PCSK9 inhibitors and methods of use thereof

Abstract

JPEG2025532670000394.jpg89128 Formula (I): ABC (wherein A is formula (Ia), and X 1 is N, B is of formula (B-1) or (B-2), and C is optionally substituted C 6~10 Carboaryl, C 5~6 Heteroaryl, and C 5~10 1. Compounds having a structure selected from the group consisting of: heterocyclyl; and their use as PCSK9 inhibitors.

Description

[Technical Field]

[0001] The present disclosure relates to compounds that inhibit PCSK9 and their use in methods of treatment. This application claims the benefit of priority to U.S. Patent Application No. 63 / 376,791, filed September 23, 2022, U.S. Patent Application No. 63 / 483,797, filed February 8, 2023, and U.S. Patent Application No. 63 / 580,500, filed September 5, 2023, which are incorporated by reference in their entireties. [Background technology]

[0002] PCSK9, also known as "proprotein convertase subtilisin / kexin type 9," is a member of the secreted proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 elevates circulating LDL cholesterol (LDL-C) levels by enhancing the degradation of the LDLR, regardless of its catalytic activity. Secreted PCSK9 binds to the epidermal growth factor domain A (EGFA) of the LDL receptor (LDLR) on the cell surface, and the PCSK9 / LDLR complex is internalized into the endosomal / lysosomal compartment. The enhanced binding affinity of PCSK9 to the LDLR at the acidic pH of late endosomes / lysosomes reduces LDLR recycling and instead targets the LDLR for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with lower plasma LDL-C levels and a reduced incidence of adverse cardiovascular events.

[0003] For cardiovascular disease, few options exist for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and primary human hepatocytes by enhancing the expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Because elevated PCSK9 levels reduce the abundance of LDLR on the cell surface, increasing the dose of statins failed to achieve a proportional LDL-C lowering effect.

[0004] Alirocumab and evolocumab, two monoclonal antibodies (mAbs) that selectively bind to extracellular PCSK9 and prevent its interaction with the LDLR, recently received FDA approval for lowering LDL-C levels. In clinical trials, alirocumab demonstrated an approximately 50% reduction in LDL levels compared to placebo (Elbitar 2016). Patients taking evolocumab demonstrated an approximately 60–75% reduction in LDL levels. The efficacy of these drugs demonstrates the potential for PCSK9 inhibitors to be effective treatments for patients with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and may trigger allergic or other adverse immune responses in the body.

[0005] Cardiovascular diseases are not temporary like infectious diseases, but often require management throughout a person's lifetime. Therefore, ease of dosing and administration are important factors in patient compliance with maintenance drug therapy. There is a need for PCSK9 inhibitors that are both highly effective and easier to administer, which can be achieved with small molecule PCSK9 inhibitors.

[0006] WO 2020 / 150473(A2) relates to heteroaryl compounds and pharmaceutical formulations thereof. It also relates to methods for treating or preventing cardiovascular disease and treating sepsis or septic shock using the novel heterocyclic compounds described.

[0007] WO 2020 / 150474(A1) relates to inhibitor pharmacophores of PCSK9 and heteroaryl compounds that bind to the PCSK9 protein. Summary of the Invention

[0008] The first aspect is a compound of formula (I): ABC (I) or a pharmaceutically acceptable salt and tautomeric form or stereoisomer thereof, wherein A is of the following formula:

[0009] [ka] where the wavy line indicates the point of attachment to B; X 1 is N; R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v) OH, C 1~6 alkylamide or C optionally substituted with one or more halo groups 1~6 Alkoxy; (vi) C 1~6 acylamides (wherein acyl is optionally substituted with H or methyl); (vii)C 1~6 thioalkyl; (viii)C 1~6 Alkyl esters; (ix) C 1~6 Alkyl acyls; (x)C 4~5 heterocyclyl; (xi) C5 heteroaryl; (xii)C 1~3 Alkylamide, CN, OH, C 2~3Alkynyl, C 4~6 Heterocyclyl, C 1~3 C optionally substituted with alkyl 1~6 Alkyl amides, such as C 1~3 C, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 Alkylamides; (xiii) OH; and (xiv)C 1~6 alkylamino; R A3 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl or C optionally substituted with one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) C optionally substituted with OH, NH, C heterocyclyl, or one or more halo groups 1~6 Alkoxy; (vii)C 1~6 acyloxy; (viii) C4 heterocyclyl; (ix)NH2; (x) C optionally substituted by CN, OH, C heterocyclyl 1~6 Alkylamino; (xi) C optionally substituted by -NH 1~6 Dialkylamino; (xii)C 1~6 acylamides (wherein the acyl substituent is H or Me); (xiii) carbimidoyl or methyl-carbimidoyl; (xiv) carboxyamino; (xv) C optionally substituted by OH or NH 1~6 thioalkyl; (xvi)C 1~6 Alkylsulfinyl; (xvii) C optionally substituted with one or more halo groups 1~6 Alkylsulfonyl; (xviii)C 1~6 Sulfonimodil (C 1-6 sulfonimodyl); (xix)C 1~6 Alkylphosphinyl; (xx) carboxy; (xxi)C(=O)NH2; (xxii)C 1~6 Alkyl esters; (xxiii) C optionally substituted with one or more halo groups 1~6 Alkyl acyls; (xxiv)C 1~6 or selected from the group consisting of alkylamides; or R A3 and R A2 along with the carbon atoms to which they are attached. (i) optionally substituted C 5~7 heterocycles; (ii) optionally substituted C 5~7 Aromatic heterocycles; (iii) an optionally substituted C6 carboaromatic ring; (iv) optionally substituted C 5~7 It forms a carbon ring, where the optional substituents are C 1~6 Alkyl, Halo, C 1~6 Alkoxy, NH2, C 1~6 selected from alkylamino, OH, and CN; B is a group represented by the formula (B-1) or (B-2): (i)

[0010] [ka] (wherein the wavy lines indicate the points of attachment to A and C; R B1 H, OH, =CHCH2-OH, OC 1~4 Alkyl, C 1~4 alkyl, C 1~4 The alkyl is optionally substituted with OH or OMe. (ii)

[0011] [ka] (wherein the wavy lines indicate the points of attachment to A and C; R B2 is C 1~2 Alkyl-OH, CH2CONHMe, or C 1~3 alkyl), C is C 6~10 Carboaryl, C 5~6 Heteroaryl, and C 5~10 heterocyclyl, which groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged heterocyclyl, C 6~12 Spiroheterocyclyl or C 6~12 a group selected from spirocarbocyclyl, These themselves include the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy or CH2-carboxy; n) optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl, C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged heterocyclyl, C 6~12 Spiroheterocyclyl or C 6~12 A group selected from spirocarbocyclyl; and / or (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, diC 1~6 Alkylamide, C 1~6 Alkyl sulfonamides, and diC 1~6 The present invention provides compounds, or pharmaceutically acceptable salts and tautomeric forms or stereoisomers thereof, optionally substituted with one or more groups selected from alkylsulfonamides.

[0012] A second aspect provides a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable diluent, carrier, or excipient.

[0013] The third aspect provides a compound of the first aspect for use in a method of treatment. The third aspect also provides the use of a compound of the first aspect in the manufacture of a medicament for treating cardiovascular disease. The third aspect also provides a compound of the first aspect for use in treating cardiovascular disease. The third aspect also provides a method of treating 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.

[0014] The present disclosure encompasses combinations of the described aspects and features unless such combinations are clearly not possible or explicitly avoided. DETAILED DESCRIPTION OF THE INVENTION

[0015] Aspects and embodiments are now described. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned herein are incorporated by reference.

[0016] The compounds of formula (I) and their use in the treatment of cardiovascular disease are described herein.The compounds disclosed herein are PCSK9 inhibitors.The compounds may exhibit stronger inhibition of PCSK9, lower hERG activity, improved secondary pharmacological profile including GSK3β and / or other kinases, good stability, and / or improved activity in the treatment of cardiovascular disease.The compounds may exhibit improved secondary pharmacological profile or improved off-target profile.

[0017] definition substituent As used herein, the phrase "optionally substituted" pertains to a parent group which may be unsubstituted or substituted.

[0018] Unless otherwise indicated, as used herein, the term "substituted" refers to a parent group that bears one or more substituents. The term "substituent" is used herein in its ordinary sense to refer to a chemical moiety that is covalently attached to a parent group or, where appropriate, fused to a parent group. A wide variety of substituents are well known, as are their methods of formation and introduction into various parent groups.

[0019] Examples of substituents are described in more detail below.

[0020] Unless otherwise specified, halo is selected from chloro (Cl), fluoro (F), bromo (Br), and iodo (I), e.g., fluoro.

[0021] Cyano (nitrile, carbonitrile): -CN.

[0022] Hydroxy: -OH.

[0023] Oxo: =O (oxygen double bonded to the rest of the molecule).

[0024] C 1~6 Hydrocarbons: The term "C 1~6 "Hydrocarbon," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 6 carbon atoms, which may be aliphatic or alicyclic, saturated or unsaturated (e.g., partially unsaturated, fully unsaturated), and optionally branched. Thus, the term "hydrocarbon" encompasses terms such as alkyl, alkenyl, alkynyl, and cycloalkyl, as defined below.

[0025] C 1~6 Alkyl: As used herein, the term "C 1~6 "Alkyl" refers 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 saturated or branched. As used herein, the term "C 1~4"Alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 4 carbon atoms that is saturated.

[0026] Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), and hexyl (C6).

[0027] Examples of saturated straight chain 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).

[0028] Examples of saturated branched alkyl groups include isopropyl (C3), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), isopentyl (C5), and neopentyl (C5).

[0029] C 2~6 Alkenyl: As used herein, the term "C 2~6 "Alkenyl" refers to a hydrocarbon group having one or more carbon-carbon double bonds.

[0030] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH), 1-propenyl (-CH=CH-CH), 2-propenyl (allyl, -CH-CH=CH), isopropenyl (1-methylvinyl, -C(CH)=CH), butenyl (C), pentenyl (C), and hexenyl (C).

[0031] C 2~6 Alkynyl: As used herein, the term "C 2~6 "Alkynyl" refers to a hydrocarbon group having one or more carbon-carbon triple bonds.

[0032] Examples of unsaturated alkynyl groups include, but are not limited to:

[0033] [ka] Examples include:

[0034] C 1~6 Alkoxy: As used herein, C 1~6 The term alkoxy refers to the OR group, where R is C 1~6 C 16 Examples of alkoxy 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).

[0035] C 1~6 Acyloxy: As used herein, C 1~6 The term acyloxy (reverse ester) refers to -OC(=O)R, where R is C 1~6 Examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, or -OC(=O)C(CH3)3.

[0036] Amino:-NR 1 R 2 (where R 1 and R 2 are independently an amino substituent, e.g., hydrogen, C 1~6 Hydrocarbon group (C 1~6 Alkylamino or C 1~6 (also called dialkylamino) or in the case of a "cyclic" amino group, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycle having 4 to 6 ring atoms. The amino group may be primary (-NH2), secondary (-NHR1), or tertiary (-NHR 1 R 2 ), and in cationic form, can be quaternary (-+ NR 1 R 2 R 3 ) 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.

[0037] C 1~6 Acylamide: Acylamide (acylamino): NR 1 C(=O)R 2 (where R 1 is an amide substituent, e.g., hydrogen or C 1~6 is a hydrocarbon group, R 2 is an acyl substituent, e.g., C 1~6 Examples of acylamide groups include, but are not limited to, NHC(=O)CH3 and NHC(=O)CH2CH3. In some embodiments, R 1 and R 2 may together form a cyclic or bicyclic structure, forming a cyclic acylamide group. 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:

[0038] [ka] Examples include:

[0039] Carbimidoyl: -C(=NH)(NH2).

[0040] Methyl-carbimidoyl: -C(=N-CH3)NH2.

[0041] Carboxyamino: -N(H)(C(=O)OH).

[0042] C 1~6 Thioalkyl: As used herein, C 1~6 The term thioalkyl refers to -SR (where R is C 1~6 C 1~6 Examples of alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3.

[0043] C 1~6 Alkyl sulfinyl: C 1~6 The term alkylsulfinyl refers to -S(=O)R, where R is C 1~6 It relates to sulfines (sulfinyl, sulfoxide) having the structure of a hydrocarbon group. 1~6 Examples of alkylsulfinyl groups include, but are not limited to, -S(=O)CH3 and -S(=O)CH2CH3.

[0044] C 1~6 Alkylsulfonyl: As used herein, C 1~6 The term alkylsulfonyl refers to the group -S(=O)R, where R is, for example, a fluorinated or perfluorinated C 1~6 Contains alkyl groups, C 1~6 C 1~6 Examples of alkylsulfonyl 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).

[0045] C 1~6 Sulfonimodil: C 1~6 The term sulfonimodil is also called sulfonamide (sulfinamoyl; sulfonic acid amide; sulfonamide), and is -S(=O)2NR 1 R 2 (where R1 and R 2 and are independently an amino substituent as defined for an amino group. Examples of sulfonamide groups include, but are not limited to, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3), -S(=O)2NH(CH2CH3), and -S(=O)2N(CH2CH3).

[0046] C 1~6 Alkylphosphinyl: C 1~6 The term alkylphosphinyl (phosphine oxide) refers to -P(=O)R2, where each R is independently C 1~6 It has the structure of a hydrocarbon group. 1~6 Examples of alkylphosphinyl groups include, but are not limited to, P(=O)(CH), P(=O)(CHCH), and P(=O)(tBu), where each R group can be the same or different.

[0047] Carboxy (carboxylic acid): C(=O)OH.

[0048] C 1~6 Alkyl ester: C 1~6 The term alkyl ester (carboxylate, carboxylic acid ester, oxycarbonyl) refers to -C(=O)OR (where R is C 1~6 Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, and -C(=O)OC(CH3)3.

[0049] C 1~6 Alkyl acyl: C also known as acyl (keto) 1~6 The term alkyl acyl refers to -C(=O)R, where R is C 1~6 It has the structure of a hydrocarbon group. 1~6Examples of alkyl acyl groups include, but are not limited to, -C(=O)CH3 (acetyl), -C(=O)CH2CH3 (propionyl), or -C(=O)C(CH3)3 (t-butyryl).

[0050] C 1~6 Alkylamide: C 1~6 The term alkylamido (also known as carbamoyl, carbamyl, aminocarbonyl, carboxamido) refers to C(=O)NR 1 R 2 (where R 1 and R 2 are independently an amino substituent as defined for an amino group, e.g., hydrogen, C 1~6 Hydrocarbon group (C 16 Alkylamide or C 16 In the case of a "cyclic" amide group, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycle having 4 to 6 ring atoms. Examples of amide 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, and R 1 and R 2 and amide groups which, together with the nitrogen atom to which they are attached, form a heterocyclic structure, such as in piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

[0051] C 3~12 Cycloalkyl: As used herein, the term "C 3~12 "Cycloalkyl" refers to an alkyl group that is also a cyclyl group, i.e., a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has 3 to 7 carbon atoms, e.g., 3 to 7 ring atoms. The carbocyclic ring can be saturated or unsaturated and bridged or unbridged. The ring can be fused or monocyclic.

[0052] Examples of cycloalkyl groups include, but are not limited to, those derived from: Monocyclic saturated 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); Monocyclic unsaturated 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 Polycyclic saturated hydrocarbon compounds: Norkarane (C7), norpinane (C7), norbornane (C7).

[0053] C 3~10 Heterocyclyl: As used herein, the term "C 3~10 "Heterocyclyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, wherein the moiety has 3 to 10 ring atoms, of which 1 to 5 are ring heteroatoms. In certain embodiments, each ring has 3 to 7 ring atoms, of which 1 to 4 are ring heteroatoms. The rings may be saturated or unsaturated, bridged or unbridged. The rings may be fused or monocyclic. For the avoidance of doubt, substituents on a heterocycloalkyl ring may be attached via either a carbon atom or a heteroatom.

[0054] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0055] In this context, prefixes (e.g., C 3~10 , C 3~7 , C 5~6 etc.) represents the number of ring atoms or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, as used herein, the term "C 5~6 "Heterocyclyl" refers to a heterocyclyl group having 5 or 6 ring atoms.

[0056] 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: oxathiols (C5) and oxathianes (thioxanes) (C6); and N1O1S1: Oxathiazine (C6).

[0057] Examples of bicyclic heterocyclyl groups include, but are not limited to, those derived from:

[0058] [Table 1]

[0059] C 6~10 Carboaryl: The term "C 6~10 "Carboaryl," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, wherein the moiety has 6 to 10 ring atoms, and the ring atoms are all carbon atoms, as in "carboaryl group." The rings can be fused or single rings. Examples of carboaryl groups include, but are not limited to, benzene (i.e., phenyl) (C6), naphthalene (C7), and cyclohexane (C8). 10 ), and azulene (C 10 ) are some of the origins.

[0060] In this context, prefixes (e.g., C 5~7 , C 5~6 , C 5~10 etc.) refers to the number of ring atoms or range of number of ring atoms. For example, as used herein, the term "C 5~6 "Aryl" refers to an aryl group having 5 or 6 ring atoms.

[0061] Examples of carboaryl groups containing fused rings, at least one of which is aromatic, include, but are not limited to, indane (e.g., 2,3-dihydro-1H-indene) (C9), indene (C9), isoindene (C9), and tetralin (1,2,3,4-tetrahydronaphthalene) (C 10 ) groups derived from

[0062] C 5~10 Heteroaryl: The term "C 5~10 "Heteroaryl," as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, the moiety having 5 to 10 ring atoms, of which 1 to 5 are ring heteroatoms. In certain embodiments, each ring has 5 to 7 ring atoms, of which 1 to 4 are ring heteroatoms. For the avoidance of doubt, substituents on a heteroaryl ring may be attached via either a carbon atom or a heteroatom. The rings may be fused or monocyclic.

[0063] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0064] Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N1: pyrrole (azole) (C5), pyridine (azine) (C6); O1: furan (oxol) (C5); S1: thiophene (thiol) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N3O1: oxatriazole (C5); N1S1: Thiazole (C5), Isothiazole (C5); N2: imidazole (1,3-diazole) (C5), pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6); N3: Triazoles (C5), triazines (C6); and N4: tetrazole (C5).

[0065] Examples of heteroaryls containing fused rings include, but are not limited to, C9 (having two fused rings) derived from:

[0066] [Table 2-1]

[0067] [Table 2-2]

[0068] Examples of heteroaryls containing fused rings include, but are not limited to, C 10 (having two fused rings).

[0069] [Table 3]

[0070] C 6~12 Spirocarbocyclyl: As used herein, C 6~12 The term spirocarbocyclyl refers to a moiety having at least two rings with only one shared atom. The simplest spiro compounds are either bicyclic (having only two rings) or have a bicyclic moiety as part of a larger ring system; in either case, the two rings are linked through a characteristic single shared atom. C 6~12Spirocarbocyclyl refers to a cyclyl group, i.e., a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has 6 to 12 carbon atoms, e.g., 3 to 7 ring atoms, where the rings share one common atom.

[0071] C 6~12 Spiroheterocyclyl: As used herein, C 6~12 The term spiroheterocyclyl refers to a moiety having at least two rings with only one shared atom. The simplest spiro compounds are either bicyclic (having only two rings) or have a bicyclic moiety as part of a larger ring system; in either case, the two rings are linked through a characteristic single shared atom. C 6~12 A spiroheterocyclyl moiety refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, the moiety having 8 to 12 ring atoms, 1 to 3 of which are ring heteroatoms, and wherein the rings share one common atom. In certain embodiments, each ring has 9 to 11 ring atoms, 1 to 2 of which are ring heteroatoms. For the avoidance of doubt, substituents on heteroaryl rings may be attached via either a carbon atom or a heteroatom.

[0072] For the avoidance of doubt, when multiple substituents are independently selected from a given group, the selected substituents may include the same or different substituents within the given group.

[0073] pharmaceutically acceptable salts The term "pharmaceutically acceptable" is used to specify that the subject (e.g., salt, dosage form, or excipient) is suitable for use in patients. An exemplary list of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I) are, for example, acid addition salts. Acid addition salts of the compound of formula (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art. Acid addition salts can be formed, for example, using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts may also be formed using organic acids 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.

[0074] Thus, in one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt of hydrochloric acid, hydrobromic acid, sulfuric 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. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a methanesulfonate salt. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mono-methanesulfonate salt, i.e., the molar ratio of the compound of formula (I) to the compound of methanesulfonic acid is 1:1.

[0075] Other forms The compounds and salts described herein can exist in solvated and unsolvated forms. For example, solvated forms can be hydrated forms, such as hemihydrate, monohydrate, dihydrate, trihydrate, or alternative amounts thereof. The compounds of formula (I) encompass all such solvated and unsolvated forms of the compounds of formula (I), particularly as long as such forms have PCSK9 kinase inhibitory activity, for example, as measured using the tests described herein.

[0076] The compounds and salts described herein contain one or more chiral centers (i.e., asymmetric centers). Unless a structure or chemical name herein indicates chirality, the structure or name is intended to encompass any single stereoisomer (i.e., any single chiral isomer) and any mixture of stereoisomers (e.g., a racemate) corresponding to that structure or name. In some embodiments, a single stereoisomer is obtained, for example, by isolating it from an isomeric mixture (e.g., a racemate) using chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained, for example, by direct synthesis from chiral starting materials.

[0077] Certain enantiomers of the compounds described herein may be more active than other enantiomers of the same compound.

[0078] According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a single enantiomer in an enantiomeric excess (%ee) of 95% or more, 98% or more, or 99% or more. Advantageously, the single enantiomer is present in an enantiomeric excess (%ee) of 99% or more.

[0079] According to another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a single enantiomer in an enantiomeric excess (%ee) of 95% or more, 98% or more, or 99% or more, together with one or more pharmaceutically acceptable excipients. Advantageously, the single enantiomer is present in an enantiomeric excess (%ee) of 99% or more.

[0080] Isotopes The atoms of the compounds and salts described herein may exist as their isotopes. Compounds of formula (I) include all compounds of formula (I) in which an atom is replaced with one or more of its isotopes (e.g., compounds in which one or more carbon atoms are replaced with one or more isotopes). 11 C or 13 C carbon isotope or one or more hydrogen atoms 2 H or 3 H isotope).

[0081] tautomers The compounds and salts described herein may exist as a mixture of tautomers. A "tautomer" is a structural isomer that exists in equilibrium due to the migration of a hydrogen atom. The compounds of formula (I) encompass all tautomers of the compounds of formula (I), particularly as long as such tautomers have PCSK9 inhibitory activity.

[0082] For example, some of the exemplified compounds (where R A3 The tautomeric forms of (wherein is OH) can be shown as follows:

[0083] [ka]

[0084] Crystalline morphology The compounds and salts described herein may be crystalline and may exhibit one or more crystalline forms. The compounds of formula (I) include any crystalline or amorphous form, or mixtures of such forms, of the compounds of formula (I) that have PCSK9 inhibitory activity.

[0085] It is generally known that crystalline materials can be characterized using conventional techniques, such as X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT), Near Infrared (NIR), and liquid and / or solid-state nuclear magnetic resonance spectroscopy. The water content of crystalline materials can be determined by Karl Fischer analysis.

[0086] Treatment, prevention, and related terms The term "treatment" is intended to have its ordinary meaning of dealing with a disease in order to completely or partially alleviate one, some, or all of the symptoms of the disease, or to correct or eliminate the underlying pathology. The term "treatment" also encompasses "prophylaxis," unless specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

[0087] The term "prevention" is intended to have its ordinary meaning and includes primary prevention, to prevent the onset of disease, and secondary prevention, where the disease has already occurred and the patient is temporarily or permanently protected from exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0088] The term "treatment" is used synonymously with "therapy." Similarly, the term "treating" can be considered as "administering therapy," where "treatment" is as defined herein.

[0089] The term "subject" to which administration is intended includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, toddlers, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or geriatrics)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals of commercial importance, including, for example, cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds of commercial importance, including, for example, chickens, ducks, geese, quail, and / or turkeys. A preferred subject is a human.

[0090] As used herein, "effective amount" refers to an amount sufficient to achieve a desired biological effect. As used herein, "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount sufficient to ameliorate at least one sign or symptom of the disease to be treated.

[0091] Pharmaceutical Composition The compounds of formula (I) and their pharmaceutically acceptable salts may be administered as pharmaceutical compositions containing one or more pharmaceutically acceptable excipients.

[0092] Thus, 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.

[0093] The excipients selected for inclusion in a particular composition depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; and Quinn, Marian. Pharmaceutically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickeners, and coating agents. As those skilled in the art will understand, a particular pharmaceutically acceptable excipient can perform more than one function, and may perform different functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

[0094] The pharmaceutical compositions may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), inhalation (e.g., as finely divided powders or liquid aerosols), insufflation (e.g., as finely divided powders), parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or rectal administration as suppositories. The compositions may be obtained by conventional procedures well known in the art. Compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0095] A suitable daily dose of the compounds disclosed herein or pharmaceutically acceptable salts thereof for therapeutic treatment of humans is about 0.0001 to 100 mg / kg body weight. Pharmaceutical formulations described herein can be formulated by methods known to those skilled in the art to provide doses of active compound ranging from 0.1 mg to 1000 mg. The daily dose will necessarily vary depending on the host treated, the particular route of administration, any concurrently administered therapies, and the severity of the disease being treated. Accordingly, the physician treating any particular patient can determine the optimum dosage.

[0096] The pharmaceutical compositions described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof and are therefore expected to be useful in therapy.

[0097] Thus, 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.

[0098] In one embodiment, there is provided a pharmaceutical composition for use in treating 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 treating 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. In one embodiment, there is provided a pharmaceutical composition for use in treating 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.

[0099] How to use The compounds described herein can be used in therapeutic methods. Also provided is a method of treatment, comprising administering a therapeutically effective amount of a compound of formula I to a subject in need of treatment. The term "therapeutically effective amount" refers to an amount sufficient to show benefit to the patient. Such benefit may be at least an improvement in at least one symptom. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of what is being treated. Prescribing treatment, e.g., determining dosage, is within the responsibility of general practitioners and other medical doctors.

[0100] The compounds may be administered alone or in combination with other treatments, either simultaneously or sequentially depending on the condition being treated.

[0101] In one embodiment, 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 therapy. In one embodiment, there is provided a use of 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. In another embodiment, there is provided a method of treatment comprising administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).

[0102] The compounds described herein are PCSK9 inhibitors. The PCSK9 gene was identified using genetic mapping techniques in DNA from subjects with autosomal dominant hypercholesterolemia (Abifadel 2003). The encoded protein is a serine protease primarily expressed in the liver, gastrointestinal tract, kidneys, and nervous system. Without wishing to be bound by any particular theory, studies of mutations within the gene have shown that its putative role is in reducing LDLR on the cell surface, independent of its catalytic activity (Abifadel 2010). Binding of PCSK9 to LDLR leads to their lysosomal degradation. This enhanced LDLR degradation leads to increased levels of circulating low-density lipoprotein (LDL). PCSK9 is upregulated by statins, SREBP-1a and SREBP-2, LXR agonists, and insulin, but downregulated by dietary cholesterol, glucagon, ethinylestradiol, chenodeoxycholic acid, and bile acid-activated farnesoid X receptor (FXR) (Maxwell 2003; Persson 2009; Langhi 2008). Because increased levels of PCSK9 reduce the abundance of LDLR on the cell surface, increasing the dose of statins cannot achieve a proportional LDL-C lowering effect. Therefore, disclosed herein are methods for treating a wide range of cardiovascular diseases and conditions that benefit from inhibiting PCSK9 and thereby lowering LDL-C.

[0103] In certain embodiments, a method of inhibiting PCSK9 is performed in a subject in need thereof, thereby treating a disease or disorder mediated by PCSK9. Also disclosed herein is a method of treating or preventing a disease or disorder mediated by PCSK9, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein is a method of treating a disease or disorder mediated by PCSK9, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein is a method of preventing a disease or disorder mediated by PCSK9, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Prevention of cardiovascular events by inhibiting PCSK9 is described, for example, in Robinson 2015.

[0104] In some embodiments, methods of treating cardiovascular disease are provided that include administering to a subject a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) is provided for use in treating cardiovascular disease. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a compound of Formula (I) is provided for the manufacture of a medicament for the treatment of cardiovascular disease.

[0105] Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, 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, dyslipidemia, atherosclerosis, fatty liver, metabolic syndrome, and coronary artery disease. In certain embodiments, the disease is hypercholesterolemia, e.g., familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In certain embodiments, the disease is hyperlipidemia. In certain embodiments, the disease is coronary artery disease.

[0106] In certain embodiments, the disclosed treatment methods can reduce high levels of circulating serum cholesterol, such as LDL-C and VLDL-cholesterol.In addition, the disclosed methods are useful for reducing 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 with gain-of-function mutations in the PCSK9 gene also benefit from treatment with the disclosed compounds and compositions, which counteract the effects of the mutations by inhibiting PCSK9.

[0107] Combination therapy The disclosed compounds and compositions can be co-administered with other therapeutic agents, such as other agents suitable for treating high levels of LDL-C and triglycerides. In certain embodiments, co-administration of one or more additional therapeutic agents with the compounds described herein results in a synergistic effect. In certain embodiments, co-administration of one or more additional therapeutic agents results in an additive effect.

[0108] In some embodiments in which combination therapy is used, the amount of the compound or salt described herein and the amount of the other pharmaceutically active agent, when combined, are therapeutically effective for treating the targeted disorder in an animal patient. In this context, the combined amounts are "therapeutically effective" if, when combined, they are sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder; treat the disorder; reverse, completely stop, or slow the progression of the disorder; or reduce the risk of the disorder becoming worse. Typically, such amounts can be determined by those skilled in the art, for example, by starting from the dosage ranges described herein for the compound of the present invention or its salt and the approved or otherwise published dosage ranges for the other pharmaceutically active compound.

[0109] The pharmaceutical compositions herein may contain one or more additional active ingredients, if desired; examples of combinations of a compound herein (or a pharmaceutically acceptable salt thereof) and one or more additional active ingredients are described herein.

[0110] The present specification further relates to combination therapy in which a compound of the present specification or a pharmaceutically acceptable salt thereof and a second active ingredient are administered simultaneously, sequentially, or as a mixture for the treatment of one or more of the conditions listed above. Such combinations may be used in combination with one or more additional active ingredients.

[0111] In one aspect, a combination (e.g., for use as a medicament for the treatment of one of the diseases or conditions enumerated herein, e.g., cardiovascular disease) is provided that includes a compound herein or a pharmaceutically acceptable salt thereof and at least one active ingredient selected from the following: i) Statins; ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors; iv) P2Y12 inhibitors; v) a citrate lyase inhibitor; and vi) Antihypertensive drugs.

[0112] In a further aspect herein, there is provided a pharmaceutical composition (e.g., for use as a medicament for the treatment of one of the diseases or conditions enumerated herein, e.g., cardiovascular disease) comprising a compound herein or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from the following: i) Statins; ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors; iv) P2Y12 inhibitors; v) citrate lyase inhibitors; vi) Antihypertensive drugs.

[0113] 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).

[0114] 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).

[0115] 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 an 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 (Fariga or Farxiga).

[0116] In another embodiment, at least one additional active ingredient selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof and a P2Y12 inhibitor is provided, wherein the P2Y12 inhibitor is selected from ticagrelor and clopidogrel (Plavix).

[0117] 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).

[0118] 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 two additional active ingredients are ezetimibe and rosuvastatin, or dapagliflozin and rosuvastatin.

[0119] In another embodiment, there is provided a combination of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one additional active ingredient selected from an antihypertensive. In some aspects, the antihypertensive 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 a combination of a compound of Formula (I) or a pharmaceutically acceptable salt thereof with: i) Valsartan; ii) metoprolol; iii) valsartan and HCTZ; iv) olmesartan; v) olmesartan and HCTZ; vi) lisinopril; vii) Amlodipine; viii) candesartan; ix) calcium channel blockers; or x)HCTZ.

[0120] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional active ingredient are provided for use in the simultaneous, separate, or sequential treatment of cardiovascular disease. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cardiovascular disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with at least one additional active substance selected from ezetimibe, rosuvastatin, dapagliflozin, and ticagrelor.

[0121] In another embodiment, a method for treating cardiovascular disease in a subject is provided, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional active agent simultaneously, separately, or sequentially, wherein the at least one additional active agent is selected from ezetimibe, rosuvastatin, dapagliflozin, and ticagrelor.

[0122] Further embodiments The following embodiments may apply to all of the above aspects or may relate to a single aspect. The embodiments may be combined with each other in any combination.

[0123] X 1 In some embodiments, X 1 is N.

[0124] R A2 In some embodiments, R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v) C optionally substituted with OH, alkylamido, or one or more halo groups 1~6 Alkoxy; (vi) C 1~6 acylamides (wherein the acyl substituent is H or Me); (vii)C 1~6 thioalkyl; (viii)C 1~6 Alkyl esters; (ix) C 1~6 Alkyl acyls; (x)C 4~5 heterocyclyl; (xi) C5 heteroaryl; (xii)C 1~3 Alkylamide, CN, OH, C 2~3 Alkynyl, C 4~6 heterocyclyl, C alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 Alkylamides; (xiii) OH; and (xiv)C 1~6 alkylamino.

[0125] In some embodiments, R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v) C optionally substituted with OH, alkylamido, or one or more halo groups 1~6 Alkoxy; (vi) C1~6 acylamides (wherein the acyl substituent is H or Me); (vii)C 1~6 thioalkyl; (viii)C 1~6 Alkyl esters; (ix) C 1~6 Alkyl acyls; (x)C 4~5 heterocyclyl; (xi) C5 heteroaryl; (xii)C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 heterocyclyl, C alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 Alkylamides; and (xiii) is selected from the group consisting of OH.

[0126] In some embodiments, R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) OH, C 1~6 alkylamide or C optionally substituted with one or more halo groups 1~6 Alkoxy; (vii)C 1~6 Alkyl esters; (viii)C 1~6 Alkyl acyls; (ix) C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 C heterocyclyl or alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6Alkylamides; and (x)C 1~6 alkylamino.

[0127] In a further embodiment, R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) OH, C 1~6 alkylamide or C optionally substituted with one or more halo groups 1~6 Alkoxy; (vii)C 1~6 Alkyl esters; (viii)C 1~6 alkyl acyls; and (ix) C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 C heterocyclyl or alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 alkylamides.

[0128] In a further embodiment, R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v) OH, C 1~6 alkylamide or C optionally substituted with one or more halo groups 1~6 Alkoxy; (vi) C 1~6 thioalkyl; (viii)C 1~6 alkyl esters; and (ix) C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 C heterocyclyl or alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 alkylamides.

[0129] In a further embodiment, R A2 teeth, (i)H; (ii) halo; (iii)C 1~6 Alkyl esters; (iv) C 1~6 hydrocarbons (v) C 1~3 Alkylamide, C 2~3 Alkynyl, C 4~6 C heterocyclyl or alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 Alkylamides; (vi) C 1~6 thioalkyl; (vii)C 1-6 Alkyl acyls; (viii) C5 heteroaryl; or (ix) C 1~6 alkylamino.

[0130] R A2 When is halo, in some embodiments it is Br or Cl. In further embodiments it is Cl.

[0131] In some embodiments, R A2 is CN, Cl, OMe, methyl, cyclopropyl, -OCHF2, -OCF3, and optionally substituted C 1~6 alkylamides.

[0132] In some embodiments, R A2 is C 1~6 alkyl esters.

[0133] In some embodiments, R A2 is CN.

[0134] In some embodiments, R A2 is H.

[0135] In some embodiments, R A2 is OH.

[0136] In some embodiments, R A2 is -C(=O)CH3.

[0137] In some embodiments, R A2 is -OCHF2.

[0138] In some embodiments, R A2 is cyclopropyl.

[0139] In some embodiments, R A2 is Cl.

[0140] In some embodiments, R A2 is methyl.

[0141] In some embodiments, R A2 is S-ethyl.

[0142] In some embodiments, R A2 is a pyrazole.

[0143] In some embodiments, R A2 is N(CH3)2.

[0144] In some embodiments, R A2 is C(=O)NH(CH2C(=O)NH2,

[0145] [ka] 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),

[0146] [ka] Or C(=O)NH(CH2CH2OH).

[0147] R A2 C 1~6 If it is a hydrocarbon, it may be an optionally substituted C 1~6 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.

[0148] R A2 is arbitrarily substituted C 1~6 When alkyl, 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.

[0149] R A2 is arbitrarily substituted C 1~6 When alkoxy, in some embodiments it is optionally substituted OMe or ethoxy.

[0150] R A2 is arbitrarily substituted C 1~6When R is alkoxy, in some embodiments, the optional substituents are selected from alkylamido or one or more halo groups. In other embodiments, the optional substituents are selected from one or more F. A2 is arbitrarily substituted C 1~6 In another embodiment where it is alkoxy, it is difluoromethoxy (OCHF2).

[0151] R A2 C 1~6 When it is an alkyl ester, in some embodiments it is -C(=O)OCH2CH3.

[0152] R A2 C 1~6 When R is an alkylamide, in some embodiments, the optional substituents are selected from one or more methyl groups, an oxetane ring, a C alkylamide, and ethyl, optionally substituted with OH or one or more halo groups. A2 C 1~6 When it is an alkylamide, 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. R A2 C 1~6 When an alkylamide, in some embodiments, the optional substituent is OH.

[0153] R A2 C 1~6 When alkylamino, in some embodiments it is NHCH, NHC(CH), N(CHCH), or N(CH). In some embodiments, R A2 C 1~6 When it is alkylamino, it is N(CH3)2.

[0154] In other embodiments, R A2is selected from —OCHF, Cl, —OMe, methyl, C(═O)CH, CN, —CHOH, H, and cyclopropyl. A2 is selected from methyl, —OCHF2, Cl, —CH2OH, H, CN, —C(═O)CH3, or —OMe.

[0155] In a further embodiment, R A2 is selected from methyl, —OCHF2, Cl, and cyclopropyl.

[0156] In a further embodiment, R A2 is selected from H, -COOH, -CHOH, methyl, CN, cyclopropyl, -C(=O)CH, -OCHF, Cl, -C(=O)OCHCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -C(=O)NHCHC(=O)NH, -C(=O)NHCHCH, -C(=O)NH-oxetane, -C(=O)NHCHCHF, -C(=O)NHCHCHOH, -C(=O)NHCHCH.

[0157] In some embodiments, R A2 is 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.

[0158] In some embodiments, R A2 is C(=O)OCH2CH3, cyclopropyl, methyl, C(=O)NH(CH2C(=O)NH2),

[0159] [ka] 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),

[0160] [ka] Cl, N(CH3)2, pyrazole, S-ethyl, C(=O)CH3, or C(=O)NH(CH2CH2OH).

[0161] In some embodiments, R A2 is selected from CN, methyl, Cl, -C(=O)CH, -C(C=O)OCHCH, cyclopropyl, -C(=O)NHCHC(=O)NH, -C(=O)NHCHCHCH, -C(=O)NH-oxetane, -C(=O)NHCHCHF, -C(=O)NHCHCHOH, -C(=O)NHCHCH, -C(=O)NH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -OCHF, H, -OMe, -OCF. These groups are as shown in the table below.

[0162] [Table 4]

[0163] In some embodiments, R A2 is selected from the following group:

[0164] [Table 5]

[0165] In some embodiments, R A2 is selected from the following group:

[0166] [Table 6]

[0167] R A3 In some embodiments, R A3 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl, or C optionally substituted with one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) C optionally substituted with OH, NH, C heterocyclyl, or one or more halo groups 1~6 Alkoxy; (vii)C 1~6 acyloxy; (viii) C4 heterocyclyl; (ix)-NH2; (x) C optionally substituted by CN, OH, or C heterocyclyl 1~6 Alkylamino; (xi) C optionally substituted by -NH 1~6 Dialkylamino; (xii)C 1~6 acylamides (wherein the acyl substituent is H or Me); (xiii) carbimidoyl or methyl-carbimidoyl; (xiv) carboxyamino; (xv) C optionally substituted by OH or NH 1~6 thioalkyl; (xvi)C 1~6 Alkylsulfinyl; (xvi) C optionally substituted with one or more halo groups 1~6 Alkylsulfonyl; (xvii)C 1~6 sulfonimodil; (xviii)C 1~6 Alkylphosphinyl; (xix) carboxy; (xx)-C(=O)NH2 (xxi)C 1~6 Alkyl esters; (xxii) C optionally substituted with one or more halo groups 1~6 alkyl acyls; and (xxiii)C 1~6 alkylamides.

[0168] In some embodiments, R A3 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl, or C optionally substituted with one or more halo groups 1~6 hydrocarbons; (v) OH; and (vi) C optionally substituted with OH, NH, C heterocyclyl, or one or more halo groups 1~6 alkoxy is selected from the group consisting of:

[0169] In some embodiments, R A3 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl, or C optionally substituted with one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) C optionally substituted with OH, NH, C heterocyclyl, or one or more halo groups 1~6 alkoxy is selected from the group consisting of:

[0170] R A3 When is halo, in some embodiments it is Br or Cl. In some embodiments it is Cl. In further embodiments, R A3 is Br.

[0171] R A3 C 1~6 If it is a hydrocarbon, it may be an optionally substituted C 1~6 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.

[0172] R A3 is arbitrarily substituted C 1~6 When alkyl, 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.

[0173] In some embodiments, R A3is OH.

[0174] R A3 is arbitrarily substituted C 1~6 When alkoxy, in some embodiments it is optionally substituted OMe or ethoxy, in further embodiments it is OMe.

[0175] R A3 is arbitrarily substituted C 1~6 When alkoxy, in some embodiments, the optional substituents are selected from alkylamido or one or more halo groups, hi other embodiments, the optional substituents are selected from one or more F.

[0176] In some embodiments, R A3 are H, CF3, CN, and C 1~2 In other embodiments, R A3 is selected from H, methyl, CN, and Cl.

[0177] In some embodiments, R A3 H, OMe, CF3, CN, C 1~2 It is selected from alkyl, NH2, and halo.

[0178] In some embodiments, R A3 is CN.

[0179] In some embodiments, R A3 is H.

[0180] In some embodiments, R A3 is methyl.

[0181] In some embodiments, R A3 is OMe. In some embodiments, R A3 is selected from methyl, H, and CN.

[0182] In some embodiments, R A3is selected from H, methyl, or OH.

[0183] R A2 and R A3 R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 When they form an aromatic heterocycle, they form an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0184] R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 When forming an aromatic heterocycle, the optional substituents are NH2, C 1~6 Alkyl, C 1~6 In another embodiment, the optional substituent is selected from methyl, ethyl, OMe, NH, F, Cl, and Br. In another embodiment, the optional substituent is selected from methyl, NH, Cl, F, and OMe. In another embodiment, the optional substituent is methyl.

[0185] In one embodiment, R A2 and R A3 together with the carbon atoms to which they are attached, optionally substituted C 5~7 When they form a heteroaromatic ring, they form an optionally substituted pyridine. In some embodiments, the optional substituent is NH. In other embodiments, R A2 and R A3 together with the carbon atoms to which they are attached form an unsubstituted pyridine. A2 and R A3 together form an optionally substituted pyrazole, an optionally substituted pyrrole, or an optionally substituted thiazole. In some embodiments, the optional substituent is methyl.

[0186] R A3 and RA2 together with the carbon atoms to which they are attached, optionally substituted C 5~7 When forming an aromatic heterocycle, the optional substituents are C 1~6 Alkyl, C 1~6 In another embodiment, the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH, and halo. In another embodiment, the optional substituents are selected from NH and methyl.

[0187] R A3 and R A2 together with the carbon atoms to which they are attached, optionally substituted C 5~7 When they form a heterocycle, they form a 5-membered ring containing 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 N. In some embodiments, R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted pyrrole or pyrazole.

[0188] R A3 and R A2 together with the carbon atoms to which they are attached, optionally substituted C 5~7 When forming a heterocycle, the optional substituents are NH2, C 1~6 Alkyl, C 1~6 In another embodiment, the optional substituent is selected from methyl, ethyl, OMe, ethoxy, NH, F, Cl, and Br. In another embodiment, the optional substituent is methyl.

[0189] In other embodiments, R A2 and R A3 together with the carbon atoms to which they are attached form: (i) an optionally substituted C6 aromatic heterocycle (wherein the optional substituent is NH2); (ii) an optionally substituted C6 carboaromatic ring (wherein the optional substituents are F, OMe, Cl); (iii) An optionally substituted C5 aromatic heterocycle or C5 heterocycle, wherein the optional substituent is methyl.

[0190] In some embodiments, R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 forming an aromatic heterocycle, wherein the optional substituents are C 1~6 It is selected from alkyl and halo.

[0191] In some embodiments, R A2 and R A3 together 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.

[0192] In some embodiments, R A2 and R A3 together form a ring selected from:

[0193] [Table 7]

[0194] B In some embodiments, B is represented by formula (B-1):

[0195] [ka] where the wavy lines indicate the points of attachment to A and C; R B1 is H, OH, -OMe, -O-ethyl, -CH2OH, -CH2CH2OH, or =CHCH2-OH.

[0196] In other embodiments, R B1 is H-CH2OH-CH2CH2OH or =CHCH2-OH.

[0197] In other embodiments, R B1 is -CH2OH, -CH2CH2OH, or =CHCH2-OH.

[0198] In other embodiments, R B1 is H.

[0199] In another embodiment, B is a group represented by formula (B-1a):

[0200] [ka] It is of the type.

[0201] In a further embodiment, B has the formula (B-1b):

[0202] [ka] It is of the type.

[0203] Thus, in some embodiments, the compound of formula (I) is the S,S-enantiomer.

[0204] In some embodiments, B is represented by formula (B-2):

[0205] [ka] where the wavy lines indicate the points of attachment to A and C; R B2 is C 1~2 Alkyl-OH, CH2CONHMe, or C 1~3 It is alkyl.

[0206] In some of these embodiments, R B2 is C 1~2Alkyl-OH or C 1~3 It is alkyl.

[0207] In some embodiments, when B is of formula (B-2), B is of formula (B-2a) below, where the wavy lines indicate the points of attachment to A and C, and R B2 is C 1~2 Alkyl-OH, CH2CONHMe, or C 1~2 It is alkyl.

[0208] [ka]

[0209] In some embodiments, B has the formula:

[0210] [ka] It is of the type.

[0211] In a further embodiment, B has the formula:

[0212] [ka] It is of the type.

[0213] C C is C 6~10 Carboaryl, C 5~6 Heteroaryl, and C 5~10 heterocyclyl, which groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl, or C 5~10 Bridged heterocyclyl, C 6~12 Spiroheterocyclyl or C 6~12 spirocarbocyclyl, These themselves include the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy or CH2-carboxy; n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl C optionally substituted with one or more of 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl, or C 5~10 Bridged heterocyclyl, C 6~12 Spiroheterocyclyl or C 6~12 spirocarbocyclyl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, diC 1~6 Alkylamide, C 1~6 Alkyl sulfonamides, and diC 1~6 one or more groups selected from alkylsulfonamide is optionally replaced by

[0214] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyl, which itself is selected from the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, or OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy or CH2-carboxy; and / or n) optionally substituted with one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0215] C is any substituted C 5~6When heteroaryl, in some embodiments, it is an optionally substituted C heteroaryl. In other embodiments, it is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl. In other embodiments, it is an optionally substituted pyridinyl.

[0216] C is any substituted C 5~6 When it is heteroaryl, it is (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, or C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyl, These themselves are a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) C, including branched and cyclic, with optional substituents selected from OH or one or more halo groups. 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy or CH2-carboxy; and / or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl C optionally substituted with one or more groups selected from 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, or C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, diC 1~6 Alkylamide, C 1~6 Alkyl sulfonamides, and diC 1~6 It may be optionally substituted with one or more groups selected from alkylsulfonamides.

[0217] C is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 When a heterocyclyl is substituted, it may have multiple substituents. a) one or two =O groups; b) one or more halo groups, CN, NH2; c) (CH3)2, C, each optionally substituted with one or more halo groups. 1~6 Alkoxy or C 1~6 Contains alkyl esters, one or more C 1~6 alkyl; d) C with optional methyl substituents 5~6 Heterocyclyl or C 5~6 Heteroaryl; e) C optionally substituted with one or more halo atoms 6~10 Carboaryl; f) P(=O)Me2; or g) selected from carboxy or CH2-carboxy.

[0218] In some embodiments, one substituent on C is in the para position.

[0219] In some embodiments, C is optionally substituted C 5~6 When heteroaryl, the optional substituents are C 1~6 In a further embodiment, the optional substituent is methyl. In a further embodiment, C is substituted with methyl at the meta position.

[0220] In other embodiments, C is optionally substituted C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 When substituted by heterocyclyl, it may be substituted by optionally substituted phenyl, optionally substituted pyridyl, optionally substituted imidazolidinyl, optionally substituted dihydroquinolinyl, optionally substituted benzimidazolyl, or optionally substituted imidazopyridinyl, which groups may themselves contain one or two ═O groups, halo, CN, one or more C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl esters, C 5~6 Optionally substituted by heterocyclyl (with optional methyl substituent), phenyl substituted at the para position by F, carboxy, CH2-carboxy, tetrazolyl, pyrazolyl, triazolyl, or P(=O)Me2.

[0221] In other embodiments, when C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, it may have multiple substituents. The substituents include optionally substituted C 5~10 Heteroaryl and C 5~10 heterocyclyl, which may themselves contain one or two =O groups, one or more halo groups, CN, one or more C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl esters, C 5~6Heterocyclyl (with optional methyl substituents), phenyl optionally substituted with one or two halo groups, carboxy, CH-carboxy, tetrazolyl, pyrazolyl, triazolyl, a pyridine ring, optionally substituted with NH, or OH. In some embodiments, the substituent is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted imidazolidine, optionally substituted dihydroquinoline, optionally substituted benzimidazolyl, or optionally substituted imidazopyridinyl.

[0222] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are: I C 6~10 Carboaryl, C 5~10 Heteroaryl, C 5~10 Heterocyclyls which themselves are selected from the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy, CH2-carboxy; and / or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl C optionally substituted with one or more of 6~10 Carboaryl, C 5~10 Heteroaryl, C 5~10 heterocyclyl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, diC 1~6 Alkylamide, C 1~6 Alkyl sulfonamides, and diC 1~6 alkylsulfonamides.

[0223] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are C 6~10 Carboaryl, C 5~10 Heteroaryl, C 5~10 heterocyclyl, which itself is selected from: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy, CH2-carboxy; and / or n) optionally substituted with one or more groups selected from tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0224] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyl, which itself is selected from the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, or OH; d) one or more C groups having substituents selected from OH or one or more halo groups, including branched and cyclic groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy or CH2-carboxy; and / or n) optionally substituted with one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0225] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyl, which itself is selected from the following groups: a) one or more halo groups; b) CN, NH2, or OH; c) one or more C groups having optional substituents selected from OH or one or more halo groups, including branched and cyclic groups 1~6 alkyl groups; d) C having one or more halo group optional substituents 1~6 Alkoxy; e)C 1~6 Alkyl esters; f) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; g) C 5~6 Heteroaryl; h) C with any methyl or ═O substituent 4~10 Carbocyclyl; i) C having one or more halo group optional substituents 6~10 Carboaryl; j) P(=O)Me2; k) carboxy or CH2-carboxy; and / or l) optionally substituted with one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0226] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyl, which itself is optionally substituted by one or two =O groups, and is selected from the following groups: a) one or more halo groups; b) CN, NH2, or OH; c) one or more C groups having substituents selected from OH or one or more halo groups, including branched and cyclic groups 1~6 alkyl groups; d) C having one or more halo group optional substituents 1~6 Alkoxy; e)C 1~6 Alkyl esters; f) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; g) C 5~6 Heteroaryl; h) C with any methyl or ═O substituent 4~10 Carbocyclyl; i) C having one or more halo group optional substituents 6~10 Carboaryl; j) P(=O)Me2; k) carboxy or CH2-carboxy; and / or l) Substituted with one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0227] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, where the optional substituents are selected from C heteroaryl or C heterocyclyl, which themselves are selected from the following: i) one or two =O groups; ii) methyl; iii) OMe; iv) Cl; v)CN; vi)CF3; vii)F; viii) pyrazolyl, triazolyl, tetrazolyl optionally substituted with methyl; ix)O-CF3; x) optionally substituted with one or more groups selected from O—CHF2.

[0228] In some embodiments, C is a substituted pyridyl substituted with a C6 heterocyclyl or a C6 heteroaryl, each of which contains 1 or 2 N atoms and is substituted with =O and another group selected from methyl, Cl, OMe, CN, and OCHF2.

[0229] In some embodiments, C is a substituted pyridyl substituted by at least one =O group and another group selected from CF3, OCF3, Cl, CN, OMe, pyrazole optionally substituted with methyl, tetrazole, F, OCHF2, or triazole.

[0230] In a further embodiment, C is optionally substituted pyridinyl, where the optional substituents are selected from phenyl and pyridyl, which themselves are optionally substituted with methyl or CN.

[0231] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, where the optional substituents are selected from pyridine, pyridazine, and pyrimidine, which themselves are selected from the following: a) one or two =O groups; b) one or more halo groups; c) methyl; d)OMe; e) CN; or f) optionally substituted with one or more groups selected from OCHF2.

[0232] In some embodiments, C is an optionally substituted pyridinyl, where the optional substituents are phenyl or pyridyl, which themselves are: a) one or more OMe groups; b) one or more F groups; c)CN; d) tetrazole; or e) optionally substituted with one or more groups selected from carboxy.

[0233] In some embodiments, C is an optionally substituted pyridinyl, where the optional substituents are C heteroaryl or C heterocyclyl, which are themselves optionally substituted with one or more substituents selected from methyl and CN. In some embodiments, C is an optionally substituted pyridinyl, where the optional substituents are pyrazole, triazole, imidazole, or oxazole, which are themselves optionally substituted with one or more substituents selected from methyl and CN. In further embodiments, the pyrazole, triazole, imidazole, or oxazole is substituted with two methyl groups and optionally one CN group.

[0234] In some embodiments, C is an optionally substituted pyridinyl, where the optional substituent is an unsubstituted C9-membered heterocyclyl containing 2 or 3 nitrogen atoms.

[0235] In another embodiment, C is a group represented by formula (C-1):

[0236] [ka] wherein D is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10heterocyclyl, which itself may be ═O, halo, CN, NH, OH, alkyl optionally substituted with one or more C 1~6 C optionally substituted with alkyl, halo 1~6 Alkoxy, C 1~6 Alkyl esters, C 5~6 Optionally substituted with heterocyclyl (with optional methyl substituent), carboxy, CH2-carboxy, P(=O)Me2, tetrazolyl, pyrazolyl, or triazolyl. In some embodiments, the optional substituents are ═O, CN, F, Cl, Br, CN, methyl, ethyl, OMe, ethoxy, O-CF3, OMe, CF3, P(=O)Me2, and C 1~2 alkyl esters.

[0237] 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, Cl, F, methyl, trifluoromethyl, OCF, —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 pyridin-2-one is unsubstituted. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0238] When C is (C-1), in some embodiments, D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of which is bonded to (C-1), the 6-membered heteroaryl is substituted in the ortho position with ═O, and other optional substituents are selected from methyl, OMe, piperazine substituted with methyl, C(═O)OH (carboxy), Cl, phenyl substituted with fluoro, CN, CF, F, pyrazolyl, triazolyl, tetrazolyl, or O—CF.

[0239] In some embodiments, C is a group represented by formula (C-1):

[0240] [ka] wherein D is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 heterocyclyl, each of which is itself i) one or two =O groups; ii) one or two C's which may be branched 1~4 alkyl groups; iii) OMe; iv) piperazinyl optionally substituted with methyl; v) C(=O)OH (carboxy); vi) Cl; vii)F; viii) phenyl optionally substituted with one or more fluoro; ix)CN; x)CF3; xi)O-CF3; xii) tetrazolyl, pyrazolyl, triazolyl, each optionally substituted with methyl; xiii)NH2; xiv) pyridinyl; xv) CH2OH; xvi)OH; xvii) P(=O)Me2; or xviii)OCHF2 is optionally replaced by

[0241] In some embodiments, C is a group represented by formula (C-1):

[0242] [ka] wherein D is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 heterocyclyl, each of which is itself i) one or two =O groups; ii) one or two C's which may be branched 1~4 alkyl groups; i)OMe; ii) piperazinyl optionally substituted with methyl; iii) C(=O)OH (carboxy); iv) Cl; v)F; vi) phenyl optionally substituted with 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 is optionally replaced by

[0243] In some embodiments, D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of which is attached to (C-1), and the 6-membered heteroaryl is substituted in the ortho position with ═O, where the optional substituent is i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v)Cl; vi) phenyl substituted with fluoro; vii)CN; viii)CF3; ix)O-CF3; x) F; or xi) selected from pyrazolyl, triazolyl, or tetrazolyl.

[0244] In some embodiments, when C is (C-1), D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of the N atoms being bonded to (C-1), and the 6-membered heteroaryl is substituted in the ortho position with ═O, where the optional substituent is i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v)Cl; vi)F; vii) phenyl substituted with fluoro; viii)CN; ix)CF3; x)O-CF3; xi) O-CHF2; xii) selected from pyrazole, triazole, tetrazole, each optionally substituted with methyl.

[0245] In some embodiments, D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of which is attached to (C-1), and the 6-membered heteroaryl is substituted in the ortho position with ═O, where the optional substituent is: i) methyl; ii) OMe; iii) Cl; iv)F; v)CN; vi)CF3; vii) O-CF3; viii) O-CHF2; or ix) selected from pyrazolyl, triazolyl, or tetrazolyl, each optionally substituted with methyl.

[0246] In some embodiments, D is a substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of which is attached to (C-1), and the 6-membered heteroaryl is substituted in the ortho position with ═O, where the substituent is i)OMe; ii) Cl; iii)F; iv)CN; v)CF3; vi) O-CF3; vii) O-CHF2; or viii) selected from pyrazolyl, triazolyl, or tetrazolyl, each optionally substituted with methyl.

[0247] In some embodiments, C is of formula (C-1), wherein D is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 heterocyclyl, each of which is itself i) one or two =O groups; ii) one or two C groups which may be branched and which are optionally substituted with one or more halo groups 1~4 alkyl groups; iii) one or more OMe groups; iv) C(=O)OH (carboxy); v) halo; vi)CN; vii) C optionally substituted with one or more halo groups 1~4 Alkoxy; viii) tetrazolyl, pyrazolyl, triazolyl, each optionally substituted with methyl; ix) P(=O)Me2 is optionally replaced by

[0248] In some embodiments, C is of formula (C-1) and D is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 heterocyclyl, each of which may itself contain one or two =O groups; methyl, CF3; OCF 3- ; pyrazole optionally substituted with Cl, CN, OMe, methyl, tetrazole, F, OCHF2, triazole, C(=O)OH, P(=O)Me2 optionally substituted.

[0249] In some embodiments, D is optionally substituted with 1, 2, or 3 substituents.

[0250] In some embodiments, D is optionally substituted with one substituent.

[0251] In some embodiments, D is optionally substituted with two or three substituents.

[0252] In some embodiments, when C is (C-1), D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of the N atoms being bonded to (C-1), and the 6-membered heteroaryl is substituted in the ortho position with ═O, where the optional substituent is i) methyl; ii) OMe; iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy); v)Cl; vi)F; vii) phenyl substituted with fluoro; viii)CN; ix)CF3; x)O-CF3; xi) selected from pyrazole, triazole, tetrazole optionally substituted with methyl.

[0253] In some embodiments, C is of formula (C-1) and D is an optionally substituted phenyl or piperidyl, with one or two optional substituents selected from F, OMe, and CN. In some embodiments, C is of formula (C-1) and D is an optionally substituted phenyl or pyridyl, with one or two optional substituents selected from F, OMe, and CN.

[0254] In some embodiments, D is an optionally substituted C5 heterocyclyl or C5 heteroaryl, where the optional substituents are selected from methyl and CN. In further embodiments, D is an optionally substituted pyrazole, imidazole, triazole, or oxazole, where 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 with two methyl groups. In further embodiments, D is an imidazole substituted with two methyl groups and CN. In further embodiments, D is an oxazole substituted with two methyl groups.

[0255] In some embodiments, D is a C heterocyclyl or C heteroaryl containing two or three nitrogen atoms. In further embodiments, D is 1H-pyrazolo[3,4-b]pyridyl, indazol-1-yl, or indazol-2-yl.

[0256] In some embodiments, D is optionally substituted with 1, 2, or 3 substituents.

[0257] In another embodiment, D is a group represented by formula (D-1):

[0258] [ka] wherein R D1 , R D2 , R D3 , and R D4 one or two of which are C optionally substituted with one or more halo groups 1~6 Alkyl; C optionally substituted with one or more halo groups 1~6 Alkoxy, C with optional methyl substituents 5~6 Heterocyclyl or C 5~6 selected from heteroaryl, carboxy, ═O, halo, NH—, CN, or phenyl optionally substituted with one or more halo atoms; or R D3 and RD4 forms an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2, and C(=O)OH; Or R D1 , R D2 , R D3 , and R D4 are all H.

[0259] In another embodiment, R D1 , R D2 , R D3 , and R D4 one or two of which are C optionally substituted with one or more halo groups 1~6 alkyl, C optionally substituted with one or more halo groups 1~6 Alkoxy, C with optional methyl substituents 5~6 Heterocyclyl or C 5~6 selected from heteroaryl, carboxy, halo, CN, or phenyl optionally substituted with one or more halo atoms, the remainder being H.

[0260] In some embodiments, D is of formula (D-1), and R D1 , R D2 , R D3 , and R D4 One or two of the i) methyl; ii) OMe; iii) methyl-substituted piperazines; iv) C(=O)OH (carboxy); v)Cl; vi) phenyl substituted with fluoro; vii)CN; viii)CF3; ix)F; x) pyrazolyl, triazolyl, tetrazolyl; xi)O-CF3 is selected from R D1 , R D2 , R D3 , and RD4 The remainder is H.

[0261] In some embodiments, D is of formula (D-1), and R D1 , R D2 , R D3 , and R D4 One or two of the i) methyl; ii) OMe; iii) Cl; iv)CN; v)CF3; vi)F; vii) pyrazolyl, triazolyl, tetrazolyl optionally substituted with methyl; viii) O-CF3 ix) O-CHF2 is selected from R D1 , R D2 , R D3 , and R D4 The remainder is H.

[0262] In another embodiment, R D1 , R D2 , R D3 , and R D4 one or two of R are selected from methyl, -OMe, halo, -C(=O)OH, CN, CF3, -OCF3, -OCHF2; D1 , R D2 , R D3 , and R D4 The remainder is H.

[0263] In one embodiment, R D1 , R D2 , R D3 , and R D4 All of them are H.

[0264] In another embodiment, R D3 is selected from H, optionally substituted phenyl (wherein the optional substituent is halo), methyl, OMe, —C(═O)OH, —OCHF, Cl, CN, and piperazinyl optionally substituted with methyl, wherein RD1 , R D2 , and R D4 are all H. In some embodiments, R D3 is selected from H, CN, OMe, Cl, pyrazole optionally substituted with methyl, tetrazole, methyl, OCHF, or triazole, where R D1 , R D2 , and R D4 are all H. In some embodiments, R D3 is selected from H, CN, OMe, Cl, pyrazole, tetrazole, methyl, OCHF, or triazole, where R D1 , R D2 , and R D4 are all H.

[0265] In some embodiments, R D2 is selected from H, OMe, Cl, and CN, where R D1 , R D3 , and R D4 are all H.

[0266] In other embodiments, R D1 is selected from H, methyl, OMe, Cl, CF3, OCF3, OCHF2, and CN; R D2 , R D3 , and R D4 are all H. In some embodiments, R D1 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole, and pyrazole optionally substituted with methyl; R D2 , R D3 , and R D4 are all H.

[0267] In another embodiment, R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic, heterocyclic, or heteroaromatic ring, where the optional substituents are selected from OH, CN, P(=O)Me2, methyl, OMe, halo, and C(=O)OH.

[0268] In some embodiments, R D3 and R D4 form an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0269] In some embodiments, R D3 and R D4 forms an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0270] In another embodiment, D is a group represented by formula (D-2):

[0271] [ka] wherein X D is NR D5a or CR D5a R D5b and; R D5a is selected from H or methyl; R D5b and R D6b are both H or together are -CH2-; R D6a is selected from H, ═O, methyl, —CHOH, or —C(═O)OH; R D6a If =O, R D6b is non-existence; R D7a is selected from H, ═O, methyl, —CHOH, or —C(═O)OH; R D7b is H and R D7a If =O, R D7b Is non-existent; or R D6a and R D7a together form a benzene ring or a C6 aromatic heterocycle, which is optionally substituted with CN, P(=O)Me2, or carboxy; R D6b and R D7b is non-existent.

[0272] In some embodiments, C is of formula (C-1), D is of formula (D-2), and X D is N and R D5a is methyl.

[0273] In some embodiments, C is of formula (C-1), D is of formula (D-2), and R D6a and R D6b are both H and R D7a is selected from =O, -CHOH, or -C(=O)OH; R D7b is H or R D7a If =O, R D7b is non-existent.

[0274] In some embodiments, C is of formula (C-1), D is of formula (D-2), and X D is N and R D5a is methyl, where R D7a is selected from H and ═O, and R D6a is H and =O, where R D7a If =O, R D6a and R D6b is H and R D7b is non-existent, where R D6a is =O and R D7a and R D7b is H and R D6b is non-existent.

[0275] In some embodiments, C is of formula (C-1), D is of formula (D-2), and R D7a is =O and R D7b is non-existent, and X D is C and R D5b and R D6b together form -CH2-, and R D6a and R D5a is methyl.

[0276] In another embodiment, R D6a and R D7atogether form a benzene ring or a C6 aromatic heterocycle, which is optionally substituted by CN, P(=O)Me2, or -C(=O)OH, and R D6b and R D7b is non-existent.

[0277] In some embodiments, R D6a and R D7a together form a benzene or pyridine ring, which is optionally substituted by CN, P(=O)Me2, or C(=O)OH, and R D6b and R D7b is non-existent.

[0278] In some embodiments, R D6a and R D7a forms an unsubstituted benzene ring, and R D6b and R D7b is absent. In some embodiments, R D6a and R D7a forms an unsubstituted pyridine ring, and R D6b and R D7b is non-existent.

[0279] In some embodiments, X D is N and R D5a is H or methyl.

[0280] In some embodiments, X D is C and R D5a is H or methyl, and R D5b is H. In a further embodiment, R D5a and R D5b Both are H.

[0281] In some embodiments, R D7a is carboxy, —CHOH, or ═O. In some embodiments, R D7a is =O and R D7b is H or R D7a If =O, R D7b is non-existent.

[0282] In some embodiments, R D6a is H or ═O. In some embodiments, R D6a is =O and R D6b is non-existent.

[0283] In some embodiments, R D7a If =O, R D6a and R D6b is H and R D7b is non-existent, and R D6a If =O, R D7a and R D7b is H and R D6a is non-existent.

[0284] In some embodiments, X D is N and R D5a is H or methyl, and R D6b is H and R D6a and R D7a together form a pyridine or benzene ring, which is optionally substituted by —C(═O)OH or —CN or —P(═O)Me2, and R D6b and R D7b is non-existent.

[0285] In some embodiments, D is selected from the table below.

[0286] [Table 8-1]

[0287] [Table 8-2]

[0288] [Table 8-3]

[0289] In some embodiments, D is selected from the following table:

[0290] [Table 9-1]

[0291] [Table 9-2]

[0292] [Table 9-3]

[0293] In some embodiments, D is selected from the following table:

[0294] [Table 10-1]

[0295] [Table 10-2]

[0296] [Table 10-3]

[0297] In another embodiment, C is a group represented by formula (C-2):

[0298] [ka] wherein R C7 , R C8 , R C9 , and R C10one or two of R are selected from methyl, OMe, halo, C(═O)OH, piperazine optionally substituted with methyl, optionally substituted phenyl (wherein the optional substituents are methyl or halo), CN, CF, —O—CF, O—CHF, tetrazolyl, pyrazolyl optionally substituted with methyl, or triazolyl; C7 , R C8 , R C9 , and R C10 the remainder are H; or R C9 and R C10 forms an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2, or -C(=O)OH; or R C7 , R C8 , R C9 , and R C10 are all H.

[0299] In some embodiments, R C7 , R C8 , R C9 , and R C10 one or two of R are selected from methyl, OMe, halo, C(═O)OH, piperazine optionally substituted with methyl, optionally substituted phenyl (wherein the optional substituents are methyl or halo), CN, CF, —O—CF, tetrazolyl, pyrazolyl, or triazolyl; C7 , R C8 , R C9 , and R C10 the remainder are H; or R C9 and R C10 forms an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2, or -C(=O)OH; or R C7 , R C8 , R C9 , and R C10 are all H.

[0300] In one embodiment, C has the formula (C-1), and R C7 , R C8 , R C9 , and R C10 All of them are H.

[0301] In another embodiment, R C7 , R C8 , R C9 , and R C10 one or two of R are selected from methyl, Cl, OMe, phenyl substituted with F at the para position, —C(═O)OH, CN, OCF, CF, F, pyrazolyl, triazolyl, tetrazolyl, piperazinyl substituted with methyl; C7 , R C8 , R C9 , and R C10 The remainder of R is H. In another embodiment, R C7 , R C8 , R C9 , and R C10 one or two of R are selected from methyl, OMe, Cl, CN, CF3, F; pyrazolyl, triazolyl, tetrazolyl optionally substituted with methyl; O-CF3, O-CHF2; D1 , R D2 , R D3 , and R D4 The remainder is H.

[0302] In another embodiment, R C7 and R C9 one of R is independently selected from methyl, -OMe, Cl, -C(=O)OH, piperazinyl optionally substituted with methyl, optionally substituted phenyl (wherein the optional substituent is F), CN, CF, -O-CF, F, pyrazolyl, triazolyl, or tetrazolyl, and the other is H; C10 and R C8 is H. In another embodiment, R C7 and R C9one of which is 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; C10 and R C8 is H.

[0303] In another embodiment, R C9 is 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; R C7 , R C8 , and R C10 are all H. In some embodiments, R C9 is selected from H, CN, OMe, Cl, pyrazole optionally substituted with methyl, tetrazole, methyl, OCHF, or triazole; R C7 , R C8 , and R C10 are all H.

[0304] In other embodiments, R C7 is selected from H, methyl, OMe, Cl, F, CF3, -OCF3, and CN; R C8 , R C9 , and R C10 are all H. In some embodiments, R C7 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole, and pyrazole optionally substituted with methyl; R C7 , R C8 , and R C10 are all H.

[0305] In some embodiments, R C8 is selected from H, OMe, Cl, and CN, where R C7 , R C9 , and R C10 are all H.

[0306] In another embodiment, C is selected from the group consisting of groups 1-48 listed in the table below.

[0307] [Table 11-1]

[0308] [Table 11-2]

[0309] In another embodiment, C is selected from the group consisting of 49 to 80 listed in the table below.

[0310] [Table 12-1]

[0311] [Table 12-2]

[0312] In another embodiment, C is selected from the group consisting of the groups listed in the table below.

[0313] [Table 13-1]

[0314] [Table 13-2]

[0315] [Table 13-3]

[0316] ABC In other embodiments, the compound of formula ABC has formula (IA):

[0317] [ka] wherein X 1 is N.

[0318] In some embodiments, R A2 teeth, (i)H; (ii) halo; (iii)C 1~6 Alkyl esters; (iv) C 1~6 hydrocarbons; (v) C 1~3 Alkylamide, C 2~3 Alkynyl, C 4~6 C heterocyclyl or alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 Alkylamides; (vi) C 1~6 thioalkyl; (vii)C 1~6 Alkyl acyls; (viii) C5 heteroaryl; or (ix) alkylamino.

[0319] In some embodiments, R A2 is selected from the group consisting of: Br, Cl, CN, H, -C(=O)CH; alkylamide is C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 heterocyclyl, C alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 optionally substituted methoxy, methyl, ethyl, or cyclopropyl, where the optional substituents are selected from OH, CN, or one or more halo groups; optionally substituted methoxy or ethoxy, where the optional substituents are selected from alkylamido or one or more halo groups. In further embodiments, R A2is selected from CN, methyl, Cl, -C(=O)CH, -C(=O)OCHCH, cyclopropyl, -C(=O)NHCHC(=O)NH, -C(=O)NHCHCHCH, -C(=O)NH-oxetane, -C(=O)NHCHCHF, -C(=O)NHCHCHOH, -C(=O)NHCHCH, -C(=O)NH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -OCHF, H, -OMe, -OCF. In some embodiments, R A2 is 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.

[0320] In some embodiments, R A3 are CN, Br, Cl, OH, H, CF3, C 1~2 Alkyl, C 1~2 In a further embodiment, R A3 is selected from H, methyl, and CN. In some embodiments, R A3 is selected from H, methyl, or OH.

[0321] In other embodiments, R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 It forms an aromatic heterocycle, and the optional substituents are NH2, C 1~6 Alkyl, C 1~6 In other embodiments, the optional substituents are selected from NH, methyl, ethyl, OMe, F, Cl, and Br.

[0322] In some embodiments, R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted pyridine, an optionally substituted benzene, a pyrrole, or a pyrazole. A2 and R A3 together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, a pyridine optionally substituted by NH-2, or a benzene optionally substituted by Cl, F, or OMe.

[0323] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the optional substituent is (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, or C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyls, which themselves are a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10Carboaryl; k) carboxy, CH2-carboxy; l) A group selected from P(=O)Me2 C optionally substituted with one or more of 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, or C 5~10 Bridged heterocyclyl, C 6~12 spiroheterocyclyl, or C 6~12 spirocarbocyclyl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, diC 1~6 Alkylamide, C 1~6 Alkyl sulfonamide, diC 1~6 alkylsulfonamides.

[0324] In other embodiments, the compound of formula ABC has formula (IB):

[0325] [ka] wherein X 1 , R A2 , and R A3 is as defined for (IA).

[0326] In some embodiments, formula (IB) can be formula (I-Ba) or (I-Bb) as shown below:

[0327] [ka]

[0328] In some embodiments, D is C 6~10Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, or C 5~10 heterocyclyl, which itself is: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l) Carboxy, CH2-carboxy m) optionally substituted with one or more groups selected from P(=O)Me2.

[0329] In some embodiments, 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 (CF), OCF, carboxy (C(=O)OH), CN, phenyl with an optional F substituent in the para position, or piperazine with a methyl substituent. In some embodiments, the pyridin-2-one is unsubstituted. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0330] In some embodiments, D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of which is bonded to C, wherein the 6-membered heteroaryl is substituted in the ortho position with =0, and the other optional substituents are selected from methyl, OMe, piperazinyl substituted with methyl, C(=0)OH (carboxy), Cl, F, pyrazolyl, triazolyl, tetrazolyl, phenyl substituted with fluoro, CN, CF, or O-CF. In some embodiments, D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of which is bonded to C, wherein the 6-membered heteroaryl is substituted in the ortho position with =0, and the other optional substituents are selected from methyl, OMe, piperazinyl substituted with methyl, C(=0)OH (carboxy), Cl, F, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, phenyl substituted with fluoro, CN, CF, OCHF, or O-CF.

[0331] In some embodiments, D is an optionally substituted C5 heterocycle or C5 heteroaryl, where the optional substituents are selected from methyl and CN. In further embodiments, D is an optionally substituted pyrazole, imidazole, triazole, or oxazole, where 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 with two methyl groups. In further embodiments, D is an imidazole substituted with two methyl groups and CN. In further embodiments, D is an oxazole substituted with two methyl groups.

[0332] In some embodiments, D is a C heterocyclyl or C heteroaryl containing two or three nitrogen atoms. In further embodiments, D is 1H-pyrazolo[3,4-b]pyridyl, indazol-1-yl, or indazol-2-yl.

[0333] In other embodiments, the compound of formula ABC has formula (IC):

[0334] [ka] wherein X 1 , R A2 , and R A3 is as defined for (IA).

[0335] In some embodiments, R D1 , R D2 , R D3 , and R D4 one or two of which are C optionally substituted with one or more halo groups 1~6 Alkyl; C optionally substituted with one or more halo groups 1~6 Alkoxy, C with optional methyl substituents 5~6 Heterocyclyl or C 5~6 selected from heteroaryl, carboxy, ═O, halo, NH—, CN, or phenyl optionally substituted with one or more halo atoms; or R D3 and R D4 form an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, where the optional substituents are selected from OH, methyl, OMe, halo, C(=O)OH.

[0336] In another embodiment, R D1 , R D2 , R D3 , and R D4 wherein one or two of R are selected from methyl, OMe, halo, C(=O)OH, CN, CF, OCF, OCHF, pyrazolyl, triazolyl, tetrazolyl, and the remainder are H. In another embodiment, R D1 , R D2 , R D3 , and R D4wherein one or two of are selected from methyl, OMe, halo, C(=O)OH, CN, CF3, OCF3, OCHF2, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, and the remainder are H.

[0337] In one embodiment, R D1 , R D2 , R D3 , and R D4 All of them are H.

[0338] In some embodiments, R D3 and R D4 forms an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0339] In other embodiments, the compound of formula ABC has the formula (ID):

[0340] [ka] It is of the type.

[0341] In some embodiments, X 1 , R A2 , and R A3 is as defined for (IA).

[0342] In some embodiments, X D is NR D5a or CR D5a R D5b and; R D5a is selected from H or methyl; R D5b and R D6b are both H or together are -CH2-; R D6a is selected from H, ═O, methyl, CHOH, or C(═O)OH; R D7a is selected from H, ═O, methyl, CHOH, or C(═O)OH; RD7b is H and R D7a If =O, R D7b Is non-existent; or R D6a and R D7a together form a benzene ring or a C6 aromatic heterocycle, which is optionally substituted with CN, P(=O)Me2, or carboxy; R D6b and R D7b is non-existent.

[0343] In some embodiments, R D6a and R D7a together form a benzene or pyridine ring, which is optionally substituted by CN, P(=O)Me2, or carboxy; R D6b and R D7a is non-existent.

[0344] In other embodiments, the compound of formula ABC has the formula (IE):

[0345] [ka] It is of the type.

[0346] In some embodiments, R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) OH, C 1~6 alkylamide or C optionally substituted with one or more halo groups 1~6 Alkoxy; (vii) carboxy; (viii)C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6heterocyclyl, C alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 alkylamides.

[0347] In some embodiments, R A2 teeth, (i)H; (ii) halo; (iii)C 1~6 Alkyl esters; (iv) C 1~6 hydrocarbons; (v) C 1~3 Alkylamide, C 2~3 Alkynyl, C 4~6 C heterocyclyl or alkyl optionally substituted with one or more halo or OH groups 1~3 C optionally substituted with alkyl 1~6 Alkylamides; (vi) C 1~6 thioalkyl; (vii)C 1~6 Alkyl acyls; (viii) C5 heteroaryl; or (ix) alkylamino.

[0348] In some embodiments, R A2 is 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; R A2 and R A3 together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, a pyridine optionally substituted by NH-2, or a benzene optionally substituted by Cl, F, or OMe.

[0349] In some embodiments, R A2 is 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.

[0350] In some embodiments, R A3 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl, or C optionally substituted with one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) C optionally substituted with OH, NH, C heterocyclyl, or one or more halo groups 1~6 Alkoxy is selected from:

[0351] In some embodiments, R A3 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl, or C optionally substituted with one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) C optionally substituted with OH, NH, C heterocyclyl, or one or more halo groups 1~6 Alkoxy is selected from:

[0352] In some embodiments, the compound is of formula (IE), where R A3 is H, methyl, or OH. In a further embodiment, the compound is of formula (IE) and R A3 is H.

[0353] In some embodiments, the compound is of formula (IE) and D is C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, or C 5~10 heterocyclyl, which itself may be ═O; halo; CN; NH; OH; one or more C alkyl optionally substituted with halo. 1~6 alkyl groups; C optionally substituted with halo 1~6 Alkoxy;C 1~6 Alkyl esters; C with optional methyl substituents 5~6 Optionally substituted with heterocyclyl; carboxy; CH-carboxy; tetrazolyl; pyrazolyl, or triazolyl. In some embodiments, the optional substituents are ═O, CN, F, Cl, Br, CN, methyl, ethyl, OMe, ethoxy, O—CF, CF, C 1~2In some embodiments, the compound is of formula (IE) and D is selected from C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, or C 5~10 Heterocyclyl, which itself may be ═O; methyl; OMe; piperazinyl substituted with methyl; C(═O)OH (carboxy); Cl; F; phenyl substituted with fluoro; CN; CF3; OCHF2, O—CF3; pyrazole, triazole, tetrazole optionally substituted with methyl. is optionally replaced by

[0354] In some embodiments, the compound is of Formula (IE) 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 (CF), OCF, carboxy (C(=O)OH), CN, phenyl with an optional F substituent in the para position, or piperazinyl with a methyl substituent. In some embodiments, the compound is of Formula (IE) 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 (CF), OCHF, OCF, carboxy (C(=O)OH), CN, phenyl with an optional F substituent in the para position, or piperazinyl with a methyl substituent. In some embodiments, the pyridin-2-one is unsubstituted. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0355] In some embodiments, the compound is of formula (IE) and D is an optionally substituted C5 heterocycle or C5 heteroaryl, where the optional substituents are selected from methyl and CN. In further embodiments, D is an optionally substituted pyrazole, imidazole, triazole, or oxazole, where 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 with two methyl groups. In further embodiments, D is an imidazole substituted with two methyl groups and CN. In further embodiments, D is an oxazole substituted with two methyl groups. In some embodiments, D is a C9 heterocyclyl or C9 heteroaryl containing two or three nitrogen atoms. In further embodiments, D is 1H-pyrazolo[3,4-b]pyridyl, indazol-1-yl, or indazol-2-yl.

[0356] In some embodiments, D is optionally substituted with 1, 2, or 3 substituents.

[0357] In another embodiment, the compound has formula (I-Ea):

[0358] [ka] wherein D and R A3 is as defined above for formula (IE).

[0359] In another embodiment, the compound has formula (I-Eb):

[0360] [ka] wherein D and R A3 is as defined above for formula (IE).

[0361] In one embodiment, the compound has formula (I): ABC (I) or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof where A is

[0362] [ka] is of; The wavy line indicates the point of attachment to B; X 1 is N; R A2 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons; (v) C optionally substituted with OH, alkylamido, or one or more halo groups 1~6 Alkoxy; (vi) C 1~6 acylamides (wherein acyl is optionally substituted with H or methyl); (vii)C 1~6 thioalkyl; (viii)C 1~6 Alkyl esters; (ix) C 1~6 Alkyl acyls; (x)C 4~5 heterocyclyl; (xi) C5 heteroaryl; (xii)C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl or C 1~3 C optionally substituted with alkyl 1~6 Alkyl amides, such as C 1~3 C, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 Alkylamides; and (xiii) selected from the group consisting of OH; R A3 teeth, (i)H; (ii) halo; (iii) CN; (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl or C optionally substituted with one or more halo groups 1~6 hydrocarbons; (v)OH; (vi) C optionally substituted with OH, NH, C heterocyclyl, or one or more halo groups 1~6 Alkoxy; (vii)C 1~6 acyloxy; (viii) C4 heterocyclyl; (ix)-NH2; (x) C optionally substituted by CN, OH, or C heterocyclyl 1~6 Alkylamino; (xi) C optionally substituted by -NH 1~6 Dialkylamino; (xii)C 1~6 acylamides (wherein the acyl substituent is H or Me); (xiii) carbimidoyl or methyl-carbimidoyl; (xiv) carboxyamino; (xv) C optionally substituted by OH or NH 1~6 thioalkyl; (xvi)C 1~6 Alkylsulfinyl; (xvi) C optionally substituted with one or more halo groups1~6 Alkylsulfonyl; (xvii)C 1~6 sulfonimodil; (xviii)C 1~6 Alkylphosphinyl; (xix) carboxy; (xx)-C(=O)NH2 (xxi)C 1~6 Alkyl esters; (xxii) C optionally substituted with one or more halo groups 1~6 alkyl acyls; and (xxiiv)C 1~6 or selected from the group consisting of alkylamides; or R A3 and R A2 along with the carbon atoms to which they are attached. (i) optionally substituted C 5~7 heterocycles; (ii) optionally substituted C 5~7 Aromatic heterocycles; (iii) an optionally substituted C6 carboaromatic ring; (iv) optionally substituted C 5~7 It forms a carbon ring, where the optional substituents are C 1~6 Alkyl, Halo, C 1~6 Alkoxy, -NH2, C 1~6 selected from alkylamino, OH, and CN; B is a group represented by the formula (B-1) or (B-2): (i)

[0363] [ka] (wherein the wavy lines indicate the points of attachment to A and C; R B1 is H, OH, =CHCH2-OH, -OC 1~4 Alkyl, or C 1~4 alkyl, C 1~4 The alkyl is optionally substituted with OH or OMe. (ii)

[0364] [ka] (wherein the wavy lines indicate the points of attachment to A and C; R B2 is C 1~2 Alkyl-OH, CH2CONHMe, or C 1~3 alkyl), C is C 6~10 Carboaryl, C 5~6 Heteroaryl, and C 5~10 heterocyclyl, which groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged heterocyclyl, C 6~12 Spiroheterocyclyl or C 6~12 spirocarbocyclyl, These themselves include the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH2, OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; 1~6 alkyl groups; e) C having one or more halo group optional substituents 1~6 Alkoxy; f)C 1~6 Alkyl esters; g) C with any methyl, OH, or ═O substituent 5~6 heterocyclyl; h)C 5~6 Heteroaryl; i) C with any methyl or ═O substituent 4~10 Carbocyclyl; j) C having one or more halo group optional substituents 6~10 Carboaryl; l)P(=O)Me2; m) carboxy or CH2-carboxy; and / or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl C optionally substituted with one or more of 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged heterocyclyl, C 6~12 Spiroheterocyclyl or C 6~12 spirocarbocyclyl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, diC 1~6 Alkylamide, C 1~6 Alkyl sulfonamides, and diC 1~6 alkylsulfonamides.

[0365] In some embodiments, the compound has formula (I): ABC (I) or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof where A is

[0366] [ka] is of; The wavy line indicates the point of attachment to B; R A2 is C 1~6 is alkylamino; X 1 , R A3 , B, and C are as defined above.

[0367] In some embodiments, the compound of formula (I) is selected from the following in Table 1:

[0368] [Table 14-1]

[0369] [Table 14-2]

[0370] [Table 14-3]

[0371] [Table 14-4]

[0372] Further compounds are shown in Table 2.

[0373] [Table 15-1]

[0374] [Table 15-2]

[0375] [Table 15-3]

[0376] [Table 15-4]

[0377] Further compounds are shown in Table 3.

[0378] [Table 16-1]

[0379]

Table 16-2

[0380]

Table 16-3

[0381]

Table 16-4

[0382]

Table 16-5

[0383]

Table 16-6

[0384]

Table 16-7

[0385]

Table 16-8

[0386]

Table 16-9

[0387]

Table 16-10

[0388] In some embodiments, the compound is selected from 50, 57, 129, 132, and 136. In some embodiments, the compound is 132.

[0389] General Synthesis Compounds of general formula (IB) can be prepared according to the following schemes 1, 2, 3, 4, and 5. The schemes and procedures described below are illustrative of the synthetic routes to compounds of general formula (IB), and are not intended to be limiting. It is clear that the order of the transformations illustrated in schemes 1, 2, 3, 4, and 5 can be varied in various ways. Therefore, the order of the transformations illustrated in these schemes is not intended to be limiting.

[0390] Routes for the preparation of compounds of general formula (IB) and corresponding intermediates are described in Schemes 1, 2, 3, 4, and 5.

[0391] [ka]

[0392] Scheme 1: Route for the preparation of compounds of general formula (IB) where X is a leaving group, PG is a protecting group, D, X 1 , R A2 , and R A3 has the meaning given for general formula (IB) above).

[0393] Monoarylated diamines of general formula (A3) are prepared by nucleophilic aromatic substitution (S) between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A2a) where X is a halogen or a leaving group such as -S(O)Me, as shown in Scheme 1. N Ar) or palladium-catalyzed Buchwald-Hartwig amination. X is, for example, fluorine or a group such as -S(O)Me. NIn the Ar approach, diamine (A1) can be reacted with A2a in the presence of an inorganic base such as K2CO3 or Na2CO3, or in the presence of an organic base such as triethylamine or DIPEA, or without any additional base, in a polar solvent such as DMSO, NMP, or nBuOH at a temperature between 100 and 130 °C. The reaction time can vary between 1 hour and 24 hours. In certain instances, it can be advantageous to apply microwave heating.

[0394] For the palladium-catalyzed Buchwald-Hartwig amination, any method known in the art can be applied. For example, diamine (A1) can be reacted with A2a in the presence of a palladium catalyst such as Pd PEPPSI-IpentCl [CAS: 1612891-29-8], Pd2(dba)3, or tBuXPhos Pd G3 [1447963-75-8] and a base such as Cs2CO3 or NaOtBu in an aprotic solvent such as 1,4-dioxane, DMF, toluene, or DMA at a temperature between room temperature and 130°C, preferably 65-100°C, for 15-24 hours.

[0395] Diamines of general formula (A1) and heteroaryls of general formula (A2a) are commercially available or can be prepared according to procedures available in the public domain. For the synthesis of diamines (A1), see, for example, WO2004004726 and references therein.

[0396] Arylated diamines of general formula (A6) can be obtained from A3 by copper-catalyzed Ullmann coupling with heterocycles (A4) or by palladium-catalyzed Suzuki coupling with boronic acid derivatives (A5). For Ullmann coupling, any method known in the art can be applied. For example, A3 can be reacted with A4 in the presence of a copper catalyst such as Cu(I)I, Cu(Otf)2, or Cu(Oac)2 and a base such as CS2CO3 or K2CO3 in a polar aprotic solvent such as 1,4-dioxane, DMF, or pyridine at a temperature between room temperature and 120°C, preferably at 100°C, for 15 to 20 hours. In some cases, N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine, TMEDA, N 1 ,N 2 A ligand such as N,N-dimethylethane-1,2-diamine, or N,N-dimethylglycine may be added to the reaction mixture.

[0397] For the Suzuki coupling to (A6), any method known in the art can be applied. For example, A3 can be reacted with a boronic acid derivative (A5) in the presence of a palladium catalyst such as 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride [CAS: 95408-45-0] or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride [CAS: 72287-26-4] and a base such as CsCO, KCO, or KPO in a polar solvent such as 1,4-dioxane, THF, and water, or a mixture thereof, at a temperature between room temperature and 120°C for 2 to 15 hours.

[0398] 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 in the public domain.

[0399] Primary amines of general formula (A7) can be obtained from monoprotected diamines of general formula (A6) by deprotection methods. Depending on the protecting group applied, these can be, for example, acidic, basic, oxidative, or hydrogenation methods. Suitable protecting moieties for amino groups and their introduction and cleavage are well known in the art. For an overview of protecting group chemistry, see, for example, Wuts 2014.

[0400] The final compound of general formula (IB) undergoes aromatic nucleophilic substitution (S N A primary amine of general formula (A7) can be synthesized from a primary amine of general formula (A7) by Ar- or palladium-catalyzed Buchwald-Hartwig amination. Primary amines of general formula (A7) can be reacted with heteroaryls of general formula (A8), where X is a halogen, such as chlorine, or a leaving group, such as -S(O)Me, applying procedures similar 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 in the public domain.

[0401] An alternative route to compounds of general formula (IB) starts with the deprotection of diamines of general formula (A3) to give primary amines of general formula (A9), as shown in Scheme 1. For deprotection, the same procedure applies as described for the synthesis of (A7) from (A6).

[0402] Primary amines of general formula (A9) can then undergo aromatic nucleophilic substitution (S) to give aryl iodides of general formula (A10), applying a procedure similar to that described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. N Ar) or palladium catalyzed Buchwald-Hartwig amination with heteroaryls of general formula (A8).

[0403] Final compounds of general formula (IB) can be synthesized from aryl iodides of general formula (10) by copper-catalyzed Ullmann coupling with heterocycles HD (A4) or by palladium-catalyzed Suzuki coupling with boronic acid derivatives (A5), applying procedures similar to those described for the synthesis of compounds (A6) from (A3) in Scheme 1.

[0404] Yet another approach to compounds of general formula (IB) involves the aromatic nucleophilic substitution (S) of a monoprotected diamine (1) or its corresponding salt and a pre-assembled heteroaryl (A11a) where X is a halogen or a leaving group such as -S(O)Me to give an arylated diamine of general formula (A6). N The synthesis begins with a palladium-catalyzed Buchwald-Hartwig amination using aryl groups (Ar) or palladium. Applicable procedures are similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A11a) are commercially available or can be prepared according to procedures available in the public domain (e.g., by Chang-Lam coupling). Specific examples of (A11a) are described in the following paragraphs.

[0405] An alternative route for the preparation of compounds of general formula (IB) and intermediates of general formula (A10) is shown in Scheme 2.

[0406] [ka]

[0407] Scheme 2: Route for the preparation of compounds of general formula (IB) and intermediate (A10) where X is a leaving group, PG is a protecting group, D, X 1 , R A2 , and R A3 has the meaning given for general formula (IB) above).

[0408] Monoarylated diamines of general formula (A12) are prepared by aromatic nucleophilic substitution (S) between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A8) where X is a halogen or a leaving group such as -S(O)Me. N Ar) or palladium-catalyzed Buchwald-Hartwig amination. The applicable procedures are similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

[0409] Deprotection of diamines of general formula (A12) can give primary amines of general formula (A13). For deprotection, the same procedure as described for the synthesis of (A7) from (A6) in Scheme 1 is applied.

[0410] The final compound of general formula (IB) is then subjected to aromatic nucleophilic substitution (S N A13 can be synthesized from a primary amine (A13) or its corresponding salt and a pre-constructed heteroaryl (A11a) where X is a halogen or a leaving group such as -S(O)Me via a palladium-catalyzed Buchwald-Hartwig amination. The applicable procedures are similar to those described for the synthesis of A6 from A1 and A11a in Scheme 1.

[0411] For the synthesis of intermediates of general formula (A10), aromatic nucleophilic substitution (S N In an Ar) or palladium-catalyzed Buchwald-Hartwig amination, primary amine (A13) or its corresponding salt can be reacted with heteroaryl (A2a) where X is a halogen or a leaving group such as -S(O)Me. The applicable procedures are similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

[0412] Carboxylic acid derivatives of general formula (A21) can be synthesized according to the route shown in Scheme 3. Nitro compounds of general formula (A15) can be synthesized by aromatic nucleophilic substitution (S NThe nitroaryls of general formula (A14) can be obtained by reacting a monoprotected diamine (A1) or its corresponding salt with a nitroaryl (A14) in which X is a leaving group such as chlorine, in the presence of an inorganic base such as K2CO3, for example, in a polar solvent such as DMSO, at a temperature between room temperature and the boiling point of the solvent for 2 to 12 hours. Nitroaryls of general formula (A14) are commercially available or can be prepared according to procedures available in the public domain.

[0413] Anilines of general formula (A16) can be obtained from nitro compounds of general formula (A15) by reduction. Any method known in the art can be applied for the reduction. For example, nitro compounds of general formula (A15) can be reacted in the presence of a metal catalyst such as palladium on carbon under a hydrogen atmosphere (1-5 bar) in a polar protic solvent such as methanol or ethanol at a temperature between 0°C and the boiling point of the solvent for 15-24 hours.

[0414] [ka]

[0415] Scheme 3: Route for the preparation of compounds of general formula (A21) where X is a leaving group, PG is a protecting group, Alk is methyl or ethyl, and X 1 , R A2 , and R A3 has the meaning given for general formula (IB) above).

[0416] Pyridones of general formula (A18) can be obtained from anilines (A16) by condensation with oxopyrans of general formula (A17), in which Alk is methyl or ethyl, in a polar protic solvent such as ethanol at a temperature between room temperature and the boiling point of the solvent for 2 to 12 hours. Oxopyrans of general formula (A17) are commercially available or can be prepared according to procedures available in the public domain.

[0417] Primary amines of general formula (A19) can be synthesized from (A18) by removal of the protecting group. For deprotection, the same procedure as described for the synthesis of (A7) from (A6) in Scheme 1 is applied.

[0418] Carboxylic acid esters of general formula (A20) can be prepared by aromatic nucleophilic substitution (S) applying a procedure similar to that described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. N Ar) or palladium-catalyzed Buchwald-Hartwig amination from primary amines (A19) and heteroaryls (A8).

[0419] The carboxylic acid derivative of general formula (A21) can be synthesized from the carboxylic acid ester of general formula (A20) by ester hydrolysis. For saponification, any method known in the art can be applied. For example, the ester (A20) can be reacted with a base such as sodium hydroxide in a polar protic solvent such as methanol, water, or a mixture thereof at a temperature between 0°C and the boiling point of the solvent for 0.5 to 2 hours.

[0420] 1,2,4-Triazines of general formula (A29) can be synthesized by the route shown in Scheme 4. The methyl-thioether moiety of 3-(methylthio)-1,2,4-triazine (A22) [CAS: 28735-21-9] can be activated for nucleophilic substitution by oxidation, and all methods known in the art for oxidation can be applied. For example, (A22) can be reacted with mCPBA or Oxone® in an inert solvent such as dichloromethane at a temperature between 0°C and the boiling point of the solvent for 0.5 to 2 hours. The crude oxidation product can be converted to a nucleophilic aromatic substitution (S) by reacting it with a primary amine of general formula (A1) in a polar solvent such as nBuOH at a temperature between room temperature and the boiling point of the solvent for 2 to 18 hours. N Ar) can be directly converted to monoarylated diamines of general formula (A23).

[0421] The aryl bromides of general formula (A24) can be obtained from the triazines of general formula (A23) by bromination. Any method known in the art can be applied for bromination. For example, the triazines (A23) can be reacted with bromine or N-bromosuccinimide (NBS) in a solvent such as methanol, water, DMF, or a mixture thereof at a temperature between 0°C and the boiling point of the solvent for 4 to 15 hours.

[0422] The 3,6-disubstituted triazine of general formula (A27) can be synthesized from aryl bromides (A24) by Suzuki coupling, and all methods known in the art for Suzuki coupling can be applied. For example, (A24) can be reacted with potassium trifluoroborate (A25) or trioxatriborinane (A26) in the presence of a palladium catalyst such as CataCXium A Pd G3 [CAS: 1651823-59-4] or 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride [CAS: 95408-45-0] and a base such as CsCO, KCO, or KPO in a polar solvent such as 1,4-dioxane, THF, and water, or a mixture thereof, at a temperature between room temperature and 120°C for 8 to 15 hours. Trifluoroborates of general formula (A25) or trioxatriborinanes (A26) are either commercially available or can be prepared according to procedures available in the public domain.

[0423] [ka]

[0424] Scheme 4: Route for the preparation of compounds of general formula (A29) where X is a leaving group, PG is a protecting group, Alk is methyl or ethyl, and X 2 and X 3 is CH or N (where X 2 If N, then X 3 is CH and vice versa), R A2is alkyl or cycloalkyl, and D has the meaning given for general formula (IB) above).

[0425] Primary amines of general formula (A28) can be obtained from A27 by removal of the protecting group. For deprotection, the same procedure as described for the synthesis of (A7) from (A6) in Scheme 1 is applied.

[0426] The final compound of general formula (A29) is a nucleophilic aromatic substitution (S N A28 can be synthesized from a primary amine (A28) or its corresponding salt and a pre-assembled heteroaryl (A11) where X is a leaving group such as a halogen, via a palladium-catalyzed Buchwald-Hartwig amination. The applicable procedure is similar to that described for the synthesis of A3 from A1 and A2a in Scheme 1.

[0427] Heteroaryls of general formula (A11) are commercially available or can be prepared according to procedures available in the public domain. Specific examples of (A11) are described in the following paragraphs.

[0428] In an alternative route to triazines of general formula (A29), a primary amine (A28) or its corresponding salt is first reacted with a nucleophilic aromatic substitution (S N Heteroaryls (A2) where X is a leaving group such as a halogen can be reacted with heteroaryls (A1) through a palladium-catalyzed Buchwald-Hartwig amination or palladium-catalyzed Buchwald-Hartwig amination. Applicable procedures are similar 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 in the public domain.

[0429] Final compounds of general formula (A29) can be synthesized from aryl iodides of general formula (A30) by copper-catalyzed Ullmann coupling with heterocycle HD (A4) or by palladium-catalyzed Suzuki coupling with boronic acid derivatives (A5), applying procedures similar to those described for the synthesis of compound (A6) from (A3) in Scheme 1.

[0430] In an alternative approach to obtain 3,6-disubstituted triazines of general formula (A27), ketoacetals of general formula (A31) can be reacted with methyl hydrazinecarbimidothioate (A32) or its corresponding salt in a polar solvent, such as methanol, at a temperature between room temperature and the boiling point of the solvent for 5-12 hours to obtain 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 commercially available or can be prepared according to procedures available in the public domain.

[0431] The triazine thioethers of general formula (A33) can then be prepared by oxidation of (A33) followed by aromatic nucleophilic substitution (S) with primary amines of general formula (A1), applying a procedure similar to that described for the synthesis of compound (A23) from (A22) in Scheme 4. N Ar) to 3,6-disubstituted triazines of general formula (A27).

[0432] Carboxylic acid ester or amide derivatives of general formula (A35) and (A37) can be synthesized according to the route shown in Scheme 5. Carboxylic acid esters of general formula (A35) can be synthesized by aromatic nucleophilic substitution (S NAr) from primary amine (A7) [see Scheme 1] and triazine of general formula (A34). For example, (A7) and (A34) can be reacted in the presence of an organic base such as DIPEA in a polar solvent such as NMP at a temperature between room temperature and the boiling point of the solvent for 0.5 to 2 hours, applying microwave heating. Triazines of general formula (A34) are commercially available or can be prepared according to procedures available in the public domain.

[0433] Carboxamides of general formula (A37) can be obtained from carboxylic acid esters (A35) by direct amidation. All methods known in the art can be applied for amidation. For example, esters (A35) can be reacted with amines (A36) in polar solvents such as methanol, ethanol, or THF at temperatures between room temperature and the boiling point of the solvent for 1 to 5 hours. If an amine (A36) with insufficient nucleophilicity is used, it is possible to increase the temperature, extend the reaction time, and / or add a Lewis acid such as AlMe3.

[0434] [ka]

[0435] Scheme 5: Route for the preparation of compounds of general formula (A35) and (A37) where Alk is methyl or ethyl and D has the meaning given for general formula (IB) above.

[0436] Alternatively, ester (A35) can be first hydrolyzed to a carboxylic acid of general formula (A38). Any method known in the art for saponification can be applied. For example, ester (A35) can be reacted with a base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide in a polar protic solvent such as water or methanol or a mixture thereof at a temperature between 0°C and the boiling point of the solvent for 0.5 to 24 hours. In certain instances, it can be advantageous to add an ether such as THF or 1,4-dioxane to the reaction mixture.

[0437] Next, carboxamides of general formula (A37) can be obtained from carboxylic acids (A38) by amide coupling with appropriate amines (A36). For amide coupling, any method known in the art of peptide chemistry can be applied. For example, acids (A38) can be reacted with amines (A36) via activated acid derivatives in polar aprotic solvents such as DMF, acetonitrile, or NMP. These activated derivatives can be obtained from acids (A38) with reagents such as HOBt, HOAt, or N-hydroxysuccinimide, and carbodiimides such as DCC or EDC, or with preformed reagents such as HATU, PyBOP, or T3P®. To enhance reactivity, a suitable base such as DIPEA or triethylamine can be used. In certain instances, the activated acid derivatives can be isolated prior to reaction with amines (A36). Amide formation may be achieved with an acid halide (e.g., which may be formed from a carboxylic acid by reaction with oxalyl chloride, thionyl chloride, or sulfuryl chloride), a mixed anhydride (e.g., which may be formed from a carboxylic acid by reaction with isobutyl chloroformate), an imidazolide (e.g., which may be formed from a carboxylic acid by reaction with CDI), or an azide (which may be formed from a carboxylic acid by reaction with DPPA).

[0438] For the synthesis of final compounds of general formula (B-2), routes and methods equivalent to those described in Schemes 1-5 can be applied. Without intending to be limiting, routes to compounds of general formula (A43) in Schemes 6-7 are provided for further illustration. Diamines of general formula (A39) are commercially available or can be prepared according to procedures available in the public domain.

[0439] [ka]

[0440] Scheme 6: Route for the preparation of compounds of general formula (A43) where X is a leaving group, PG is a protecting group, D, X 1 , R A2 , R A3 , and R B2 has the meaning given for general formulae (IB) and (B-2) above).

[0441] [ka]

[0442] Scheme 7: Route for the preparation of compounds of general formula (A43) and intermediates (A45) where X is a leaving group, PG is a protecting group, D, X 1 , R A2 , R A3 , and R B2 has the meaning given for general formulae (IB) and (B-2) above).

[0443] Additional compounds having different formulas as above may be prepared by similar methods.

[0444] Examples Section NMR peak shapes are reported as they appear in the spectra and possible higher order effects have not been taken into account.

[0445] The following table lists the abbreviations used in this paragraph and in the Examples section unless explained in the text. Other abbreviations have their customary meanings to those skilled in the art.

[0446] [Table 17-1]

[0447] [Table 17-2]

[0448] [Table 17-3]

[0449] [Table 18]

[0450] The various embodiments described in this application are illustrated by the following examples, which are not intended to limit the compounds of formula (I) in any way.

[0451] The experiments testing the examples described herein serve to illustrate embodiments of the invention and are not limited to the examples shown.

[0452] Experimental Section - General Provisions General conditions (i) The operations were carried out at room temperature (rt), i.e., in the range of 17-28°C, and required under an atmosphere of an inert gas such as N2; (ii) When referring to a reaction being degassed or purged, this can be done, for example, by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (e.g., 5-10 minutes), or by repeatedly evacuating the vessel and filling it with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g)); (iii) If the reaction refers to the use of a microwave reactor, one of the following microwave reactors was used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer; (iv) The course of the reaction was usually followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC), usually coupled to a mass spectrometer (LCMS); (v) To remove excess water, the organic solution was dried over anhydrous MgSO or NaSO, or an ISOLUTE® Phase Separator was used, and work-up procedures were carried out using conventional phase separation techniques; (vi) evaporation was carried out by rotary evaporation under reduced pressure or in a Genevac™ HT-4 / EZ-2 or Biotage® V10; (vii) Unless otherwise specified, flash column chromatography was performed manually or by Grace on normal-phase silica using either Merck Silica Gel (product number: 9385) or pre-packed cartridges, e.g., 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 Column Silica-CS cartridges (80-330 g). performed in an automated manner using the Reveleris® X2 Flash system or a similar system; (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either MS- and / or UV-triggered fraction collection instruments, using either isocratic or mobile phase gradients as described in the Experimental Section; The relevant fractions were collected, combined, lyophilized or evaporated to give the purified compound, or the relevant fractions were collected, combined, concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried over Na2SO4 or by using a phase separator, and then concentrated under reduced pressure to give the purified compound; (ix) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC equipment, respectively, using either isocratic or gradient elution with mobile phases as described in the Experimental Section; (x) Preparative thin-layer chromatography (TLC) was performed using TLC glass plates and applying appropriate solvents or solvent mixtures; (xi) yields, when presented, are not necessarily the maximum achievable, and some reactions were repeated when larger amounts of reaction product were required; (xii) When a particular compound was obtained as an acid addition salt, e.g., a monohydrochloride or dihydrochloride, the molar ratio of the salt was based on the number and nature of the basic groups in the compound, and the exact molar ratio of the salt was generally not determined by, e.g., elemental analysis data; where specified, the salt was treated by procedures known in the literature to generate the corresponding free base before use; (xiii) In general, the structure of the final product of formula (I) was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; the proton NMR chemical shift values ​​were 300, 400, 500, and 600 MHz, respectively. 1Measurements were made on a Bruker Avance III 300, 400, 500, and 600 spectrometer operating at H frequencies on the delta scale. Experiments were typically recorded at 25°C. Chemical shifts are given in ppm using the solvent as the internal standard. Protons on heteroatoms, such as NH and OH protons, are reported only if detected by NMR and may therefore be missing. In certain instances, protons may be masked or partially masked by the solvent peak, resulting in missing and not reported, or reported as a solvent-overlapping multiplet. The following abbreviations (and their derivatives, e.g., dd: doublet of doublets, etc.) were used: s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet; br: broad line; qn: quintet; p: quintet. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar instrument, which acquires both positive and negative ion data. Generally, only ions associated with the parent structure are reported; High-resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar instrument, which acquires both positive and negative ion data. Generally, only ions associated with the parent structure are reported; (xiv) In certain instances, intermediates were not fully purified, but their structure 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 may therefore contain excess TFA. The excess can be calculated from the weight of the crude sample. Where indicated, salts were treated by literature-known procedures to generate the corresponding free bases prior to use; (xvi) Unless otherwise specified, compounds containing asymmetric carbon and / or sulfur atoms were not resolved; (xvii) In general, the examples and intermediate compounds are named using ChemDraw Professional version 21.0.0.28 from PerkinElmer. ChemDraw Professional version 21.0.0.28 generates 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 distinguished from one another by stereodescriptors that are specified in the names and assigned according to the CIP rules.

[0453] When applicable, ChemDraw uses labels such as "&" and "or" in the depiction of stereocenters to represent the configuration of stereochemical centers present in a structure. A numerical value following the "&" and "or" flags is assigned to each stereocenter present.

[0454] In some instances, such purification methods may result in compounds of Formula (I) having sufficiently basic or acidic functional groups in salt form, such as trifluoroacetate or formate salts for sufficiently basic compounds of Formula (I), or ammonium salts for sufficiently acidic compounds of Formula (I). Salts of this type may be converted to their free base or free acid forms, respectively, by various methods known in the art, or may be used as salts in subsequent bioassays. It should be understood that a particular form (e.g., salt, free base, etc.) of a compound of Formula (I) as isolated and described herein is not necessarily the only form in which the compound may be applied to a bioassay to quantify a particular biological activity.

[0455] Purification method Preparative HPLC method: Preparative Method A: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeOH in H2O / NH4HCO3 (10 mM) / NH3 (0.1% in water) buffer system as the mobile phase; Preparative method B: Compounds were 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% aqueous) buffer system as the mobile phase; Preparative Method C: Compounds were purified by preparative HPLC on an Xbridge™ Shield RP18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1% aqueous) buffer system as the mobile phase; Preparative Method D: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1% in water) buffer system as the mobile phase; Preparative method E: Compounds were 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 the mobile phase; Preparative method F: Compounds were purified by preparative HPLC on an 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 the mobile phase; Preparative method G: Compounds were purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) buffer system as the mobile phase; Preparative method H: Compounds were purified by preparative HPLC on an 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 the mobile phase; Preparative method I: Compounds were purified by preparative HPLC on an 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 the mobile phase; Preparative method J: Compounds were 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 the mobile phase; Preparative method K: Compounds were 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% aqueous) buffer system as the mobile phase; Preparative Method L: Compounds were purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.1% aqueous) buffer system as the mobile phase; Preparative method M: Compounds were 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% aqueous) buffer system as the mobile phase; Preparative Method N: Compounds were purified by preparative HPLC on an Xbridge™ OBD Phenyl column (5 μm, 150 × 19 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.1% in water) buffer system as the mobile phase; Preparative Method O: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05% aqueous) buffer system as the mobile phase; Preparative method P: Compounds were 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 the mobile phase; Preparative Method Q: Compounds were purified by preparative HPLC on an Xbridge™ Shield RP18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05% aqueous) buffer system as the mobile phase; Preparative Method R: Compounds were 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 the mobile phase; Preparative Method S: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) buffer system as the mobile phase; Preparative Method T: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of 20 mM NaOH + 10% MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05% aqueous solution) buffer system as the mobile phase; Preparative method U: Compounds were purified by preparative HPLC on an Xbridge™ OBD Phenyl column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05% aqueous) buffer system as the mobile phase; Preparative Method V: Compounds were purified by preparative HPLC on an Xbridge™ OBD Phenyl column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H O / TFA (0.05%) buffer system as the mobile phase; Preparative method X: Compounds were 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% aqueous solution) buffer system as the mobile phase; Preparative method Y: Compounds were purified by preparative HPLC on an Xbridge™ Shield RP18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05% aqueous) buffer system as the mobile phase; Preparative method Z: Compounds were 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 the mobile phase; Preparative method Z1: Compounds were 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 / NH4HCO3 (10 mM) / NH3 (0.1% aqueous) buffer system as the mobile phase; Preparative method Z2: Compounds were 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 / NH4HCO3 (10 mM) / NH3 (0.05% aqueous) buffer system as the mobile phase; Preparative method Z3: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05% aqueous) buffer system as the mobile phase; Preparative method Z4: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in H2O / TFA (0.005%) buffer system as the mobile phase; Preparative method Z5: Compounds were purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeOH in H2O / NH4HCO3 (10 mM) / NH3 (0.05% aqueous) buffer system as the mobile phase; Preparative method Z6: Compounds were purified by preparative HPLC on an Xbridge™ Shield RP18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.1% aqueous) buffer system as the mobile phase; Preparative method Z7: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 100 × 50 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.1% in water) buffer system as the mobile phase; Preparative method Z8: Compounds were purified by preparative HPLC on an Xbridge™ RP18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1% in water) buffer system as the mobile phase; Preparative method Z9: Compounds were purified by preparative HPLC on an Xbridge™ C8 column (5 μm, 250 × 20 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) buffer system as the mobile phase; Preparative Method Z10: Compounds were purified by preparative HPLC on an Xbridge™ C8 column (5 μm, 250×50 mm ID) using a gradient of MeCN in a H 2 O / MeCN / NH 3 (95 / 5 / 0.2) buffer system as the mobile phase.

[0456] Preparative SFC method: Preparative method SFC-A: Compounds were purified by preparative SFC on a Waters™ BEH (5 μm, 250 × 30 mm ID) using MeOH / H O (NH , 50 mM) (97 / 3) in CO as the mobile phase; Preparative method SFC-B: Compounds were purified by preparative SFC on a Phenomenex Luna Hilic (3.5 μm, 100 × 3 mm ID) using MeOH / NH3 (20 mM) in CO2 as the mobile phase; Preparative method SFC-C: Compounds were purified by preparative SFC on a Waters™ Acquity UPC2 BEH (3.5 μm, 100 × 3 mm ID) using MeOH / H O (NH , 50 mM) (97 / 3) in CO as the mobile phase; Preparative method SFC-D: Compounds were purified by preparative SFC on a Waters™ BEH (5 μm, 250 × 30 mm ID) using MeOH / NH (20 mM) in CO as the mobile phase; Preparative Method SFC-E: Compounds were purified by preparative SFC on a Phenomenex Luna Hilic (5 μm, 250×30 mm ID) using MeOH / NH 3 (20 mM) in CO 2 as the mobile phase.

[0457] Preparative HPLC method in a parallel experimental setup: Preparative Method Parallel A: Compounds were purified by preparative HPLC on a Waters™ Xbridge™ C18 column (5 μm, 100 × 10 mm ID) using a gradient of MeCN (2–94%) in H2O / NH3 (pH 10) buffer system as the mobile phase; Preparative Method Parallel B: Compounds were purified by preparative HPLC on a Waters™ Xselect™ CSH Fluoro Phenyl column (5 μm, 100 × 10 mm ID) using a gradient of MeCN (2–94%) in H O / FA (pH 3) buffer system as the mobile phase; Preparative method parallel C: Compounds were purified by preparative HPLC on a Waters™ Xbridge™ C18 OBD column (5 μm, 150 × 19 mm ID) using a gradient of MeCN (5–95%) in H2O / MeCN / NH3 (95 / 5 / 0.2) (pH 10) buffer system as the mobile phase; Preparative Method Parallel D: Compounds were purified by preparative HPLC on an Xbridge™ C18 OBD column (5 μm, 150 × 19 mm ID) using a gradient of MeCN (5-95%) in a HO / NH4HCO3 (10 mM) (pH 9) buffer system as the mobile phase.

[0458] Synthesis method General Method 1 (GM1): Aromatic Nucleophilic Substitution (S N Ar) Condition A (GM1A): Conventional heating To a solution of the respective amine nucleophile or its salt (1 equivalent) in DMSO (or NMP, n-BuOH, or 1,4-dioxane), a base (1-7 equivalents) and the respective heteroaryl electrophile (0.9-2 equivalents) are added at room temperature, and the resulting mixture is stirred under heating (100-130°C) until TLC and / or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is concentrated under reduced pressure, and the resulting crude product is subjected to chromatography or preparative TLC and / or preparative HPLC to obtain the desired aniline product.

[0459] In an alternative aqueous workup, the reaction mixture is poured into saturated brine or water and extracted with EtOAc. The combined organic layers are washed with water or brine, dried over Na2SO4, filtered, evaporated, and the resulting crude material is subjected to silica chromatography to give the desired aniline product.

[0460] Condition B (GM1B): Microwave heating To a mixture of the respective amine nucleophile or its salt (1 equivalent) and the respective heteroaryl electrophile (1-1.5 equivalents) in a microwave-safe vial, NMP and base (1-3 equivalents) are added, the vial is capped, and heated under microwave irradiation until TLC and / or LCMS indicate the consumption of the starting material (typically 0.5-2 h). The reaction mixture is concentrated under reduced pressure, and the resulting crude is subjected to preparative HPLC to obtain the desired aniline product.

[0461] General Method 2 (GM2): Buchwald-Hartwig amination A solution of the respective amine nucleophile or its salt (1 equiv.) in 1,4-dioxane is treated with the respective heteroaryl electrophile (0.5–4 equiv.), CsCO (1.2–5 equiv.), and Pd PEPPSI-IpentCl [CAS: 1612891-29-8] (3–7 mol %) at room temperature under nitrogen. The reaction mixture is stirred under heat (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is filtered through either a Celite pad or silica, the filter cake is washed with EtOAc, and the combined filtrates are concentrated under reduced pressure. The resulting crude is either triturated with PE / EtOAc or subjected to preparative TLC and / or preparative HPLC to afford the desired aniline product.

[0462] In an alternative aqueous workup, the reaction mixture is concentrated under reduced pressure and the residue is 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, evaporated, and the resulting crude material is subjected to preparative TLC and / or preparative HPLC to give the desired aniline product.

[0463] General Method 3 (GM3): Ullmann Coupling A solution of each aryl halide (1 equiv.) in 1,4-dioxane was treated with each heteroatom nucleophile HD(A4) (1–10 equiv.), Cs2CO3 (3–6 equiv.), Cu(I)I (0.2–2 equiv.), and rel-(1R,2R)-N 1 ,N 2The resulting mixture is treated with 1,2-dimethylcyclohexane-1,2-diamine [CAS: 67579-81-1] (0.2-2 equiv.) at room temperature under nitrogen, and the reaction mixture is stirred under heat (80-100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically 15-18 h). 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 is extracted with EtOAc. The organic layer is dried over Na2SO4, filtered, and evaporated. The resulting crude material is either triturated with PE / EtOAc or subjected to preparative TLC and / or preparative HPLC to afford the desired coupling product.

[0464] In an alternative non-aqueous workup, the reaction mixture is filtered through a pad of Celite, the filter cake is washed with DCM, and the combined filtrates are concentrated under reduced pressure. The resulting crude material is subjected to preparative TLC and / or preparative HPLC to afford the desired coupling product.

[0465] General Method 4 (GM4): Suzuki Coupling Condition A (GM4A): Coupling with boronic acid derivatives A solution of the respective aryl halide (1 equivalent) in a mixture of 1,4-dioxane and water is treated with the respective boronic acid derivative (A5) (1.5-2 equivalents) or (A26) (10 equivalents), CsCO (3 equivalents), KCO (3 equivalents), or KPO (2-3 equivalents), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride [CAS: 95408-45-0] (5-10 mol%) or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride [CAS: 72287-26-4] (10 mol%) at room temperature under nitrogen. The reaction mixture is stirred under heating (80-100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (2-18 hours). The reaction mixture is filtered through a pad of Celite, the filter cake is washed with DCM, and the combined filtrates are concentrated under reduced pressure. The resulting crude material is subjected to preparative TLC and / or preparative HPLC to afford the desired coupling product.

[0466] In an alternative aqueous workup, the reaction mixture is diluted with water, the phases are separated, and the aqueous phase is extracted with EtOAc. The combined organic layers are dried over Na2SO4, filtered, evaporated, and the resulting crude material is subjected to preparative TLC and / or C18 flash chromatography or preparative HPLC to afford the desired coupling product.

[0467] Condition B (GM4B): Coupling with trifluoroborate A solution of each aryl halide (1 equivalent) in 1,4-dioxane is treated with the respective potassium trifluoroborate (A25) (4 equivalents), CsCO (4 equivalents), and CataCXium A Pd G3 [CAS: 1651823-59-4] (20 mol%) at room temperature under nitrogen. The reaction mixture is stirred under heating (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically 15 h). The reaction mixture is filtered through a Celite pad, the filter cake is washed with DCM, and the combined filtrate is concentrated under reduced pressure. The resulting crude is subjected to preparative TLC and / or preparative HPLC to obtain the desired coupling product.

[0468] General Method 5 (GM5): Chang-Lam Coupling A mixture of the respective heteroatom nucleophile HD(A4) (1 equivalent) in 1,4-dioxane is treated with the respective boronic acid (2-3 equivalents), TMEDA (3 equivalents), and Cu(Otf)2 (1.2-2 equivalents) at room temperature. The reaction mixture is stirred under heat (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically 16 h). The reaction mixture is filtered through a Celite pad, the filtrate is concentrated under reduced pressure, and the residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc, and the combined organic layers are washed with water, dried over Na2SO4, filtered, and evaporated. The resulting crude is subjected to C18 flash chromatography to afford the desired coupling product.

[0469] General Method 6 (GM6): Boc Deprotection Condition A (GM6A): Deprotection with HCl A solution of each Boc-protected amine (1 equiv.) in MeOH was treated with 4 M HCl in MeOH (13–77 equiv.) at room temperature, and the reaction mixture was stirred under heating (60–80°C) until TLC and / or LCMS indicated complete consumption of the starting material (typically 2–3 h). The reaction mixture was concentrated under reduced pressure to give the desired amine as an (unspecified) HCl salt.

[0470] Condition B (GM6B): Deprotection with TFA A solution of each Boc-protected amine (1 equiv.) in DCM was treated with TFA (11–190 equiv.) at room temperature, and the reaction mixture was stirred at room temperature until TLC and / or LCMS indicated complete consumption of the starting material (3–16 h). The reaction mixture was concentrated under reduced pressure to give the desired amine as an (unspecified) TFA salt.

[0471] General Method 7 (GM7): Amide Formation A solution of the respective ester (A35) in MeOH in a microwave-safe vial is treated with the respective amine or its salt (A36) (4-100 equivalents, neat or as a solution in THF), followed by DIPEA (4-8 equivalents), if applicable, at room temperature. The vial is capped, and the reaction mixture is stirred at room temperature or heated (60-70 °C) until TLC and / or LCMS indicate complete consumption of the starting material (3 hours-5 days). The reaction mixture is concentrated under reduced pressure, and the resulting crude material is subjected to preparative HPLC to afford the desired amide.

[0472] General Method 8 (GM8): Methyl-thioether oxidation A solution of dimethyl sulfide (1 equiv.) in DCM is cooled to 0 °C, and 3-chlorobenzoperoxoic acid (m-CPBA) [CAS: 937-14-4] (0.9-1.2 equiv.) is slowly added. The resulting mixture is stirred at room temperature until TLC and / or LCMS indicate complete consumption of the starting material (0.5-2 h). The reaction mixture is used directly in the next step.

[0473] Alternatively, the reaction mixture is concentrated under reduced pressure and the resulting crude material is subjected to silica flash chromatography to afford the desired oxidation product.

[0474] Intermediates Intermediate 1 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Step Ai-1a tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate

[0475] [ka]

[0476] 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 under a nitrogen atmosphere for 18 h. 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 product was purified by silica flash chromatography (gradient: 0 to 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.

[0477] Step Bi-1b tert-Butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0478] [ka]

[0479] GM3 was slightly modified to rel-(1R,2R)-N 1 ,N 2 1,2-Dimethylcyclohexane-1,2-diamine (CAS Registry Number: 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), KCO (3.08 g, 22.3 mmol), and pyridin-2(1H)-one (CAS Registry Number: 142-08-5) (1.42 g, 14.9 mmol) in 1,4-dioxane (20 mL). The resulting solution was stirred at 110 °C under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with EtOAc (25 mL) and subsequently washed 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.

[0480] Step Ci-1c 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0481] [ka]

[0482] In a modification of GM6A, HCl (2 M in diethyl ether, 27 mL, 54 mmol) was slowly added 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 synthetic 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 recrystallized using 5:1 EtOAc:PE to give a solid, which was collected by filtration and dried under vacuum to give the unspecified HCl salt of the title compound (2.5 g, 100%) as a yellow solid. MS (ESI, m / z): [M+H] + 270.9.

[0483] Intermediate 3. 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one 2HCl Step Ai-3a tert-Butyl ((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0484] [ka]

[0485] According to GM3, ((1S,3S)-tert-butyl 3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate (compound i-1a) (500 mg, 1.24 mmol), 3-methoxypyridin-2(1H)-one (CAS registration number: 20928-63-6) (776 mg, 6.20 mmol), rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (176 mg, 1.24 mmol), CsCO (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 the title compound (387 mg, 78%) as a brown solid after aqueous workup and preparative TLC (MeOH:DCM = 1:20). MS (ESI, m / z): [M+H] + 401.3.

[0486] Step Bi-3b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one 2HCl

[0487] [ka]

[0488] 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.

[0489] Intermediate 6 i-6a 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0490] [ka]

[0491] According to GM5, (6-chloropyridin-3-yl)boronic acid (CAS Registry Number: 444120-91-6) (1.29 g, 8.21 mmol), 1,8-naphthyridin-2(1H)-one (CAS Registry Number: 15936-09-1) (600 mg, 4.11 mmol), N 1 ,N 1 ,N 2 ,N 2 -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 the title compound (252 mg, 23%) as a pale yellow solid after purification by C18 flash chromatography (gradient: 5 to 43% MeCN in water + 0.1% NH3 (aq)). MS (ESI, m / z): [M+H] + 257.9.

[0492] Intermediate 7. 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione Step Ai-7a (6-Chloropyridin-3-yl)carbamic acid 4-nitrophenyl ester

[0493] [ka]

[0494] 4-Nitrophenyl carbonochloridate (CAS Registry Number: 7693-46-1) (1.73 g, 8.56 mmol) was added to 6-chloropyridin-3-amine (CAS Registry Number: 5350-93-6) (1.0 g, 7.8 mmol) in MeCN (20 mL) at 20 °C, and the resulting solution was 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.

[0495] Step Bi-7b 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione

[0496] [ka]

[0497] 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. After stirring the resulting suspension at 20 °C for 15 min, 4-nitrophenyl (6-chloropyridin-3-yl)carbamate (compound i-7a) (2.18 g, 7.44 mmol) was added and stirring was continued at 20 °C for 10 min. The mixture was concentrated under reduced pressure, and the resulting crude was purified by silica flash chromatography (gradient: 65-70% EtOAc in PE) to afford the title compound (1.55 g, 92%) as a white solid. MS (ESI, m / z): [M+H] + 225.8.

[0498] Intermediate 8 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile Step Ai-8a 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid methyl ester

[0499] [ka]

[0500] 6-Chloropyridin-3-amine (CAS Registry Number: 5350-93-6) (1.0 g, 7.8 mmol) was added to a solution of methyl 2-oxo-2H-pyran-5-carboxylate (CAS Registry Number: 6018-41-3) (1.2 g, 7.8 mmol) in EtOH (20 mL) at 15 °C, which 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.

[0501] Step Bi-8b 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid

[0502] [ka]

[0503] 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 THF (8 mL) and water (2 mL) at 20 °C, and the resulting solution was stirred at 20 °C for 15 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (5 mL), and the pH was adjusted to less than 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 NaSO, filtered, and evaporated to give the crude title compound (230 mg, 81%) as a white solid. MS (ESI): m / z [M+H] + 251.

[0504] Step Ci-8c 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide

[0505] [ka]

[0506] 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, then cooled to room temperature, quenched with saturated brine (100 mL), and extracted with EtOAc (3 × 75 mL). The organic layer was dried over Na2SO4, filtered, and evaporated, and the resulting residue was 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.

[0507] Step Di-8d 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile

[0508] [ka]

[0509] 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, which was stirred at 20 °C for 1 hour. The synthesis procedure was repeated for 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.

[0510] Intermediate 9 3-(trifluoromethoxy)pyridin-2-ol Step Ai-9a 2-((4-methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine

[0511] [ka]

[0512] KotBu (682 mg, 6.07 mmol) was added to (4-methoxyphenyl)methanol (CAS Registry Number: 105-13-5) (629 mg, 4.56 mmol) in 1,4-dioxane (2 mL) at 20 °C, which was stirred at 20 °C for 2 hours. 2-Chloro-3-(trifluoromethoxy)pyridine (CAS Registry Number: 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 hours. The reaction mixture was poured into saturated brine (125 mL) and extracted with EtOAc (3 × 75 mL). The organic layer was dried over NaSO, filtered, and evaporated, and the resulting 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.

[0513] Step Bi-9b 3-(trifluoromethoxy)pyridin-2-ol

[0514] [ka]

[0515] 2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine (compound i-9a) (500 mg, 1.67 mmol) was added to TFA (10 mL) at 25 °C, which was then warmed to 60 °C, and the resulting solution was stirred at this temperature for 15 h. The solvent was removed under reduced pressure, and the resulting residue was 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.

[0516] Intermediate 10 i-10a 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0517] [ka]

[0518] In a modification of GM5, pyridine (0.81 mL, 10 mmol) was added to a mixture of 2-oxo-1,2-dihydropyridine-3-carbonitrile (CAS Registry Number: 20577-27-9) (600 mg, 5.00 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry Number: 444120-91-6) (1.57 g, 10 mmol), Cu(OAc) (1.82 g, 10 mmol), and 5 Å molecular sieves (500 mg, dried at 200 °C for 24 h) in DCM (100 mL) and DMF (15 mL) at 25 °C. Air was diffused into the reaction mixture through a CaCl tube. The resulting mixture was stirred at 25 °C for 15 h and then filtered through Celite. The filter cake was washed with DCM (3 × 10 mL), the combined filtrates were concentrated under reduced pressure, and the residue was partitioned between EtOAc (400 mL) and water (150 mL). The aqueous layer was extracted with EtOAc (5 × 200 mL), and the combined organic layers were washed with saturated brine (5 × 100 mL), dried over NaSO, filtered, and evaporated. The dried solid was triturated with DMF (3 × 5 mL), the solid was filtered off, and the filter cake was washed with MTBE (3 × 5 mL). The solid was dried under reduced pressure to give the title compound (105 mg, 9%) as a gray solid. MS (ESI): m / z [M+H] + 232.1.

[0519] Intermediate 11 i-11a 2-(5-Bromopyrazin-2-yl)pyridazin-3(2H)-one

[0520] [ka]

[0521] GM3 was slightly modified to contain 2-bromo-5-iodopyrazine (CAS Registry Number: 622392-04-5) (1.00 g, 3.51 mmol), pyridazin-3(2H)-one (CAS Registry Number: 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)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (0.499 g, 3.51 mmol) was reacted in 1,4-dioxane (25 mL) at 60 °C for 1 h to give the title compound (300 mg, 33%) as a white solid after non-aqueous workup followed by preparative TLC (EtOAc:PE = 1:1). The product also contained the corresponding iodo compound. MS (ESI): m / z [M+H] + 252.9.

[0522] Intermediate 12 i-12a 6'-chloro-1-methyl-[3,3'-bipyridin]-2(1H)-one

[0523] [ka]

[0524] 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), CsCO (1.04 g, 3.19 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium 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 afford the title compound (230 mg, 98%) as a pale yellow solid after non-aqueous workup followed by preparative TLC (100% EtOAc). MS(ESI):m / z[M+H] + 221.0.

[0525] Intermediate 13 i-13a 3-chloro-6'-fluoro-2H-[1,3'-bipyridin]-2-one

[0526] [ka]

[0527] GM3 was slightly modified to contain 2-fluoro-5-iodopyridine (CAS Registry Number: 171197-80-1) (560 mg, 2.51 mmol), 3-chloropyridin-2(1H)-one (CAS Registry Number: 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)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (357 mg, 2.51 mmol) was reacted in 1,4-dioxane (60 mL) at 100 °C for 18 hours. The reaction mixture was poured into saturated brine (350 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3 x 250 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by silica flash chromatography (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.

[0528] Intermediate 14 i-14a 6'-chloro-3-fluoro[2,3'-bipyridine]-6-carbonitrile

[0529] [ka]

[0530] 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 Registry Number: 1416713-45-5) (300 mg, 1.49 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry Number: 444120-91-6) (352 mg, 2.24 mmol), and KPO (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 workup and purification by preparative TLC (EtOAc:PE = 2:1) afforded the title compound (214 mg, 61%) as a white solid. MS (ESI) m / z [M+H] + =234.0.

[0531] Intermediate 17 (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Step Ai-17a (1S,3S)-N 1 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine x 3HCl

[0532] [ka]

[0533] 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 give the title compound (1.27 g, 96%) as a beige solid. MS (ESI): m / z [M+H] + 303.90.

[0534] Step Bi-17b (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0535] [ka]

[0536] According to GM1A, (1S,3S)-N 1 -(5-Iodopyridin-2-yl)cyclopentane-1,3-diamine (compound i-17a) (1.26 g, 3.05 mmol), 2,5-dichloropyrazine (CAS registrar number: 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 was purified by flash C18 chromatography (gradient: 10 to 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.

[0537] Intermediate 21 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one Step Ai-21a 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one

[0538] [ka]

[0539] According to GM5, quinolin-2(1H)-one (CAS Registry Number: 59-31-4) (500 mg, 3.44 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry Number: 444120-91-6) (1.63 g, 10.3 mmol), Cu(Otf) (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 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one (211 mg, 24%) as a green solid after purification by C18 flash chromatography (gradient: 5-46% MeCN in water containing 0.1% NH3, aq.). MS(ESI):m / z[M+H] + 256.95.

[0540] Step Bi-21b tert-Butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0541] [ka]

[0542] 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 Registry Number: 645400-44-8) (211 mg, 1.05 mmol), CsCO (571 mg, 1.75 mmol), and Pd-PEPPSI-IpentCl were mixed. 2-Methylpyridine (29.5 mg, 0.04 mmol) was reacted in 1,4-dioxane (10 mL) at 100° C. for 15 hours to give, after aqueous workup 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.

[0543] Step Ci-21c 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[0544] [ka]

[0545] 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 hours to afford the 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.

[0546] Intermediate 22 (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Step Ai-22a tert-Butyl ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0547] [ka]

[0548] m-CPBA (5.60 g, 25.95 mmol) was added portionwise to a solution of 3-(methylthio)-1,2,4-triazine (CAS Registry Number: 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, and the residue was dissolved in n-butanol (40 mL). tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number: 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 give the crude product as a brown solid, which was purified by silica flash chromatography (gradient: 5-60% EtOAc in PE) to give the title compound (3.7 g, 56%) as a yellow solid. MS (ESI): m / z [M+H] + 280.

[0549] Step Bi-22b tert-Butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0550] [ka]

[0551] A solution of Br in 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 room temperature for 15 h. The solvent was removed under reduced pressure, and the residue was poured into saturated NaSO (aq) (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the crude product as a brown solid, which was purified by silica flash chromatography (gradient: 5–30% EtOAc in PE) to give the title compound (3.5 g, 74%) as a yellow solid. MS (ESI): m / z [M+H] + 358.

[0552] Step Ci-22c tert-Butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0553] [ka]

[0554] 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), CsCO (5.46 g, 16.8 mmol), and CataCXium A Pd G3 (CAS Registry Number: 1651823-59-4) (0.61 g, 0.84 mmol) were reacted in dioxane (70 mL) at 100 °C for 15 h. After combining with a second batch (prepared similarly, 1.12 mmol scale), the material was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound (1.12 g, 66%) as a pale yellow solid. MS(ESI):m / z[M+H] + 320.

[0555] Step Di-22d (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 4TFA

[0556] [ka]

[0557] 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 room temperature for 15 hours to give the title compound (940 mg, 89%) as a yellow gum (containing 4 mol equivalents of residual TFA). MS (ESI): m / z [M+H] + 220.

[0558] Step Ei-22e (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0559] [ka]

[0560] According to GM1A, (1S,3S)-N 1 -(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 afford the title compound (369 mg, 67%) as a pale yellow solid after aqueous workup and purification by preparative TLC (EtOAc:PE = 3:1). MS (ESI): m / z [M+H] + 423.

[0561] Intermediate 23 i-23a 1-(6-chloropyridin-3-yl)-3-methylimidazolidine-2,4-dione

[0562] [ka]

[0563] CuI (0.230 g, 1.57 mmol) was added to a mixture of 2-chloro-5-iodopyridine (CAS Registry Number: 69045-79-0) (0.50 g, 2.09 mmol), 3-methylimidazolidine-2,4-dione (CAS Registry Number: 6843-45-4) (0.48 g, 4.18 mmol), N,N-dimethylglycine hydrochloride (0.22 g, 1.57 mmol), and CsCO (1.36 g, 4.18 mmol) in dioxane (20 mL), and the resulting suspension was stirred under nitrogen at 100 °C for 15 h. 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 give the crude product as a yellow gum, which was purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (0.25 g, 53%) as a pale yellow oil that solidified upon standing. MS (ESI): m / z [M+H] + 226.

[0564] Intermediate 24 i-24a 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0565] [ka]

[0566] According to GM5, (6-chloropyridin-3-yl)boronic acid (CAS RN: 444120-91-6) (2.93 g, 18.6 mmol), 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (CAS RN: 50339-06-5) (1.11 g, 7.44 mmol), Cu(Otf) (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 the title compound (0.235 g, 12%) as a white solid after workup and purification by C18 flash chromatography (gradient: 5 to 40% MeCN in water containing 0.1% NH3, aq.). MS (ESI): m / z [M+H] + 261.

[0567] Intermediate 25 i-25a 6'-chloro-3-methoxy-2H-[1,3'-bipyridin]-2-one

[0568] [ka]

[0569] 3-Methoxypyridin-2(1H)-one (CAS Registry Number: 20928-63-6) (1.35 g, 10.8 mol) and 2-chloro-5-iodopyridine (CAS Registry Number: 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 CsCO (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 give the title compound (250 mg, 55%) as a pale yellow solid. MS (ESI): m / z [M+H] + 237.

[0570] Intermediate 26 i-26a 6'-chloro-5-methoxy-2H-[1,3'-bipyridin]-2-one

[0571] [ka]

[0572] 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 Registry Number: 61941-79-5) (523 mg, 4.18 mmol), and CsCO (1.63 mg, 5.01 mmol) in dioxane (8 mL), and the resulting suspension was stirred at 100 °C under nitrogen for 15 h. The mixture was filtered through a Celite pad, the solvent was removed under reduced pressure, and the crude product was purified by preparative TLC (EtOAc:PE = 3:1) to give the title compound (179 mg, 45%) as a white solid. MS (ESI): m / z [M+H] + 237.

[0573] Intermediate 27 i-27a 6'-chloro-3-methyl-2H-[1,3'-bipyridin]-2-one

[0574] [ka]

[0575] GM3 was slightly modified and treated with 2-chloro-5-iodopyridine (600 mg, 2.51 mmol), 3-methylpyridin-2(1H)-one (CAS Registry Number: 1003-56-1) (273 mg, 2.51 mmol), KPO (1.60 g, 7.52 mmol), Cu(I)I (239 mg, 1.25 mmol), and rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (178 mg, 1.25 mmol) was reacted in dioxane (20 mL) at 100 °C for 1 h to give the title compound (261 mg, 47%) as a brown solid after aqueous workup and purification by preparative TLC (DCM:MeOH = 20:1). MS (ESI): m / z [M+H] + 221.

[0576] Intermediate 28 (1S,3S)-N 1 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 2TFA Step Ai-28a tert-Butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0577] [ka]

[0578] According to GM4A, ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl) tert-butyl carbamate (compound i-22b) (300 mg, 0.84 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.10 g, 8.37 mmol), KPO (356 mg, 1.67 mmol), and 1,1′-bis(di-tert-butyl) Phosphino)ferrocenepalladium dichloride (CAS reg. no.: 95408-45-0) (55 mg, 0.08 mmol) was reacted in a mixture of dioxane (4 mL) and water (1 mL) at 100 °C for 15 h to give the title compound (103 mg, 42%) as a brown solid after aqueous workup and preparative TLC (MeOH:DCM = 1:20) followed by purification by C18 flash chromatography (gradient: 0 to 49% MeOH in water). MS (ESI): m / z [M+H] + 294.

[0579] Step Bi-28b (1S,3S)-N 1 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 2TFA

[0580] [ka]

[0581] According to GM6B, ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl) tert-butyl carbamate (compound i-28a) (100 mg, 0.34 mmol) was reacted in TFA (5 mL) and DCM (5 mL) at room temperature for 15 hours to give the title compound (100 mg, 95%) as a white solid. MS (ESI): m / z [M+H] + 194.

[0582] Intermediate 29 i-29a 6'-chloro-2H-[1,3'-bipyridin]-2-one

[0583] [ka]

[0584] According to GM3, 2-chloro-5-iodopyridine (3.0 g, 12.5 mmol), pyridin-2(1H)-one (CAS Registry Number: 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)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (0.891 g, 6.26 mmol) was reacted in dioxane (80 mL) at 100 °C for 15 h to give a solid after aqueous workup and trituration with PE:EtOAc (1:1, 30 mL), which was collected by filtration and dried under vacuum to give the title compound (0.60 g, 23%) as a yellow solid. MS (ESI): m / z [M+H] +207.

[0585] 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

[0586] [ka]

[0587] 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) were added to a vial, and the mixture was stirred at room temperature for 0.5 h. The compound was purified by preparative HPLC (Preparative Method G, gradient: 5-45%) to give the title compound (17 mg, 86%) as an off-white solid. MS (ESI): m / z [M+H] + 394.

[0588] Intermediate 31 (1S,3S)-N 1 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine Step Ai-31a tert-Butyl ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate

[0589] [ka]

[0590] The reaction was carried out in three batches in parallel.

[0591] According to GM2, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number: 645400-44-8) (420 mg, 2.10 mmol), 2-bromo-5-methylpyrazine (CAS Registry Number: 98006-90-7) (363 mg, 2.10 mmol), CsCO (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. The batches were combined, and after nonaqueous workup and trituration (PE:EtOAc = 2:1, 20 mL), the solid was collected by filtration and dried under reduced pressure to give the title compound (1.2 g, 63%) as a gray solid. MS(ESI):m / z[M+H] + 293.3. 1 H NMR(300MHz,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).

[0592] Step Bi-31b (1S,3S)-N 1 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine

[0593] [ka]

[0594] 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 the unspecified TFA salt of the title compound (704 mg, 91%) as a brown gum. MS (ESI): m / z [M+H] + 193.0. 1H NMR(300MHz,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).

[0595] Intermediate 35 Step Ai-35a tert-Butyl ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0596] [ka]

[0597] In a slight modification 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 Registry Number: 645400-44-8) (1.13 g, 5.66 mmol), CsCO (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 Celite pad, the filter cake was washed with DCM (3 × 10 mL), and the combined filtrate was concentrated under reduced pressure. The resulting material was purified by C18 flash chromatography (gradient: 10-100% MeCN in water + 0.1% NH3 (aq); 910 mg of material isolated) followed by preparative TLC (EtOAc:PE = 3:1) to afford the title compound (174 mg, 23%) as a grey solid. MS (ESI): m / z [M+H] + 396.20.

[0598] Step Bi-35b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile 4HCl

[0599] [ka]

[0600] 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.

[0601] Intermediate 36 Step Ai-36a 6-methyl-3-(methylthio)-1,2,4-triazine

[0602] [ka]

[0603] Methyl hydrazinecarbimidothioate HI (CAS Registry Number: 35600-34-1) (9.87 g, 42.4 mmol) was added to a stirred solution of 1,1-dimethoxypropan-2-one (CAS Registry Number: 6342-56-9) (5.00 g, 42.3 mmol) in ethanol (250 mL) at room temperature, and the resulting solution was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure, and the resulting residue was purified by silica flash chromatography (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. 1H NMR (300MHz, DMSO-d6) δ ppm 2.56 (3H, s), 2.59 (3H, s), 8.56 (1H, s).

[0604] Step Bi-36b 6-methyl-3-(methylsulfinyl)-1,2,4-triazine

[0605] [ka]

[0606] 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 room temperature for 2 h to give the title compound (1.36 g, 61%) as a yellow oil after purification by silica flash chromatography (gradient: 10-20% MeOH in DCM). MS (ESI): m / z [M+H] + 157.8. 1 H NMR (300MHz, DMSO-d6) δ ppm 2.71(3H,s), 2.96(3H,s), 8.95(1H,s).

[0607] Intermediate 37 i-37a 6'-Fluoro-5-methyl-2H-[1,3'-bipyridin]-2-one

[0608] [ka]

[0609] According to GM3, 2-fluoro-5-iodopyridine (CAS Registry Number: 171197-80-1) (150 mg, 0.67 mmol), 2-hydroxy-5-methylpyridine (CAS Registry Number: 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 ,N 2 -Dimethylcyclohexane-1,2-diamine (96 mg, 0.67 mmol) was reacted in 1,4-dioxane (15 mL) at 100 °C for 15 hours. The reaction mixture was filtered through a Celite pad, the filter cake was washed with EtOAc (3 × 5 mL), and the combined filtrate was 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 washed with water (2 × 50 mL), dried over Na2SO4, filtered, evaporated, and the crude 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. 1 H NMR (300MHz, 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).

[0610] Intermediate 38 i-38a 6'-Fluoro-3-methyl-2H-[1,3'-bipyridin]-2-one

[0611] [ka]

[0612] According to GM3, 2-fluoro-5-iodopyridine (CAS Registry Number: 171197-80-1) (105 mg, 0.47 mmol), 2-hydroxy-3-methylpyridine (CAS Registry Number: 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)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (67 mg, 0.47 mmol) was reacted in 1,4-dioxane (10 mL) at 100 °C for 15 hours. The reaction mixture was filtered through a Celite pad, the filter cake was washed with EtOAc (3 × 5 mL), and the combined filtrate was 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, evaporated, and the crude 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. 1 H NMR(300MHz,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).

[0613] Intermediate 39 i-39a (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[0614] [ka]

[0615] According to GM1A, 2-fluoro-5-iodopyridine (203 mg, 0.91 mmol) was dissolved in DMSO (15 mL) to prepare (1S,3S)-N 1To a mixture of the dihydrochloride salt of -(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) was added. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting material was dissolved in EtOAc (300 mL). The organic layer was washed with saturated brine (4 × 125 mL), dried over Na2SO4, filtered, and evaporated. The crude product 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. 1 H NMR(300MHz,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).

[0616] Intermediate 42 Step Ai-42a tert-Butyl ((1S,3S)-3-((5-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0617] [ka]

[0618] rel-(1R,2R)-N 1 ,N 2

[0047] 1,4-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), CsCO (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 subsequently washed with water (3 × 75 mL). The organic layer was dried over NaSO, 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.

[0619] Step Bi-42b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one

[0620] [ka]

[0621] 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.

[0622] Intermediate 44 Step Ai-44a tert-Butyl ((1S,3S)-3-((5-chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0623] [ka]

[0624] rel-(1R,2R)-N 1 ,N 2 1-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 CsCO (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 subsequently washed with water (3 × 25 mL) and saturated brine (3 × 20 mL). The organic layer was dried over NaSO, 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.

[0625] Step Bi-44b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one

[0626] [ka]

[0627] 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 crude TFA salt of the title compound (432 mg, 91%) as a brown gum. MS (ESI) m / z [M+H] + 304.9.

[0628] Intermediate 47 i-47a (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyrimidin-2-yl)cyclopentane-1,3-diamine

[0629] [ka]

[0630] KCO (126 mg, 0.91 mmol) was dissolved in (1S,3S)-N 1 -(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (compound i-22d) (200 mg, 0.91 mmol) and 2-chloro-5-iodopyrimidine (CAS reg. no. 32779-38-7) (329 mg, 1.37 mmol) were added at room temperature, and the resulting suspension was stirred at 120 °C for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and subsequently washed with water (2 × 25 mL) and brine (25 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the crude product, which was purified by flash C18 chromatography (elution gradient: 0–60% MeCN in water) to give the title compound (150 mg, 39%) as a yellow solid. MS (ESI): m / z [M+H] + 424.0.

[0631] Intermediate 48 Step Ai-48a 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzoic acid methyl ester

[0632] [ka]

[0633] The reaction was carried out in three parallel batches (2 × 500 mg and 1 × 600 mg of 6-chloropyridin-3-amine). Methyl 4-fluoro-3-nitrobenzoate (CAS Registry Number: 329-59-9) (929 mg, 4.67 mmol) was added to 6-chloropyridin-3-amine (CAS Registry Number: 5350-93-6) (500 mg, 3.89 mmol), Xantphos (338 mg, 0.58 mmol), Pd(OAc) (66 mg, 0.29 mmol), and KCO (1.61 g, 11.7 mmol) in 1,4-dioxane (25 mL) at room temperature, and the resulting mixture was stirred at 80 °C under nitrogen for 18 h. The three reaction mixtures were combined, dissolved in EtOAc (200 mL), loaded onto silica gel, and subjected to silica flash chromatography (gradient: 10-20% EtOAc in n-heptane) to afford the title compound (851 mg, 71% combined yield) as a yellow solid. MS (ESI): m / z [M+H] + 307.9.

[0634] Step Bi-48b 3-amino-4-((6-chloropyridin-3-yl)amino)benzoic acid methyl ester

[0635] [ka]

[0636] 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 room temperature, 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 give the crude title compound (761 mg) as a pale pink solid (containing salts), which was used in the next step without further purification. MS (ESI): m / z [M+H] + 277.9.

[0637] Step Ci-48c 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

[0638] [ka]

[0639] 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 room temperature, and the resulting solution was stirred at 80° C. for 18 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL), followed by washing with brine (3×100 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the crude product. The crude solid was triturated with MeCN to give a solid, which was collected by filtration and dried under reduced pressure to give the title compound (226 mg, 69%) as a pale pink solid. MS (ESI): m / z [M+H] + 303.8.

[0640] Step Di-48d 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate methyl ester

[0641] [ka]

[0642] CHCl (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 NaCO (367 mg, 3.47 mmol) in DMF (20 mL) at room temperature, and the resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was concentrated and diluted with EtOAc (250 mL), followed by washing with brine (3 × 100 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the crude product (92 mg, 25%) as a pale yellow solid, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 317.9.

[0643] Steps Ei-48e 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 methyl ester

[0644] [ka]

[0645] Pd-PEPPSI-IpentCl 2-Methylpyridine (CAS RN: 1612891-29-8) (29 mg, 0.03 mmol) was dissolved in 1,4-dioxane (20 mL) with 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate methyl ester (compound i-48d) (110 mg, 0.35 mmol), CsCO (338 mg, 1.04 mmol), and (1S,3S)-N 1 To the resulting solution was added -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (compound i-22d) (76 mg, 0.35 mmol) at room temperature, and the resulting mixture was stirred at 100 °C under nitrogen for 18 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL), followed by washing with brine (3 × 75 mL). The organic layer was dried over NaSO, filtered, and evaporated, and the resulting residue was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound (90 mg, 52%) as a pale yellow solid. MS (ESI): m / z [M+H] + 510.1.

[0646] Intermediate 49 Step Ai-49a 6'-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[0647] [ka]

[0648] 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 room temperature, and the resulting suspension was stirred at 100 °C under nitrogen for 16 h. The mixture was filtered through a Celite pad, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound (410 mg, 100%) as a white solid. MS (ESI): m / z [M+H] + 394.0.

[0649] Step Bi-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

[0650] [ka]

[0651] Pd-PEPPSI-IpentCl 2-Methylpyridine (CAS reg. no.: 1612891-29-8) (21 mg, 0.03 mmol) was dissolved in 1,4-dioxane (10 mL) with 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)-N 1To the mixture was added -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (compound i-22d) (167 mg, 0.76 mmol) and CsCO (331 mg, 1.02 mmol) at room temperature, and the resulting mixture was stirred at 100 °C under nitrogen for 15 hours. The reaction mixture was diluted with EtOAc (100 mL) and subsequently washed with water (50 mL) and brine (25 mL). The organic layer was dried (NaSO), filtered, and evaporated, and the resulting residue was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound (166 mg, 57%) as a yellow solid. MS (ESI): m / z [M+H] + 577.2.

[0652] Step Ci-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

[0653] [ka]

[0654] In a manner similar to that described for compound i-49b, 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), (1S,3S)-N 1 Prepared from the 4xTFA salt of -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (compound i-28b) (340 mg, 0.55 mmol), CsCO (451 mg, 1.38 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (23 mg, 0.03 mmol) and purified by preparative TLC (7M NH in MeOH:DCM = 1:20) to give the title compound (22 mg, 14%) as a brown solid. MS (ESI): m / z [M+H]+ 551.0.

[0655] Intermediate 50 Step Ai-50a 5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol

[0656] [ka]

[0657] A mixture of XPhos (0.431 g, 0.90 mmol), XPhos Pd G3 (CAS Registry Number: 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 Registry Number: 110539-88-0) (2.13 g, 6.79 mmol), 5-iodopyridin-2-ol (CAS Registry Number: 13472-79-2) (1.0 g, 4.5 mmol), and CsCO3 (4.42 g, 13.6 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 80 °C under a nitrogen atmosphere 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 chromatography (elution gradient: 0-50% MeCN in water) to give the title compound (160 mg, 13%) as a white solid. MS (ESI): m / z [M+H] + 282.0.

[0658] Step Bi-50b 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[0659] [ka]

[0660] Cu(I)I (102 mg, 0.53 mmol) was dissolved in 1,4-dioxane (10 mL) with 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol (compound i-50a) (150 mg, 0.53 mmol), 2-chloro-5-iodopyridine (CAS Registry Number: 69045-79-0) (128 mg, 0.53 mmol), rel-(1R,2R)-N 1 ,N 2 To the resulting suspension was added 1,2-dimethylcyclohexane-1,2-diamine (114 mg, 0.80 mmol) and CsCO (347 mg, 1.07 mmol) at room temperature, and the resulting suspension was stirred at 60 °C under nitrogen for 5 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. The resulting residue was purified first by preparative TLC (MeOH:DCM = 1:10) and then by flash C18 flash chromatography (elution gradient: 0 to 30% MeCN in water) to give the title compound (150 mg, 72%) as a white solid. MS (ESI): m / z [M+H] + 393.0.

[0661] Step Ci-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

[0662] [ka]

[0663] Pd-PEPPSI-IpentCl 2-Methylpyridine (CAS reg. no.: 1612891-29-8) (14 mg, 0.02 mmol) was dissolved in 1,4-dioxane (10 mL) with 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)-N 1To the mixture was added -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (compound i-22d) (109 mg, 0.50 mmol) and CsCO (216 mg, 0.66 mmol) at room temperature, and the resulting mixture was stirred at 100 °C under nitrogen for 15 hours. The reaction mixture was diluted with EtOAc (100 mL) and subsequently washed with water (50 mL) and brine (25 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the crude product, which was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound (117 mg, 61%) as a yellow solid. MS (ESI): m / z [M+H] + 576.3.

[0664] Step Di-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

[0665] [ka]

[0666] 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one (compound i-50b) and (1S,3S)-N 1 This was prepared from -(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.

[0667] Step Ei-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

[0668] [ka]

[0669] 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one (compound i-50b) and (1S,3S)-N 1 This was prepared from -(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.

[0670] Intermediate 51 Step Ai-51a 5-Bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0671] [ka]

[0672] TMEDA (1.33 mL, 8.81 mmol) was added to 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CAS Registry Number: 84712-08-3) (1.0 g, 4.4 mmol), (6-fluoropyridin-3-yl)boronic acid (CAS Registry Number: 351019-18-6) (1.55 g, 11.0 mmol), and Cu(OTf) (3.19 g, 8.81 mmol) in DCM (30 mL) at room temperature. Air was diffused into the reaction mixture through the CaCl tube at the top of the flask, and the resulting mixture was stirred at room temperature for 15 hours. 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 (NaSO), filtered, and evaporated. The resulting material was purified by silica flash chromatography (gradient: 0-60% EtOAc in n-heptane) to afford the title compound (0.38 g, 27%) as a white solid. MS (ESI): m / z [M+H] + 321.8 / 323.8 (Br isotope pattern).

[0673] Step Bi-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

[0674] [ka]

[0675] KCO (219 mg, 1.59 mmol) was dissolved in 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)-N 1To the resulting mixture was added 116 mg (0.53 mmol) of 6-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (compound i-22d) at room temperature, and the resulting mixture was stirred at 120 °C for 15 h. The mixture was filtered through a Celite pad, and the filter cake was washed with DCM (4 × 5 mL). The filtrate was concentrated under reduced pressure and purified by flash C18 chromatography (elution gradient: 0 to 100% MeOH in water) to give the title compound (95 mg, 34%) as a white solid. MS (ESI): m / z [M+H] + 521 / 523 (Br isotope pattern).

[0676] Intermediate 52 Step Ai-52a tert-Butyl ((1S,3S)-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0677] [ka]

[0678] m-CPBA (733 mg, 3.40 mmol) was added portionwise to a stirred solution of 5-methyl-3-(methylthio)-1,2,4-triazine (CAS Registry Number: 28735-24-2) (400 mg, 2.83 mmol) in DCM (8 mL) at room temperature, and the resulting solution was stirred at this temperature for 2 hours. The solvent was removed under reduced pressure to give a pale yellow solid, which was dissolved in n-BuOH (8 mL). tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number: 645400-44-8) (567 mg, 2.83 mmol) was added, and the resulting solution was stirred at 120° C. for 15 hours. 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, evaporated, and the residue was purified by preparative TLC (EtOAc:PE=3:1) to give the title compound (220 mg, 26%) as an orange solid. MS (ESI): m / z [M+H] +294.2.

[0679] Step Bi-52b (1S,3S)-N 1 -(5-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[0680] [ka]

[0681] 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 was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated NaHCO (100 mL) and extracted with 7 M NH in MeOH:DCM = 1:20 (3 × 75 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to afford the title compound (120 mg, 87%) as an orange solid, which was used without further purification. MS (ESI): m / z [M+H] + 194.1.

[0682] Intermediate 53 Step Ai-53a tert-Butyl ((1S,3S)-3-((5,6-dimethyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0683] [ka]

[0684] 5,6-Dimethyl-3-(methylthio)-1,2,4-triazine (CAS Registry Number: 7275-70-9) (400 mg, 2.58 mmol) was added portionwise to a stirred solution of 3-chlorobenzoperoxoic acid (667 mg, 3.09 mmol) in DCM (10 mL) at room temperature, and the resulting solution was stirred at this temperature for 2 hours. The solvent was removed under reduced pressure to give a pale yellow solid, which was dissolved in n-BuOH (10 mL). tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number: 645400-44-8) (567 mg, 2.83 mmol) was added, and the resulting solution was stirred at 120 °C for 15 hours. The reaction mixture was quenched with 1 M aqueous NaOH (100 mL) and extracted with EtOAc (3 × 75 mL). The combined organic layers were dried (Na2SO4), filtered, evaporated, and the resulting material was purified by preparative TLC (EtOAc:PE=2:1) ​​to give the title compound (115 mg, 14%) as an orange solid. MS (ESI): m / z [M+H] + 308.2.

[0685] Step Bi-53b (1S,3S)-N 1 -(5,6-dimethyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 3TFA

[0686] [ka]

[0687] 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 room temperature for 3 h and the organic solvent was removed by evaporation to give the crude title compound (112 mg, 63%) as a brown oil, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 208.0.

[0688] Intermediate 54 Step Ai-54a tert-Butyl ((1S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0689] [ka]

[0690] 3-(Trifluoromethyl)pyridin-2(1H)-one (CAS Registry Number: 22245-83-6) (324 mg, 1.98 mmol) was dissolved in 1,4-dioxane (20 mL) with 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), CsCO (970 mg, 2.98 mmol), and rel-(1R,2R)-N 1 ,N 2 To the resulting mixture was added dimethylcyclohexane-1,2-diamine (70 mg, 0.50 mmol) at room temperature, and the resulting mixture was stirred at 100 °C under nitrogen for 15 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (5 × 100 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give the crude product. The residue was first purified by preparative TLC (MeOH: EtOAc = 1:1) and then by flash C18 flash chromatography (gradient: 0 to 100% MeCN in water) to give the title compound (235 mg, 54%) as a pale yellow solid. MS (ESI): m / z [M+H] + 439.2.

[0691] Step Bi-54b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-(trifluoromethyl)-2H-[1,3'-bipyridin]-2-one

[0692] [ka]

[0693] 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 MeOH (2 mL, 8 mmol) and 4 M HCl in MeOH (8 mL) at room temperature, and the resulting mixture was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure, and the material was purified by flash C18 flash chromatography (gradient: 0-100% MeCN in water) to afford the title compound (148 mg, 87%) as a yellow solid. MS (ESI): m / z [M+H] + 339.0.

[0694] Intermediate 57 i-57a 3-(5-bromopyrazin-2-yl)-1-methylpyridin-2(1H)-one

[0695] [ka]

[0696] 2-Bromo-5-iodopyrazine (CAS Registry Number: 622392-04-5) (1.68 g, 5.88 mmol) was added to (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (CAS Registry Number: 1454558-46-3) (300 mg, 1.96 mmol), KOAc (578 mg, 5.88 mmol), and PdCl(dppf)·DCM (160 mg, 0.20 mmol) in 1,4-dioxane (16 mL) and water (4 mL) at room temperature, and the resulting mixture was stirred under nitrogen at 100 °C for 2 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (4 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, evaporated and the resulting material purified by silica flash chromatography (gradient: 0-100% EtOAc in n-heptane) to afford the title compound (360 mg, 69%) as a brown solid. MS (ESI): m / z [M+H] + 265.8 / 267.8.

[0697] Intermediate 58 i-58a 3-(6-chloropyridin-3-yl)pyrimidin-4(3H)-one

[0698] [ka]

[0699] TMEDA (0.942 mL, 6.24 mmol) was added to (6-chloropyridin-3-yl)boronic acid (CAS Registry Number: 444120-91-6) (983 mg, 6.24 mmol), pyrimidin-4(3H)-one (CAS Registry Number: 4562-27-0) (300 mg, 3.12 mmol), and Cu(OTf) (2.26 g, 6.24 mmol) in DCM (35 mL) at room temperature. Air was diffused into the reaction mixture through the CaCl tube at the top of the flask. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (150 mL) and subsequently washed with water (2 × 50 mL). The organic layer was dried (Na2SO4), filtered, evaporated, and the residue was purified by preparative TLC (EtOAc:PE=2:1) ​​to give the title compound (243 mg, 37%) as a white solid. MS (ESI): m / z [M+H] + 207.9.

[0700] Intermediate 59 i-59a 3-(2-chloropyrimidin-5-yl)-1-methylpyridin-2(1H)-one

[0701] [ka]

[0702] 3-Bromo-1-methylpyridin-2(1H)-one (CAS Registry Number: 81971-38-2) (300 mg, 1.60 mmol) was added to (2-chloropyrimidin-5-yl)boronic acid (CAS Registry Number: 1003845-06-4) (505 mg, 3.19 mmol), KCO (662 mg, 4.79 mmol), and Pd-118 / PdCl (dtbpf) (104 mg, 0.16 mmol) in 1,4-dioxane (8 mL) and water (2 mL) at room temperature, and the resulting mixture was stirred under nitrogen at 100° C. for 15 hours. 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, evaporated, and the residue was purified by preparative TLC (MeOH:DCM=1:20) to give the title compound (105 mg, 30%) as a yellow solid. MS (ESI): m / z [M+H] + 221.9.

[0703] Intermediate 60 Step Ai-60a 3-((6-chloropyridin-3-yl)amino)-4-nitrobenzonitrile

[0704] [ka]

[0705] K2CO3 (6.45 g, 46.7 mmol) was added to 3-fluoro-4-nitrobenzonitrile (CAS Registry Number: 218632-01-0) (3.10 g, 18.7 mmol), 6-chloropyridin-3-amine (CAS Registry Number: 5350-93-6) (2.0 g, 15.6 mmol), Pd(OAc)2 (0.262 g, 1.17 mmol), and Xantphos (1.35 g, 2.33 mmol) in MeCN (40 mL) at room temperature, and the resulting mixture was stirred at 80 °C under nitrogen for 15 h. The reaction mixture was filtered through Celite, and the filter cake was washed with DCM (3 × 50 mL). The combined filtrate was concentrated under reduced pressure and dissolved in EtOAc (250 mL). The organic layer was then washed with saturated NaHCO (3 x 250 mL), dried (NaSO), filtered, and evaporated. The resulting residue was purified by preparative TLC (DCM) to afford the title compound (0.63 g, 15%) as a yellow solid. MS (ESI): m / z [M+H] + 275.1.

[0706] Step Bi-60b 4-Amino-3-((6-chloropyridin-3-yl)amino)benzonitrile

[0707] [ka]

[0708] 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 room temperature, and the resulting mixture was stirred at 60 °C for 5 h. The reaction mixture was filtered through Celite, and the filter cake was washed with EtOH (3 × 50 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (363 mg, 80%) as a brown solid, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 245.1.

[0709] Step Ci-60c 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0710] [ka]

[0711] 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 room temperature, and the resulting mixture was stirred at 80° C. for 24 hours. The solid was filtered off to give the crude product, which was triturated with MeCN and dried under reduced pressure to give the title compound (242 mg, 73%) as a pale pink solid. MS (ESI): m / z [M+H] + 271.0.

[0712] Step Di-60d 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0713] [ka]

[0714] CsCO (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 CHCl (118 mg, 0.83 mmol) in DMF (5 mL) at room temperature, which was stirred at 100° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL) and subsequently washed with brine (3×50 mL). The organic layer was dried (NaSO), filtered, and evaporated, and the resulting material was triturated with MeCN. The solid formed was collected by filtration and dried under reduced pressure to give the title compound (110 mg, 70%) as a pale pink solid. MS (ESI): m / z [M+H] + 285.1.

[0715] Intermediate 61 Step Ai-61a 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzonitrile

[0716] [ka]

[0717] Pd(OAc) (0.262 g, 1.17 mmol) was added to a mixture of KCO (6.45 g, 46.7 mmol), 4-fluoro-3-nitrobenzonitrile (CAS Registry Number: 1009-35-4) (2.84 g, 17.1 mmol), 6-chloropyridin-3-amine (CAS Registry Number: 5350-93-6) (2.0 g, 15.6 mmol), and Xantphos (1.35 g, 2.33 mmol) in MeCN (40 mL) at room temperature, which was stirred at 80 °C under nitrogen for 15 h. The reaction mixture was filtered through Celite, and the filter cake was washed with DCM (3 × 200 mL). The combined filtrate was concentrated under reduced pressure and dissolved in EtOAc (300 mL). The organic layer was then washed with saturated NaHCO (3 × 400 mL), dried over NaSO, filtered, and evaporated. The resulting material was purified by preparative TLC (DCM) to give the title compound (0.70 g, 16%) as a yellow solid. MS (ESI): m / z [M+H] + 275.0.

[0718] Step Bi-61b 3-Amino-4-((6-chloropyridin-3-yl)amino)benzonitrile

[0719] [ka]

[0720] 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 room temperature, and the resulting mixture was stirred at 60 °C for 5 h. The reaction mixture was filtered through Celite, and the filter cake was washed with EtOH (3 × 50 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (0.51 g, 81%) as a brown solid, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 245.1.

[0721] Step Ci-61c 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0722] [ka]

[0723] 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 room temperature, and the resulting mixture was stirred at 80° C. for 24 hours. The solid was filtered off to give the crude product, which was triturated with MeCN and dried under reduced pressure to give the title compound (342 mg, 69%) as a pale pink solid. MS (ESI, m / z): [M+H] + 270.9.

[0724] Step Di-61d 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0725] [ka]

[0726] CHCl (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 CsCO (722 mg, 2.22 mmol) in DMF (8 mL) at room temperature, which was stirred at 100 °C for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and subsequently washed with brine (3 × 100 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the title compound (119 mg, 57%) as a yellow solid, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 285.0.

[0727] Intermediate 62 i-62a 2-(6-fluoropyridin-3-yl)pyridazin-3(2H)-one

[0728] [ka]

[0729] 2-Fluoro-5-iodopyridine (CAS Registry Number: 171197-80-1) (300 mg, 1.35 mmol) was dissolved in 1,4-dioxane (20 mL) with pyridazin-3(2H)-one (CAS Registry Number: 504-30-3) (259 mg, 2.69 mmol), Cu(I)I (128 mg, 0.67 mmol), CsCO (1315 mg, 4.04 mmol), and rel-(1R,2R)-N 1 ,N 2 The resulting mixture was added to a mixture of 1,2-dimethylcyclohexane-1,2-diamine (96 mg, 0.67 mmol) at room temperature, which was stirred at 100° C. under nitrogen for 15 hours. The reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (8×30 mL). The combined organic layers were dried (NaSO), filtered, and evaporated, and the residue was purified by preparative TLC (EtOAc) to give the title compound (242 mg, 94%) as a brown solid. MS (ESI): m / z [M+H] +191.9.

[0730] Intermediate 63 Step Ai-63a 5-((tert-butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one

[0731] [ka]

[0732] Cs2CO3 (2.23 g, 6.86 mmol) was dissolved in 1,4-dioxane (20 mL) with 5-((tert-butyldimethylsilyl)ethynyl)pyridin-2(1H)-one (CAS Registry Number: 2448766-74-1) (800 mg, 3.43 mmol), 2-chloro-5-iodopyridine (CAS Registry Number: 69045-79-0) (821 mg, 3.43 mmol), Cu(I)I (653 mg, 3.43 mmol), and rel-(1R,2R)-N 1 ,N 2 To the resulting solution was added dimethylcyclohexane-1,2-diamine (731 mg, 5.14 mmol) at room temperature, and the resulting suspension was stirred at 60 °C under nitrogen for 5 h. The mixture was combined with a second batch prepared similarly and filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL), and the combined filtrate was concentrated under reduced pressure. The crude product was purified by silica flash chromatography (gradient: 0 to 50% EtOAc in n-heptane) to give the title compound (590 mg, 25%) as a white solid. MS (ESI): m / z [M+H] + 345.0.

[0733] Step Bi-63b 6'-chloro-5-ethynyl-2H-[1,3'-bipyridin]-2-one

[0734] [ka]

[0735] A solution of TBAF (1 M, 8.55 mL, 8.55 mmol) in THF was added to 5-((tert-butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one (compound i-63a) (590 mg, 1.71 mmol) in THF (15 mL) at room temperature, and the resulting solution was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (2:1 EtOAc:PE) followed by flash C18 flash chromatography (elution gradient: 0-30% MeCN in water) to give the title compound (290 mg, 74%) as a beige solid. MS (ESI): m / z [M+H] + 231.0.

[0736] Intermediate 67 Step Ai-67a 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ol

[0737] [ka]

[0738] A mixture of 5-iodo-2(1H)-pyridinone (CAS Registry Number: 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 Registry Number: 761446-44-0) (565 mg, 2.71 mmol), and XPhos (CAS Registry Number: 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 Registry Number: 1445085-55-1) (192 mg, 0.23 mmol) under nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filter cake was washed with EtOAc (100 mL) and the combined filtrates were concentrated under reduced pressure. The resulting material was purified by silica flash chromatography (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.

[0739] Step Bi-67b 6'-chloro-5-(1-(methyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[0740] [ka]

[0741] 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)-N 1 ,N 2Reaction of 203 mg (1.43 mmol) of dimethylcyclohexane-1,2-diamine, CsCO (1.4 g (4.3 mmol)), and Cu(I)I (272 mg (1.43 mmol)) in 8 mL of 1,4-dioxane at 100 °C for 18 h afforded the title compound (250 mg, 61%) as a green solid after nonaqueous workup (EtOAc) and silica flash chromatography (gradient: 0-10% MeOH in DCM). m / z [M+H] + 287.1 / 289 (Cl isotope pattern).

[0742] 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

[0743] [ka]

[0744] 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 dissolved in 1,4-dioxane (16 mL) and water (4 mL) to give 1-(tetrahydro-2H-pyran-2-yl)-5-(4-pyridin-2-yl)-2H-pyridine. To a mixture of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (CAS Registry Number: 2710298-24-9) (393 mg, 1.41 mmol), CsCO (688 mg, 2.11 mmol), XPhos (CAS Registry Number: 564483-18-7) (34 mg, 0.07 mmol), and XPhos Pd G (CAS Registry Number: 1445085-55-1) (59 mg, 0.07 mmol) was added under nitrogen. The resulting reaction mixture was stirred at 100 °C for 15 h and then poured into saturated brine (150 mL). It was extracted with EtOAc (4 × 150 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated. The crude was purified by preparative TLC (7M NH3 in 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.

[0745] Intermediate 76 i-76a (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid

[0746] [ka]

[0747] 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 Registry Number: 444120-95-0) (1.81 g, 8.11 mmol) and KCO (2.25 g, 16.3 mmol), and the resulting mixture was stirred at 80 °C for 20 h. The mixture was cooled to room temperature, the solid was filtered off, and the filtrate was purified by preparative HPLC (Preparative Method G, gradient: 0-50%) to give the title compound (1.07 g, 66%) as a red solid. MS (ESI) m / z [M+H] + 315.

[0748] Intermediate 77 Step Ai-77a (1S,3S)-N 1 -(5-(2,4-dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-N 3 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[0749] [ka]

[0750] 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 Registry Number: 930-62-1), Cu(OAc) (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 room temperature for 24 h. The solid was filtered off and washed with MeOH. The combined filtrate was concentrated and purified by preparative HPLC (Preparative Method F, gradient: 20-60%) to give the title compound (52 mg, 36%) as a beige solid. MS (ESI) m / z [M+H] + 365.

[0751] Step Bi-77b (1S,3S)-N 1 -(5-(5-iodo-2,4-dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-N 3 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[0752] [ka]

[0753] 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 room temperature for 2 hours. The mixture was concentrated, and the residue was dissolved in DCM and washed with water. The organic layer was concentrated and purified by preparative HPLC (Preparative Method H, gradient: 20-60%) to give the title compound (55 mg, 80%) as a beige solid. MS (ESI) m / z [M+H] + 491.

[0754] Intermediate 80 i-80a 6-methyl-3-(methylsulfinyl)-1,2,4-triazin-5(4H)-one

[0755] [ka]

[0756] 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 with 3-chlorobenzoperoxoic acid (494 mg, 2.29 mmol) in DCM (25 mL) in portions at room temperature for 2 h to give the title compound (200 mg, 61%) as a white solid after purification by preparative TLC (DCM:MeOH=10:1). MS (ESI): m / z [M+H] + 174. 1 H NMR (400MHz, DMSO-d6) δ ppm 2.15(3H,s), 2.71(3H,s).

[0757] Intermediate 81 Step Ai-81a N-(6-chloropyridin-3-yl)-6-methyl-3-nitropyridin-2-amine

[0758] [ka]

[0759] Xantphos (CAS Registry Number: 161265-03-8) (34 mg, 0.06 mmol) was added to a mixture of 2-chloro-6-methyl-3-nitropyridine (CAS Registry Number: 56057-19-3) (1.00 g, 8.69 mmol), 6-chloropyridin-3-amine (CAS Registry Number: 5350-93-6) (1.12 g, 7.8 mmol), NaCO (1.84 g, 17.4 mmol), and Pd(OAc) (13 mg, 0.06 mmol) in THF (15 mL) under nitrogen at room temperature, which was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (250 mL). The organic layer was washed with saturated brine (4 × 125 mL), dried over NaSO, filtered, and evaporated. The crude material was purified by silica flash chromatography (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).

[0760] Step Bi-81b N 2 -(6-chloropyridin-3-yl)-6-methylpyridine-2,3-diamine

[0761] [ka]

[0762] 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 room temperature, which was stirred at 60 °C for 15 h. The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure, and the crude was 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).

[0763] Step Ci-81c 3-(6-chloropyridin-3-yl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0764] [ka]

[0765] N in DMF (5 mL) 2 -(6-Chloropyridin-3-yl)-6-methylpyridine-2,3-diamine (compound i-81b) (65 mg, 0.28 mmol) was treated with CDI (CAS Registry Number: 530-62-1) (225 mg, 1.38 mmol) at room temperature under nitrogen, and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3 × 50 mL). The organic layer was dried over NaSO, filtered, evaporated, and the crude product was 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).

[0766] Step Di-81d 3-(6-chloropyridin-3-yl)-1,5-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0767] [ka]

[0768] 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 mL) in a vial was treated with iodomethane (1.85 g, 13.0 mmol) at room temperature under nitrogen and 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, evaporated, and the crude product was purified by silica flash chromatography (gradient: 0 to 50% EtOAc in PE) to give the title compound (305 mg, 85%) as a pale pink film. MS (ESI): m / z [M+H] + 275.0 / 277 (Cl isotope pattern).

[0769] Step Ei-81e 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonitrile

[0770] [ka]

[0771] The reaction was carried out in three parallel batches (2 × 100 mg starting amount and 1 × 150 mg starting amount of compound i-81d). 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 Registry Number: 524-38-9) (45 mg, 0.27 mmol), and tert-butyl nitrite (CAS Registry Number: 540-80-7) (169 mg, 1.64 mmol) in MeCN (4 mL) in a vial was treated with Pd(OAc) (12 mg, 0.05 mmol) under nitrogen at room temperature and stirred at 80 °C for 24 h. The reaction mixtures of three parallel batches were combined and poured into water (200 mL), and the mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered, evaporated, and the crude material was 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).

[0772] Intermediate 82 Step Ai-82a 6-((6-chloropyridin-3-yl)amino)-5-nitronicotinotrile

[0773] [ka]

[0774] Na2CO3 (1.73 g, 16.3 mmol) was added to a mixture of 6-chloro-5-nitronicotinotrile (CAS Registry Number: 160906-98-9) (1.00 g, 5.45 mmol), 6-chloropyridin-3-amine (CAS Registry Number: 5350-93-6) (1.40 g, 10.9 mmol), Xantphos (CAS Registry Number: 161265-03-8) (315 mg, 0.54 mmol), and Pd(OAc)2 (61 mg, 0.27 mmol) in 1,4-dioxane (15 mL) under nitrogen at room temperature, which was stirred at 80 °C for 3 hours. The reaction mixture was filtered through a filter membrane and concentrated under reduced pressure, and the crude 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).

[0775] Step Bi-82b 5-amino-6-((6-chloropyridin-3-yl)amino)nicotinotril

[0776] [ka]

[0777] 6-((6-chloropyridin-3-yl)amino)-5-nitronicotinotrile (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 room temperature, which was stirred at 60 °C for 2 h. The reaction mixture was filtered through a filter membrane, the filtrate was concentrated under reduced pressure, and the crude was 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).

[0778] Step Ci-82c 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[0779] [ka]

[0780] 5-Amino-6-((6-chloropyridin-3-yl)amino)nicotinotrile (compound i-82b) (1.26 g, 5.13 mmol) in DMF (15 mL) was treated with CDI (CAS Registry Number: 530-62-1) (4.16 g, 25.6 mmol) under nitrogen at room temperature, and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into water (100 mL), and the mixture was extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over NaSO, filtered, evaporated, and the crude was 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).

[0781] Step Di-82d 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[0782] [ka]

[0783] 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 mL) in a vial was treated with iodomethane (3.03 g, 21.4 mmol) under nitrogen at room temperature and stirred at 60 °C for 1 h. The reaction mixture was poured into water (100 mL), and the mixture was extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over Na2SO4, filtered, evaporated, and the crude was 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).

[0784] Intermediate 83 Step Ai-83a (1S,3S)-N 1 -(1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[0785] [ka]

[0786] 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 the crude unspecified HCl salt of the title compound (265 mg, 100%) as a brown gum, which was used directly in the next step. MS (ESI): m / z [M+H] + 179.8.

[0787] Step Bi-83b 6'-(((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0788] [ka]

[0789] (1S,3S)-N 1 -(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 under a nitrogen atmosphere for 15 h. The crude product was purified by C18 flash chromatography (gradient: 40 to 55% MeCN in water) to afford the title compound (175 mg, 72%) as a brown gum. MS (ESI): m / z [M+H] + 349.9.

[0790] Intermediate 84 Step Ai-84a (1S,3S)-N 1 -(6-Bromo-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[0791] [ka]

[0792] 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 was stirred at this temperature for 5 h. The reaction mixture was concentrated and diluted with MeOH:DCM = 1:10 (300 mL), followed by washing with saturated NaHCO (3 × 125 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude title compound (0.563 g, 65%) as a black gum, which was used directly in the next step. MS (ESI): m / z [M+H] + 259.8.

[0793] Step Bi-84b 6'-(((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0794] [ka]

[0795] (1S,3S)-N 1 -(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 and diluted with EtOAc (250 mL), followed by washing with saturated brine (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated, and the resulting 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.

[0796] Intermediate 85 Step Ai-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

[0797] [ka]

[0798] CsCO (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 Registry Number: 903550-26-5) (466 mg, 1.67 mmol), and PdCl(dtbpf) (55 mg, 0.08 mmol) in 1,4-dioxane (5 mL) at 20 °C, and the resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over NaSO, filtered, evaporated, and the residue was purified by preparative TLC (7M NH in MeOH:DCM = 1:20) to give the title compound (273 mg, 76%) as a brown solid. MS (ESI): m / z [M+H] + 430.1.

[0799] Step Bi-85b (1S,3S)-N 1 -(6-(1H-pyrazol-5-yl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[0800] [ka]

[0801] 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 (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 was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (7 M NH in MeOH:DCM = 1:20) to give the title compound (431 mg, 100%) as a brown gum. MS (ESI): m / z [M+H] + 245.9.

[0802] Intermediate 86 Step Ai-86a tert-Butyl ((1S,3S)-3-((6-(ethylthio)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0803] [ka]

[0804] 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 was purified by preparative TLC (7 M NH in MeOH:DCM = 1:20) to give the title compound (84 mg, 44%) as an orange solid. MS (ESI): m / z [M+H] + 339.9.

[0805] Step Bi-86b (1S,3S)-N 1-(6-(ethylthio)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 3.3TFA

[0806] [ka]

[0807] 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.

[0808] Intermediate 87 Step Ai-87a ((1R,3R)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate rel-tert-butyl ester

[0809] [ka]

[0810] DIPEA (0.94 mL, 5.4 mmol) and rel-tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (CAS Registry Number: 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 was cooled to room temperature and 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 repeatedly extracted with DCM (3 times). The organic phases were combined, passed through a phase separator, and concentrated. The resulting brown solid was further purified by silica flash chromatography (gradient: 0-100% EtOAc:MeOH = 95:5 in n-heptane) to give the title compound (0.280 g, 53%) as a yellow solid. MS (ESI): m / z [M+H] + 294.1.

[0811] Step Bi-87b rel-(1R,3R)-N 1 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3HCl

[0812] [ka]

[0813] A solution of rel-tert-butyl ((1R,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 room temperature, and the resulting slurry was stirred at room temperature for 20 hours. The mixture was concentrated to dryness to give the crude title compound (312 mg) as a pale yellow solid. MS (ESI): m / z [M+H] + 194.1.

[0814] Intermediate 90 Step Ai-90a 6-Bromo-3-(methylthio)-1,2,4-triazine

[0815] [ka]

[0816] tert-Butyl nitrite (10.6 g, 103 mmol) was added dropwise over 10 minutes 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 room temperature under atmospheric pressure, and the resulting solution was stirred at this temperature for 16 hours. The solvent was removed under reduced pressure. The crude product was combined with three other equivalent batches prepared similarly and purified by silica flash chromatography (gradient: 0 to 20% EtOAc in n-heptane) to give the title compound (8.60 g, 60%) as a yellow solid. MS (ESI): m / z [M+H] + 205.8 / 207.8 (Br isotope pattern).

[0817] Step Bi-90b Ethyl 3-(methylthio)-1,2,4-triazine-6-carboxylate

[0818] [ka]

[0819] 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 room temperature under atmospheric pressure. The resulting suspension was placed under a carbon monoxide atmosphere (20 atm) and stirred at 85 °C for 16 h. The mixture was combined with three other similarly prepared batches and filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL), and the combined filtrate was concentrated under reduced pressure. The resulting material was purified by silica flash chromatography (gradient: 0 to 20% EtOAc in n-heptane) to afford the title compound (6.10 g, 73%) as a yellow oil. MS(ESI):m / z[M+H] + 200.

[0820] Step Ci-90c 3-(methylthio)-1,2,4-triazine-6-carboxylic acid

[0821] [ka]

[0822] NaOH (1M 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 THF (20 mL) and water (10 mL) at 0 °C, and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water / ice (150 mL), and 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 (NaSO), filtered, and evaporated to give the title compound (2.5 g, 97%) as a brown gum, which was used without further purification. MS (ESI): m / z [M+H] + 172.

[0823] Step Di-90d 3-(Methylthio)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide

[0824] [ka]

[0825] T3P (50% w / w) (18.6 g, 29.2 mmol) in EtOAc 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 room temperature, and the resulting solution was stirred at 60 °C for 15 h. The reaction mixture was poured into saturated NaHCO3 (aq) (150 mL) and extracted with EtOAc (3 × 125 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give a yellow gum. This material was triturated with 10 mL of 1:3 EtOAc:PE to give the title compound (1.0 g, 30%) as a pale yellow solid. MS(ESI):m / z[M+H] + 227.1.

[0826] Step Ei-90e 3-(((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide

[0827] [ka]

[0828] 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 room temperature, and the resulting solution was stirred at room temperature for 30 minutes. (1S,3S)-N 1-(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, which was stirred at room temperature for an additional 8 hours. The reaction mixture was poured into 1 M aqueous NaOH (150 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried (NaSO), filtered, and evaporated to give a yellow oil, which solidified upon standing. This material was purified by preparative TLC (7 M NH in MeOH:DCM=1:20) to give the title compound (0.50 g, 23%) as a yellow solid. MS (ESI): m / z [M+H] + 481.7.

[0829] Intermediate 91 Step Ai-91a 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzoate methyl ester

[0830] [ka]

[0831] CataCXium A Pd G3 (55 mg, 0.08 mmol) was added to a mixture of methyl 3-bromo-4-fluoro-2-methoxybenzoate (CAS Registry Number: 1935415-04-05) (200 mg, 0.76 mmol), 2-chloropyridine-5-boronic acid (CAS Registry Number: 444120-91-6) (179 mg, 1.14 mmol), KCO (210 mg, 1.52 mmol), and water (2 mL) in 1,4-dioxane (8 mL) at room temperature under nitrogen, which was stirred at 80 °C for 8 hours. 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 NaSO, filtered, and evaporated. The resulting material was purified by preparative TLC (PE: EtOAc = 3:1) to give the title compound (160 mg, 71%) as a yellow solid. MS (ESI): m / z [M+H] + 296.0.

[0832] Step Bi-91b 3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-fluoro-2-methoxybenzoate methyl ester

[0833] [ka]

[0834] (1S,3S)-N 1 -(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 CsCO (496 mg, 1.52 mmol) in 1,4-dioxane (10 mL) at room temperature under nitrogen, and the mixture was stirred at 100 °C for 8 hours. 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 (NaSO), filtered, and evaporated. The resulting material was purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (90 mg, 37%) as a white solid. MS (ESI): m / z [M+H] + 479.2.

[0835] Intermediate 92 Step Ai-92a 3-Bromo-4-fluoro-2-methoxybenzamide

[0836] [ka]

[0837] 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 room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous NH4Cl (3 × 50 mL), dried (Na2SO4), filtered, evaporated, and the residue was purified by preparative TLC (DCM:MeOH = 30:1) to give the title compound (400 mg, 76%) as a white solid. MS (ESI): m / z [M+H] + 249.8.

[0838] Step Bi-92b 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide

[0839] [ka]

[0840] 3-Bromo-4-fluoro-2-methoxybenzamide (compound i-92a) (320 mg, 1.29 mmol) was added to a mixture of PdCl(dppf)DCM adduct (105 mg, 0.13 mmol), NaCO (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 room temperature, which 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 (3x), and the combined organic layers were dried (NaSO), filtered, and evaporated. The resulting material was purified by preparative TLC (EtOAc:PE=1:2) to give the title compound (130 mg, 36%) as a white solid. MS (ESI): m / z [M+H] + 281.

[0841] Step Ci-92c 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzonitrile

[0842] [ka]

[0843] 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 room temperature and stirred at room temperature 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 (NaSO), filtered, and evaporated, and the resulting material was purified by preparative TLC (PE: EtOAc = 3:1) to afford the title compound (100 mg, 82%) as a yellow solid. MS (ESI): m / z [M+H] + 263.

[0844] Intermediate 100 i-100a 6'-Fluoro-2H-[1,3'-bipyridin]-2-one

[0845] [ka]

[0846] rel-(1R,2R)-N 1 ,N 2To a mixture of pyridin-2(1H)-one (CAS Registry Number: 142-08-5) (5.0 g, 52.6 mmol), 2-fluoro-5-iodopyridine (CAS Registry Number: 171197-80-1) (17.6 g, 78.9 mmol), Cu(I)I (4.01 g, 21.0 mmol), and KCO (14.53 g, 105.2 mmol) in 1,4-dioxane (50 mL) was added dimethylcyclohexane-1,2-diamine (1.50 g, 10.5 mmol), which was stirred at 90 °C under a nitrogen atmosphere for 18 h. The solvent was removed under reduced pressure, and the residue was purified by silica flash chromatography (gradient: 0 to 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. 1 H NMR(300MHz,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).

[0847] Intermediate 104 Step Ai-104a tert-Butyl ((1S,3S)-3-((6-(1-ethoxyvinyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0848] [ka]

[0849] Bis(triphenylphosphine)palladium(II) dichloride (CAS Registry Number: 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)cyclopentyl)carbamate (Compound i-22b) (300 mg, 0.84 mmol), tributyl(1-ethoxyvinyl)tin (CAS Registry Number: 97674) (605 mg, 1.67 mmol), and lithium chloride (177 mg, 4.19 mmol) in 1,4-dioxane (20 mL) under a nitrogen atmosphere at 20° C., and the mixture was stirred at 100° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by silica flash chromatography (gradient: 2-25% EtOAc in PE) to give the title compound as a yellow solid (500 mg) with a tin impurity. MS (ESI): m / z [M+H] + 350.1.

[0850] Step Bi-104b 1-(3-(((1S,3S)-3-aminocyclopentyl)amino)-1,2,4-triazin-6-yl)ethan-1-one

[0851] [ka]

[0852] 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. Removal of the solvent under reduced pressure gave the 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.

[0853] Intermediate 107 Step Ai-107a 4-Bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0854] [ka]

[0855] 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 CsCO (15.6 g, 47.8 mmol) in MeCN (80 mL) at 15 °C, which was stirred at 60 °C for 3 h. The mixture was filtered through a Celite pad, the filter cake was washed with DCM (3 × 20 mL), and the combined filtrate was concentrated under reduced pressure. The resulting material was triturated with 1:5 EtOAc:PE (25 mL), and the solid formed was collected by filtration and dried under reduced pressure 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).

[0856] Step Bi-107b 6-chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0857] [ka]

[0858] RockPhos Pd G3 (CAS Registry Number: 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), (£)-benzaldehyde oxime (3.70 g, 30.6 mmol), and CsCO3 (15.6 g, 47.8 mmol) in DMF (40 mL) and water (10 mL) at 15 °C, which was stirred at 80 °C for 15 h. The reaction mixture was poured into saturated brine (100 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated brine (3 x 100 mL), dried over Na2SO4, filtered, evaporated, and the residue purified by silica flash chromatography (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).

[0859] Step Ci-107c 6-chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0860] [ka]

[0861] CsCO (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), which was stirred at 20 °C for 1.5 h. Sodium chlorodifluoroacetate (CAS Registry Number: 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 saturated brine (50 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL), dried over NaSO, filtered, evaporated, and the residue was purified by preparative 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).

[0862] Step Di-107d 4-(Difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0863] [ka]

[0864] 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 under a hydrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (576 mg, 95%) as a white solid, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 283.0.

[0865] Step Ei-107e 4-(Difluoromethoxy)pyridazin-3(2H)-one

[0866] [ka]

[0867] 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 the 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.

[0868] Intermediate 108 Step Ai-108a 2-Bromo-1-(6-fluoropyridin-3-yl)propan-1-one

[0869] [ka]

[0870] A solution of 1-(6-fluoropyridin-3-yl)propan-1-one (CAS Registry Number: 949154-27-2) (201 mg, 1.31 mmol) in HOAc (2 mL) was treated with HBr (CAS Registry Number: 10035-10-6) (33 wt% in HOAc, 238 μL, 1.31 mmol) and bromine (67 μL, 1.3 mmol), and the mixture was stirred at room temperature for 2 hours. 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.

[0871] Step Bi-108b 4-(6-fluoropyridin-3-yl)-2,5-dimethyloxazole

[0872] [ka]

[0873] A mixture of crude 2-bromo-1-(6-fluoropyridin-3-yl)propan-1-one (compound i-108a) (270 mg, 1.2 mmol) in xylene (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 resulting residue was purified by preparative HPLC (Preparative Method Z9, gradient: 20-60%) to afford the title compound (83 mg, 37%) as a brown solid. MS (ESI): m / z [M+H] + 193.0. 1 H NMR (500MHz, CDCl3) δ ppm 2.44 (3H, s), 2.47 (3H, s), 6.96 (1H, dd), 8.04 (1H, dt), 8.42 (1H, d).

[0874] Intermediate 109 Step Ai-109a 2-(2-(benzyloxy)ethyl)malonamide

[0875] [ka]

[0876] Reactions were carried out in parallel in 10 batches of equal size.

[0877] Diethyl 2-(2-(benzyloxy)ethyl)malonate (CAS Registry Number: 41478-45-9) (2.0 g, 6.8 mmol) was treated with NH3 (7 M in MeOH, 25 mL, 140 mmol) at room temperature, and the mixture was stirred at 60 °C for 16 h. The 10 reaction mixtures were combined and concentrated under reduced pressure. The resulting material was triturated with EtOAc (50 mL), and the solid was 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.

[0878] Step Bi-109b Di-tert-butyl (2-(2-(benzyloxy)ethyl)propane-1,3-diyl)dicarbamate

[0879] [ka]

[0880] A solution of 2-(2-(benzyloxy)ethyl)malonamide (compound i-109a) (13.5 g, 57.1 mmol) in THF (250 mL) was treated with BH×SMe (10 M in SMe, 45.7 mL, 457 mmol) at 20° C., and the reaction mixture was stirred at 60° C. for 16 hours. 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 NaCO (18.2 g, 171 mmol) in water (250 mL), followed by BocO (39.8 mL, 171 mmol), and the resulting suspension was stirred at 20° C. for 15 hours. The reaction mixture was poured into saturated brine (500 mL), and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na2SO4, filtered, evaporated and the resulting material purified by silica flash chromatography (gradient: 2-20% EtOAc in PE) to give the title compound (9.0 g, 39%) as a colorless gum. MS (ESI): m / z [M+H] + 409.3.

[0881] Step Ci-109c Di-tert-butyl (2-(2-hydroxyethyl)propane-1,3-diyl)dicarbamate

[0882] [ka]

[0883] 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 filled with hydrogen gas three times and stirred under a hydrogen atmosphere at 20 °C for 16 h. The mixture was concentrated under reduced pressure to give the title compound (7.0 g, quantitative) as a colorless gum, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 319.2.

[0884] Step Di-109d (2-(aminomethyl)-4-hydroxybutyl)carbamic acid rac-tert-butyl ester

[0885] [ka]

[0886] 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 resulting material was triturated with EtOAc (20 mL). The solid that formed (fully deprotected title compound) was filtered off, and the filtrate was concentrated under reduced pressure to give the unidentified HCl salt of the title compound (1.4 g, 70% pure) as a pale yellow gum, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 219.2.

[0887] Step Ei-109e rac-tert-butyl (4-hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)carbamate

[0888] [ka]

[0889] A suspension of crude rac-tert-butyl (2-(aminomethyl)-4-hydroxybutyl)carbamate (compound i-109d) (1.4 g) and KCO (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 room temperature and concentrated under reduced pressure, and the resulting material was purified by silica flash chromatography (gradient: 0 to 5% 7M NH in MeOH:DCM) to afford the title compound (700 mg, 10% over three steps) as a pale yellow gum. MS (ESI): m / z [M+H] + 312.

[0890] Step Fi-109f rac-4-amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol

[0891] [ka]

[0892] 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 the unspecified HCl salt of the title compound (530 mg) as a yellow gum, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 212.1.

[0893] Step Gi-109g rac-4-((5-iodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol

[0894] [ka]

[0895] According to GM1A, 2-fluoro-5-iodopyridine (CAS Registry Number: 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 KCO (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 room temperature, and poured into saturated brine (250 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated to give a brown gum. The resulting material was purified by preparative TLC (7M NH3 in 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. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.49(2H,q),1.99(1H,quintet),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). [Example]

[0896] Example 10 3-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxylate ethyl ester

[0897] [ka]

[0898] 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 registrar number: 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 hour, and the title compound (182 mg, 52%) was obtained as a yellow solid after purification by preparative HPLC (preparative method F, gradient: 15-55%). 21 H 24 HRMS (ESI) m / z [M+H] for N7O3 + Calculated value: 422.1936, measured value: 422.1924. 1 H NMR (500 MHz, DMSO-d6, mixture of two rotamers, approximately 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),7.9 3(1H,d), 8.58(d, minor rotamer), 8.63-8.71(1H,m), 9.09(1H,d, major rotamer).

[0899] Example 50. 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0900] [ka]

[0901] K3PO4 (60 mg, 0.28 mmol) was dissolved in (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (compound i-22e) (40 mg, 0.09 mmol), pyridin-2(1H)-one (CAS Registry Number: 142-08-5) (27 mg, 0.28 mmol), Cu(I)I (9.0 mg, 0.05 mmol), and N 1 ,N 2 To a mixture of 1,2-dimethylethane-1,2-diamine (4.2 mg, 0.05 mmol) was added HCl, and the resulting suspension was heated at 100 °C under nitrogen for 16 h. The solvent was removed under reduced pressure, and the residue was poured into water (50 mL), extracted with EtOAc (2 x 100 mL), dried (NaSO), filtered, and evaporated to give the crude product, which was purified by preparative TLC (MeOH:DCM = 1:40) followed by preparative HPLC (Preparative Method A, gradient: 33-58%) to give the title compound (12.4 mg, 34%) as a white solid. 21 H 24 HRMS (ESI) m / z [M+H] for NO + Calculated value: 390.2036, measured value: 390.2042. 1H NMR(300MHz,DMSO-d6)δ 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).

[0902] 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

[0903] [ka]

[0904] According to GM3, (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (compound i-22e) (90 mg, 0.21 mmol), 3-(trifluoromethyl)pyridin-2(1H)-one (CAS Registry Number: 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)-N 1 ,N 2 C-dimethylcyclohexane-1,2-diamine (121 mg, 0.85 mmol) was reacted in 1,4-dioxane (10 mL) at 100 °C for 15 h to give the title compound (33 mg, 33%) as a pale yellow solid after aqueous workup and preparative TLC (7 M NH in MeOH:DCM = 1:20) followed by purification by preparative HPLC (Preparative Method B, 34-54%). 22 H 23HRMS (ESI) m / z [M+H]+ calculated for F3N7O: 458.1910, found: 458.1928. 1 H NMR(300MHz,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).

[0905] 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

[0906] [ka]

[0907] As in Example 51, (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 This compound was prepared from -(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 (7M NH in MeOH:DCM = 1:20) followed by preparative HPLC (preparative method B, gradient: 38-58%) to give a white solid (20 mg, 19%). 22 H 23 HRMS(ESI)m / z[M+H] for F3N7O2 + Calculated value: 474.1860, measured value: 474.1816. 1H NMR(300MHz,DMSO-d6)δ 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(1 H,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).

[0908] Example 53 (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-(2,6-difluorophenyl)pyridin-2-yl)cyclopentane-1,3-diamine

[0909] [ka]

[0910] According to GM4A, (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-Iodopyridin-2-yl)cyclopentane-1,3-diamine (compound i-22e) (95 mg, 0.22 mmol), (2,6-difluorophenyl)boronic acid (CAS Registry Number: 162101-25-9) (71 mg, 0.45 mmol), PdCl2(dppf) (CAS Registry Number: 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 hours. Aqueous workup of the reaction mixture and preparative TLC (1:1 EtOAc:PE) followed by purification by preparative HPLC (method D, gradient: 44-59%) afforded the title compound (18 mg, 19%) as a white solid. 22 H 23 HRMS (ESI) m / z [M+H] for F2N6 + Calculated value: 409.1946, measured value: 409.1960. 1H NMR(300MHz,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,1 H),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).

[0911] Example 54 (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)cyclopentane-1,3-diamine

[0912] [ka]

[0913] 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (CAS registration number: 95408-45-0) (15 mg, 0.02 mmol) was applied, and (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 This compound was prepared in the same manner as in Example 53 from -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (compound i-22e) (95 mg, 0.22 mmol) and (2-fluoro-6-methoxyphenyl)boronic acid (CAS registration number: 78495-63-3) (76 mg, 0.45 mmol). The resulting solid was purified by preparative TLC (EtOAc:PE = 2:1) followed by preparative HPLC (preparative method C, gradient: 40-65%) to give a white solid (46 mg, 48%). 23 H 26 HRMS (ESI) m / z [M+H] for FN6O + Calculated value: 421.2146, measured value: 421.2166. 1H NMR(300MHz,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).

[0914] 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

[0915] [ka]

[0916] According to GM1A, (1S,3S)-N 1 A mixture of 6-(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) in DMSO (15 mL) at 120 °C for 15 h afforded the title compound (45 mg, 29%) as a pale yellow solid after nonaqueous workup and preparative TLC (EtOAc:PE = 2:1), followed by purification by preparative HPLC (preparative method D, gradient: 24-44%). 21 H 23 HRMS (ESI) m / z [M+H] for ClNO + Calculated value: 424.1648, measured value: 424.1650. 1H NMR(300MHz,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).

[0917] 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

[0918] [ka]

[0919] According to GM2, (1S,3S)-N 1 A mixture of 6-(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), CsCO (563 mg, 1.73 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (18 mg, 0.02 mmol) in 1,4-dioxane (12 mL) was reacted at 100 °C for 15 h to afford the title compound (71 mg, 39%) as a white solid after nonaqueous workup and purification by preparative HPLC (Preparative Method D, gradient: 23–43%). 22 H 23 HRMS (ESI) m / z [M+H] for NO + Calculated value: 415.1990, measured value: 415.1970. 1H NMR(300MHz,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(2 H,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).

[0920] 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

[0921] [ka]

[0922] According to GM2, Cs2CO3 (238 mg, 0.73 mmol) was dissolved in (1S,3S)-N in 1,4-dioxane (3 mL). 1 To a mixture of 128 mg (0.59 mmol) of 1-(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (compound i-22d), 110 mg (0.49 mmol) of 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione (compound i-7b), and 20.50 mg (0.02 mmol) of Pd-PEPPSI-IpentCl was added at 25° C. The resulting suspension was stirred at 100° C. for 16 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure, and the residue was dissolved in water (50 mL) and extracted with DCM (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated, and the resulting residue was purified by preparative TLC (7M NH3 in MeOH:DCM = 1:20) followed by preparative HPLC (Preparative Method D, gradient: 20-35%) to afford the title compound (10 mg, 5%) as a white solid. 20 H 25 HRMS (ESI) m / z [M+H] for N8O2+ Calculated value: 409.2094, measured value: 409.2104. 1 H NMR(300MHz,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).

[0923] [Table 19-1]

[0924] [Table 19-2]

[0925] [Table 19-3]

[0926] Example 67 6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0927] [ka]

[0928] According to GM2, Cs2CO3 (329 mg, 1.01 mmol) was dissolved in (1S,3S)-N dioxane (5 mL). 1To a mixture of 6-(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) was added at room temperature, and the resulting suspension was stirred at 100 °C under nitrogen for 15 h. The reaction mixture was diluted with EtOAc (200 mL) and subsequently washed with saturated brine (2 × 15 mL) and water (2 × 15 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to give the crude product, which was purified by preparative TLC (MeOH:DCM = 1:25) followed by preparative HPLC (Preparative Method C, gradient: 10-30%) to give the title compound (35 mg, 48%) as a white solid. 19 H 22 HRMS (ESI) m / z [M+H] for NO + Calculated value: 364.1880, measured value: 364.1866. 1 H NMR(300MHz,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).

[0929] 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

[0930] [ka]

[0931] According to GM7, ethyl 3-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)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 Registry Number: 1668-10-6) (17 mg, 0.16 mmol) and stirred at 70 °C overnight. The volatiles were removed and the residue was redissolved in MeOH (1 mL). Additional amounts of DIPEA (55 μL, 0.32 mmol) and 2-aminoacetamide HCl (17 mg, 0.16 mmol) were added, and the reaction mixture was stirred at 70 °C for 1 week. Purification by preparative SFC (preparative method SFC-A) gave the title compound (1.8 mg, 5%). 21 H 24 HRMS (ESI) m / z [M+H] for N9O3 + Calculated value: 450.1996, measured value: 450.1984. 1 H NMR(600MHz,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),6.9 4(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).

[0932] [Table 20-1]

[0933] [Table 20-2]

[0934] [Table 20-3]

[0935] 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)

[0936] [ka]

[0937] According to GM1A, (1S,3S)-N 1 The free base of -(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 under a nitrogen atmosphere for 15 h. 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 was purified by preparative TLC (MeOH:DCM=1:10) followed by preparative HPLC (Preparative Method D, gradient: 18-32%) to give the title compound (15 mg, 12%) as a white solid. 19 H 21 HRMS (ESI) m / z [M+H] for ClNO + Calculated value: 398.1490, measured value: 398.1468. 1 H NMR(300MHz,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),6.2 4(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).

[0938] 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)

[0939] [ka]

[0940] In a slight modification 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 room temperat...

Claims

1. Formula (I): A-B-C (I) or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof, In the formula, A is 【Chemical 1】 of; The wavy line indicates the point of attachment to B; X １ is N; R Ａ２ but, (i) H; (ii) halo; (iii) CN; (iv) OH, CN, C １～６ Acyl, C １～６ C optionally substituted with alkoxy or one or more halo groups １～６ hydrocarbons; (v) C optionally substituted with OH, alkylamido, or one or more halo groups １～６ Alkoxy; (vi) C １～６ acylamides (wherein acyl is optionally substituted with H or methyl); (vii) C １～６ Thioalkyl; (viii) C １～６ Alkyl esters; (ix) C １～６ Alkyl acyl; (x) C ４～５ heterocyclyl; (xi) C ５ heteroaryl; (xii) C １～３ Alkylamide, CN, OH, C ２～３ Alkynyl, C ４～６ heterocyclyl, or C １～３ C optionally substituted with alkyl １～６ Alkylamides, wherein the C １～３ C, wherein the alkyl is optionally substituted with one or more halo or OH groups; １～６ Alkylamides; and (xiii) OH; and (xiv) C １～６ alkylamino; R Ａ３ but, (i) H; (ii) halo; (iii) CN; (iv) OH, CN, C １～６ Thioalkyl, C １～６ Alkoxy, C １～６ Alkyl acyl, C １～６ Acyloxy, carboxy, C １～６ Alkyl esters, C １～６ Alkylamino, —C(═O)NH ２ , C １～６ Alkylamide, C １～６ Alkyl acylamido, C １～６ Alkylsulfinyl, C １～６ alkylsulfonyl, or C optionally substituted with one or more halo groups １～６ hydrocarbons; (v) OH; (vi) OH, NH ２ , C ４ C optionally substituted with one or more heterocyclyl or halo groups １～６ Alkoxy; (vii) C １～６ acyloxy; (viii) C ４ heterocyclyl; (ix)-NH ２ ; (x) CN, OH, or C ４ C optionally substituted by heterocyclyl １～６ alkylamino; (xi) -NH ２ C optionally substituted with １～６ Dialkylamino; (xii) C １～６ acylamides (wherein the acyl substituent is H or Me); (xiii) carbimidoyl or methyl-carbimidoyl; (xiv) carboxyamino; (xv) OH or —NH ２ C optionally substituted with １～６ Thioalkyl; (xvi) C １～６ Alkylsulfinyl; (xvi) C optionally substituted with one or more halo groups １～６ Alkylsulfonyl; (xvii) C １～６ Sulfonimodil; (xviii) C １～６ Alkylphosphinyl; (xix) carboxy; (xx)-C(=O)NH ２ (xxi) C １～６ Alkyl esters; (xxii) C optionally substituted with one or more halo groups １～６ Alkyl acyl; (xxiii) C １～６ alkylamides; or R Ａ３ and R Ａ２ along with the carbon atoms to which they are attached. (i) optionally substituted C ５～７ heterocycles; (ii) optionally substituted C ５～７ Aromatic heterocycles; (iii) optionally substituted C ６ carbon aromatic rings; (iv) optionally substituted C ５～７ It forms a carbon ring, wherein the optional substituent is C １～６ Alkyl, halo, C １～６ Alkoxy, —NH ２ , C １～６ selected from alkylamino, OH, and CN; B is a compound represented by formula (B-1) or (B-2): i) 【Chemistry 2】 where the wavy lines indicate the points of attachment to A and C; R Ｂ１ is H, OH, =CHCH ２ —OH, —O—C １～４ Alkyl, or C １～４ alkyl, １～４ The alkyl is optionally substituted with OH or OMe. (ii) 【Chemistry 3】 where the wavy lines indicate the points of attachment to A and C; R Ｂ２ But C １～２ Alkyl-OH, CH ２ C(═O)NHMe, or C １～３ alkyl), C is C ６～１０ Carboaryl, C ５～６ Heteroaryl, and C ５～１０ heterocyclyl, wherein these groups are selected from the group consisting of: (i) C ６～１０ Carboaryl, C ４～１０ Carbocyclyl, C ５～１０ Heteroaryl, C ４～１０ heterocyclyl, or C ５～１０ Bridged heterocyclyl, C ６～１２ Spiroheterocyclyl or C ６～１２ spirocarbocyclyl, These themselves include the following groups: a) one or two =O groups; b) one or more halo groups; c)CN、NH ２ 、OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; １～６ alkyl groups; e) C having one or more halo group optional substituents １～６ Alkoxy; f) C １～６ Alkyl esters; g) C with optional methyl, OH, or ═O substituents ５～６ heterocyclyl; h) C ５～６ heteroaryl; i) C with optional methyl or ═O substituents ４～１０ Carbocyclyl; j) C having one or more halo group optional substituents ６～１０ Carboaryl; ,)@(=O)Me ２ ; m) carboxy or CH ２ -carboxy; n) tetrazolyl, CH ２ -Tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl C optionally substituted with one or more of ６～１０ Carboaryl, C ４～１０ Carbocyclyl, C ５～１０ Heteroaryl, C ４～１０ heterocyclyl, or C ５～１０ Bridged heterocyclyl, C ６～１２ Spiroheterocyclyl or C ６～１２ Spirocarbocyclyl; (ii) Carboxy, CN, halo, nitro, C １～６ Alkyl, C １～６ Thioalkyl, C １～６ Alkoxy, C １～６ Alkyl acyl, C １～６ Alkylamide, diC １～６ Alkylamide, C １～６ Alkyl sulfonamides, and diC １～６ Alkyl sulfonamides or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof, optionally substituted with one or more groups selected from:

2. R Ａ２ but, (i) H; (ii) halo; (iii) C １～６ Alkyl esters; (iv) C １～６ hydrocarbons; (v) C １～３ Alkylamide, C ２～３ Alkynyl, C ４～６ heterocyclyl or alkyl optionally substituted with one or more halo or OH groups １～３ C optionally substituted with alkyl １～６ Alkylamides; (vi) C １～６ Thioalkyl; (vii) C １～６ Alkyl acyl; (viii) C ５ heteroaryl; or (ix) C １～６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkylamino.

3. R Ａ２ is -C(=O)OCH ２ CH ３ , cyclopropyl, methyl, H, Cl, —C(═O)CH ３ , —S-ethyl, pyrazole, —N(CH ３ ) ２ , -C(=O)NH(CH ２ C(=O)NH ２ , 【Chemistry 4】 -C(=O)NH(オキセタン)、-C(=O)NH(CH ２ CHF ２ )、-C(=O)NH(CH ２ CH ３ )、-C(=O)NH ２ 、-C(=O)NH(CH ３ )、-C(=O)N(CH ３ ) ２ 、-C(=O)N(CH ３ )(CH ２ CH ２ OH)、 【Chemistry 5】 or -C(=O)NH(CH ２ CH ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

4. R Ａ３ but, (i) H; (ii) halo; (iii) CN; (iv) OH, CN, C １～６ Thioalkyl, C １～６ Alkoxy, C １～６ Alkyl acyl, C １～６ Acyloxy, carboxy, C １～６ Alkyl esters, C １～６ Alkylamino, —C(═O)NH ２ , C １～６ Alkylamide, C １～６ Alkyl acylamido, C １～６ Alkylsulfinyl, C １～６ alkylsulfonyl, or C optionally substituted with one or more halo groups １～６ hydrocarbons; (v) OH; (vi) OH, NH ２ , C ４ C optionally substituted with one or more heterocyclyl or halo groups １～６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkoxy.

5. R Ａ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of H, methyl, and OH.

6. B has the following formula: 【Chemistry 6】 a) 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is

7. C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, where any of the optional substituents is C ６～１０ Carboaryl, C ４～１０ Carbocyclyl, C ５～１０ Heteroaryl, C ５～１０ Heterocyclyl, C ５～１０ Bridged heterocyclyl, C ６～１２ spiroheterocyclyl, or C ６～１２ spirocarbocyclyl, which itself is selected from the following groups: a) one or two =O groups; b) one or more halo groups; c) CN, NH ２ , or OH; d) one or more C groups, including branched and cyclic, with optional substituents selected from OH or one or more halo groups; １～６ alkyl groups; e) C having one or more halo group optional substituents １～６ Alkoxy; f) C １～６ Alkyl esters; g) C with optional methyl, OH, or ═O substituents ５～６ heterocyclyl; h) C ５～６ heteroaryl; i) C with optional methyl or ═O substituents ４～１０ Carbocyclyl; j) C having one or more halo group optional substituents ６～１０ Carboaryl; ,)@(=O)Me ２ ; m) carboxy or CH ２ -carboxy; and / or n) tetrazolyl, CH ２ -Tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more of:

8. C is, a) optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are C ６ Heteroaryl or C ６ heterocyclyl, which itself is selected from: i) one or two =O groups; ii) methyl; iii) OMe; iv) Cl; v) CN; vi)CF ３ ; vii) F; viii) pyrazolyl, triazolyl, tetrazolyl optionally substituted with methyl; ix)O-CF ３ ; x)O-CHF ２ an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, optionally substituted with one or more groups selected from b) optionally substituted pyridinyl, where the optional substituents are phenyl or pyridyl, which themselves are: f) one or more OMe groups; g) one or more F groups; h) CN; i) tetrazole; or j) Carboxy an optionally substituted pyridinyl, optionally substituted with one or more groups selected from c) optionally substituted pyridinyl, wherein the optional substituents are C ５ Heteroaryl or C ５ 8. The compound of any one of claims 1 to 7, wherein the compound is an optionally substituted pyridinyl, which is heterocyclyl, which is itself optionally substituted by one or more substituents selected from methyl and CN, or a pharmaceutically acceptable salt thereof.

9. C is a compound represented by formula (C-1): 【Chemistry 7】 wherein D is C ６～１０ Carboaryl, C ５～１０ Heteroaryl, or C ５～１０ heterocyclyl, each of which is itself i) one or two =0 groups; ii) one or two C groups which may be branched １～４ alkyl groups; iii) OMe; iv) piperazinyl optionally substituted with methyl; v) C(=O)OH (carboxy); vi) Cl; vii) F; viii) phenyl optionally substituted with one or more fluoro; ix) CN; x)CF ３ ; x)) ３ 4 xii) tetrazolyl, pyrazolyl, triazolyl, each optionally substituted with methyl; xiii)NH ２ ; xiv) pyridinyl; xv)CH ２ OH; xvi) OH; xvii) P(=O)Me ２ or xviii)OCHF ２ 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted by:

10. D is a compound represented by formula (D-1): 【Chemistry 8】 wherein R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ One or two of the i) C optionally substituted with one or more halo groups １～６ Alkyl; ii) C optionally substituted with one or more halo groups １～６ Alkoxy; iii) C with optional methyl substituents ５～６ Heterocyclyl or C ５～６ heteroaryl; iv) carboxy or CH ２ -carboxy; v)=O, halo, NH ２ , or CN; vi) phenyl optionally substituted with one or more halo atoms; the remainder is H; or R Ｄ３ and R Ｄ４ form an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, and C(═O)OH; or R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ are all H, or a pharmaceutically acceptable salt thereof.

11. a) R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ One or two of the i) methyl; ii) OMe; iii) Cl; iv) CN; v)CF ３ ; vi) F; vii) pyrazolyl, triazolyl, tetrazolyl optionally substituted with methyl; v))) ３ ix) O-CHF ２ is selected from R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ the remainder is H; b) R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ are all H; c) R Ｄ３ is optionally substituted by H, CN, OMe, Cl, methyl, pyrazole, tetrazole, methyl, OCHF ２ or triazole, R Ｄ１ , R Ｄ２ , and R Ｄ４ are all H; d) R Ｄ１ H, OMe, Cl, CF ３ , OCF ３ , OCHF ２ , CN, F, pyrazole optionally substituted with methyl, or triazole; R Ｄ２ , R Ｄ３ , and R Ｄ４ are all H; or e) R Ｄ３ and R Ｄ４ The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein

12. D is a compound represented by formula (D-2): 【Chemistry 9】 wherein X Ｄ But NR Ｄ５ａ or CR Ｄ５ａ R Ｄ５ｂ and R Ｄ５ａ is selected from H or methyl; R Ｄ５ｂ and R Ｄ６ｂ are both H or together form -CH ２ - and; R Ｄ６ａ is H, ═O, methyl, —CH ２ OH, or —C(═O)OH; R Ｄ６ａ When =O, R Ｄ６ｂ is non-existent; R Ｄ７ａ is H, ═O, methyl, —CH ２ OH, or —C(═O)OH; R Ｄ７ｂ is H and R Ｄ７ａ When =O, R Ｄ７ｂ is non-existent; or R Ｄ６ａ and R Ｄ７ａ Both of them are benzene rings or C ６ Aromatic heterocycles are formed, and these are CN, P(=O)Me ２ or carboxy, and R Ｄ６ｂ and R Ｄ７ｂ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is absent.

13. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: 【Table 1-1】 【Table 1-2】 【Table 1-3】

14. C is a compound represented by formula (C-2): 【Chemistry 10】 wherein R Ｃ７ , R Ｃ８ , R Ｃ９ , and R Ｃ１０ is methyl; OMe; piperazinyl optionally substituted with methyl; C(=O)OH (carboxy); Cl; F; pyrazolyl optionally substituted with methyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituents are methyl or halo); CN; CF ３ ; O-CHF ２ , O-CF ３ R Ｃ７ , R Ｃ８ , R Ｃ９ , and R Ｃ１０ the remainder is H; or R Ｃ９ and R Ｃ１０ forms a benzene or 6-membered aromatic heterocycle, and R Ｃ７ and R Ｃ８ are both H; or R Ｃ７ , R Ｃ８ , R Ｃ９ , and R Ｃ１０ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein all of are H.

15. a) R Ｃ７ , R Ｃ８ , R Ｃ９ , and R Ｃ１０ are all H; or b) R Ｃ９ is optionally substituted by H, CN, OMe, Cl, methyl, pyrazole, tetrazole, methyl, OCHF ２ or triazole, R Ｃ７ , R Ｃ８ , and R Ｃ１０ are all H; or c) R Ｃ７ H, OMe, Cl, CF ３ , OCF ３ , OCHF ２ , CN, F, triazole, or pyrazole optionally substituted with methyl; R Ｃ７ , R Ｃ８ , and R Ｃ１０ are all H, or a pharmaceutically acceptable salt thereof.

16. C is, 【Table 2-1】 【Table 2-2】 【Table 2-3】 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

17. ABC is of the formula (IA), (IB), (I-Ba), (I-Bb), (IC), (ID), (IE), (I-Ea), or (I-Eb): 【Chemistry 11】 【Chemistry 12】 wherein X １ , 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 Ｄ６ｂ , and R Ｄ７ａ 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein:

18. A compound of Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt thereof.

19. 20. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in therapy.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.

21. 21. The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use in treating cardiovascular disease, optionally wherein the cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure, or congestive heart failure.

22. The compound is vii) statins; viii) cholesterol absorption inhibitors; ix) SGLT2 inhibitors; x) P2Y12 inhibitors; xi) citrate lyase inhibitors; and xii) Antihypertensive drugs 22. The compound for use according to claim 21, or a pharmaceutically acceptable salt thereof, administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of:

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