H).

TABLE 7

The following Examples (58-66) where prepared in analogy to Example 57 starting

from compound i-22d and the given electrophile intermediate, applying Buchwald-Hartwig

amination (GM2). For the preparation of Example 58 DMF was used as solvent.

Work-Up/

Purification

Ex
Structure/Name
Analytical Data
Method/ Yield
Intermediate

58

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₃N₈O: 415.1990, found: 415.2022. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.81- 1.04 (4H, m), 1.4-1.7 (2H, m), 1.81-2.23 (5H, m), 4.24-4.44 (2H, m), 6.47 (1H, t), 6.55 (1H, d), 7.06 (1H, d), 7.46 (1H, dd), 7.55 (1H, d), 7.99
Aqueous work- up; Prep. TLC (EtOAc) and prep. HPLC applying PrepMethod B (gradient: 29- 49%); (15 mg, 2%)
compound i-10a (DMF used as solvent)

6′-(((1 S,3S)-3-((6-Cyclopropyl-
(1H, d), 8.06 (1H, dd),

1,2,4-triazin-3-yl)amino)cyclo-
8.19 (1H, s), 8.23 (1H,

pentyl)amino)-2-oxo-2H-[1,3′-
dd)

bipyridine]-3-carbonitrile

59

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₁₉H₂₂N₉O: 392.1942, found: 392.1946. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.83- 1.07 (4H, m), 1.46-1.69 (2H, m), 1.85-2.29 (5H, m), 4.22-4.49 (2H, m), 7.06 (1H, dd), 7.50 (1H, dd), 7.58 (2H, d), 7.86
Non-aqueous work-up; Prep. TLC (MeOH: DCM = 1:20) and prep. HPLC applying PrepMethod B (gradient: 18- 36%);
compound i-11a

(1H, d), 8.02 (1H, dd),
(50 mg, 18%)

2-(5-(((1 S,3S)-3-((6-
8.13 (1H, d), 8.19 (1H,

Cyclopropyl-1,2,4-triazin-3-
s).

yl)amino)cyclo-

pentyl)amino)pyrazin-2-

yl)pyridazin-3(2H)-one

60

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₆N₇O: 404.2194, found: 404.2190. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84- 1.03 (4H, m), 1.4-1.67 (2H, m), 1.78-2 (2H, m), 2-2.22 (3H, m), 3.48 (3H, s), 4.24-4.44 (2H, m), 6.27 (1H, t), 6.46
Non-aqueous work-up; Prep. HPLC applying PrepMethod D (gradient: 24- 35%); (47 mg, 25%)
compound i-12a

(1H, d), 6.70 (1H, d),

6′-(((1 S,3S)-3-((6-Cyclopropyl-
7.47-7.61 (2H, m), 7.64

1,2,4-triazin-3-yl)amino)cyclo-
(1H, dd), 7.75 (1H, dd),

pentyl)amino)-1-methyl-[3,3′-
8.18 (1H, s), 8.33 (1H,

bipyridin]-2(1H)-one
d).

61

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₂FN₈: 417.1946, found: 417.1958. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.85 − 1.01 (m, 4H), 1.57 (m, 2H), 1.85 − 2.07 (m, 3H), 2.16 (m, 2H), 4.39 (m, 2H), 6.62 (d, 1H), 7.32 (d, 1H), 7.56 (d, 1H), 7.91 − 8.07 (m, 3H), 8.18 (s, 1H), 8.59 (m, 1H).
Aqueous work- up; Prep. TLC (EtOAc:PE = 2:1) and prep. HPLC applying PrepMethod D (gradient: 35- 55%); (75 mg, 20%)
compound i-14a

6′-(((1 S,3S)-3-((6-Cyclopropyl-

1,2,4-triazin-3-yl)amino)

cyclopentyl)amino)-3-fluoro-[2,3′-

bipyridine]-6-carbonitrile

62

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₀H₂₅N₈O₂: 409.2094, found: 409.2054. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 - 1.03 (4H, m), 1.41 − 1.63 (2H, m), 1.79 − 1.98 (2H, m), 2.00 − 2.21 (3H, m), 2.92 (3H, s), 4.18 − 4.43 (4H, m), 6.50 (1H, d),
Aqueous work- up; Prep. TLC (MeOH (7 M NH₃):DCM = 1:25) and prep. HPLC applying PrepMethod B (gradient: 24- 44%);
compound i-23a

6.62 (1H, d), 7.53 (1H,
(28 mg, 22%)

1-(6-(((1 S,3S)-3-((6-
s), 7.63 (1H, dd), 8.10

Cyclopropyl-1,2,4-triazin-3-
(1H, d), 8.18 (1H, s).

yl)amino)cyclo-

pentyl)amino)pyridin-3-yl)-3-

methylimidazolidine-2,4-dione

63

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₃H₂₆N₉O: 444.2254, found: 444.2226. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.78 - 1.04 (4H, m), 1.44 − 1.65 (2H, m), 1.79 − 2.28 (5H, m), 3.39 (3H, s), 4.34 (2H, t), 6.58 (1H, d), 6.91 (1H, d), 7.12 (1H, dd),
Aqueous work- up; Prep. TLC (MeOH (7 M NH₃):DCM = 1:25) and prep. HPLC applying PrepMethod D (gradient: 18- 48%); (50 mg, 33%)
compound i-24a

7.43 − 7.63 (3H, m), 7.92

3-(6-(((1 S,3S)-3-((6-
(1H, d), 8.08 (1H, d),

Cyclopropyl-1,2,4-triazin-3-
8.17 (1H, s).

yl)amino)cyclo-

pentyl)amino)pyridin-3-yl)-1-

methyl-1,3-dihydro-2H-

imidazo[4,5-b]pyridin-2-one

64

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₆N₇O₂: 420.2142, found: 420.2154. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.8-1.0 (4H, m), 1.43 − 1.67 (2H, m), 1.84 − 2.23 (5H, m), 3.73 (3H, s), 4.25 − 4.45 (2H, m), 6.20 (1H, t), 6.53 (1H, d), 6.86 (1H, dd), 6.93 (1H, d), 7.17
Non-aqueous work-up; Prep. TLC (MeOH (7 M NH₃):DCM = 1:20) and prep. HPLC applying PrepMethod B (gradient: 23- 41%); (51 mg, 19%)
compound i-25a

6′-(((1 S,3S)-3-((6-Cyclopropyl-
(1H, dd), 7.38 (1H, dd),

1,2,4-triazin-3-yl)amino)cyclo-
7.55 (1H, d), 7.91 (1H,

pentyl)amino)-3-methoxy-2H-
d), 8.18 (1H, s).

[1,3′-bipyridin]-2-one

65

[Image Omitted]

6′-(((1 S,3S)-3-((6-Cyclopropyl- 1,2,4-triazin-3-yl)amino)cyclopentyl)
HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₆N₇O₂: 420.2142, found: 420.2148. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.70 - 1.07 (4H, m), 1.40 − 1.60 (2H, m), 1.8 − 2.0 (2H, m), 2.0 − 2.25 (3H, m), 3.63 (3H, s), 4.03 − 4.58 (2H, m), 6.46 (2H, dd), 6.89 (1H, d), 7.17 (1H, d), 7.26 − 7.46 (2H, m), 7.53 (1H, s), 7.77 − 8.05 (1H, m), 8.17 (1H, s).
Aqueous work- up; Prep. TLC (MeOH (7 M NH₃):DCM = 1:20) and prep. HPLC applying PrepMethod B (gradient: 26- 46%); (60 mg, 23%)
compound i-26a

amino)-5-methoxy-2H-

[1,3′-bipyridin]-2-one

66

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₆N₇O: 404.2194, found: 404.2226. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 - 1.01 (4H, m), 1.4 − 1.7 (2H, m), 1.8 − 2.2 (8H, m), 4.51 − 4.22 (2H, m), 6.19 (1H, t), 6.53 (1H, d), 6.92 (1H, d), 7.33 − 7.42 (2H, m), 7.46 (1H, dd),
Non-aqueous work-up; Prep. TLC (MeOH (7 M NH₃):DCM = 1:20) and prep. HPLC applying PrepMethod B (gradient: 25- 55%); (51 mg, 28%)
compound i-27a

7.50 − 7.62 (1H, m), 7.92

6′-(((1 S,3S)-3-((6-Cyclopropyl-
(1H, d), 8.18 (1H, s).

1,2,4-triazin-3-yl)amino)

cyclopentyl)amino)-3-methyl-2H-

[1,3′-bipyridin]-2-one

Example 67
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 67

[Image Omitted]

According to GM2 Cs₂CO₃(329 mg, 1.01 mmol) was added to a mixture of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 2TFA compound i-28b (85 mg, 0.20 mmol), 6′-chloro-2H-[1,3′-bipyridin]-2-one compound i-29a (62 mg, 0.30 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (8.5 mg, 10 μmol) in dioxane (5 mL) at rt and the resulting suspension was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (200 mL) and washed sequentially with saturated brine (2×15 mL) and water (2×15 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford crude product which was purified by preparative TLC (MeOH:DCM=1:25) followed by preparative HPLC (PrepMethod C, gradient: 10-30%) to give (35 mg, 48%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₂N₇O: 364.1880, found: 364.1866. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.66 (2H, m), 1.85-2.00 (2H, m), 2.06-2.24 (2H, m), 2.39 (3H, s), 4.25-4.45 (2H, m), 6.27 (1H, td), 6.44 (1H, ddd), 6.53 (1H, dd), 6.94 (1H, d), 7.37-7.65 (4H, m), 7.90-7.96 (1H, m), 8.17 (1H, s).

Example 68
N-(2-Amino-2-oxoethyl)-3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide—compound 68

[Image Omitted]

According to GM7, ethyl 3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclo-pentyl)amino)-1,2,4-triazine-6-carboxylate compound 10 (33.3 mg, 0.08 mmol) was mixed with DMSO (0.5 mL), DIPEA (0.055 mL, 0.32 mmol) and 2-aminoacetamide HCl (CAS Reg. No. 1668-10-6) (17 mg, 0.16 mmol) and it was stirred at 70° C. overnight. The volatiles were removed and the residue redissolved in MeOH (1 mL). Another amount of DIPEA (55 PL, 0.32 mmol) and 2-aminoacetamide HCl (17 mg, 0.16 mmol) was added and the reaction mixture stirred at 70° C. for one week. Purification by preparative SFC (PrepMethod SFC-A) gave the title compound (1.8 mg, 5%). HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₄N₉O₃: 450.1996, found: 450.1984. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.51-1.66 (2H, m), 1.88-2.01 (2H, m), 2.1-2.22 (2H, m), 3.85 (2H, d), 6.27-6.31 (1H, m), 6.44 (1H, d), 6.53 (1H, d), 6.94 (1H, s), 7.08 (1H, s), 7.39 (1H, dd), 7.43 (1H, s), 7.48 (1H, ddd), 7.58 (1H, d), 7.90 (1H, d), 8.66 (1H, s), 8.80 (1H, s).

TABLE 8

The following Examples (69-76) where prepared in analogy to Example 68 starting

from compound 10 and the given amine, applying GM7.

Amine

(CAS Reg.

Purification
No.)/

Method/
Equivalents

Ex
Structure/Name
Analytical Data
Yield
used

69

[Image Omitted]

HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₃N₈O₂: 431.1938, found: 431.1970. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.58 (2H, d), 1.95 (2H, d), 2.18 (2H, tt), 3.04 (1H, t), 4.03 (2H, dd), 4.29-4.59 (2H, m), 6.29 (1H, td), 6.45 (1H, dt), 6.53 (1H, d), 6.94 (1H, d), 7.39 (1H, dd), 7.48 (1H, ddd), 7.58 (1H, dd), 7.90 (1H, d), 8.37 (0.5H, s, NH
preparative SFC applying PrepMethod SFC-B; (6 mg, 19%)
2450-71-7; 12 eq.

rotamer), 8.66 (1H, s),

3-(((1 S,3S)-3-((2-Oxo-2H-[1,3′-
8.81 (0.5H, s, NH

bipyridin]-6′-yl)amino)cyclo-
rotamer), 9.17 (1H, s).

pentyl)amino)-N-(prop-2-yn-1-

yl)-1,2,4-triazine-6-

carboxamide

70

[Image Omitted]

N-(Oxetan-3-yl)-3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide
HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₂₅N₈O₃: 449.2044, found: 449.2052. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.58 (2H, d), 1.87-2.02 (2H, m), 2.11-2.19 (2H, m), 4.33 (1H, q), 4.62-4.68 (3H, m), 4.71 (2H, dd), 4.99-5.06 (1H, m), 6.29 (1H, td), 6.41-6.47 (1H, m), 6.53 (1H, d), 6.94 (1H, d), 7.39 (1H, dd), 7.46-7.5 (1H, m), 7.57 (1H, dd), 7.90 (1H, d),
preparative SFC applying PrepMethod SFC-B; (9 mg, 27%)
21635-88-1; 12 eq.

8.37 (0.5H, s, NH

rotamer), 8.63 (1H, s),

8.81 (0.5H, s, NH

rotamer), 9.48 (1H, d).

71

[Image Omitted]

N-(2,2-Difluoroethyl)-3- (((1 S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide
HRMS (ESI) m/z [M + H]⁺ calcd for C₂₁H₂₃F₂N₈O₂: 457.1906, found: 457.1920. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.48- 1.69 (2H, m), 1.92-2.03 (2H, m), 2.13-2.21 (2H, m), 3.1-3.22 (2H, m), 4.24-4.39 (2H, m), 6.10 (1H, s), 6.29 (1H, td), 6.45 (1H, d), 6.53 (1H, d), 6.94 (1H, d), 7.39 (1H, dd), 7.46-7.5 (1H, m), 7.58 (1H, dd), 7.90 (1H, d), 8.39 (0.43H, s, NH rotamer), 8.67 (1H, s), 8.85 (0.57H, s, NH rotamer), 9.08 (1H, s).
preparative HPLC applying PrepMethod I (gradient: 5-95%); (13 mg, 41%)
430-67-1; 10 eq. (no additional DIPEA added)

72

[Image Omitted]

N-(2-Hydroxyethyl)-3- (((1 S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-
HRMS (ESI) m/z [M + H]⁺ calcd for C₂₁H₂₅N₈O₃: 437.2044, found: 437.2044. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.59 (2H, d), 1.95 (2H, d), 2.12-2.24 (2H, m), 3.37 (2H, d), 3.51 (2H, t), 4.29-4.61 (2H, m), 4.77 (1H, s), 6.27 (1H, td), 6.44 (1H, dt), 6.53 (1H, d), 6.97 (1H, d), 7.40 (1H, dd), 7.47 (1H, ddd), 7.60 (1H, dd), 7.92 (1H, d), 8.67 (2H, s), 8.82 (1H, s).
preparative SFC applying PrepMethod SFC-C; (14 mg, 44%)
141-43-5; 12 eq.

yl)amino)cyclopentyl)amino)-

1,2,4-triazine-6-carboxamide

73

[Image Omitted]

N-Ethyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)- 1,2,4-triazine-6-carboxamide
HRMS (ESI) m/z [M + H]⁺ calcd for C₂₁H₂₅N₈O₂: 421.2094, found: 421.2108. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11 (3H, t), 1.46-1.69 (2H, m), 1.84-2.05 (2H, m), 2.11-2.24 (2H, m), 3.26- 3.32 (2H, m), 4.28-4.63 (2H, m), 6.27 (1H, td), 6.41-6.47 (1H, m), 6.5- 6.56 (1H, m), 6.96 (1H, d), 7.40 (1H, dd), 7.47 (1H, ddd), 7.60 (1H, ddd), 7.9-7.96 (1H, m), 8.66 (1H, s), 8.73-8.91 (2H, m).
Prep. SFC applying PrepMethod SFC-C; (21 mg, 65%)
75-04-7; 26 eq. (no additional DIPEA added)

74

[Image Omitted]

3-(((1 S,3S)-3-((2-Oxo-2H-[1,3′- bipyridin]-6′-yl)amino)cyclo- pentyl)amino)-1,2,4-triazine-6- carboxamide
HRMS (ESI) m/z [M + H]⁺ calcd for C₁₉H₂₁N₈O₂: 393.1782, found: 393.1740. ¹H NMR (500 MHz, DMSO-d6, mixture of two rotamers ca 1/1) δ ppm 1.48-1.7 (2H, m), 1.87- 2.04 (2H, m), 2.12-2.25 (2H, m), 4.28-4.64 (2H, m), 6.27 (1H, td), 6.44 (1H, dt), 6.53 (1H, d), 6.97 (1H, d), 7.40 (1H, dd), 7.47 (1H, ddd), 7.54-7.63 (2H, m), 7.93 (1H, d), 8.16 (1H, s), 8.67 (1H, s), 8.34 and 8.79 correspond to (1H,
Preparative HPLC applying PrepMethod H (gradient: 10-50%); (10 mg, 47%)
7664-41-7; 32 eq. (no additiona I DIPEA added and stirred at rt for 3 h)

s (rotamers)).

75

[Image Omitted]

N-Methyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′- yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide
HRMS (ESI) m/z [M + H]⁺ calcd for C₂₀H₂₃N₈O₂: 407.1938, found: 407.1916. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.5-1.7 (2H, m), 1.89-2.07 (2H, m), 2.13-2.24 (2H, m), 2.80 (3H, d), 3.44 (1H, qd), 4.15-4.48 (2H, m), 6.28 (1H, td), 6.45 (1H, dt), 6.54 (1H, d), 6.97 (1H, d), 7.41 (1H, dd), 7.48 (1H, ddd), 7.61 (1H, ddd), 7.91-7.95 (1H, m), 8.67 (1H, s), 8.79 (1H, s).
preparative HPLC applying PrepMethod H (gradient: 15-55%); (20 mg, 99%)
74-89-5; 80 eq. (no additional DIPEA added and stirred at rt for 3 h)

76

[Image Omitted]

N,N-Dimethyl-3-(((1 S,3S)-3- ((2-oxo-2H-[1,3′-bipyridin]-6′-
HRMS (ESI) m/z [M + H]⁺ calcd for C₂₁H₂₅N₈O₂: 421.2094, found: 421.2100. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.59- 1.76 (2H, m), 1.99-2.16 (2H, m), 2.31 (2H, tdd), 3.14 (3H, s), 3.25 (3H, s), 4.39 (1H, p), 4.56 (1H, s), 6.46 (1H, td), 6.59-6.66 (2H, m), 7.45 (1H, dd), 7.56-7.64 (2H, m), 7.92-7.98 (1H, m), 8.49 (1H, s).
preparative HPLC applying PrepMethod H (gradient: 15-55%); (4.7 mg, 24%)
124-40-3; 40 eq. (no additiona I DIPEA added and stirred at 60° C. for 72 h)

yl)amino)cyclopentyl)amino)-

1,2,4-triazine-6-carboxamide

Example 129
3-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 129

[Image Omitted]

According to GM1A the free base of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 2TFA compound i-28b (60 mg, 0.31 mmol) was added to a mixture of 3-chloro-6′-fluoro-2H-[1,3′-bipyridin]-2-one compound i-13a (139 mg, 0.62 mmol) and K₂CO₃(129 mg, 0.93 mmol) in DMSO (5 mL). The resulting mixture was stirred at 120° C. for 15 h under a nitrogen atmosphere. The reaction mixture was diluted with saturated brine (100 mL) and extracted with EtOAc (5×75 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (MeOH:DCM=1:10) followed by preparative HPLC (PrepMethod D, gradient: 18-32%) to give (15 mg, 12%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₁ClN₇O: 398.1490, found: 398.1468. ¹H NMR (300 MHz, MeOH-d₄) δ ppm 1.58-1.70 (2H, m), 1.98-2.09 (2H, m), 2.22-2.35 (2H, m), 2.44 (3H, s), 4.33-4.49 (2H, m), 6.24 (1H, dd), 6.62 (1H, d), 7.46 (1H, dd), 7.59 (1H, dd), 7.81 (1H, dd), 7.97 (1H, dd), 8.20 (1H, s).

Example 132
3-Methoxy-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 132

[Image Omitted]

In a slight variation of GM1A the free base of 6′-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3′-bipyridin]-2-one 2HCl compound i-3b (160 mg, 0.53 mmol) was added to a solution of 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (167 mg, 1.07 mmol) in 1,4-dioxane (20 mL) at rt and the resulting mixture stirred at 100° C. for 15 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc:MeOH=2:1) followed by preparative HPLC (PrepMethod K, gradient: 21-31%) to give (32 mg, 15%) of the title compound as a white solid. MS (ESI): m/z [M+H]⁺ 394.15. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.59 (2H, m), 1.83-1.98 (2H, m), 2.07-2.20 (2H, m), 2.37 (3H, s), 3.71 (3H, s), 4.28-4.39 (2H, m), 6.18 (1H, t), 6.52 (1H, d), 6.85 (1H, dd), 6.93 (1H, d), 7.15 (1H, dd), 7.36 (1H, dd), 7.56 (1H, br s), 7.90 (1H, d), 8.16 (1H, s).

Example 128
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile—compound 128

[Image Omitted]

In a slight variation of GM2 6′-chloro-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile compound i-8d (70 mg, 0.30 mmol) was added to a mixture of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3TFA compound i-28b (162 mg, 0.30 mmol), K₂CO₃(125 mg, 0.91 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (13 mg, 20 μmol) in dioxane (10 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was filtered through a pad of Celite, the filter cake washed with EtOAc (3×20 mL) and the combined filtrates concentrated under reduced pressure. The obtained material was purified by preparative TLC (MeOH:DCM=1:10) followed by preparative HPLC (PrepMethod E, gradient: 8-28%) to give (30 mg, 26%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C₂₀H₂₁N₈O: 389.1832, found: 389.1800. ¹H NMR (300 MHz, MeOH-d₄) δ ppm 1.56-1.72 (2H, m), 1.96-2.11 (2H, m), 2.21-2.34 (2H, m), 2.44 (3H, s), 4.33-4.48 (2H, m), 6.62 (2H, t), 7.45 (1H, dd), 7.69 (1H, dd), 7.98 (1H, d), 8.20 (1H, s), 8.36 (1H, dd).

Example 130
5-Methyl-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 130

[Image Omitted]

According to GM1A 6′-fluoro-5-methyl-2H-[1,3′-bipyridin]-2-one compound i-37a (100 mg, 0.49 mmol) was added to a mixture of the 2HCl salt of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (391 mg, 1.47 mmol) and Na₂CO₃(415 mg, 3.92 mmol) in DMSO (5 mL). The resulting mixture was stirred at 120° C. for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the obtained material was purified by C18-flash chromatography (gradient: MeCN in water) followed by preparative HPLC (PrepMethod D, gradient: 17-34%) to give (50 mg, 27%) of the title compound as a pale yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O: 378.2036, found: 378.2034. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.63 (2H, m), 1.84-1.99 (2H, m), 2.03 (3H, s), 2.10-2.19 (2H, m), 2.38 (3H, s), 4.29-4.40 (2H, m), 6.39 (1H, d), 6.52 (1H, d), 6.91 (1H, d), 7.33-7.40 (3H, m), 7.56 (1H, brd), 7.91 (1H, d), 8.17 (1H, s).

Example 131
3-Methyl-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 131

[Image Omitted]

According to GM1A 6′-fluoro-3-methyl-2H-[1,3′-bipyridin]-2-one compound i-38a (80 mg, 0.39 mmol) was added to a mixture of the 2HCl salt of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (209 mg, 0.78 mmol) and Na₂CO₃(332 mg, 3.13 mmol) in DMSO (4 mL). The resulting mixture was stirred at 120° C. for 20 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the obtained material was purified by C18-flash chromatography (gradient: MeCN in water) followed by preparative HPLC (PrepMethod D, gradient: 18-34%) to give (30 mg, 20%) of the title compound as a pale yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O: 378.2036, found: 378.2056. ¹H NMR (300 MHz, DMSO-de) b ppm 1.46-1.62 (2H, m), 1.86-1.97 (2H, m), 2.02 (3H, s), 2.07-2.19 (2H, m), 2.38 (3H, s), 4.27-4.40 (2H, m), 6.19 (1H, t), 6.53 (1H, d), 6.92 (1H, d), 7.34-7.40 (2H, m), 7.44-7.47 (1H, m), 7.56 (1H, brs), 7.91 (1H, d), 8.17 (1H, s).

Example 136
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-3-carbonitrile—compound 136

[Image Omitted]

In a slight variation of GM1A the free base of 6′-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-3-carbonitrile 4HCl compound i-35b (110 mg, 0.37 mmol) was added to a solution of 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (117 mg, 0.74 mmol) in 1,4-dioxane (3 mL) at rt and the resulting mixture stirred at 100° C. for 15 h. The reaction mixture was concentrated under reduced pressure and the obtained material was purified by preparative TLC (MeOH:DCM=1:25) followed by preparative HPLC (PrepMethod D, gradient: 10-35%) to give (11 mg, 8%) of the title compound as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₁N₈O: 389.1832, found: 389.1842. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.60 (2H, m), 1.89-1.97 (2H, m), 2.10-2.19 (2H, m), 2.38 (3H, s), 4.27-4.42 (2H, m), 6.46 (1H, t), 6.54 (1H, d), 7.06 (1H, d), 7.45 (1H, dd), 7.57 (1H, brs), 7.98 (1H, d), 8.05 (1H, dd), 8.17 (1H, s) 8.22 (1H, dd).

Example 138
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(trifluoromethoxy)-2H-[1,3′-bipyridin]-2-one—compound 138

[Image Omitted]

According to GM3 (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (130 mg, 0.33 mmol), the 5HCl salt of 3-(trifluoromethoxy)pyridin-2-ol compound i-9b (142 mg, 0.39 mmol), Cs₂CO₃(534 mg, 1.64 mmol), Cu(I)I (75 mg, 0.85 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (56 mg, 0.39 mmol) were reacted in 1,4-dioxane (20 mL) at 100° C. for 15 h. The reaction mixture was concentrated under reduced pressure and the obtained material was taken up with EtOAc (250 mL). The organic layer was washed with saturated brine (5×75 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) followed by preparative HPLC (PrepMethod C, 18-45%) the title compound (27 mg, 18%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₁F₃N₇O₂: 448.1704, found: 448.1676. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.63 (2H, m), 1.84-1.99 (2H, m), 2.07-2.23 (2H, m), 2.38 (3H, s), 4.28-4.43 (2H, m), 6.32 (1H, t), 6.54 (1H, d), 7.03 (1H, d), 7.44 (1H, dd), 7.58 (1H, brd), 7.69-7.73 (2H, m), 7.97 (1H, d), 8.17 (1H, s).

Example 112
5-Chloro-6′-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 112

[Image Omitted]

(1R,2R)—N′,N²-Dimethylcyclohexane-1,2-diamine (182 mg, 1.28 mmol) was added to (1S,3S)-M-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (180 mg, 0.43 mmol), 5-chloropyridin-2(1H-one (CAS Reg. No. 4214-79-3) (828 mg, 6.39 mmol), Cu(I)I (244 mg, 1.28 mmol) and Cs₂CO₃(694 mg, 2.13 mmol) in 1,4-dioxane (25 mL) at rt and the resulting suspension was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (150 mL) and washed sequentially with water (3×75 mL) and brine (3×50 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford the crude product. The residue was first purified by preparative TLC (7 M NH³in MeOH:DCM=1:20) and then by preparative HPLC (PrepMethod D, gradient 25-45%) to afford (40 mg, 22%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₃ClN₇O: 424.1648, found: 424.1610. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.82-1.01 (4H, m), 1.42-1.62 (2H, m), 1.79-2.2 (5H, m), 4.27-4.38 (2H, m), 6.49 (2H, t), 6.96 (1H, d), 7.34-7.63 (3H, m), 7.91 (2H, dd), 8.17 (1H, s).

Example 113
3-(5-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyrazin-2-yl)-1-methylpyridin-2(1H)-one—compound 113

[Image Omitted]

Pd-PEPPSI-IpentCl 2-methylpyridine (24 mg, 0.03 mmol) was added to 3-(5-bromopyrazin-2-yl)-1-methylpyridin-2(1H-one compound i-57a (150 mg, 0.56 mmol), (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (148 mg, 0.68 mmol) and Cs₂CO₃(1.47 g, 4.51 mmol) in 1,4-dioxane (5 mL) at rt and the resulting solution was stirred at 100° C. for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (3×25 mL) and brine (3×20 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) and then by preparative HPLC (PrepMethod D, gradient 19-39%) to afford (15 mg, 7%) of the title compound as a white solid. HRMS (ESI) m/z[M+H]⁺ calcd for C₂₁H₂₅N₈O: 405.2146, found: 405.2166. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84-1.03 (4H, m), 1.44-1.68 (2H, m), 1.85-2.22 (5H, m), 3.52 (3H, s), 4.26-4.47 (2H, m), 6.35 (1H, t), 7.29 (1H, d), 7.55 (1H, d), 7.72 (1H, dd), 7.96 (1H, d), 8.08-8.25 (2H, m), 9.16 (1H, d).

Example 114
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one—compound 114

[Image Omitted]

(1S,3S)—N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (137 mg, 0.63 mmol) was added to 3-(6-chloropyridin-3-yl)pyrimidin-4(3H)-one compound i-58a (100 mg, 0.48 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (20 mg, 0.02 mmol) and Cs₂CO₃(785 mg, 2.41 mmol) in 1,4-dioxane (5 mL) at rt and the resulting suspension was stirred at 100° C. for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with water (3×25 mL) and brine (2×20 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) and then by preparative HPLC (PrepMethod C, gradient 17-37%) to afford (56 mg, 30%) of the title compound as a pale-yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.75-1.06 (4H, m), 1.30-1.73 (2H, m), 1.80-1.96 (2H, m), 1.97-2.05 (1H, m), 2.07-2.23 (2H, m), 4.32 (2H, m), 6.46 (1H, d), 6.53 (1H, d), 7.03 (1H, d), 7.43 (1H, dd), 7.48-7.65 (1H, m), 7.89-8.00 (2H, m), 8.17-8.21 (1H, m), 8.41 (1H, s).

Example 115
3-(2-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)-1-methylpyridin-2(1H)-one—compound 115

[Image Omitted]

3-(2-Chloropyrimidin-5-yl)-1-methylpyridin-2(1H)-one compound i-59a (90 mg, 0.41 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (134 mg, 0.61 mmol), Cs₂CO₃(397 mg, 1.22 mmol) Pd-PEPPSI-IpentCl 2-methylpyridine (17 mg, 0.02 mmol) in 1,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was poured into water (150 mL) and the aqueous layer was extracted with EtOAc (4×150 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford the crude product. The residue was first purified by preparative TLC (MeOH:DCM=1:20) and then by preparative HPLC (PrepMethod A, gradient 35-50%) to afford (54 mg, 33%) of the title compound as a pale yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₅N₈O: 405.2146, found: 405.2142. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84-1.00 (4H, m), 1.45-1.62 (2H, m), 1.90-2.16 (2H, m), 1.97-2.20 (3H, m), 3.48 (3H, s), 4.31-4.45 (2H, m), 6.28 (1H, t), 7.39 (1H, d), 7.52 (1H, d), 7.64 (2H, dd), 8.16 (1H, s), 8.62 (2H, s).

Example 116
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile—compound 116

[Image Omitted]

3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-60d (150 mg, 0.53 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (139 mg, 0.63 mmol), Cs₂CO₃(515 mg, 1.58 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (22 mg, 0.03 mmol) in 1,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 100° C. for 18 under nitrogen. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2×5 mL) and the combined filtrates were concentrated under reduced pressure to afford the crude product. The residue was first purified by preparative TLC (EtOAc:PE=1:1) and the by preparative HPLC (PrepMethod D, gradient 30-50%) to afford (48 mg, 20%) of the title compound as a grey solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₅H₂₆N₉O: 468.2254, found: 468.2266. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.82-1.05 (4H, m), 1.45-1.68 (2H, m), 1.84-2.01 (2H, m), 2.01-2.09 (1H, m), 2.11-2.2 (2H, m), 3.44 (3H, s), 4.28-4.45 (2H, m), 6.62 (1H, d), 7.04 (1H, d), 7.31 (1H, d), 7.42 (1H, d), 7.39-7.52 (1H, m), 7.57 (1H, d), 7.57-7.65 (1H, m), 8.07 (1H, d), 8.19 (1H, s).

Example 117
1-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile—compound 117

[Image Omitted]

1-(6-Chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-61d (100 mg, 0.35 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (92 mg, 0.42 mmol), Cs₂CO₃(343 mg, 1.05 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (15 mg, 0.02 mmol) in 1,4-dioxane (10 mL) at rt and the resulting suspension was stirred at 100° C. for 18 h under nitrogen. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2×5 mL) and the combined filtrates were concentrated under reduced pressure to afford the crude product. The residue was first purified by preparative TLC (EtOAc:PE=1:1) and then by preparative HPLC (PrepMethod C, gradient 28-52%) to afford (30 mg, 18%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₅H₂₆N₉O: 468.2254, found: 468.2208. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.91 (2H, m), 0.96 (2H, m), 1.45-1.68 (2H, m), 1.90-2.25 (5H, m), 3.42 (3H, s), 4.36 (2H, dt), 6.62 (1H, d), 7.00-7.08 (2H, m), 7.45-7.51 (2H, m), 7.55 (1H, s), 7.79 (1H, d), 8.06 (1H, d), 8.19 (1H, s).

Example 118
2-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H-one—compound 118

[Image Omitted]

2-(6-Fluoropyridin-3-yl)pyridazin-3(2H)-one compound i-62a (200 mg, 1.05 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (344 mg, 1.57 mmol) and K₂CO₃(578 mg, 4.18 mmol) in DMSO (5 mL) at rt and the resulting mixture was stirred at 120° C. for 15 h. The reaction mixture was poured into brine (150 mL), extracted with EtOAc (4×100 mL). The organic layers were combined and washed with saturated brine (3×100 mL), dried (Na₂SO₄), filtered and evaporated to afford crude product.

The residue was first purified by preparative TLC (MeOH:DCM=1:20) and then by preparative HPLC (PrepMethod C, gradient 17-37%) to afford (70 mg, 17%) of the title compound as a pale-yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₃N₈O: 391.1990, found: 391.1984. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84-0.98 (4H, m), 1.53 (2H, m), 1.80-1.97 (2H, m), 2.01-2.22 (3H, m), 4.27-4.40 (2H, m), 6.51 (1H, d), 6.91-7.04 (2H, m), 7.40-7.59 (3H, m), 8.00 (1H, dd), 8.09 (1H, d), 8.17 (1H, s).

Example 119
2-(2-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)pyridazin-3(2H)-one—compound 119

[Image Omitted]

Cu(I)I (63 mg, 0.33 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyrimidin-2-yl)cyclopentane-1,3-diamine compound i-47a (140 mg, 0.33 mmol), pyridazin-3(2H)-one (CAS Reg. No. 504-30-3) (33 mg, 0.35 mmol), Cs₂CO₃(216 mg, 0.66 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (71 mg, 0.50 mmol) in 1,4-dioxane (10 mL) at rt under nitrogen. The resulting suspension was stirred at 80° C. for 16 h and subsequently filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the combined filtrates were concentrated under reduced pressure. The residue was first purified by preparative TLC (MeOH:DCM=1:10) and then by preparative HPLC (PrepMethod M, gradient 23-43%) to afford (80 mg, 62%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₂N₉O: 392.1942, found: 392.1930. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86-1.03 (4H, m), 1.50-1.63 (2H, m), 1.94 (2H, t), 2.01-2.09 (1H, m), 2.09-2.19 (2H, m), 4.30-4.45 (2H, m), 7.07 (1H, dd), 7.49 (2H, dd), 7.70 (1H, d), 8.06 (1H, dd), 8.18 (1H, s), 8.47 (2H, s).

Example 120
2′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-6H-[1,5′-bipyrimidin]-6-one—compound 120

[Image Omitted]

rel-(1R,2R)—N¹,N²-Dimethylcyclohexane-1,2-diamine (118 mg, 0.83 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyrimidin-2-yl)cyclopentane-1,3-diamine compound i-47a (70 mg, 0.17 mmol), pyrimidin-4(3H)-one (CAS Reg. No. 4562-27-0) (79 mg, 0.83 mmol), Cu(I)I (157 mg, 0.83 mmol) and Cs₂CO₃(108 mg, 0.33 mmol) in 1,4-dioxane (10 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (4×100 mL). The organic layers were combined, washed with water (2×50 mL), dried (Na₂SO₄), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (EtOAc) and then by preparative HPLC (PrepMethod D, gradient 15-30%) to afford (4 mg, 6%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₂N₉O: 392.1942, found: 392.1912. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85-1 (4H, m), 1.47-1.63 (2H, m), 1.86-2.19 (5H, m), 4.24-4.46 (2H, m), 6.51 (1H, d), 7.54 (1H, s), 7.77 (1H, d), 7.98 (1H, d), 8.19 (1H, s), 8.37 (2H, s), 8.46 (1H, s).

Example 121
1-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid—compound 121

[Image Omitted]

Methyl 1-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate compound i-48e (75 mg, 0.15 mmol) was added to a mixture of NaOH (10 mg, 0.25 mmol) in MeOH (9 mL) and water (3 mL) rt and the resulting mixture was stirred at 30° C. for 18 h. The solvent was removed under reduced pressure and the residue first purified by preparative TLC (EtOAc) and then by preparative HPLC (PrepMethod N, gradient 6-23%) to afford (6 mg, 8%) of the title compound as a pale-yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₅H₂₇N₈O₃: 487.2200, found: 487.2182. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-1.03 (4H, m), 1.49-1.65 (2H, m), 1.84-2.22 (5H, m), 3.43 (4H, s), 4.31-4.44 (2H, m), 6.62 (1H, d), 6.92 (1H, d), 7.02 (1H, d), 7.48 (1H, dd), 7.57 (1H, d), 7.67-7.78 (2H, m), 8.06 (1H, d), 8.19 (1H, s).

Example 122
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 122

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-49b (140 mg, 0.24 mmol) was dissolved in TFA (5 mL) at rt and the resulting solution was stirred at 80° C. for 2 h. Excess TFA was removed under reduced pressure and the residue adjusted to pH 8 with sat. Na₂CO₃(aq). The reaction mixture was extracted with DCM (100 mL) and the organic layer washed sequentially with water (2×25 mL) and brine (25 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated and the residue was first purified by preparative TLC (DCM MeOH=15:1) and then by preparative HPLC (PrepMethod K, gradient 15-28%) to afford (27 mg, 24%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₅N₁₀O: 457.2208, found: 457.2168. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88-0.99 (4H, m), 1.55 (2H, ddt), 1.88-1.99 (2H, m), 2.02-2.21 (3H, m), 4.30-4.40 (2H, m), 6.56 (1H, br d), 6.60 (1H, d), 6.99 (1H, d), 7.48 (1H, dd), 7.56 (1H, br s), 7.99 (1H, dd), 8.02 (1H, d), 8.17 (1H, d), 8.19 (1H, s), 8.24 (1H, s), 15.04 (1H, s).

Example 123
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 123

[Image Omitted]

6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-50c (110 mg, 0.19 mmol) was dissolved in TFA (5 mL) at rt and the resulting solution was stirred at 80° C. for 5 h. Excess TFA was removed under reduced pressure and the residue adjusted to pH 8 with sat. Na₂CO₃(aq). The reaction mixture was extracted with DCM (100 mL) and the organic layer washed sequentially with water (2×25 mL) and brine (25 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated and the residue was first purified by preparative TLC (DCM MeOH=15:1) and then by preparative HPLC (PrepMethod C, gradient 18-38%) to afford (20 mg, 23%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₄H₂₆N₉O: 456.2254, found: 456.2242. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87-1.02 (4H, m), 1.48-1.63 (2H, m), 1.88-1.98 (2H, m), 2.02-2.21 (3H, m), 4.18-4.44 (2H, m), 6.51 (1H, d), 6.55 (1H, d), 6.96 (1H, d), 7.45 (1H, dd), 7.57 (1H, s), 7.82 (1H, dd), 7.95 (3H, d), 8.08 (1H, s), 8.19 (1H, s), 12.84 (1H, s).

Example 124
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-tetrazol-5-yl)-2H-[1,3′-bipyridin]-2-one—compound 124

[Image Omitted]

DMF (1.5 mL) was added to a vial charged with 6′-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile Example 56 (29 mg, 0.07 mmol), sodium azide (13.7 mg, 0.21 mmol) and triethylamine hydrochloride (29 mg, 0.21 mmol) and the mixture was heated to 110° C. for 16 h. The reaction mixture was combined with a second batch made in the same way (0.02 mmol scale), evaporated and the residue purified by preparative SFC (PrepMethod SFC-D) to afford (18 mg, 42%) of the title compound. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₄N₁₁O: 458.2160, found: 458.2192. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.83-0.91 (2H, m), 0.91-1 (2H, m), 1.43-1.65 (2H, m), 1.9-1.97 (3H, m), 2.13-2.2 (2H, m), 4.28-4.4 (2H, m), 6.57 (1H, d), 6.65 (1H, d), 6.94 (1H, s, NH), 7.38 (1H, s, NH), 7.47 (1H, dd), 7.99-8.06 (2H, m), 8.13 (1H, s), 8.29 (1H, s).

Example 125
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5-(dimethylphosphoryl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one—compound 125

[Image Omitted]

Dimethylphosphine oxide (15.9 mg, 0.20 mmol) was added to 5-bromo-3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one compound i-51b (70 mg, 0.10 mmol), XantPhos Pd G3 (CAS: 1445085-97-1) (4.85 mg, 5.10 μmol), XantPhos (5.9 mg, 10.2 μmol) and K₂CO₃(28 mg, 0.20 mmol) in 1,4-dioxane (5 mL) at rt and the resulting suspension was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (4×50 mL). The organic layers were combined and washed with water (2×20 mL), dried (Na₂SO₄), filtered and evaporated to afford crude product. The residue was first purified by preparative TLC (MeOH:DCM=1:20) and then by preparative HPLC (PrepMethod C, gradient 15-33%) to afford (2 mg, 4%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₆H₃₂N₈O₂P: 519.2380, found: 519.2386. ¹H NMR (300 MHz, Methanol-d₄) δ ppm 0.93-1.08 (4H, m), 1.59-1.71 (2H, m), 1.73 (3H, s), 1.77 (3H, s), 1.96-2.14 (3H, m), 2.22-2.37 (2H, m), 3.53 (3H, s), 4.37-4.50 (2H, m), 6.69 (1H, d), 7.31-7.43 (2H, m), 7.51 (1H, m), 7.50-7.66 (1H, m), 8.07 (1H, d), 8.17 (1H, s).

Example 126
6′-(((1S,3S)-3-((5-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one-compound 126

[Image Omitted]

(1S,3S)—N¹-(5-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-52b (80 mg, 0.41 mmol) was added to Pd-PEPPSI-IpentCl 2-methylpyridine (17.41 mg, 0.02 mmol), 6′-chloro-2H-[1,3′-bipyridin]-2-one compound i-29a (128 mg, 0.62 mmol) and Cs₂CO₃(405 mg, 1.24 mmol) in 1,4-dioxane (8 mL). The resulting mixture was stirred at 100° C. for 15 h under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the filter cake washed with EtOAc (3×20 mL). The combined filtrates were concentrated under reduced pressure and the crude product purified by preparative TLC (MeOH:DCM=1:10) and then by preparative HPLC (PrepMethod E, gradient: 2-19%) to give the title compound (35 mg, 23%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₂N₇O: 364.1880, found: 364.1848. ¹H NMR (300 MHz, MeOH-d₄) δ ppm 1.58-1.74 (2H, m), 2.00-2.12 (2H, m), 2.22-2.35 (2H, m), 2.38 (3H, s), 4.30-4.59 (2H, m), 6.44-6.53 (1H, m), 6.59-6.68 (2H, m), 7.47 (1H, dd), 7.57-7.69 (2H, m), 7.96 (1H, d), 8.42 (1H, s).

Example 127
6′-(((1S,3S)-3-((5,6-Dimethyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 127

[Image Omitted]

(1S,3S)—N¹-(5,6-Dimethyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3TFA compound i-53b (100 mg, 0.18 mmol) was added to Pd-PEPPSI-IpentCl 2-methylpyridine (7.66 mg, 9.10 μmol), Cs₂CO₃(178 mg, 0.55 mmol) and 6′-chloro-2H-[1,3′-bipyridin]-2-one compound i-29a (37.6 mg, 0.18 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100° C. for 15 h under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the filter cake washed with EtOAc (3×20 mL). The combined filtrates were concentrated under reduced pressure and the residue purified by preparative TLC (MeOH:DCM=1:10) followed by preparative HPLC (PrepMethod E, gradient: 3-14%) to give the title compound (8.4 mg, 12%) as a grey solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O: 378.2036, found: 378.2048. ¹H NMR (300 MHz, MeOH-d₄) δ ppm 1.6-1.7 (2H, m), 2.03-2.12 (2H, m), 2.24-2.35 (2H, m), 2.43 (6H, d), 4.29-4.5 (2H, m), 6.47 (1H, t), 6.59-6.72 (2H, m), 7.51 (1H, dd), 7.57-7.65 (2H, m), 7.96 (1H, s).

Example 133
5-Methoxy-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 133

[Image Omitted]

6′-(((1S,3S)-3-Aminocyclopentyl)amino)-5-methoxy-2H-[1,3′-bipyridin]-2-one compound i-42b (100 mg, 0.33 mmol) was added to 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (105 mg, 0.67 mmol) in 1,4-dioxane (6 mL) and i-PrOH (2 mL) at 30° C. The resulting solution was stirred at 100° C. for 18 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (EtOAc:MeOH=3:1) and then by preparative HPLC (PrepMethod K, gradient: 16-34%) to give the title compound (46 mg, 35%) as a pale-yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O₂: 394.1986, found: 394.1990. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.65 (2H, m), 1.82-2.04 (2H, m), 2.07-2.24 (2H, m), 2.39 (3H, s), 3.65 (3H, s), 4.21-4.49 (2H, m), 6.43 (1H, d), 6.54 (1H, d), 6.93 (1H, d), 7.19 (1H, d), 7.36 (1H, dd), 7.42 (1H, dd), 7.59 (1H, br s), 7.97 (1H, d), 8.18 (1H, s).

Example 134
5-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 134

[Image Omitted]

6-Methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (155 mg, 0.98 mmol) was added to 6′-(((1S,3S)-3-aminocyclopentyl)amino)-5-chloro-2H-[1,3′-bipyridin]-2-one compound i-44b (150 mg, 0.49 mmol) in 1,4-dioxane (6 mL) and i-PrOH (2 mL) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (EtOAc:MeOH=3:1) and then by preparative HPLC (PrepMethod D, gradient: 15-45%) to give the title compound (24 mg, 12%) as a white solid. HRMS (ESI) m/z[M+H]⁺ calcd for C₁₉H₂₁ClN₇O: 398.1490, found: 398.1494. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.42-1.68 (2H, m), 1.84-2.01 (2H, m), 2.06-2.23 (2H, m), 2.38 (3H, s), 4.23-4.49 (2H, m), 6.50 (2H, t), 6.99 (1H, d), 7.41 (1H, dd), 7.5-7.65 (2H, m), 7.93 (2H, dd), 8.18 (1H, s).

Example 135
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(trifluoromethyl)-2H-[1,3′-bipyridin]-2-one—compound 135

[Image Omitted]

6-Methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (130 mg, 0.83 mmol) was added to 6′-(((1S,3S)-3-aminocyclopentyl)amino)-3-(trifluoromethyl)-2H-[1,3′-bipyridin]-2-one compound i-54b (140 mg, 0.41 mmol) in 1,4-dioxane (15 mL) at 30° C. The resulting mixture was stirred at 100° C. for 15 h. The solvent was removed under reduced pressure and the residue purified by preparative TLC (MeOH:EtOAc=1:1) and then by preparative HPLC (PrepMethod L, gradient: 23-43%) to give the title compound (15 mg, 8%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₁F₃N₇O: 432.1754, found: 432.1724. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.64 (2H, m), 1.85-2.00 (2H, m), 2.08-2.20 (2H, m), 2.39 (3H, s), 4.22-4.47 (2H, m), 6.43 (1H, t), 6.55 (1H, d), 7.04 (1H, d), 7.46 (1H, dd), 7.58 (1H, brs), 7.92-8.06 (3H, m), 8.18 (1H, s).

Example 137
3-Fluoro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 137

[Image Omitted]

rel-(1R,2R)—N¹,N²-Dimethylcyclohexane-1,2-diamine (25.1 mg, 0.18 mmol) was added to (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (70 mg, 0.18 mmol), 3-fluoropyridin-2-ol (CAS Reg. No. 1547-29-1) (100 mg, 0.88 mmol), Cu(I)I (33.6 mg, 0.18 mmol) and Cs₂CO₃(173 mg, 0.53 mmol) in 1,4-dioxane (2 mL) at 20° C. The resulting suspension was stirred at 100° C. for 15 h under a nitrogen atmosphere. The reaction mixture was evaporated, the residue taken up with EtOAc (100 mL) and washed sequentially with sat. brine (3×100 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the crude product was purified by flash chromatography on a C18 column (gradient: 40-50% water in MeCN) to give the title compound (28.2 mg, 42%) as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₁FN₇O: 382.1786, found: 382.1756. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.64 (2H, m), 1.82-2.03 (2H, m), 2.05-2.23 (2H, m), 2.39 (3H, s), 4.2-4.45 (2H, m), 6.19-6.31 (1H, m), 6.55 (1H, d), 7.02 (1H, d), 7.41-7.54 (2H, m), 7.58 (1H, brs), 7.87-8.02 (1H, m), 8.18 (1H, s), 12.13 (1H, brs).

Example 151
N-(2-Hydroxyethyl)-N-methyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide—compound 151

[Image Omitted]

HATU (43 mg, 0.11 mmol) was added to a solution of the crude lithium salt of 3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxylic acid compound i-30a (30 mg, 0.075 mmol), 2-(methylamino)ethan-1-ol (9.0 μl, 0.11 mmol) and DIPEA (0.039 mL, 0.23 mmol) in DMF (0.75 mL) at rt and the reaction was stirred at rt for 1.5 h. The mixture was diluted with DMSO (ca 1 mL) and purified by preparative SFC (PrepMethod SFC-A) to give (11 mg, 31%) of the title compound. MS (ESI): m/z [M+H]⁺ 451.2. ¹H NMR (600 MHz, DMSO-d₆, mixture of rotamers ca 2/1) δ ppm 1.46-1.69 (2H, m), 1.86-2.02 (2H, m), 2.1-2.24 (2H, m), 3.01 and 3.16 (3H, s, N-Me two rotamers), 4.34 (1H, q), 6.28 (1H, td), 6.44 (1H, dt), 6.49-6.61 (1H, m), 6.95 (1H, d, NH), 7.34-7.43 (1H, m), 7.48 (1H, ddd), 7.58 (1H, ddd), 7.91 (1H, d), 8.9 and 8.45 (1H, two singlets, rotamers). (Some protons are hidden in the solvent/water peaks).

Example 152
N-Methyl-3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(prop-2-yn-1-yl)-1,2,4-triazine-6-carboxamide—compound 152

[Image Omitted]

HATU (43 mg, 0.11 mmol) was added to a solution of the crude lithium salt 3-(((1S,3S)-3-((2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxylic acid compound i-30a (30 mg, 0.075 mmol), N-methylprop-2-yn-1-amine (9.5 PL, 0.11 mmol) and DIPEA (39 μL, 0.23 mmol) in DMF (0.75 mL) and the reaction was stirred at rt for 1.5 h. The mixture was diluted with DMSO (ca 1 mL) and purified by preparative SFC (PrepMethod SFC-A) to give (11 mg, 34%) of the title compound. MS (ESI): m/z [M+H]⁺ 445.2. ¹H NMR (600 MHz, DMSO-d₆, mixture of two rotamers ca 1.4/1) δ ppm δ 1.47-1.58 (1H, m), 1.58-1.67 (1H, m), 1.9-2.03 (2H, m), 2.13-2.22 (2H, m), 3.04 and 3.17 (3H, s, rotamers), 3.23 and 3.27 (1H, s, rotamers), 4.26-4.39 (1H, m), 4.31 and 4.45 (2H, s, rotamers), 6.28 (1H, td), 6.44 (1H, dt), 6.54 (1H, d), 6.96 (1H, brs, NH), 7.39 (1H, dd), 7.48 (1H, ddd), 7.55-7.62 (1H, m), 7.85-7.96 (1H, m), 8.48 (1H, s). (not all signals seen due to broadening/rotamers).

Example 153
3-(((1S,3S)-3-((3-Methoxy-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide—compound 153

[Image Omitted]

rel-(1R,2R)—N¹,N²-Dimethylcyclohexane-1,2-diamine (32 mg, 0.23 mmol) was added to 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (110 mg, 0.23 mmol), 3-methoxypyridin-2(1H)-one (CAS Reg. No. 20928-63-6) (57 mg, 0.46 mmol), Cs₂CO₃(74 mg, 0.23 mmol) and Cu(I)I (44 mg, 0.23 mmol) in 1,4-dioxane (15 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was poured into water (125 mL) and extracted with EtOAc (4×100 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated and the residue was first purified by preparative TLC (7 M NH₃in MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod K, gradient: 53-68%) to afford (51 mg, 47%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₇N₈O₄: 479.2150, found: 479.2168. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.43-1.73 (2H, m), 1.82-2.27 (4H, m), 3.71 (3H, s), 4.22-4.48 (2H, m), 4.63-4.78 (4H, m), 5.06 (1H, sxt), 6.21 (1H, t), 6.52 (1H, d), 6.78-7.01 (2H, m), 7.10-7.23 (1H, m), 7.39 (1H, dd), 7.90 (1H, d), 8.35-8.95 (2H, s, rotamers), 9.52 (1H, d).

Example 154
3-(((1S,3S)-3-((5-Methoxy-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide—compound 154

[Image Omitted]

Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (110 mg, 0.23 mmol) and 5-methoxypyridin-2(1H-one (CAS Reg. No 61941-79-5) (57 mg, 0.46 mmol). PrepMethod 0, gradient: 7-28%. Yield 13 mg (12%). White solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₇N₈O₄: 479.2150, found: 479.2176. ¹H NMR (300 MHz, DMSO-_d6) δ ppm 1.43-1.71 (2H, m), 2.00 (2H, s), 2.10-2.33 (2H, m), 3.65 (3H, s), 4.28-4.64 (2H, m), 4.65-4.80 (4H, m), 4.9-5.1 (1H, m), 6.43 (1H, d), 6.54 (1H, d), 6.93 (1H, d), 7.19 (1H, d), 7.36 (1H, dd), 7.43 (1H, dd), 7.98 (1H, d), 8.35-8.95 (2H, s, rotamers), 9.52 (1H, d).

Example 155
3-(((1S,3S)-3-((3-Methyl-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide—compound 155

[Image Omitted]

Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (120 mg, 0.25 mmol) and 3-methylpyridin-2(1H-one (54 mg, 0.50 mmol) (CAS Reg. No 1003-56-1). PrepMethod M, gradient: 16-34%. Yield 30 mg (26%). HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₇N₈O₃: 463.2200, found: 463.2202. ¹H NMR (300 MHz, DMSO-_d6) δ ppm 1.45-1.75 (2H, m), 2.03 (5H, s), 2.1-2.3 (2H, m), 4.37-3.45 (2H, m), 4.65-4.8 (4H, m), 4.98-5.12 (1H, m), 6.20 (1H, t), 6.54 (1H, d), 6.96 (1H, d), 7.32-7.51 (3H, m), 7.93 (1H, d), 8.35-8.95 (2H, s, rotamers), 9.54 (1H, d).

Example 156
3-(((1S,3S)-3-((5-Methyl-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide—compound 156

[Image Omitted]

Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (150 mg, 0.31 mmol) and 5-methylpyridin-2(1H-one (CAS Reg. No 1003-68-5) (41 mg, 0.37 mmol). PrepMethod P, gradient: 5-26%. Yield 27 mg (19%). White solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₇N₈O₃: 463.2200, found: 463.2208. ¹H NMR (300 MHz, DMSO-_d6) δ ppm 1.5-1.7 (2H, m), 1.85-2.00 (2H, m), 2.04 (3H, d), 2.15-2.22 (2H, m), 4.26-4.56 (2H, m), 4.65-4.8 (4H, m), 5.0-5.1 (1H, m), 6.39 (1H, d), 6.53 (1H, d), 6.94 (1H, d), 7.27-7.48 (3H, m), 7.92 (1H, d), 8.35-8.95 (2H, s, rotamers), 9.54 (1H, d).

Example 157
3-(((1S,3S)-3-((3-Chloro-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide—compound 157

[Image Omitted]

Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (120 mg, 0.25 mmol) and 3-chloropyridin-2(1H-one (CAS Reg. No 13466-35-8) (65 mg, 0.50 mmol). PrepMethod P, gradient: 5-28%. Yield 70 mg (58%). Yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₄ClN₈O₃: 483.1654, found: 483.1646. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.75 (2H, m), 1.88-2.02 (2H, m), 2.1-2.3 (2H, m), 4.29-4.57 (2H, m), 4.67-4.75 (4H, m), 4.95-5.15 (1H, m), 6.31 (1H, t), 6.55 (1H, d), 7.03 (1H, d), 7.45 (1H, dd), 7.66 (1H, dd), 7.82 (1H, dd), 7.97 (1H, d), 8.35-8.95 (2H, s, rotamers), 9.54 (1H, d).

Example 158
3-(((1S,3S)-3-((5-Chloro-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide—compound 158

[Image Omitted]

Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (150 mg, 0.31 mmol) and 5-chloropyridin-2(1H-one (CAS Reg. No 4214-79-3) (81 mg, 0.62 mmol). PrepMethod D, gradient: 26-38%. Yield 27 mg (18%). White solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₄ClN₈O₃: 483.1654, found: 483.1670. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.50-1.70 (2H, m), 1.90-2.05 (2H, m), 2.07-2.38 (2H, m), 4.22-4.55 (2H, m), 4.64-4.76 (4H, m), 5.05 (1H, sxt), 6.46-6.56 (2H, m), 7.00 (1H, d), 7.42 (1H, dd), 7.55 (1H, dd), 7.93 (2H, d), 8.35-8.95 (2H, s, rotamers), 9.54 (1H, d).

Example 159
3-(((1S,3S)-3-((3-Cyano-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide—compound 159

[Image Omitted]

m-CPBA (330 mg, 1.63 mmol) was added to a stirred solution of 3-(methylthio)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90d (184 mg, 0.81 mmol) in DCM (10 mL) which was cooled to 0° C. in an ice bath. The temperature was increased to room temperature and the resulting solution was stirred for 3 h. 6′-(((1S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-3-carbonitrile compound i-35b (120 mg, 0.41 mmol) and TEA (0.227 mL, 1.63 mmol) were added and the resulting solution was stirred at rt for an additional 15 h. The reaction mixture was diluted with sat. NaHCO₃(aq, 50 mL) and extracted with EtOAc (4×100 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated and the residue purified by preparative TLC (EtOAc) followed by preparative HPLC (PrepMethod D, gradient: 14-25%) to afford (15 mg, 8%) of the title compound as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₄N₉O₃: 474.1996, found: 474.2026. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.48-1.73 (2H, m), 1.9-2.1 (2H, s), 2.14-2.24 (2H, m), 4.27-4.80 (6H, m), 5.04 (1H, sxt), 6.47 (1H, t), 6.56 (1H, d), 7.09 (1H, d), 7.47 (1H, dd), 7.95-8.10 (2H, m), 8.23 (1H, dd), 8.35-8.95 (2H, s, rotamers), 9.53 (1H, d).

Example 160
N-(Oxetan-3-yl)-3-(((1S,3S)-3-((2-oxo-3-(trifluoromethoxy)-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide—compound 160

[Image Omitted]

Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (80 mg, 0.17 mmol) and 3-(trifluoromethoxy)pyridin-2(1H-one (CAS Reg. No 1361696-33-4) (36 mg, 0.20 mmol). PrepMethod R, gradient: 10-27%. Yield 17 mg (19%). Yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₄F₃N₈O₄: 533.1868, found: 533.1912. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.75 (2H, m), 1.9-2.1 (2H, m), 2.12-2.22 (2H, m), 4.35 (2H, d), 4.6-4.8 (4H, m), 5.02 (1H, sxt), 6.32 (1H, t), 6.54 (1H, d), 7.03 (1H, d), 7.44 (1H, dd), 7.65-7.8 (2H, m), 7.97 (1H, d), 8.35-8.95 (2H, s, rotamers), 9.52 (1H, d).

Example 161
N-(Oxetan-3-yl)-3-(((1S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxamide—compound 161

[Image Omitted]

Prepared in a similar way as described for Example 153 starting from 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90e (110 mg, 0.23 mmol) and 3-(trifluoromethyl)pyridin-2(1H)-one (CAS Reg. No 22245-83-6) (75 mg, 0.46 mmol). PrepMethod D, gradient: 20-40%. Yield 51 mg (43%). Pale-yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₄F₃N₈O₃: 517.1918, found: 517.1958. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.47-1.75 (2H, m), 1.9-2.1 (2H, d), 2.11-2.27 (2H, m), 4.29-4.61 (2H, m), 4.64-4.77 (4H, m), 4.98-5.12 (1H, m), 6.43 (1H, t), 6.56 (1H, d), 7.06 (1H, d), 7.47 (1H, dd), 7.95-8.07 (3H, m), 8.34-8.97 (2H, s, rotamers), 9.54 (1H, d).

Example 165
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(difluoromethoxy)-2H-[1,3′-bipyridin]-2-one—compound 165

[Image Omitted]

Prepared in a similar way as described in Example 153 starting from (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (85 mg, 0.20 mmol) and 3-(difluoromethoxy)pyridin-2(1H)-one (CAS Reg. No. 1241752-48-6) (130 mg, 0.81 mmol). PrepMethod D, gradient: 29-40%. Yield 28 mg (31%). Pale-yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₄F₂N₇O₂: 456.1954, found: 456.1932. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.86-1.01 (4H, m), 1.43-1.72 (2H, m), 1.88-1.98 (2H, m), 2.01-2.18 (3H, m), 4.25-4.46 (2H, m), 6.30 (1H, t), 6.55 (1H, d), 7.00 (1H, brd), 7.16 (1H, t, OCHF₂), 7.38-7.49 (2H, m), 7.59 (2H, brd), 7.97 (1H, d), 8.19 (1H, s).

Example 166
6′-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(difluoromethoxy)-2H-[1,3′-bipyridin]-2-one—compound 166

[Image Omitted]

Prepared in a similar way as described in Example 153 from (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-22e (70 mg, 0.17 mmol) and 5-(difluoromethoxy)pyridin-2(1H)-one (CAS Reg. No. 130318-75-1) (53 mg, 0.33 mmol). PrepMethod 0, gradient: 21-51%. Yield 21 mg (28%). White solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₄F₂N₇O₂: 456.1954, found: 456.1960 ¹H NMR (300 MHz, DMSO-d₆) b ppm 0.61-1.11 (4H, m), 1.4-1.7 (2H, m), 1.8-1.98 (2H, m), 1.98-2.27 (3H, m), 4.25-4.45 (2H, m), 6.52 (2H, brt), 6.69-7.31 (2H, m), 7.03 (1H, t, OCHF₂), 7.31-7.65 (2H, m), 7.76 (1H, s), 7.96 (1H, s), 8.19 (1H, s).

Example 167
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzoic acid—compound 167

[Image Omitted]

NaOH (20 mg, 0.50 mmol) was added to methyl 3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzoate compound i-91b (80 mg, 0.17 mmol) in water (1 mL) and THE (4 mL) at rt and the resulting mixture was stirred at rt for 4 h. The reaction mixture was adjusted to pH=6 with 0.1 M HCl (aq). The solvent and water was removed under reduced pressure and the crude was purified by preparative HPLC (PrepMethod 0, gradient: 17-30%) to afford (69 mg, 89%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₄H₂₆FN₆O₃: 465.2044, found: 465.2052. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.86-1.03 (4H, m), 1.37-1.67 (2H, m), 1.81-1.99 (2H, m), 1.99-2.21 (3H, m), 3.80 (3H, s), 4.06-4.48 (2H, m), 6.52 (1H, d), 6.74 (1H, d), 6.99 (1H, d), 7.33 (1H, d), 7.45-7.61 (1H, m), 7.82 (1H, t), 7.91 (1H, s), 8.19 (1H, s).

Example 168
3-(6-(((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzonitrile—compound 168

[Image Omitted]

3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzonitrile compound i-92c (40 mg, 0.15 mmol) was added to (1S,3S)—N¹-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (40 mg, 0.18 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (12.8 mg, 0.02 mmol) and Cs₂CO₃(99 mg, 0.30 mmol) in 1,4-dioxane (2 mL) at rt under nitrogen and the resulting solution was stirred at 100° C. for 8 h. The reaction mixture was poured into water (20 mL), filtered through a Celite pad and extracted with EtOAc (3×20 mL). The combined organic layers were dried over (Na₂SO₄), filtered and evaporated and the residue purified by preparative HPLC (PrepMethod T, gradient: 42-55%) to afford (24 mg, 36%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₄H₂₅FN₇O: 446.2098, found: 446.2134. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83-1.01 (3H, m), 1.45-1.65 (2H, m), 1.84-2.21 (4H, m), 3.66 (3H, s), 4.30-4.44 (2H, m), 6.57 (1H, d), 6.95 (1H, d), 7.29 (1H, t), 7.41-7.47 (1H, m), 7.54 (1H, d), 7.85 (1H, dd), 8.02 (1H, br s), 8.19 (1H, s).

Example 169
(1S,3S)—N¹-(6-Cyclopropyl-1,2,4-triazin-3-yl)-N³-(5-(6-fluoro-2-methoxy-3-(1H-tetrazol-5-yl)phenyl)pyridin-2-yl)cyclopentane-1,3-diamine—compound 169

[Image Omitted]

(nBu)₂Sn(OAc)₂(118 mg, 0.34 mmol) was added to 3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzonitrile Example 168 (50.0 mg, 0.11 mmol) and trimethylsilyl azide (65 mg, 0.56 mmol) in toluene (5 mL) at 0° C. under nitrogen and the resulting mixture was stirred at 100° C. for 16 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue purified by preparative HPLC (PrepMethod U, gradient: 20-34%) to afford (5 mg, 9%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₄H₂₆FN₁₀O: 489.2270, found: 489.2288. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84-1.04 (4H, m), 1.43-1.65 (2H, m), 1.84-1.99 (2H, m), 1.99-2.22 (3H, m), 3.35 (3H, s), 4.26-4.43 (2H, m), 6.58 (1H, d), 7.23 (1H, t), 7.48 (1H, d), 7.87 (1H, dd), 8.04 (1H, s), 8.18 (1H, s).

Example 173
rel-3-Methyl-6′-(((1 R,3R)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 173

[Image Omitted]

rel-(1 R,3R)—N¹-(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3HCl compound i-87b (0.312 g, 1.03 mmol), 6′-fluoro-3-methyl-2H-[1,3′-bipyridin]-2-one compound i-38a (0.211 g, 1.03 mmol) and K₂CO₃(0.570 g, 4.12 mmol) was added to a vial. The vial was capped and the reaction was stirred at 100° C. for 48 h. The mixture was cooled to rt, EtOAc and brine were added and the phases were separated. The aqueous phase was extracted once more with EtOAc. The organic phases were combined and washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure and the residue purified by preparative HPLC (PrepMethod F, gradient: 10-70%). The collected compound was concentrated and freeze dried overnight. The obtained solid was dissolved in DCM and washed with a small amount of water. The phases were separated and the organic phase was evaporated. The residue was dissolved in MeCN/water (1:1) and freeze dried overnight to give the title compound (0.190 g, 48%) as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O: 378.2036, found: 378.2038. ¹H NMR (500 MHz, MeOH-d₄) δ 1.55-1.74 (2H, m), 1.96-2.11 (2H, m), 2.11-2.19 (3H, m), 2.22-2.37 (2H, m), 2.44 (3H, s), 4.31-4.53 (2H, m), 6.37 (1H, t), 6.62 (1H, dd), 7.41-7.45 (2H, m), 7.45-7.49 (1H, m), 7.93 (1H, dd), 8.19 (1H, s).

Example 180
4-Methoxy-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 180

[Image Omitted]

Cs₂CO₃(247 mg, 0.76 mmol) was added to (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (100 mg, 0.25 mmol), 4-methoxypyridin-2(1H)-one (CAS Reg. No. 92545-13-8) (158 mg, 1.26 mmol), (1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (36 mg, 0.25 mmol) and Cu(I)I (48 mg, 0.25 mmol) in 1,4-dioxane (5 mL) at rt and the resulting mixture was stirred at 100° C. for 16 h under nitrogen. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (4×100 mL), the combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford the crude product. The residue was first purified by preparative TLC (MeOH:DCM=1:30) and then by preparative HPLC (PrepMethod 0, gradient: 10-39%) to afford (28 mg, 28%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O₂: 394.1986, found: 394.1980. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.65 (2H, m), 1.85-2.0 (2H, m), 2.1-2.25 (2H, m), 2.39 (3H, s), 3.77 (3H, s), 4.25-4.45 (2H, m), 5.85 (1H, d), 6.00 (1H, dd), 6.52 (1H, d), 6.90 (1H, d), 7.35 (1H, dd), 7.51 (1H, d), 7.56 (1H, s), 7.88 (1H, d), 8.18 (1H, s).

Example 182
4-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 182

[Image Omitted]

Prepared in a similar way as described for Example 180 using (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (80 mg, 0.20 mmol) and 4-chloropyridin-2(1H-one (CAS Reg. No 40673-25-4) (131 mg, 1.01 mmol) and purified by preparative HPLC (PrepMethod T, gradient: 25-45%). Yield 37 mg (46%). White solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₁ClN₇O: 398.1490, found: 398.1474. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49-1.61 (2H, m), 1.85-2.0 (2H, m), 2.12-2.21 (2H, m), 2.39 (3H, s), 4.30-4.42 (2H, m), 6.41 (1H, dd), 6.53 (1H, d), 6.62 (1H, d), 6.99 (1H, d), 7.40 (1H, dd), 7.56 (1H, s), 7.72 (1H, d), 7.93 (1H, d), 8.18 (1H, s).

Example 183
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3′-bipyridine]-4-carbonitrile—compound 183

[Image Omitted]

Prepared in a similar way as described for Example 180 using (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (100 mg, 0.25 mmol) and 2-oxo-1,2-dihydropyridine-4-carbonitrile (CAS Reg. No 94805-51-3) (152 mg, 1.26 mmol) and purified by preparative HPLC (PrepMethod T, gradient: 25-45%). Yield 28 mg (29%). Yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₁N₈O: 389.1832, found: 389.1820. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49-1.61 (2H, m), 1.85-2.05 (2H, m), 2.11-2.23 (2H, m), 2.39 (3H, s), 4.25-4.45 (2H, m), 6.59 (1H, d), 6.59 (1H, dd), 7.04 (1H, d), 7.11 (1H, d), 7.43 (1H, dd), 7.56 (1H, brs), 7.88 (1H, d), 7.95 (1H, d), 8.18 (1H, s).

Example 185
5-(Difluoromethoxy)-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 185

[Image Omitted]

Prepared in a similar way as described for Example 180 using (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (150 mg, 0.38 mmol) and 5-(difluoromethoxy)pyridin-2(1H-one (CAS Reg. No 130318-75-1) (183 mg, 1.14 mmol) and purified by preparative HPLC (PrepMethod M, gradient: 25-40%). Yield 79 mg (49%). White solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₂F₂N₇O₂: 430.1798, found: 430.1772. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.43-1.68 (2H, m), 1.85-2.0 (2H, m), 2.07-2.24 (2H, m), 2.39 (3H, s), 4.24-4.46 (2H, m), 6.47-6.54 (2H, m), 6.96 (1H, d), 7.02 (1H, t, OCHF₂) 7.42 (1H, dd), 7.5-7.6 (2H, m), 7.75 (1H, d), 7.96 (1H, d), 8.18 (1H, s).

Example 187
3-(Difluoromethoxy)-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 187

[Image Omitted]

Prepared in a similar way as described for Example 180 (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (100 mg, 0.25 mmol) and 3-(difluoromethoxy)pyridin-2(1H-one (CAS Reg. No 1241752-48-6) (81 mg, 0.50 mmol) and purified by preparative HPLC (PrepMethod O, gradient: 20-40%). Yield 45 mg (41%). White solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₂F₂N₇O₂: 430.1798, found: 430.1832. ¹H NMR (300 MHz, DMSO-de) b ppm 1.43-1.66 (2H, m), 1.86-2.02 (2H, m), 2.1-2.25 (2H, m), 2.39 (3H, s), 4.26-4.45 (2H, m), 6.30 (1H, t), 6.55 (1H, d), 7.01 (1H, d), 7.16 (1H, t, CHF₂), 7.37-7.49 (2H, m), 7.52-7.63 (2H, m), 7.97 (1H, d), 8.18 (1H, s).

Example 197
1-(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one—compound 197

[Image Omitted]

(1S,3S)—N¹-(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4.5HCl compound i-28b (250 mg, 0.70 mmol) was added to 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H-one compound i-6a (150 mg, 0.58 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (24.5 mg, 0.03 mmol) and K₂CO₃(241 mg, 1.75 mmol) in 1,4-dioxane (10 mL) at 15° C. The resulting mixture was stirred at 100° C. for 15 h under a nitrogen atmosphere. The reaction mixture was poured into sat. brine (100 mL) and extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the residue purified by preparative TLC (7 M NH₃in MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod D, gradient: 15-31%) to give the title compound (90 mg, 37%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₃N₈O: 415.1990, found: 415.2008. ¹H NMR (300 MHz, DMSO-d₆) 1.49-1.66 (2H, m), 1.88-2.03 (2H, m), 2.08-2.28 (2H, m), 2.39 (3H, s), 4.29-4.46 (2H, m), 6.59 (1H, d), 6.76 (1H, d), 6.84 (1H, d), 7.20-7.35 (2H, m), 7.57 (1H, d), 7.79 (1H, d), 8.04 (1H, d), 8.15-8.24 (2H, m), 8.44 (1H, dd).

Example 198
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 198

[Image Omitted]

3-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one Example 129 (100 mg, 0.25 mmol) was added to (1-methyl-1H-pyrazol-4-yl)boronic acid (CAS Reg. No. 847818-55-7) (63 mg, 0.50 mmol), Cs₂CO₃(246 mg, 0.75 mmol), XPhos Pd G3 (21 mg, 0.03 mmol) and XPhos (12 mg, 0.03 mmol) in 1,4-dioxane (12 mL) and water (3 mL) at rt and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was poured into sat. brine (125 mL) and extracted with EtOAc (4×100 mL), the combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford the crude product. The crude was first purified by preparative TLC (MeOH:EtOAc=1:40) followed by preparative HPLC (PrepMethod Z1, gradient: 15-29%) to afford (50 mg, 45%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₆N₉O: 444.2254, found: 444.2264. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.65 (2H, m), 1.84-2.04 (2H, m), 2.1-2.25 (2H, m), 2.39 (3H, s), 3.85 (3H, s), 4.25-4.45 (2H, m), 6.36 (1H, t), 6.55 (1H, d), 6.95 (1H, d), 7.45 (1H, dd), 7.5-7.65 (2H, m), 7.85 (1H, dd), 7.97 (1H, d), 8.01 (1H, s), 8.18 (1H, s), 8.31 (1H, s).

Example 199
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 199

[Image Omitted]

3-Chloro-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one Example 129 (150 mg, 0.38 mmol) was added to (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (CAS Reg. No. 1188405-87-9) (160 mg, 0.75 mmol), XPhos (18 mg, 0.04 mmol), Cs₂CO₃(369 mg, 1.13 mmol) and XPhos Pd 3G (32 mg, 0.04 mmol) in 1,4-dioxane (8 mL) and water (2 mL) at rt and the resulting solution was stirred at 100° C. for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with water (3×75 mL) and sat. brine (3×25 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford crude product. The crude was first purified by preparative TLC (MeOH (7 M NH₃): DCM=1:20) followed by preparative HPLC (PrepMethod X, gradient: 8-38%) to afford (47 mg, 29%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₄N₉O: 430.2098, found: 430.2120. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.38-1.67 (2H, m), 1.79-2.03 (2H, m), 2.17 (2H, m), 2.39 (3H, s), 4.25-4.45 (2H, m), 6.36 (1H, t), 6.56 (1H, d), 6.95 (1H, d), 7.45 (1H, dd), 7.5-7.65 (2H, m), 7.85-7.92 (1H, m), 7.96 (1H, d), 8.08 (1H, s), 8.18 (1H, s), 8.34 (1H, s), 12.86 (1H, s).

Example 200
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 200

[Image Omitted]

4-Methylbenzenesulfonic acid (44 mg, 0.25 mmol) was added to 6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-68a (130 mg, 0.25 mmol) in EtOH (8 mL) and water (0.1 mL) at rt and the resulting solution was stirred at 60° C. for 8 h. The reaction mixture was diluted with EtOAc (125 mL) and washed sequentially with sat. aq NaHCO₃(3×75 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated to afford the crude product. The crude product was purified by preparative HPLC (PrepMethod Z2, gradient: 9-30%) to afford (39 mg, 36%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₃N₁₀O: 431.2050, found: 431.2040. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.47-1.65 (2H, m), 1.87-2.02 (2H, m), 2.08-2.25 (2H, m), 2.39 (3H, s), 4.29-4.45 (2H, m), 6.48 (1H, t), 6.57 (1H, d), 6.98 (1H, brd), 7.48 (1H, dd), 7.53-7.61 (1H, m), 7.72 (1H, brd), 8.00 (1H, d), 8.18 (1H, s), 8.28 (1H, brs), 8.38 (1H, brs), 15.17 (1H, brs)

Example 201
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 201

[Image Omitted]

A mixture of 6′-chloro-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one compound i-67b (90 mg, 0.31 mmol), (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine×2HCl compound i-28b (125 mg, 0.47 mmol), Cs₂CO₃(511 mg, 1.57 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (13 mg, 0.02 mmol) in DMF (4 mL) was stirred under an atmosphere of nitrogen at 100° C. for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with sat. brine (4×35 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated and the residue was first purified by preparative TLC (MeOH:EtOAc=1:5) followed by preparative HPLC (PrepMethod D, gradient: 12-29%) to afford (8 mg, 6%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₆N₉O: 444.2254, found: 444.2288. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.66 (2H, m), 1.85-2.0 (2H, m), 2.09-2.28 (2H, m), 2.39 (3H, s), 3.82 (3H, s), 4.25-4.45 (2H, m), 66.49-6.56 (2H, m), 6.95 (1H, d), 7.45 (1H, dd), 7.51-7.63 (1H, m), 7.7-7.8 (2H, m), 7.88 (1H, d), 7.98 (1H, d), 8.03 (1H, s), 8.18 (1H, s).

Example 202
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-pyrazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 202

[Image Omitted]

5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one compound i-50d (74 mg, 0.13 mmol) in TFA (7 mL) was stirred at 80° C. for 5 h. The reaction mixture was evaporated to afford crude product which was purified by preparative HPLC (PrepMethod Z3, gradient: 34-64%) to afford the title compound (17 mg, 30%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₄N₉O: 430.2098, found: 430.2098. ¹H NMR (300 MHz, DMSO-de) b ppm 1.45-1.66 (H, m), 1.88-2.01 (2H, m), 2.12-2.23 (2H, m), 2.39 (3H, s), 4.3-4.45 (2H, m), 6.49-6.57 (2H, m), 6.95 (1H, d), 7.45 (1H, m), 7.57 (1H, d), 7.81 (1H, dd), 7.86 (1H, s), 7.91 (1H, d), 7.99 (1H, d), 8.10 (1H, s), 8.18 (1H, s), 12.86 (1H, s).

Example 208
6′-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1H-1,2,3-triazol-4-yl)-2H-[1,3′-bipyridin]-2-one—compound 208

[Image Omitted]

5-(1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)-6′-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one compound i-49c (20 mg, 0.04 mmol) was added into TFA (2.5 mL) at rt and the resulting suspension was stirred at 80° C. for 2 h under nitrogen. The solvent was removed under reduced pressure to afford crude product which was purified by preparative HPLC (PrepMethod 0, gradient: 2-27%) to afford (0.64 mg, 4%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₃N₁₀O: 431.2050, found: 431.2050. ¹H NMR (300 MHz, Methanol-d₄) δ 1.55-1.81 (2H, m), 1.88-2.14 (2H, m), 2.21-2.34 (2H, m), 2.47 (3H, s), 4.28-4.52 (2H, m), 6.57-6.75 (2H, m), 7.53 (1H, dd), 7.99 (1H, s), 8.05 (1H, d), 8.07-8.12 (2H, m), 8.22 (1H, s).

Example 210
1-Methyl-3-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile—compound 210

[Image Omitted]

In a slight variation of GM2 Pd-PEPPSI-IpentCl 2-methylpyridine (19 mg, 0.02 mmol) was added to a mixture of M-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 2HCl compound i-28b (120 mg, 0.45 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-60d (141 mg, 0.50 mmol) and Cs₂CO₃(441 mg, 1.35 mmol) in DMF (15 mL) at rt and the resulting mixture was stirred at 90° C. for 18 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (200 mL). The organic layer was washed with sat. brine (5×75 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (EtOAc) followed by preparative HPLC (PrepMethod 0, gradient: 30-47%) to give (48 mg, 24%) of the title compound as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₄N₉O: 442.2098, found: 442.2132. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.50-1.61 (2H, m), 1.87-2.02 (2H, m), 2.11-2.24 (2H, m), 2.38 (3H, s), 3.43 (3H, s), 4.30-4.43 (2H, m), 6.62 (1H, d), 7.03 (1H, d), 7.30 (1H, d), 7.42 (1H, d), 7.47 (1H, dd), 7.53-7.62 (2H, m), 8.07 (1H, d), 8.17 (1H, s).

Example 211
3-Methyl-1-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile—compound 211

[Image Omitted]

In analogy to Example 210 M-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 2HCl compound i-28b (100 mg, 0.38 mmol), 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-61d (118 mg, 0.41 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (16 mg, 0.02 mmol) and Cs₂CO₃(367 mg, 1.13 mmol) were reacted in 1,4-dioxane (15 mL) at 100° C. for 18 h under nitrogen. Upon aqueous work-up (EtOAc) and preparative TLC (EtOAc) the title compound (38 mg, 23%) was obtained. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₄N₉O: 442.2098, found: 442.2122. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49-1.62 (2H, m), 1.89-1.99 (2H, m), 2.12-2.21 (2H, m), 2.38 (3H, s), 3.42 (3H, s), 4.32-4.42 (2H, m), 6.63 (1H, d), 7.01-7.08 (2H, m), 7.45-7.58 (3H, m), 7.78 (1H, d), 8.06 (1H, d), 8.18 (1H, s).

Example 212
1-Methyl-3-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one—compound 212

[Image Omitted]

In analogy to Example 210 M-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4.5HCl compound i-28b (247 mg, 0.69 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-24a (150 mg, 0.58 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (24 mg, 0.03 mmol) and K₂CO₃(239 mg, 1.73 mmol) were reacted in 1,4-dioxane (15 mL) at 100° C. for 15 h under nitrogen. Upon aqueous work-up (EtOAc), preparative TLC (7 M NH₃in MeOH:DCM=1:25) followed by preparative HPLC (PrepMethod D, gradient: 15-35%) the title compound (40 mg, 17%) was obtained as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₄N₉O: 418.2098, found: 418.2132. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.64 (2H, m) 1.86-2.02 (2H, m), 2.07-2.27 (2H, m), 2.38 (3H, s), 3.40 (3H, s), 4.32-4.42 (2H, m), 6.59 (1H, d), 6.92 (1H, d), 7.13 (1H, dd), 7.48-7.57 (3H, m), 7.93 (1H, d), 8.10 (1H, d), 8.17 (1H, s).

Example 213
1-Methyl-3-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonitrile—compound 213

[Image Omitted]

In analogy to Example 210 N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (135 mg, 0.70 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonitrile compound i-81e (100 mg, 0.35 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (29 mg, 0.04 mmol) and Cs₂CO₃(342 mg, 1.05 mmol) were reacted in DMF (15 mL) at 100° C. for 15 h under nitrogen. Upon Celite filtration, aqueous work-up (EtOAc), preparative TLC (EtOAc:PE=3:1) followed by preparative HPLC (PrepMethod Z5, gradient: 42-88%) the title compound (6 mg, 4%) was obtained as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₃N₁₀O: 443.2050, found: 443.2076. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49-1.64 (2H, m), 1.87-2.02 (2H, m), 2.13-2.21 (2H, m), 2.38 (3H, s), 3.44 (3H, s), 4.30-4.44 (2H, m), 6.61 (1H, d), 7.01 (1H, d), 7.49 (1H, dd), 7.55-7.57 (1H, m), 7.73 (1H, d), 7.81 (1H, d), 8.08 (1H, d), 8.17 (1H, s).

Example 214
1-Methyl-3-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile—compound 214

[Image Omitted]

In analogy to Example 210 M-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (135 mg, 0.70 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile compound i-82d (100 mg, 0.35 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (29 mg, 0.04 mmol) and Cs₂CO₃(342 mg, 1.05 mmol) were reacted in DMF (10 mL) at 100° C. for 16 h under nitrogen. Upon aqueous work-up (EtOAc), preparative TLC (EtOAc:PE=1:1) followed by preparative HPLC (PrepMethod 0, gradient: 22-40%) the title compound (27 mg, 17%) was obtained as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₃N₁₀O: 443.2050, found: 443.2056. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.64 (2H, m), 1.85-2.01 (2H, m), 2.12-2.20 (2H, m), 2.38 (3H, s), 3.42 (3H, s), 4.29-4.43 (2H, m), 6.59 (1H, d), 7.01 (1H, d), 7.49 (1H, dd), 7.57 (1H, brs), 8.07-8.09 (2H, m), 8.17 (1H, s), 8.42 (1H, d).

Example 220
4-Methoxy-2-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one—compound 220

[Image Omitted]

rel-(1R,2R)—N₁,N²-Dimethylcyclohexane-1,2-diamine (64.6 mg, 0.45 mmol) was added to (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (180 mg, 0.45 mmol), 4-methoxypyridazin-3(2H)-one (CAS Reg. No. 38732-07-9) (115 mg, 0.91 mmol), Cu(I)I (87 mg, 0.45 mmol) and K₂CO₃(188 mg, 1.36 mmol) in DMF (10 mL) at 20° C. The resulting mixture was stirred at 100° C. for 15 h under a nitrogen atmosphere. The reaction mixture was poured into sat. brine (100 mL) and extracted with EtOAc (5×125 mL). The combined organic layers were washed with sat. brine (4×100 mL), dried over Na₂SO₄, filtered and evaporated. The residue was purified by preparative TLC (MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod 0, gradient: 5-35%) to give the title compound (95 mg, 53%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₃N₈O₂: 395.1938, found: 395.1936. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.4-1.68 (2H, m), 1.82-2.03 (2H, m), 2.1-2.25 (2H, m), 2.39 (3H, s), 3.85 (3H, s), 4.23-4.49 (2H, m), 6.53 (1H, d), 6.81 (1H, d), 6.93 (1H, d), 7.43-7.63 (2H, m), 7.90 (1H, d), 8.08 (1H, d), 8.17 (1H, s).

Example 221

4-Chloro-2-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one—compound 221

[Image Omitted]

rel-(1R,2R)—N¹,N²-Dimethylcyclohexane-1,2-diamine (71.8 mg, 0.50 mmol) was added to (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (200 mg, 0.50 mmol), 4-chloropyridazin-3(2H)-one (CAS Reg. No. 1677-79-8) (132 mg, 1.01 mmol), Cu(I)I (96 mg, 0.50 mmol) and K₂CO₃(209 mg, 1.51 mmol) in DMF (15 mL) at 25° C. The resulting solution was stirred at 100° C. for 18 h under a nitrogen atmosphere. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with sat. brine (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the residue was purified by preparative TLC (MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod C, gradient: 18-33%) to give the title compound (55.4 mg, 27%) as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C18H₂₀ClN₈O: 399.1442, found: 399.1428. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.66 (2H, m), 1.83-2.03 (2H, m), 2.08-2.25 (2H, m), 2.39 (3H, s), 4.25-4.47 (2H, m), 6.54 (1H, d), 7.02 (1H, d), 7.48-7.61 (2H, m), 7.84 (1H, d), 8.00 (1H, d), 8.12 (1H, d), 8.18 (1H, s).

Example 222
6-Chloro-2-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H-one—compound 222

[Image Omitted]

rel-(1R,2R)—N¹,N²-Dimethylcyclohexane-1,2-diamine (71.8 mg, 0.50 mmol) was added to (1S,3S)—N¹-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (200 mg, 0.50 mmol), 6-chloropyridazin-3(2H)-one (CAS Reg. No. 19064-67-6) (132 mg, 1.01 mmol), Cu(I)I (96 mg, 0.50 mmol) and K₂CO₃(209 mg, 1.51 mmol) in DMF (15 mL) at 25° C. The resulting solution was stirred at 100° C. for 18 h under a nitrogen atmosphere. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed sequentially with sat. brine (3×75 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated and the residue was purified by preparative TLC (MeOH:DCM=1:20) followed by preparative HPLC (PrepMethod D, gradient: 20-30%) to give the title compound (38 mg, 19%) as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₈H₂₀ClN₈O: 399.1442, found: 399.1464. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.40-1.65 (2H, m), 1.82-1.99 (2H, m), 2.05-2.22 (2H, m), 2.39 (3H, s), 4.25-4.45 (2H, m), 6.53 (1H, d), 7.03 (1H, d), 7.13 (1H, d), 7.45-7.72 (3H, m), 8.11 (1H, d), 8.18 (1H, s).

Example 247
2-(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)benzonitrile—compound 247

[Image Omitted]

A mixture of (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (0.099 g, 0.32 mmol), 2-bromobenzonitrile (CAS Reg. No. 2042-37-7) (0.132 g, 0.72 mmol), Pd-118 (0.021 g, 0.03 mmol) and K₂CO₃1.8 M (700 PL, 1.26 mmol) in 1,4-dioxane (3 mL) was stirred a 90° C. for 2 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 30-70%) to afford (67 mg, 57%) of the title compound as a beige solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₂N₇: 372.1932, found: 372.1938; ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.57-1.72 (2H, m), 1.97-2.12 (2H, m), 2.23-2.35 (2H, m), 2.43 (3H, s), 4.33-4.49 (2H, m), 6.63 (1H, d), 7.45 (1H, td), 7.5-7.55 (1H, m), 7.62-7.72 (2H, m), 7.78 (1H, dd), 8.16 (1H, d), 8.18 (1H, s).

Example 248
(1S,3S)—N¹-(6-Methyl-1,2,4-triazin-3-yl)-N¹-(3-methyl-[2,3′-bipyridin]-6′-yl)cyclopentane-1,3-diamine—compound 248

[Image Omitted]

A mixture of (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (0.104 g, 0.33 mmol), 2-bromo-3-methylpyridine (CAS Reg. No. 3430-17-9) (74 μL, 0.66 mmol), Pd-118 (22 mg, 0.03 mmol) and aq K₂CO₃(1.8 M, 736 PL, 1.32 mmol) in 1,4-dioxane (3 mL) was stirred at 90° C. for 2 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 20-60%) to afford (58 mg, 49%) of the title compound as a beige solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇: 362.2088, found: 362.2074. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.58-1.73 (2H, m), 1.97-2.13 (2H, m), 2.24-2.36 (2H, m), 2.38 (3H, s), 2.44 (s, 3H), 4.33-4.5 (2H, m), 6.63 (1H, d), 7.27 (1H, dd), 7.60 (1H, dd), 7.73 (1H, dd), 8.11 (1H, s), 8.19 (1H, s), 8.38 (1H, d).

Example 249
(1S,3S)—N¹-(5-(3,5-Dimethyl-1H-pyrazol-1-yl)pyridin-2-yl)-N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 249

[Image Omitted]

A mixture of 6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (0.122 g, 0.39 mmol), 3,5-dimethyl-1H-pyrazole (CAS Reg. No. 67-51-6) (0.149 g, 1.55 mmol), diacetoxycopper (0.169 g, 0.93 mmol) and pyridine (0.17 mL, 2.1 mmol) in DCM (4 mL) and DMF (0.8 mL) was stirred at rt for 20 h. Solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 20-60%) to yield a pale-blue solid. DCM and water were added to the solid. Phases were separated on a phase separator and the organic layer concentrated to afford (73 mg, 52%) of the title compound as an off-white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₅N₈: 365.2196, found: 365.2186; ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.56-1.71 (2H, m), 1.96-2.11 (2H, m), 2.19 (3H, s), 2.22 (3H, s), 2.24-2.33 (2H, m), 2.44 (3H, s), 4.36 (1H, p), 4.44 (1H, p), 6.02 (1H, s), 6.61 (1H, d), 7.42 (1H, dd), 7.96 (1H, d), 8.19 (1H, s).

Example 250
2,4-Dimethyl-1-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1H-imidazole-5-carbonitrile—compound 250

[Image Omitted]

A mixture of (1S,3S)—N¹-(5-(5-iodo-2,4-dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-77b (40 mg, 0.08 mmol), cyanocopper (29 mg, 0.33 mmol) and Pd(OAc)₂(7.33 mg, 0.03 mmol) in NMP (1 mL) was stirred at 120° C. for 5 h. The mixture was concentrated, the residue dissolved in DCM and washed with water. The organic layer was concentrated under reduced pressure and purified by preparative HPLC (PrepMethod F, gradient 10-50%) to afford (3 mg, 9%) of the title compound as a beige solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₉: 390.2150, found: 390.2166. ¹H NMR (500 MHz, MeOH-d₄) δ 1.6-1.72 (2H, m), 2-2.12 (2H, m), 2.25-2.34 (5H, m), 2.34 (3H, s), 2.45 (3H, s), 4.36-4.5 (2H, m), 6.65 (1H, dd), 7.44 (1H, dd), 8.01 (1H, d), 8.20 (1H, s).

Example 254
6′-(((1S,3S)-3-((6-Methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 254

[Image Omitted]

According to GM1A 6′-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one HCl compound i-1c (283 mg, 0.92 mmol), 6-methyl-3-(methylsulfinyl)-1,2,4-triazin-5(4H)-one compound i-80a (160 mg, 0.92 mmol) and DIPEA (484 μL, 2.77 mmol) were reacted in 1,4-dioxane (10 mL) at 100° C. for 15 h. The reaction mixture was diluted with sat. brine (100 ml) and extracted with EtOAc (3×75 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative HPLC (PrepMethod E, gradient: 2-28%) to give the title compound (42 mg, 12%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₂N₇O₂: 380.1830, found: 380.1846. ¹H NMR (300 MHz, MeOH-d₄) δ ppm 1.54-1.66 (2H, m), 2.00 (2H, t), 2.14 (3H, s), 2.21-2.32 (2H, m), 4.30-4.40 (2H, m), 6.47 (1H, dt), 6.60-6.64 (2H, m), 7.45 (1H, dd), 7.57-7.64 (2H, m), 7.95 (1H, brd).

Example 255
6′-(((1S,3S)-3-((6-Chloro-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 255

[Image Omitted]

N-chlorosuccinimide (NCS) (19 mg, 0.14 mmol) was added to a mixture of 6′-(((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one compound i-83b (50 mg, 0.14 mmol) in MeCN (2 mL) at 25° C. and it was stirred for 17 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) followed by preparative HPLC (PrepMethod 0, gradient: 12-42%) to give the title compound (5.7 mg, 10%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₈H₁₉ClN₇O: 384.1334, found: 384.1310. ¹H NMR (300 MHz, MeOH-d₄) δ ppm 1.62-1.76 (2H, m), 2.10 (2H, t), 2.26-2.38 (2H, m), 4.45-4.54 (1H, m), 4.58-4.67 (1H, m), 6.47 (1H, dt), 6.60-6.64 (1H, m), 7.58-7.64 (2H, m), 7.69 (1H, d), 8.00 (1H, d), 8.25 (1H, d), 8.46 (1H, d).

Example 256
6′-(((1S,3S)-3-((6-(Dimethylamino)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 256

[Image Omitted]

According to GM2 Cs₂CO₃(183 mg, 0.56 mmol) was added to a mixture of 6′-(((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one compound i-84b (80 mg, 0.19 mmol), dimethylamine in THE (2 M, 0.28 mL, 0.56 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (16 mg, 2 μmol) in dioxane (5 mL) at rt and the resulting suspension was stirred at 100° C. for 16 h under nitrogen. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated to afford crude product which was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:25) followed by preparative HPLC (PrepMethod C, gradient: 15-33%) to give (17 mg, 23%) of the title compound as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₅N₈O: 393.2146, found: 393.2140. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.43-1.61 (2H, m), 1.82-1.97 (2H, m), 2.07-2.18 (2H, m), 2.96 (6H, s), 4.23-4.34 (2H, m), 6.27 (1H, dt), 6.44 (1H, d), 6.53 (1H, d), 6.77 (1H, d), 6.92 (1H, d), 7.39 (1H, dd), 7.47 (1H, ddd), 7.61 (1H, dd), 7.92 (1H, d), 8.23 (1H, s).

Example 257
6′-(((1S,3S)-3-((6-(1H-Pyrazol-5-yl)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 257

[Image Omitted]

According to GM1A (1S,3S)—N¹-(6-(1H-pyrazol-5-yl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-85b 4TFA (370 mg, 0.53 mmol), 6′-fluoro-2H-[1,3′-bipyridin]-2-one (CAS Reg. No. 2062643-92-7) compound i-100a (150 mg, 0.79 mmol) and K₂CO₃(365 mg, 2.64 mmol) were reacted in DMSO (5 mL) at 100° C. for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with sat. brine (3×50 mL), dried (Na₂SO₄), filtered and evaporated to afford crude product which was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:30) followed by preparative HPLC (PrepMethod D, gradient: 7-37%) the title compound (3.0 mg, 1.4%) as a pale yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₂ClN₉O: 416.1942, found: 416.1940. ¹H NMR (300 MHz, DMSO-de) b ppm 1.50-1.68 (2H, m), 1.92-2.05 (2H, m), 2.13-2.24 (2H, m), 4.30-4.51 (2H, m), 6.27 (1H, dt), 6.44 (1H, d), 6.54 (1H, d), 6.81 (1H, d), 6.96 (1H, d), 7.40 (1H, dd), 7.47 (1H, ddd), 7.61 (1H, dd), 7.85-7.93 (3H, m), 8.75 (1H, s), 13.10 (1H, brs).

Example 258
6′-(((1S,3S)-3-((6-(Ethylthio)-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 258

[Image Omitted]

According to GM1A (1S,3S)—N¹-(6-(ethylthio)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-86b 3.3TFA (123 mg, 0.20 mmol), 6′-fluoro-2H-[1,3′-bipyridin]-2-one (CAS Reg. No. 2062643-92-7) compound i-100a (57 mg, 0.30 mmol) and Na₂CO₃(106 mg, 1.00 mmol) were reacted in DMSO (5 mL) at 120° C. for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with sat. brine (3×50 mL), dried (Na₂SO₄), filtered and evaporated to afford crude product which was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:20) followed by preparative HPLC (PrepMethod T, gradient: 25-43%) to give the title compound (3.0 mg, 1.4%) as a pale-yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇OS: 410.1758, found: 410.1750. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.26 (3H, t), 1.48-1.64 (2H, m), 1.88-1.99 (2H, m), 2.11-2.20 (2H, m), 3.10 (2H, q), 4.30-4.40 (2H, m), 6.27 (1H, t), 6.44 (1H, d), 6.53 (1H, d), 6.94 (1H, d), 7.40 (1H, dd), 7.47 (1H, ddd), 7.60 (1H, dd), 7.77 (1H, brs), 7.92 (1H, d), 8.28 (1H, s).

Example 260
6′-(((1S,3S)-3-((6-Acetyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one—compound 260

[Image Omitted]

In a slight variation of GM2 Pd-PEPPSI-IpentCl 2-methylpyridine (17 mg, 0.02 mmol) was added to a mixture of 1-(3-(((1S,3S)-3-aminocyclopentyl)amino)-1,2,4-triazin-6-yl)ethan-1-one compound i-104b (180 mg, 0.81 mmol), 6′-chloro-2H-[1,3′-bipyridin]-2-one compound i-29a (84 mg, 0.41 mmol) and Cs₂CO₃(398 mg, 1.22 mmol) in DMF (10 mL) at 25° C. and the resulting mixture was stirred at 100° C. for 15 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (200 mL). The organic layer was washed with sat. brine (3×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (DCM:MeOH=15:1) followed by preparative HPLC (PrepMethod 0, gradient: 15-36%) to give (17 mg, 5.4%) of the title compound as a white solid. HRMS (ESI) m/z [M+H] calcd for C₂₀H₂₂N₇O₂: 392.1830, found: 392.1850. ¹H NMR (500 MHz, DMSO-d₆, 2 rotamers) b ppm 1.53-1.69 (2H, m), 1.89-2.04 (2H, m), 2.13-2.26 (2H, m), 2.60 (3H, s), 4.33-4.45 (1.5H, m), 4.66 (0.5H, q), 6.27 (1H, dt), 6.44 (1H, d), 6.54 (1H, dd), 6.97 (1H, dd), 7.41 (1H, dd), 7.47 (1H, ddd), 7.60 (1H, d), 7.93 (1H, d), 8.62 (0.5H, d), 8.66 (1H, d), 9.10 (0.5H, d).

Example 277
2-(6-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile—compound 277

[Image Omitted]

A mixture of 4-chloro-2-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one compound 221 (75 mg, 0.19 mmol), XPhos Pd G3 (CAS Reg. No. 1445085-55-1) (48 mg, 0.06 mmol), XPhos (27 mg, 0.06 mmol) and zinc cyanide (44 mg, 0.38 mmol) in DMF (10 mL) was sealed in a microwave tube under a nitrogen atmosphere and the resulting mixture was stirred at 140° C. for 1 h under microwave irradiation. The reaction mixture was quenched with sat. brine (150 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the residue was purified by preparative TLC (MeOH:DCM=1:10) followed by preparative HPLC PrepMethod 0, gradient: 18-37%) to give the title compound (50 mg, 68%) as an orange solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₀N₉O: 390.1786, found: 390.1802. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.63 (2H, m), 1.84-2.00 (2H, m), 2.07-2.23 (2H, m), 2.38 (3H, s), 4.29-4.43 (2H, m), 6.55 (1H, d), 7.08 (1H, d), 7.52-7.56 (2H, m), 8.14 (1H, d), 8.17 (1H, s), 8.19 (1H, d), 8.22 (1H, d).

Example 281
4-(Difluoromethoxy)-2-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one—compound 281

[Image Omitted]

In a slight variation of GM3 (1S,3S)—N-(5-iodopyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-39a (150 mg, 0.38 mmol), 4-(difluoromethoxy)pyridazin-3(2H)-one compound i-107e (184 mg, 1.14 mmol), K₂CO₃(157 mg, 1.14 mmol), Cu(I)I (72 mg, 0.38 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (56 mg, 0.39 mmol) were reacted in DMF (10 mL) at 100° C. for 18 h. The reaction mixture was diluted with EtOAc (150 mL) and the organic layer was washed sequentially with water (3×75 mL) and sat. brine (3×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod D, gradient: 10-40%) to give the title compound (76 mg, 47%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₁F₂N₈O₂: 431.1750, found: 431.1742. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.63 (2H, m), 1.84-2.00 (2H, m), 2.07-2.23 (2H, m), 2.38 (3H, s), 4.28-4.43 (2H, m), 6.54 (1H, d), 7.00 (1H, d), 7.24 (1H, d), 7.46 (1H, t), 7.52 (1H, dd), 7.57 (1H, brs), 8.02 (1H, d), 8.11 (1H, d), 8.17 (1H, s). ¹⁹F NMR (282 MHz, DMSO-d₆) b ppm −84.49 (2F, s).

Example 304
(1S,3S)—N′-(3-Methoxy-[2,3′-bipyridin]-6′-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 304

[Image Omitted]

According to GM4A (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-3-methoxypyridine (CAS Reg. No. 24100-18-3) (60 mg, 0.32 mmol), aq. K₂CO₃(1.8 M, 354 μL, 0.64 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (10 mg, 0.02 mmol) were reacted in 1,4-dioxane (1.5 mL) at 90° C. for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by multiple preparative HPLC runs (PrepMethod Z10, gradient: 30-70% followed by PrepMethod G, gradient: 0-50% followed by PrepMethod Z9, gradient: 30-70%) to give the title compound (27 mg, 45%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O: 378.2036, found: 378.2044. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.57-1.72 (2H, m), 1.98-2.13 (2H, m), 2.24-2.35 (2H, m), 2.44 (3H, s), 3.90 (3H, s), 4.37 (1H, p), 4.45 (1H, p), 6.59 (1H, d), 7.29 (1H, dd), 7.50 (1H, dd), 7.92 (1H, dd), 8.14 (1H, dd), 8.19 (1H, s), 8.49 (1H, s).

Example 305
(1S,3S)—N′-(6-Methoxy-[2,3′-bipyridin]-6′-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 305

[Image Omitted]

According to GM4A (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-6-methoxypyridine (CAS Reg. No. 40473-07-2) (39 μL, 0.32 mmol), aq. K₂CO₃(1.8 M, 354 μL, 0.64 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Reg. No. 95408-45-0) (10 mg, 0.02 mmol) were reacted in 1,4-dioxane (1.5 mL) at 90° C. for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (18 mg, 30%) as an off-white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₄N₇O: 378.2036, found: 378.2030. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.57-1.73 (2H, m), 1.97-2.12 (2H, m), 2.23-2.35 (2H, m), 2.44 (3H, s), 3.97 (3H, s), 4.37 (1H, p), 4.44 (1H, p), 6.60 (2H, ddd), 7.27 (1H, dd), 7.63 (1H, dd), 8.09 (1H, dd), 8.19 (1H, s), 8.67 (1H, d).

Example 306
(1S,3S)—N′-(5-(2-Methoxyphenyl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 306

[Image Omitted]

According to GM4A (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 1-bromo-2-methoxybenzene (CAS Reg. No. 578-57-4) (40 μL, 0.32 mmol), aq. K₂CO₃(1.8 M, 354 μL, 0.64 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1,4-dioxane (1.5 mL) at 90° C. for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (30 mg, 50%) as an off-white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₅N₆O: 377.2084, found: 377.2086. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.56-1.72 (2H, m), 1.96-2.12 (2H, m), 2.23-2.35 (2H, m), 2.44 (3H, s), 3.80 (3H, s), 4.32 (1H, p), 4.44 (1H, p), 6.56 (1H, dd), 6.98 (1H, td), 7.03 (1H, dd), 7.23 (1H, dd), 7.27 (1H, ddd), 7.60 (1H, dd), 8.06 (1H, d), 8.18 (1H, s).

Example 307
(1S,3S)—N¹-(5-(2,6-Dimethoxyphenyl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 307

[Image Omitted]

According to GM4A (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-1,3-dimethoxybenzene (CAS Reg. No. 16932-45-9) (69 mg, 0.32 mmol), aq. K₂CO₃(1.8 M, 354 PL, 0.64 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1,4-dioxane (1.5 mL) at 90° C. for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (45 mg, 70%) as an off-white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₇N₆O₂: 407.2190, found: 407.2200. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.56-1.71 (2H, m), 1.96-2.12 (2H, m), 2.22-2.34 (2H, m), 2.43 (3H, s), 3.71 (6H, s), 4.30 (1H, p), 4.44 (1H, p), 6.54 (1H, d), 6.69 (2H, d), 7.24 (1H, t), 7.35 (1H, dd), 7.79-7.86 (1H, m), 8.18 (1H, s).

Example 308
(1S,3S)—N′-(5-(2-Fluoro-6-methoxyphenyl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 308

[Image Omitted]

According to GM4A (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromo-1-fluoro-3-methoxybenzene (CAS Reg. No. 446-59-3) (65 mg, 0.32 mmol), aq. K₂CO₃(1.8 M, 354 PL, 0.64 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1,4-dioxane (1.5 mL) at 90° C. for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 30-70%) to give the title compound (39 mg, 62%) as an off-white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₄FN₆O: 395.1990, found: 395.1964. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.56-1.72 (2H, m), 1.97-2.12 (2H, m), 2.23-2.35 (2H, m), 2.44 (3H, s), 3.78 (3H, s), 4.33 (1H, p), 4.44 (1H, p), 6.57 (1H, dd), 6.77 (1H, ddd), 6.87 (1H, dt), 7.27 (1H, td), 7.44 (1H, ddd), 7.92 (1H, s), 8.18 (1H, s).

Example 309
(1S,3S)—N′-([2,3′-Bipyridin]-6′-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 309

[Image Omitted]

According to GM4A (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (50 mg, 0.16 mmol), 2-bromopyridine (CAS Reg. No. 109-04-6) (30 μL, 0.32 mmol), aq. K₂CO₃(1.8 M, 354 μL, 0.64 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were reacted in 1,4-dioxane (1.5 mL) at 90° C. for 2 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z10, gradient: 10-60%) to give the title compound (3 mg, 5%) as an off-white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₂N₇: 348.1932, found: 348.1904.

Example 310
(1S,3S)—N′-(5-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 310

[Image Omitted]

A mixture of 6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (96 mg, 0.31 mmol), 1H-pyrazolo[3,4-b]pyridine (CAS Reg. No. 271-73-8) (0.109 g, 0.92 mmol), diacetoxycopper (0.133 g, 0.73 mmol) and pyridine (0.14 mL, 1.7 mmol) in DCM (3 mL) and DMF (0.6 mL) was stirred at rt for 20 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z9, gradient: 0-60%) to give the title compound (8 mg, 7%) as an off-white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₂N₉: 388.1992, found: 388.2024. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.59-1.73 (2H, m), 2-2.16 (2H, m), 2.31 (2H, ddt), 2.44 (3H, s), 4.39 (1H, p), 4.46 (1H, p), 6.70 (1H, d), 7.29 (1H, dd), 8.01 (1H, dd), 8.20 (1H, s), 8.26 (1H, s), 8.29 (1H, dd), 8.57 (1H, dd), 8.59 (1H, d).

Example 311
(1S,3S)—N′-(5-(1H-Indazol-1-yl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 311

[Image Omitted]

A mixture of 6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (100 mg, 0.32 mmol), indazole (CAS Reg. No. 271-44-3) (0.113 g, 0.95 mmol), diacetoxycopper (0.156 g, 0.86 mmol) and pyridine (0.15 mL, 1.9 mmol) in DCM (3 mL) and DMF (0.6 mL) was stirred at rt for 20 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z9, gradient: 30-70%) to give the title compound (7 mg, 6%) as solid along with its 2-regiosiomer (see compound 312).

HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₃N₈: 387.2040, found: 387.2030. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.59-1.73 (2H, m), 2-2.14 (2H, m), 2.24-2.37 (2H, m), 2.44 (3H, s), 4.40 (1H, p), 4.46 (1H, p), 6.71 (1H, d), 7.23 (1H, ddd), 7.45 (1H, ddd), 7.54 (1H, dd), 7.67 (1H, dd), 7.83 (1H, dt), 8.14-8.26 (3H, m).

Example 312
(1S,3S)—N¹-(5-(2H-Indazol-2-yl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 312

[Image Omitted]

Isolated from the above reaction mixture: yield 2 mg, 1.6%. MS (ESI) m/z [M+H]⁺ 387.4.

¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.59-1.74 (2H, m), 1.99-2.13 (2H, m), 2.24-2.37 (2H, m), 2.45 (3H, s), 4.37-4.5 (2H, m), 6.69 (1H, d), 7.11 (1H, ddd), 7.33 (1H, ddd), 7.66 (1H, dd), 7.75 (1H, dt), 7.93 (1H, dd), 8.20 (1H, s), 8.50 (1H, d), 8.59 (1H, d).

Example 313
(1S,3S)—N¹-(5-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 313

[Image Omitted]

A mixture of 6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (100 mg, 0.32 mmol), 3,5-dimethyl-4H-1,2,4-triazole (0.093 g, 0.95 mmol) (CAS Reg. No. 7343-34-2) (93 mg, 0.95 mmol), diacetoxycopper (0.139 g, 0.76 mmol) and pyridine (0.15 mL, 1.9 mmol) in DCM (3 mL) and DMF (0.6 mL) was stirred at rt for 20 h. The solids were filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the obtained material was purified by preparative HPLC (PrepMethod Z9, gradient: 20-60%) to give the title compound (31 mg, 27%) as solid. HRMS (ESI) m/z [M+H]⁺ calcd for C18H₂₄N₉: 366.2150, found: 366.2160. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.57-1.72 (2H, m), 1.98-2.11 (2H, m), 2.22-2.32 (2H, m), 2.33 (3H, s), 2.39 (3H, s), 2.44 (3H, s), 4.34-4.49 (2H, m), 6.62 (1H, dd), 7.48 (1H, dd), 8.02-8.07 (1H, m), 8.19 (1H, s).

Example 314
(1S,3S)—N¹-(5-(2,5-Dimethyloxazol-4-yl)pyridin-2-yl)-N³-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine—compound 314

[Image Omitted]

According to GM1A 4-(6-fluoropyridin-3-yl)-2,5-dimethyloxazole compound i-108b (83 mg, 0.43 mmol) was added to a mixture of the 3 TFA salt of (1S,3S)—N¹-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (393 mg, 0.73 mmol) and K₂CO₃(537 mg, 3.89 mmol) in DMSO (3 mL). The resulting mixture was stirred at 80° C. for 1 week under a nitrogen atmosphere. The solids were filtered off and the filtrate was purified by preparative HPLC (PrepMethod Z9, gradient: 20-60%) to give the title compound (55 mg, 35%) as brown solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₉H₂₄N₇O: 366.2036, found: 366.2032. ¹H NMR (500 MHz, MeOH-d₄) δ ppm 1.55-1.71 (2H, m), 1.96-2.11 (2H, m), 2.22-2.33 (2H, m), 2.42 (6H, s), 2.43 (3H, s), 4.33 (1H, p), 4.43 (1H, p), 6.59 (1H, d), 7.62 (1H, dd), 8.15 (1H, d), 8.18 (1H, s).

Example 315
rac-6′-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)-3-methyl-2H-[1,3′-bipyridin]-2-one—compound 315

[Image Omitted]

According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109g (90 mg, 0.22 mmol), 3-methylpyridin-2(1H-one (CAS Reg. No. 1003-56-1) (24 mg, 0.22 mmol), Cs₂CO₃(142 mg, 0.43 mmol), Cu(I)I (21 mg, 0.11 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (15 mg, 0.11 mmol) were reacted in 1,4-dioxane (15 mL) at 80° C. for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (150 mL) and the organic layer was washed sequentially with water (3×75 mL) and sat. brine (3×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod X, gradient: 8-38%) to give the title compound (46 mg, 54%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₆N₇O₂: 396.2142, found: 396.2158. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (2H, q), 2.02-2.06 (4H, m), 2.37 (3H, s), 3.32-3.38 (4H, m, partly covered by water peak), 3.52 (2H, q), 4.47 (1H, t), 6.19 (1H, t), 6.55 (1H, d), 6.86 (1H, brt), 7.35-7.40 (2H, m), 7.44-7.50 (2H, m), 7.89 (1H, d), 8.16 (1H, s).

Example 316
rac-6′-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)-5-methyl-2H-[1,3′-bipyridin]-2-one—compound 316

[Image Omitted]

According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109g (100 mg, 0.24 mmol), 5-methylpyridin-2(1H-one (CAS Reg. No 1003-68-5) (53 mg, 0.48 mmol), Cs₂CO₃(157 mg, 0.48 mmol), Cu(I)I (23 mg, 0.12 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (17 mg, 0.12 mmol) were reacted in 1,4-dioxane (15 mL) at 80° C. for 15 h under nitrogen. The reaction mixture was filtered through a filter membrane and the obtained residue purified by preparative TLC (DCM:MeOH=10:1) followed by preparative HPLC (PrepMethod D, gradient: 10-28%) to give the title compound (35 mg, 37%) as a yellow solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₆N₇O₂: 396.2142, found: 396.2128. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.53 (2H, q), 2.03-2.06 (4H, m), 2.38 (3H, s), 3.30-3.39 (4H, m, partly covered by water peak), 3.53 (2H, q), 4.45 (1H, t), 6.39 (1H, d), 6.56 (1H, d), 6.83 (1H, t), 7.33-7.40 (3H, m), 7.48 (1H, brs), 7.89 (1H, d), 8.16 (1H, s).

Example 317
rac-6′-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)-5-methoxy-2H-[1,3′-bipyridin]-2-one—compound 317

[Image Omitted]

According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109g (90 mg, 0.22 mmol), 5-methoxypyridin-2(1H-one (CAS Reg. No. 61941-79-5) (54 mg, 0.43 mmol), Cs₂CO₃(142 mg, 0.43 mmol), Cu(I)I (21 mg, 0.11 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (15 mg, 0.11 mmol) were reacted in 1,4-dioxane (15 mL) at 80° C. for 18 h under nitrogen. The reaction mixture was diluted with EtOAc (150 mL) and the organic layer was washed sequentially with water (3×75 mL) and sat. brine (3×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:15, 96 mg isolated) followed by preparative HPLC (PrepMethod X, gradient: 8-38%) to give the title compound (43 mg, 48%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₀H₂₆N₇O₃: 412.2092, found: 412.2090.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (2H, q), 2.03 (1H, qn), 2.33 (3H, s), 3.31-3.38 (4H, m, partly covered by water peak), 3.52 (2H, q), 3.64 (3H, s), 4.47 (1H, t), 6.42 (1H, d), 6.56 (1H, d), 6.86 (1H, t), 7.18 (1H, d), 7.35 (1H, dd), 7.42 (1H, dd), 7.50 (1H, brs), 7.95 (1H, d), 8.16 (1H, s).

Example 318
rac-1-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3-yl)quinolin-2(1H)-one—compound 318

[Image Omitted]

According to GM2 the crude HCl salt of rac-4-amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109f (150 mg, 0.53 mmol), 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one compound i-21a (203 mg, 0.79 mmol), Cs₂CO₃(516 mg, 1.58 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (22 mg, 0.03 mmol) were reacted in 1,4-dioxane (10 mL) at 100° C. for 18 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (150 mL). The organic layer was washed with sat. brine (3×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (MeOH:DCM=1:20) followed by preparative HPLC (PrepMethod 0, gradient: 19-34%) to give the title compound (37 mg, 16%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₃H₂₆N₇O₂: 432.2142, found: 432.2148. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.56 (2H, q), 2.04-2.13 (1H, m), 2.37 (3H, s), 3.32-3.42 (4H, m, partly covered by water peak), 3.55 (2H, q), 4.49 (1H, t), 6.64-6.74 (3H, m), 6.93 (1H, brt), 7.23 (1H, t), 7.30 (1H, dd), 7.45 (1H, t), 7.52 (1H, brs), 7.75 (1H, d), 7.82 (1H, t), 8.01 (1H, d), 8.16 (1H, s).

Example 319
rac-3-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one—compound 319

[Image Omitted]

According to GM2 the crude HCl salt of rac-4-amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109f (153 mg, 0.54 mmol), 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-24a (140 mg, 0.54 mmol), Cs₂CO₃(875 mg, 2.69 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (36 mg, 0.04 mmol) were reacted in 1,4-dioxane (20 mL) at 100° C. for 18 h under nitrogen and subsequently filtered through Celite. The filter cake was washed with DCM (2×10 mL), the combined filtrates concentrated under reduced pressure and the residue was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod 0, gradient: 13-28%) to give the title compound (30 mg, 13%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₂₆N₉O₂: 436.2204, found: 436.2220. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.53 (2H, q), 2.01-2.09 (1H, m), 2.37 (3H, s), 3.30-3.40 (7H, m, partly covered by water peak), 3.53 (2H, q), 4.48 (1H, t), 6.62 (1H, d), 6.86 (1H, t), 7.14 (1H, dd), 7.49-7.58 (3H, m), 7.94 (1H, dd), 8.08 (1H, d), 8.16 (1H, s).

Example 320
rac-1-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one—compound 320

[Image Omitted]

According to GM3 the crude HCl salt of rac-4-amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109f (248 mg, 0.87 mmol), 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one compound i-6a (150 mg, 0.58 mmol), Cs₂CO₃(569 mg, 1.75 mmol), Cu(I)I (111 mg, 0.58 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (83 mg, 0.58 mmol) were reacted in 1,4-dioxane (10 mL) at 80° C. for 15 h under nitrogen. The reaction mixture was poured into water (125 mL) and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (7 M NH₃in MeOH:DCM=1:15) followed by preparative HPLC (PrepMethod 0, gradient: 13-25%) to give the title compound (48 mg, 19%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₅N₈O₂: 433.2094, found: 433.2126. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (2H, q), 2.02-2.11 (1H, m), 2.38 (3H, s), 3.33-3.41 (4H, m, partly covered by water peak), 3.55 (2H, q), 4.49 (1H, t), 6.61 (1H, d), 6.75 (1H, d), 6.78 (1H, t), 7.25 (1H, dd), 7.29 (1H, dd), 7.54 (1H, brs), 7.78 (1H, d), 8.03 (1H, d), 8.16 (1H, s), 8.20 (1H, dd), 8.44 (1H, dd).

Example 321
rac-1-(6-((4-Hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one—compound 321

[Image Omitted]

According to GM3 rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol compound i-109g (60 mg, 0.14 mmol), 1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CAS Reg. No. 1849-01-0) (43 mg, 0.29 mmol), Cs₂CO₃(142 mg, 0.43 mmol), Cu(I)I (28 mg, 0.14 mmol) and rel-(1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (21 mg, 0.14 mmol) were reacted in 1,4-dioxane (10 mL) at 80° C. for 15 h under nitrogen. The reaction mixture was concentrated under reduced pressure and taken up with EtOAc (200 mL). The organic layer was washed with sat. brine (3×50 mL), dried over Na₂SO₄, filtered and evaporated and the crude material was purified by preparative TLC (MeOH:DCM=1:15) followed by flash C18-flash chromatography (gradient: 0-40% MeCN in water) to give the title compound (20 mg, 32%) as a white solid. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₂₇N₈O₂: 435.2252, found: 435.2282. ¹H NMR (300 MHz, MeOH-d₄) δ ppm 1.67 (2H, q), 2.10-2.19 (1H, m), 2.43 (3H, s), 3.37-3.58 (7H, m), 3.74 (2H, t), 6.71 (1H, dd), 6.94 (1H, d), 7.07-7.22 (3H, m), 7.48 (1H, dd), 8.08 (1H, dd), 8.19 (1H, s).

Assays and Methods Used
Assay 1—Biochemical Human PCSK9 Assay

This assay measures binding of compounds to PCSK9 by homogenous time-resolved fluorescence resonance energy transfer (TR-FRET).

To determine the IC₅₀of inhibitors of the interaction between the human PCSK9 and Alexa647 labelled small molecule, fluorescent probe displacement was monitored by homogenous TR-FRET technology. Upon binding of a terbium (Tb) cryptate conjugated anti-His mouse antibody (mAb Anti-6His Tb cryptate Gold, Cisbio) to PCSK9-TEV-His6, the displacement of the probe from PCSK9 was assessed by reduction of the proximity and FRET signal between the Tb cryptate that serves as a FRET-donor and the Alexa647 probe that serves as acceptor.

Recombinantly expressed and purified PCSK9-TEV-His6 (1 nM) was mixed with a fluorescent probe (5 nM) and anti His-Tb-cryptate antibody (0.2 nM) in assay buffer (10 mM HEPES/NaOH, pH 7.4, 150 mM NaCl, 0.005 (v/v) % Tween 20). 6 μL were subsequently added to an assay-ready plate containing 0.06 μL of controls and test compound 10 dose-response serial dilutions starting at a concentration of 10 mM (with 100 μM top and 3.2 nM lowest final concentration) by using Certus flex dispenser. The plate was sealed, and the reaction was incubated overnight (18-24 h) at RT in the dark.

FRET signal quantification was achieved by PHERAstar FSX (BMG) plate reader. The created data file contained the emission of FRET acceptor channel (665 nm, probe), FRET donor channel (620 nm, Tb-cryptate, excitation at 337 nm) and the FRET ratio (665 nm/620 nm signal×10.000) which was used for calculation of a test compound's IC₅₀.

Assay 2—Biophysical Human PCSK9 Assay

This assay measures binding of compounds to PCSK9 by SPR (“surface plasmon resonance”, a biophysical method).

The SPR binding experiments were performed on a Biacore S200 optical biosensor unit at 30° C. A Series S Sensor Chip SA that is designed to bind biotinylated molecules for interaction analysis in Biacore systems was equilibrated at room temperature prior to use. The running buffer for protein tethering and subsequent ligand binding experiments was 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% (v/v) Tween 20 pH 7.4.

For the surface tethering of PCSK9, biotinylated human PCSK9 (31-692)-Avi-His6 at a concentration of 0.5 mg/mL was used. Prior to the surface tethering, the surface was exposed to a solution of 50 mM NaOH, 500 mM NaCl via 3 consecutive injections of this solution with a contact time of 60 s and a flowrate of 10 μL min⁻¹to remove non-conjugated streptavidin. The PCSK9 protein was diluted to a concentration of 20 μg/mL using running buffer and injected with a contact time of 180-300 s and a flowrate of 10 μL min⁻¹over a single flow channel (typically flow channel 2 or flow channel 4) with the aim to achieve protein capture levels of >5000 response units (RU). Remaining biotin binding sites were blocked via 2 consecutive injections of a 10 μM D-biotin solution in running buffer with a contact time of 60 s and a flowrate of 10 μL min⁻¹over all flow-channels. Flow-channels 1 and 3 typically served as a reference surface throughout the subsequent binding experiments.

The binding experiments were all performed at a flow rate of 30 PL min⁻¹and by employing the method of single-cycle kinetics. This approach involves the sequential injection of a compound concentration series without regeneration steps. A contact time between 90-150 s was selected, which was followed by a 40 min dissociation phase to allow for a proper estimation of the dissociation rate constant. Test compounds were delivered in DMSO at a concentration of 10 mM and a digital dispenser HP D300 was used to set up the compound concentration series using 6 concentrations. The tested concentrations have been 30, 100, 300, 1000, 3000 and 10000 nM. Prior to injecting any compound, the surfaces were equilibrated by injecting running buffer over them in three separate pulses. The data collection rate was set to 10 Hz.

The raw sensorgrams of the compound injections were first subjected to reference subtraction (subtracting the signal from flow channel 1 and/or 3 from the signal from channels 2 and/or 4 respectively) and then blank subtraction (subtracting the signal from injecting DMSO controls from the reference subtracted data). The resulting double-referenced sensorgrams were then fitted using a 1:1 binding interaction model using the manufactures software package to extract kinetic- and affinity data. Active compounds have been defined by creating a detectable binding signal at the highest compound concentration (10 mM) of 3 RUs. Kinetic- and affinity data on active compounds are only provided for those compounds where the binding signal at the highest compound concentration (10 mM) is 50% of the theoretical maximum binding signal for a 1:1 binding interaction (R_max, typically between 15-20 RUs) in order to enable a proper fitting of the data.

Assay 3—PCSK9 LDL-C Uptake Assay

This assay measures for PCSK9 antagonist activity based on a test compound's capacity to restore LDL-C-uptake in HepG2 cells. The assay is based on exogenous PCSK9 and LDL-C complexed with a pH-sensitive dye. Outside the cells, at neutral pH, the pHrodo Red-LDL is dimly fluorescent but upon LDLR mediated endocytosis it fluoresces brightly. PCSK9 traffics the LDLR to intracellular degradation and reduces uptake of LDL-C. Inhibition of PCSK9 reduces LDLR degradation and the increased LDL-C uptake is quantified by fluorescence microscopy.

Preparation of Assay Reagents

- Cell medium: MEM supplemented with 10% FBS, 1×NEAA and Sodium Pyruvate
- Assay medium: OptiMem supplemented with penicillin/streptomycin
- Cells: HepG2 (ATCC #HB-8065)

PCSK9: Sequence:

MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE

LVLALRSEED GLAEAPEHGT TATFHRCAKD PWRLPGTYVV

VLKEETHLSQ SERTARRLQA QAARRGYLTK ILHVFHGLLP

GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER

ITPPRYRADE YQPPDGGSLV EVYLLDTSIQ SDHREIEGRV

MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG

VAKGASMRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV

GPLVVLLPLA GGYSRVLNAA CQRLARAGVV LVTAAGNFRD

DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD

LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML

SAEPELTLAE LRQRLIHFSA KDVINEAWFP EDQRVLTPNL

VAALPPSTHG AGWQLFCRTV WSAHSGPTRM ATAIARCAPD

EELLSCSSFS RSGKRRGERM EAQGGKLVCR AHNAFGGEGV

YAIARCCLLP QANCSVHTAP PAEASMGTRV HCHQQGHVLT

GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC

CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG

TSHVLGAYAV DNTCVVRSRD VSTTGSTSEE AVTAVAICCR

SRHLAQASQE LQENLYFQGH HHHHH

Step by step protocol for running the assay:

Day 1

- 1. Cryopreserved HepG2 cells were thawed in assay medium and centrifuged for 5 min at 250 g. Supernatant was discarded and the cell pellet resuspended in cell medium and counted with a Nucleocounter. Cells were again centrifuged 5 min at 250 g and the pellet was resuspended to 500000 cells/mL in assay medium.
- 2. 20 μL of above cell mix was dispensed into black μclear TC treated 384 well plates with Multidrop Combi and left at room temperature for 20 minutes.
- 3. Plates were incubated at 37° C., 5% CO₂for 24 h

Day 2

- 1. Test compounds were prepared in concentration response in DMSO with a half-log dilution factor in DMSO in Echo 384 LDV plates starting at 10 mM.
- 2. 30 nL of above test compounds were dispensed with Echo 655 to cells for a top concentration of 10 μM
- 3. 10 μL PCSK9 in assay medium was dispensed to cells with Multidrop Combi for 125 nM final concentration in the wells.
- 4. Plates were incubated at 37° C., 5% CO₂for 24 h

Day 3

- 1. 10 μL pHrodo Red-LDL in assay medium was dispensed to cells with Multidrop Combi for 6 ag/mL
- 2. Plates were incubated at 37° C., 5% CO₂and imaged with the Incucyte S3 after 4 h and 24 h

Image data was processed using Incucyte 2021, a software to identify cells and red fluorescent intensity. Screener was used to further process data. Data was normalized as % effect of the signal between median values of the on-plate controls of DMSO and 100 nM Evolocumab according to the formula % effect=−100*(x−DMSO)/(Evolocumab−DMSO) where x equals the measured signal. Concentration response data of the normalized values were fitted using a four-parameter logistic fit.

Assay 4—In Vivo Assessment of Compound Effects on Plasma LDL-C Levels

A liver-specific human PCSK9 knock-in mouse model (hPCSK9-KI) was generated by expressing human PCSK9 under the control of a mouse albumin promoter/enhancer in C_5-7BL/6N mice as previously described in Carreras 2019. For all in vivo studies, heterozygous male hPCSK9-KI mice and their wildtype littermates were housed individually, and heterozygous female hPCSK9-KI mice were house in groups of 4-6 mice per cage. All animals had free access to enrichment and were housed in a temperature-controlled room (22° C.) with a 12:12-h light/dark cycle. They were fed a chow diet and water ad libitum.

For in vivo assessment of test compound activity, mice were randomised into experimental groups of for example 8 mice per group. Mice were ˜ 12 weeks of age at the time of study start. On day −1, blood samples were drawn from the tail vein and baseline levels of plasma LDL-C were assessed using an enzymatic method. Baseline plasma levels of human PCSK9 were assessed by ELISA. Starting on day 0, test compounds were dosed by oral gavage at for examplel5 mg/kg BID for up to 21 days. Blood samples were drawn from the tail vein and plasma levels of LDL-C and human PCSK9 were assessed using the afore mentioned methods.

Assay 5—hERG Assay (Human Ether-a-go-go-Related Gene)

This assay (human Ether-d-go-go-Related Gene) measures activity of the compounds at the potassium ion channel hERG (human Ether-d-go-go-Related Gene).

Experiments were performed on the SyncroPatch 384PE high throughput patch clamp platform at room temperature and medium resistance chips with 4 patch holes per site. Chinese hamster ovary K1 (CHO) cell lines over-expressing the ion channel of choice (hERG) were used in assay-ready format and kept in liquid nitrogen or were used from live culture. Cells were either thawed and diluted in HBSS or were detached from flasks and resuspended in HBSS. HBSS comprised 140 mM NaCl, 4 mM KCl, 10 mM HEPES and 5 mM Glucose (pH7.4). The internal patch clamp solution was KF 120 mM, KCl 20 mM, HEPES 10 mM, EGTA 10 mM, and 25 PM Escin (pH 7.2). After the sealing process was complete, the external solution was exchanged for external patch clamp solution comprising NaCl 80 mM, KCl 4 mM, HEPES 10 mM, CaCl₂2 mM, MgCl₂1 mM, glucose 5 mM, and NMDG 60 mM (pH 7.4). All solutions were stored at room temperature, except Escin, which was stored at 4° C. All test compounds were dispensed in greiner-bio 384 well plates and tested in a 6 point cumulative assay (final DMSO concentration 0.33%). Only wells that passed previously agreed acceptance criteria for this platform were used in this analysis (30 MegaOhm seal resistance, Z prime >0.4 and current size >0.2 nA).

High Concentration hERG

Experiments were performed on the QPatchII high throughput patch clamp platform at room temperature using single holes QChips. Chinese hamster ovary K1 (CHO) cell lines over-expressing the ion channel of choice (hERG) were used from live culture. All solutions were stored at 4° C. or −20° C. All compounds were dispensed as 10 or 50 mM DMSO stocks, in 96 well plates and diluted to a format that allowed testing in a 6 point cumulative assay (final DMSO concentration 2% or 0.4% DMSO). Only wells that passed previously agreed acceptance criteria for this platform were used in this analysis (500 MegaOhm seal resistance and current size >0.2 nA, with positive controls including Verapamil and DMSO being consistent).

Assay 6—GSK3β Assay (ThermoFisher assay)

This assay measures the activity of the compounds at GSK33 (Glycogen synthase kinase-3 beta).

The test compounds were screened in 1% DMSO (final) in the well. For 10 point titrations, 3-fold serial dilutions are conducted from the starting concentration of 10 PM.

Assay Protocol

Bar-coded Corning, low volume NBS, black 384-well plate

- 1. 2.5 μL—4× Test Compound or 100 nL 100× plus 2.4 μL kinase buffer
- 2. 5 μL—2× Peptide/Kinase Mixture
- 3. 2.5 μL—4×ATP Solution
- 4. 30-second plate shake
- 5. 60-minute Kinase Reaction incubation at room temperature
- 6. 5 μL—Development Reagent Solution
- 7. 30-second plate shake
- 8. 60-minute Development Reaction incubation at room temperature
- 9. Read on fluorescence plate reader and analyse the data

In step 2, the 2×GSK3β (GSK3 beta)/Ser/Thr (Glycogen synthase kinase-3 beta/Serine/Threonine) 09 mixture is prepared in 50 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA (egtazic acid). The final 10 μL Kinase Reaction consists of 0.22-0.92 ng GSK3β (GSK3 beta) and 2 PM Ser/Thr 09 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA.

In step 3 the ATP Solution is diluted to a 4× working concentration in Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA).

In Step 6 the Development Reagent is diluted 1:512 in Development Buffer (10× Novel PKC Lipid Mix: 2 mg/mL Phosphatidyl Serine, 0.2 mg/mL DAG in 20 mM HEPES, pH 7.4, 0.3% CHAPS).

Graphing Software

SelectScreen® Kinase Profiling Service uses XLfit from IDBS. The dose response curve is curve fit to model number 205 (sigmoidal dose-response model). If the bottom of the curve does not fit between −20% & 20% inhibition, it is set to 0% inhibition. If the top of the curve does not fit between 70% and 130% inhibition, it is set to 100% inhibition.

TABLE 10

Activity results in Assays 1, 2, 5 and 6 for compounds 1-80

Assay 6

Assay 5
(GSK3β

Assay 1
Assay 2
(hERG Hu
FRET-Z-

(PCSK9
(PCSK9
CHO if
Lyte Cr)

Hu Bind
BIAcore
EPh CR-
GMean IC₅₀

TRf)
DBA Cr)
Syncro)
(μM)

GMean
GMean
GMean IC₅₀
ATP Conc: 10

Example
IC₅₀(nM)
Kd (nM)
(μM)
(μM)

10
797

>40.0
>10.0

50
8.0
9.8
>40.0
>10.0

51
1.8
0.9
10.8
>10.0

52
2.3
0.7
39.9
>10.0

53
70

3.4
>10.0

54
33

4.3
>10.0

55
1.0
0.4
30.3
1.6

56
9.0
7.4
34.9
>10.0

57
11
7.5
>40.0
>10.0

58
1.6
2.2
>40.0
>10.0

59
45

>40.0
>10.0

60
9.1

21.0
>10.0

61
184

5.6
>10.0

62
6.5
4.3
36.3
>10.0

63
1.2
1.4
>40.0
>10.0

64
1.5
0.4
>40.0
0.385

65
11.8
5.8
38.8
0.014

66
1.7
1.5
>40.0
>10.0

67
16
17
>40.0
2.1

68
168

>40.0
>10.0

69
20
12
>40.0
>10.0

70
19
21
>40.0
>10.0

71
46
63
>40.0
>10.0

72
205
170
>40.0
>10.0

73
75
48
>40.0
>10.0

74
85
80
>40.0
8.3

75
33
16
>40.0
>10.0

76
485
125
>40.0
>10.0

TABLE 11

Activity results in Assays 1, 2, 5 and 6 for compounds 112-138

Assay 6

Assay 5
(GSK3β

Assay 1
Assay 2
(hERG Hu
FRET-Z-

(PCSK9
(PCSK9
CHO if
Lyte Cr)

Hu Bind
BIAcore
EPh CR-
GMean IC₅₀

TRf)
DBA Cr)
Syncro)
(μM)

GMean
GMean
GMean IC₅₀
ATP Conc: 10

Example
IC₅₀(nM)
Kd (nM)
(μM)
(μM)

112
4.7
3.9
>40.1
6.4

113
41

>40.0
>10.0

114
7.6
5.3
18.6
>10.0

115
17

>40.0
>10.0

116
0.7
0.3
12.0
>10.0

117
1.0
0.9
6.3
>10.0

118
7.4
8.5
>40.0
>10.0

119
73

>40.0
>10.0

120
143

>40.1
>10.0

121
1.0
1.6
>40.0
5.05

122
1.4

>40.1
6.17

123
1.4

>40.1
8.84

124
1.0

>40.1
1.07

125
2.7

>40.1
>10.0

126
744
954
>40.0
>10.0

127
193
248
>40.0
>10.0

128
20
30
>40.0
>10.0

129
1.6
1.3
>40.0
4.85

130
14

>40.1
5.70

131
2.7
2.4
>72.6
>10.0

132
2.3
1.5
>40.0
2.06

133
17
17
>40.0
0.032

134
8.4
9.1
>40.0
0.439

135
2.8
3.9
>40.0
>10.0

136
3.0

>40.1
>10.0

137
10

>40.1
3.52

138
4.0

>40.1
>10.0

TABLE 12

Activity results in Assay 3

Assay 3 LDL uptake

Example
potency (μM)

50
0.3

51
0.1

52
0.1

55
0.1

56
0.3

57
0.5

58
0.1

62
0.3

63
0.1

64
0.2

65
0.5

66
0.1

67
0.6

69
0.2

70
0.2

75
0.7

112
0.2

114
0.3

116
0.1

117
0.3

118
0.5

121
0.1

122
0.1

123
0.1

124
0.1

125
0.1

128
0.8

129
0.1

130
0.2

131
0.1

132
0.1

133
0.4

134
0.5

135
0.1

136
0.2

137
0.7

138
0.2

TABLE 13

Activity results in Assays 1, 2, 3, 5 and 6 for compounds 151-314

Assay 6

Assay 5
(GSK3β

Assay 1
Assay 2
(hERG Hu
FRET-Z-

(PCSK9
(PCSK9
CHO if
Lyte Cr)
Assay 3

Hu Bind
BIAcore
EPh CR-
GMean IC₅₀
LDL

TRf)
DBA Cr)
Syncro)
(μM)
uptake

Exam-
GMean
GMean
GMean IC₅₀
ATP Conc: 10
potency

ple
IC₅₀(nM)
Kd (nM)
(μM)
(μM)
(μM)

151
2254

>40.1
>10.0

152
244

>40.1
>10.0

153
3.3

>40.1
>10.0
0.1

154
14

>40.1
3.9
0.2

155
2.7

>40.1
>10.0
0.1

156
14

>40.1
>10.0
0.1

157
2.1

>40.1
7.78
0.1

158
7.6

>40.1
>10.0
0.2

159
4.1

>40.1
>10.0
0.1

160
6.9

>40.1
>10.0
0.2

161
3.8

>40.1
>10.0
0.1

165
1.3

25.5
5.1
0.1

166
7.2

38.2
2.2
0.3

167
258

>40.1
>10.0

168
16

3.1
>10.0

169
27

>40.1
0.31

173
4.2

>40.1
1.95
0.1

180
6.0

>40.1
>10.0
0.3

182
9.4

>40.1
>10.0
0.6

183
30

>40.1
>10.0

185
13

>40.1
2.42
0.2

187
2.1
3.7
>40.1
3.78
0.1

197
2.5
2.3
>40.1
>10.0
0.1

198
2.9
3.8
>40.1
>10.0
0.1

199
2.0

>40.1
>10.0
0.1

200
2.5

>40.1
>10.0
0.1

201
8.6

>40.1
2.38
0.2

202
3.7

>40.1
7.66
0.1

208
6.5

>40.1
1.71
0.3

210
0.9
0.6
>40.1
>10.0
0.1

211
1.4

16.5
>10.0
0.1

212
1.8
1.7
>40.1
>10.0
0.1

213
1.6

>40.1
>10.0
0.2

214
3.4

>40.1
>10.0
0.7

220
1.7

>200
>10.0
0.2

221
1.6
1.7
>40.1
>10.0
0.3

222
8.3

>40.1
>10.0

247
75

6.6
>10.0

248
13

>40.1
>10.0

249
16

>40.1
>10.0

250
108

>40.1
>10.0

254
330

>40.1
6.14

255
78

>40.1
5.33

256
119

>40.1
1.68

257
62

>40.1
2.81

258
15

26.1
0.237

260
101

>40.0
1.32

277
4.9

>40.1
9.56

281
2.5

>40.1
>10.0
0.3

304
96

>40.1
>10.0

305
91

3.2
>10.0

306
302

4.5
>10.0

307
1665

23.3
>10.0

308
51

12.0
>10.0

309
534

11.4
>10.0

310
22
19
35.0
>10.0

311
5.5
6.9
7.6
>10.0

312
37

4.2
>10.0

313
16

>40.1
>10.0

314
110

25.7
>10.0

315
1287

>40.1
>10.0

316
7426

>40.0

317
4430

>40.0

>0.8

318
284

>40.0

319
705

>40.0

320
559

>40.0

321
297

>40.0

The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the disclosure in diverse forms thereof.

While the disclosure has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the disclosure.

For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example +/−10%.

REFERENCES

A number of publications are cited above in order to more fully describe and disclose the compound of formula (1) and the state of the art to which it pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

Full Reference
DOI

Elbitar 2016
Elbitar et al., Expert Opin
10.1080/13543776.2016.1206080

Therapeutic Patents 2016 26: 1377-

1392.

Abifadel 2003
Abifadel, et al. Nat. Genet. 2003
10.1038/ng1161

34: 154-6.

Abifadel 2010
Abifadel, et al. Expert Opin. Ther.
10.1517/13543776.2010.518615

Pat. 2010 20: 1547-71.

Maxwell 2003
Maxwell, et al. J. Lipid Res. 2003
10.1194/jlr.M300203-JLR200

44: 2109-19.

Persson 2009
Persson et al. Endocrinology 2009
10.1210/en.2008-1281

150: 1140-6.

Langhi 2008
Langhi et al. FEBS Lett. 2008
10.1016/j.febslet.2008.02.038

582: 949-55.

Robinson
Robinson et al., Artherosclerosis
10.1016/j.atherosclerosis.2015.10.023

2015
2015 243: 593-597.

Duan 2012
W. Duan et al., ChemMedChem
10.1002/cmdc.201200145

2012, 7, 1276-1285.

Carreras
Carreras, A., et al. (2019). In vivo
10.1186/s12915-018-0624-2

2019
genome and base editing of a

human PCSK9 knock-in

hypercholesterolemic mouse model.

BMC biology 17, 4.

Wuts 2014
P. G. M. Wuts, Greene's Protective
ISBN: 978-1118057483

Groups in Organic Synthesis 5th ed.,

J. Wiley & Sons, 2014

For standard molecular biology techniques, see Sambrook, J., Russel, D. W. Molecular Cloning, A Laboratory Manual. 3 ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

Numbered Statements

1. A compound of Formula (I)

A-B-C (I)

- or a pharmaceutically acceptable salt, tautomeric forms or stereoisomers thereof, wherein A is of the following:

[Image Omitted]

- wherein the wavy line indicates the point of attachment to B;
- X¹is N;
- R^A2is selected from the group consisting of:
- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) C_1-6alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups;
- (vi) C_1-6acyl amido (wherein the acyl is optionally substituted by H or methyl);
- (vii) C_1-6thioalkyl;
- (viii) C_1-6alkyl ester;
- (ix) C_1-6alkyl acyl;
- (x) C_4-5heterocyclyl;
- (xi) C₅heteroaryl;
- (xii) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, OH, C_2-3alkynyl, C_4-6heterocyclyl or C_1-3alkyl wherein the C_1-3alkyl is optionally substituted with one or more halo or OH groups; and
- (xiii) OH; and
- (xiv) C_1-6alkylamino;
- R^A3is selected from the group consisting of:
- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl, C_1-6acyloxy, carboxy, C_1-6alkyl ester, C_1-6alkylamino, —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkyl acylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups;
- (vii) C_1-6acyloxy;
- (viii) C₄heterocycyl;
- (ix) —NH₂;
- (x) C_1-6alkylamino, optionally substituted by CN, OH or C₄heterocyclyl;
- (xi) C_1-6dialkylamino, optionally substituted by —NH₂;
- (xii) C_1-6acylamido (where acyl substituent is H or Me);
- (xiii) carbaimidoyl or methyl-carbaimidoyl;
- (xiv) carboxyamino;
- (xv) C_1-6thioalkyl, optionally substituted by OH or NH₂;
- (xvi) C_1-6alkyl sulfinyl;
- (xvii) C_1-6alkyl sulfonyl, optionally substituted by one or more halo groups;
- (xviii) C_1-6sulfonimodyl;
- (xix) C_1-6alkyl phosphinyl;
- (xx) carboxy;
- (xxi) C(═O)NH₂
- (xxii) C_1-6alkyl ester;
- (xxiii) C_1-6alkyl acyl, optionally substituted by one or more halo groups;
- (xxiv) C_1-6alkyl amido;
- or wherein R^A3and R^A2together with the carbon atoms to which they are bound form:
- (i) an optionally substituted C_5-7heterocycle ring;
- (ii) an optionally substituted C_5-7heteroaromatic ring;
- (iii) an optionally substituted C₆carboaromatic ring;
- (iv) an optionally substituted C_5-7carbocyclic ring
  - wherein the optional substituents are selected from C_1-6alkyl, halo, C_1-6alkoxy, NH₂, C_1-6alkylamino, OH, and CN;
- wherein B is of formula (B-1) or (B-2)

[Image Omitted]

- wherein the wavy line indicates the point of attachment to A and C;
- R^B1is H, OH, ═CHCH₂—OH, —O—C_1-4alkyl or C_1-4alkyl, wherein the C_1-4alkyl is optionally substituted by OH or OMe;

[Image Omitted]

- wherein the wavy line indicates the point of attachment to A and C;
- R^B2is C_1-2alkyl-OH, CH₂CONHMe or C_1-3alkyl;
- wherein C is selected from the group consisting of C_6-10carboaryl, C_5-6heteroaryl and C_5-10heterocyclyl, which groups are optionally substituted by:
  - (i) C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl C_4-10heterocyclyl, or C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl,
- which are themselves optionally substituted by one or more of the following groups:
  - a) one or two ═O groups;
  - b) one or more halo groups;
  - c) CN, NH₂, OH;
  - d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
  - e) C_1-6alkoxy with optional substituents of one or more halo groups;
  - f) C_1-6alkylester;
  - g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
  - h) C_5-6heteroaryl;
  - i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
  - j) C_6-10carboaryl with optional substituents of one or more halo groups;
  - l) P(═O)Me₂;
  - m) carboxy or CH₂-carboxy;
  - n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;
  - (ii) one or more groups selected from carboxy, CN, halo, nitro, C_1-6alkyl, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkylacyl, C_1-6alkyl amido, di-C_1-6alkyl amido, C_1-6alkyl sulfonamido, and di-C_1-6alkyl sulfonamido.

2. The compound of statement 1 or a pharmaceutically acceptable salt thereof, wherein R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) C_1-6alkoxy, optionally substituted by OH, alkyl amido, or one or more halo groups;
- (vi) C_1-6acyl amido (wherein the acyl is optionally substituted by H or methyl);
- (vii) C_1-6thioalkyl;
- (viii) C_1-6alkyl ester;
- (ix) C_1-6alkyl acyl;
- (x) C_4-5heterocyclyl;
- (xi) C₅heteroaryl;
- (xii) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl or C_1-3alkyl wherein the C_1-3alkyl is optionally substituted with one or more halo or OH groups; and
- (xiii) OH.

3. The compound of statement 1 or a pharmaceutically acceptable salt thereof, wherein R^A2is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, C_1-6alkyl amido, or one or more halo groups;
- (vii) C_1-6alkyl ester;
- (viii) C_1-6alkyl acyl;
- (ix) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups; and
- (x) C_1-6alkylamino.

4. The compound of any one of statements 1-3 or a pharmaceutically acceptable salt thereof, wherein R^A2is selected from the group consisting of:
- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6acyl, C_1-6alkoxy or one or more halo groups;
- (v) OH;
- (vi) C_1-6alkoxy, optionally substituted by OH, C_1-6alkyl amido, or one or more halo groups;
- (vii) C_1-6alkyl ester;
- (viii) C_1-6alkyl acyl; and
- (ix) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, CN, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups.

5. The compound of any of statements 1, 3, or 4 or a pharmaceutically acceptable salt thereof, wherein R^Ais selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) C_1-6alkyl ester;
- (iv) C_1-6hydrocarbon;
- (v) C_1-6alkyl amido optionally substituted by C_1-3alkyl amido, C_2-3alkynyl, C_4-6heterocyclyl, or C_1-3alkyl which alkyl is optionally substituted with one or more halo or OH groups;
- (vi) C_1-6thioalkyl;
- (vii) C_1-6alkyl acyl;
- (viii) C₅heteroaryl; or
- (ix) C_1-6alkylamino.

6. The compound of any one of statements 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R^Ais selected from the group consisting of —CN, methyl, Cl, —C(═O)CH₃, —C(═O)OCH₂CH₃, cyclopropyl, —C(═O)NHCH₂C(═O)NH₂, —C(═O)NHCH₂CHCH, —C(═O)NH-oxetane, —C(═O)NHCH₂CHF₂, —C(═O)NHCH₂CH₂OH, —C(═O)NHCH₂CH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OCHF₂, H, —OMe, and —OCF₃.

7. The compound of any one of statement 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R^Ais selected from the group consisting of —C(═O)OCH₂CH₃, cyclopropyl, methyl, H, Cl, —C(═O)CH₃, S-ethyl, pyrazole, —N(CH₃)₂, —C(═O)NH(CH₂C(═O)NH₂, —C(═O)NHCH₂C≡CH, —C(═O)NH(oxetane), —C(═O)NH(CH₂CHF₂), —C(═O)NH(CH₂CH₃), —C(═O)NH₂, —C(═O)NH(CH₃), —C(═O)N(CH₃)₂, —C(═O)N(CH₃)(CH₂CH₂OH), —C(═O)N(CH₃)(CH₂C≡CH or —C(═O)NH(CH₂OCH₂OH).

8. The compound of any one of statements 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R^Ais selected from the group consisting of —OCHF₂, methyl, and cyclopropyl.

9. The compound of any one of statements 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R^A3is selected from the group consisting of:

- (i) H;
- (ii) halo;
- (iii) CN;
- (iv) C_1-6hydrocarbon, optionally substituted by OH, CN, C_1-6thioalkyl, C_1-6alkoxy, C_1-6alkyl acyl C_1-6acyloxy, carboxy, C_1-6alkylester, C_1-6alkylamino; —C(═O)NH₂, C_1-6alkyl amido, C_1-6alkylacylamido, C_1-6alkyl sulfinyl, C_1-6alkyl sulfonyl or one or more halo groups;
- (v) OH; and
- (vi) C_1-6alkoxy, optionally substituted by OH, NH₂, C₄heterocyclyl or one or more halo groups.

10. The compound of any one of statements 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R^A3is selected from the group consisting of H, CF₃, CN, C_1-2alkyl, NH₂and halo.

11. The compound of any one of statements 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R^A3is selected from the group consisting of H, CN and methyl.

12. The compound of any one of statements 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R^A3is selected from the group consisting of H, methyl and OH.

13. The compound of statement 1 or a pharmaceutically acceptable salt thereof, wherein R^A3and R^A2together with the carbon atoms to which they are bound form an optionally substituted C carboaromatic ring or C heteroaromatic ring, wherein the optional substituents are selected from methyl, NH₂, Cl, F and OMe.

14. The compound of statement 13 or a pharmaceutically acceptable salt thereof, wherein R^A2and R^A3together with the carbon atoms to which they are bound form:

- (i) an optionally substituted C₆heteroaryl ring; wherein the optional substituent is NH₂
- (ii) an optionally substituted C₆carboaryl ring, wherein the optional substituent is f, OMe, Cl; or
- (iii) an optionally substituted C₅heteroaryl or C₅heterocyclic ring wherein the optional substituents are methyl.

15. The compound of statement 13 or a pharmaceutically acceptable salt thereof, wherein R^A3and R^A2together with the carbon atoms to which they are bound form: an unsubstituted 2-pyrazole; a 2-pyrrole substituted by methyl; a pyridine optionally substituted by NH₂; or a phenyl optionally substituted by Cl, F or OMe.

16. The compound of any one of statements 1 to 15 or a pharmaceutically acceptable salt thereof, wherein B is of formula (B-1)

[Image Omitted]

- wherein the wavy line indicates the point o attachment to A and C;
- wherein R^B1is selected from the group consisting of H, OH, OMe, —O-Ethyl, —CH₂OH, —CH₂CH₂OH and ═CHCH₂—OH.

17. The compound of statement 16 or a pharmaceutically acceptable salt thereof, wherein R^B1is selected from the group consisting of —CH₂OH, —CH₂CH₂OH and ═CHCH₂—OH.

18. The compound of any one of statements 1 to 16 or a pharmaceutically acceptable salt thereof, wherein B is of the following formula (B-1a):

[Image Omitted]

19. The compound of any one of statements 1 to 16 or claim 18 or a pharmaceutically acceptable salt thereof, wherein B is of the following formula (B-1b):

[Image Omitted]

20. The compound of any one of statements 1 to 15 or a pharmaceutically acceptable salt thereof, wherein B is of the following formula:

[Image Omitted]

21. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted C_5-6heteroaryl.

22. The compound of any one of statements 1 to 21 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C_6-10carboaryl, C_4-10carbocyclyl, C_5-10heteroaryl, C_5-10heterocyclyl, C_5-10bridged heterocyclyl, spiro C_6-12heterocyclyl or a spiro C_6-12carbocyclyl, which are themselves optionally substituted by one or more of the following groups:

- a) one or two ═O groups;
- b) one or more halo groups;
- c) CN, NH₂or OH;
- d) one or more C_1-6alkyl groups including branched and cyclic and with an optional substituent selected from OH or one or more halo groups;
- e) C_1-6alkoxy with optional substituents of one or more halo groups;
- f) C_1-6alkylester;
- g) C_5-6heterocyclyl with an optional methyl, OH or ═O substituent;
- h) C_5-6heteroaryl;
- i) C_4-10carbocyclyl with an optional methyl or ═O substituent;
- j) C_6-10carboaryl with optional substituents of one or more halo groups;
- l) P(═O)Me₂;
- m) carboxy or CH₂-carboxy; and/or
- n) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

23. The compound of any one of statements 1 to 22 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl wherein the optional substituents are selected from C₆heteroaryl or C₆heterocyclyl, which are themselves optionally substituted by one or more groups selected from the following:

- i) one or two ═O groups;
- ii) methyl;
- iii) OMe;
- iv) Cl;
- v) CN;
- vi) CF₃;
- vii) F;
- viii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl;
- ix) O—CF₃;
- x) O—CHF₂.

24. The compound of any one of statements 1 to 22 or a pharmaceutically acceptable salt thereof, wherein C is substituted by C_6-10carboaryl, C_5-10heteroaryl, or C_5-10heterocyclyl, which are themselves optionally substituted by:

- a) one or two ═O groups;
- b) one or more halo groups, CN or NH₂;
- c) one or more C_1-6alkyl groups, C_1-6alkoxy, or C_1-6alkylester, wherein each group is optionally substituted by one or more halo groups;
- d) C_5-6heterocyclyl or C_5-6heteroaryl with an optional methyl substituent;
- e) C_6-10carboaryl optionally substituted by one or more halo atoms;
- f) carboxy or CH₂-carboxy; or
- g) tetrazolyl, CH₂-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

25. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is a C_6-10carboaryl, C_5-6heteroaryl and C_5-10heterocyclyl, wherein each group is substituted by methyl.

26. The compound of statement 25 or a pharmaceutically acceptable salt thereof, wherein the methyl group on C is at the para position.

27. The compound of any one of statements 1 to 24 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl wherein the optional substituent is phenyl or pyridyl which are themselves optionally substituted by one or more groups selected from the following:

- a) one or more OMe groups;
- b) one or more F groups;
- c) CN;
- d) tetrazole; or
- e) carboxy.

28. The compound of any one of statements 1 to 22 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl wherein the optional substituent is a C₅heteroaryl or Cs heterocyclyl which are themselves optionally substituted by one or more substituents selected from methyl and CN.

29. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-1):

[Image Omitted]

- wherein D is C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, each which are themselves optionally substituted by:
  - i) one or two ═O groups;
  - ii) one or two C₁a alkyl groups which can be branched;
  - iii) OMe;
  - iv) piperazinyl, optionally substituted by methyl;
  - v) C(═O)OH (carboxy);
  - vi) Cl;
  - vii) F;
  - viii) phenyl, optionally substituted by one or more fluoro;
  - ix) CN;
  - x) CF₃;
  - xi) O—CF₃;
  - xii) tetrazolyl, pyrazolyl, triazolyl each of which is optionally substituted by methyl;
  - xiii) NH₂;
  - xiv) pyridinyl;
  - xv) CH₂OH;
  - xvi) OH;
  - xvii) P(═O)Me₂; or
  - xviii) OCHF₂.

30. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-1):

[Image Omitted]

- wherein D is C_6-10carboaryl, C_5-10heteroaryl or C_5-10heterocyclyl, each which are themselves optionally substituted by:
- i) one or two ═O groups;
- ii) one or two C_1-4alkyl groups which can be branched;
- iii) OMe;
- iv) piperazinyl, optionally substituted by methyl;
- v) C(═O)OH (carboxy);
- vi) Cl;
- vii) F;
- viii) phenyl, optionally substituted by one or more fluoro;
- ix) CN;
- x) CF₃;
- xi) O—CF₃;
- xii) tetrazolyl, pyrazolyl, triazolyl;
- xiii) NH₂;
- xiv)(CH₃)₂;
- xv) pyridinyl;
- xvi) CH₂OH;
- xvii) OH;
- xviii) P(═O)Me₂.

31. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position, wherein the optional substituents are selected from:

- i) methyl;
- ii) OMe;
- iii) piperazinyl substituted by methyl;
- iv) C(═O)OH (carboxy);
- v) Cl;
- vi) phenyl substituted by fluoro;
- vii) CN;
- viii) CF₃;
- ix) O—CF₃;
- x) F; or
- xi) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl.

32 The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is an optionally substituted 6 membered heteroaryl which contains 1 or 2 N atoms, one of which is bonded to (C-1), which is substituted by ═O at the ortho position, wherein the optional substituents are selected from:

- i) methyl;
- ii) OMe;
- iii) Cl;
- iv) F;
- v) CN;
- vi) CF₃;
- vii) O—CF₃;
- viii) O—CHF₂; or
- ix) pyrazolyl, triazolyl or tetrazolyl each of which is optionally substituted by methyl.

33. The compound of any one of statements 29 to 32 or a pharmaceutically acceptable salt thereof, wherein D is of the formula (D-1):

[Image Omitted]

- wherein one or two of R^D1, R^D2, R^D3and R^D4are selected from
  - i) C_1-6alkyl, optionally substituted by one or more halo groups;
  - ii) C_1-6alkoxy, optionally substituted by one or more halo groups;
  - iii) C_5-6heterocyclyl or C_5-6heteroaryl with an optional methyl substituent;
  - iv) carboxy or CH₂-carboxy;
  - v)═O, halo, NH₂or CN;
  - vi) phenyl, optionally substituted by one or more halo atoms;
- and the rest are H; or
- wherein R^D3and R^D4form an optionally substituted 6 membered carboaromatic, heterocycle or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo and C(═O)OH;
- or wherein R^D1, R^D2, R^D3and R^D4are all H.

34. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein

- one or two of R^D1, R^D2, R^D3and R^D4are selected from:
  - i) methyl;
  - ii) OMe;
  - iii) piperazinyl substituted by methyl;
  - iv) C(═O)OH (carboxy);
  - v) Cl;
  - vi) phenyl substituted by fluoro;
  - vii) CN;
  - viii) CF₃;
  - ix) O—CF₃
  - x) F;
  - xi) pyrazolyl, triazolyl or tetrazolyl;
- and the rest of R^D1, R^D2, R^D3and R^D4are H.

35. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein

- one or two of R^D1, R^D2, R^D3and R^D4are selected from:
  - i) methyl;
  - ii) OMe;
  - iii) Cl;
  - iv) CN;
  - v) CF₃;
  - vi) F;
  - vii) pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl;
  - viii) O—CF₃
  - ix) O—CHF₂
- and the rest of R^D1, R^D2, R^D3and R^D4are H.

36. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein R^D1, R^D2, R^D3and R^D4are H.

37. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein R^D3is selected from the group consisting of: H; optionally substituted phenyl, wherein the optional substituent is halo, methyl, OMe, C(═O)OH, Cl, CN; or piperazinyl optionally substituted by methyl; or pyrazolyl, triazolyl, or tetrazolyl, and wherein R^D1, R^D2and R^D4are all H.

38. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein R^D3is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF₂, or triazole and wherein R^D1, R^D2and R^D4are all H.

39. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein R^D1is selected from H, methyl, OMe, Cl, F, CF₃, OCF₃, and CN, and wherein R^D2, R^D3and R^D4are all H.

40. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein R^D1is selected from H, OMe, Cl, CF₃, OCF₃, OCHF₂, CN, F, pyrazole optionally substituted by methyl and triazole and R^D2, R^D3and R^D4are all H.

41. The compound of statement 33 or a pharmaceutically acceptable salt thereof, wherein R^D3and R^D4form an unsubstituted benzene ring or an unsubstituted pyridine ring.

42. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-1) and D is an optionally substituted phenyl or piperidyl, wherein there are one or two optional substituents selected from F, OMe and CN.

43. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is of the formula (D-2):

[Image Omitted]

- wherein X^Dis NR^D5aor CR^D5aR^D5b,
- R^D5ais selected from H or methyl;
- either R^D5band R^D6bare both H or together they are —CH₂—;
- R^D6ais selected from H, ═O, methyl, —CH₂OH or —C(═O)OH, wherein when R^D6ais ═O, R^D6bis absent;
- R^D7ais selected from H, ═O, methyl, —CH₂OH or —C(═O)OH;
- R^D7bis H, wherein when R^D7ais ═O, R^D7bis absent;
- or wherein R^D6aand R^D7atogether form a benzene ring or a C heteroaromatic ring which is optionally substituted by CN, P(═O)Me₂or carboxy and R^D6band R^D7bare absent.

44. The compound of statement 43 or a pharmaceutically acceptable salt thereof, wherein:

- a) when R^D6aand R^D6bare H, R^D7ais selected from ═O, carboxy or CH₂OH and R^D7bis H or when R^D7ais ═O, R^D7bis absent;
- b) when R^D7ais H, R^D7bis H, R^D6ais ═O and R^D6bis absent.

45. The compound of statement 43 or a pharmaceutically acceptable salt thereof, wherein

- R^D6aand R^D7atogether form a benzene ring or a C₆heteroaromatic ring which is optionally substituted by CN, C(═O)OH or P(═O)Me₂and R^D6band R^D7bare absent.

46. The compound of statement 43 or a pharmaceutically acceptable salt thereof, wherein

- R^D6aand R^D7aform an unsubstituted benzene ring or an unsubstituted pyridine ring and R^D6band R^D7bare absent.

47. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is selected from the following groups:

Name
Structure

2-oxo-1-pyridyl

[Image Omitted]

3-methyl-2-oxo-

1-pyridyl

3-methoxy-2- oxo-1-pyridyl

[Image Omitted]

5-methoxy-2- oxo-1- pyridyl

[Image Omitted]

5-chloro-2-oxo- 1-pyridyl

[Image Omitted]

2-oxo-1,8- naphthyridin-1-yl

[Image Omitted]

2-oxo-1-quinolyl

[Image Omitted]

3-methyl-2-oxo- benzimidazol-1-yl

[Image Omitted]

3-methyl-2,4- dioxo- imidazolidin-1-yl

[Image Omitted]

3-methyl-2,5- dioxo-imidazolidin- 1-yl

[Image Omitted]

3-chloro-2-oxo- 1-pyridyl

[Image Omitted]

3-cyano-2-oxo-1- pyridyl

[Image Omitted]

5-cyano-2-oxo-1- pyridyl

[Image Omitted]

3-fluoro-2-

oxopyridin-1(2H)-yl

5-methyl-2-oxo-

1-pyridyl

5-carboxy-2-oxo-1-

pyridyl

2-oxo-5-(1H-

pyrazol-4-yl)-1-

pyridyl

2-oxo-5-(1 H-triazol-

4-yl)-1-pyridyl

5-cyano-3-

methyl-2-oxo-

benzimidazol-

1-yl

5-carboxy-3-

methyl-2-oxo-

benzimidazol-1-yl

6-carboxy-3-

methyl-2-oxo-

benzimidazol-1-

yl

(6-

dimethylphosphoryl-

3-methyl-2-oxo-

benzimidazol-1-yl)

2-oxo-3H- benzimidazol-1- yl

[Image Omitted]

2-oxo-1 H- imidazo[4,5- b]pyridin-3-yl

[Image Omitted]

6-oxopyridazin- 1-yl

[Image Omitted]

6-oxopyrimidin- 1-yl

[Image Omitted]

1-methyl-2-oxo- 3-pyridyl

[Image Omitted]

2-oxo-3- (trifluoromethyl)-1- pyridyl

[Image Omitted]

2-oxo-3- (trifluoromethoxy)- 1-pyridyl

[Image Omitted]

2-oxo-5-(1H- tetrazol-5-yl)-1- pyridyl

[Image Omitted]

48. The compound of statements 29 or 30 or a pharmaceutically acceptable salt thereof, wherein D is selected from the following groups:

[Image Omitted]

49. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-2):

[Image Omitted]

- wherein one of R^C7, R^C8, R^C9and R^C10are selected from the group consisting of: methyl; OMe; piperazinyl optionally substituted by methyl; C(═O)OH (carboxy); Cl; F; pyrazolyl optionally substituted by methyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN; CF₃; O—CHF₂, O—CF₃; and the rest of R^C7, R^C8, R^C9and R^C10are H; or
- R^C9and R^C10form a benzene or 6 membered heteroaromatic ring, and R^C7and R^C8are both H; or wherein R^C7, R^C8, R^C9and R^C10are all H.

50. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is of the formula (C-2):

[Image Omitted]

wherein one of R^C7, R^C8, R^C9and R^C10are selected from the group consisting of: methyl; OMe; piperazinyl optionally substituted by methyl; C(═O)OH (carboxy); Cl; F; pyrazolyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN; CF₃; O—CF₃; and the rest of R^C7, R^C8, R^C9and R^C10are H; or R^C9and R^C10form a benzene or 6 membered heteroaromatic ring, and R^C7and R^C8are both H; or wherein R^C7, R^C8, R^C9and R^C10are all H.

51. The compound of statements 49 or 50 or a pharmaceutically acceptable salt thereof, wherein:

- a) all of R^C7, R^C8, R^C9and R^C10are H; or
- b) R^C9is selected from H, optionally substituted phenyl (wherein the optional substituent is F), methyl, OMe, C(═O)OH, Cl, F, pyrazolyl, triazolyl, tetrazolyl, CN and piperazinyl optionally substituted by methyl, and R^C7, R^C8and R^C10are all H; or
- c) R^C7is selected from H, methyl, OMe, O—CF₃, CF₃, Cl, F and CN and R^C8, R^C9and R^C10are all H.

52. The compound of statement 51 or a pharmaceutically acceptable salt thereof, wherein:

- a) all of R^C7, R^C8, R^C9and R^C10are H; or
- b) R^C9is selected from H, CN, OMe, Cl, pyrazole optionally substituted by methyl, tetrazole, methyl, OCHF₂, or triazole and R^C7, R^C8and R^C10are all H; or
- c) R^C7is selected from H, OMe, Cl, CF₃, OCF₃, OCHF₂, CN, F, triazole or pyrazole optionally substituted by methyl, and R^C7, R^C8and R^C10are all H.

53. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of:

No.
Structure

1

[Image Omitted]

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

54. The compound of any one of statements 1 to 20 or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of:

[Image Omitted]

55. The compound of any of the preceding statements or a pharmaceutically acceptable salt thereof, wherein A-B-C is of the formula (I-A), (I-B), (I-Ba), (I-Bb), (I-C), (I-D), (I-E), (I-Ea) or (I-Eb):

[Image Omitted]

- wherein X¹, R^A2, R^A3, C, D, R^D1, R^D2, R^D3, R^D4, R^D1a, R^D2a, R^D3a, R^D4a, X^D, R^D6a, R^D6, R^D7aand R^D7bare as defined in any of the preceding claims.

56. The compound of Table 1, Table 2 or Table 3 or a pharmaceutically acceptable salt thereof.

57. The compound of any one of statements 1 to 56 or a pharmaceutically acceptable salt thereof, for use in therapy.

58. A pharmaceutical composition comprising the compound of any one of statements 1 to 56 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.

59. The compound of any one of statements 1 to 56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 for use in the treatment of a cardiovascular disease.

60. The compound for use according to statement 59 wherein the compound is administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of:

- i) a statin;
- ii) a cholesterol absorption inhibitor;
- iii) a SGLT2 inhibitor;
- iv) a P2Y12 inhibitor;
- v) a citrate lyase inhibitor; and
- vi) anti-hypertensive drugs.

61. The compound use according to statement 59 or 60 when the cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure or congestive heart failure.

62. Use of a compound of any one of statements 1 to 56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 in a method of medical treatment.

63. A method of medical treatment comprising administering to the patient the pharmaceutical composition of statement 58.

64. Use of a compound of any one of statements 1 to 56 in the manufacture of a medicament for use in therapy.

65. A method of treating PCSK9-mediated disease or disorder in a patient need thereof comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of statements 1 to 56 or the pharmaceutical composition according to statement 58.

66. The method according to statement 65, wherein the disease or disorder is a cardiovascular disease or disorder.

67. The method according to statement 66, wherein the cardiovascular disease or disorder is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease heart failure or congestive heart failure.