Imidazo[4,5-B]pyridine derivatives as PCSK9 inhibitors and methods of use thereof

Abstract

A compound having the formula (I): ABC, wherein A is of the following formula (AA): 1 is selected from O, S, or NH, and X 2 is either N or CH, and X 3 is N or CR A3 Either X 1 is NH and X 2 If is CH, then X 3 is CR A3 wherein B is of formula (B-1) or (B-2), and C is optionally substituted C 6~10 Carboaryl, C 5~6 Heteroaryl, or C 5~10 1. Compounds selected from the group consisting of heterocyclyls, and their use as PCSK9 inhibitors. [Formula 1] JPEG2026500304000392.jpg91128

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. Application No. 63 / 387,731, filed December 16, 2022, and U.S. Application No. 63 / 603,163, filed November 28, 2023. Each of the above-listed applications is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] PCSK9, also known as "proprotein convertase subtilisin / kexin 9," is a member of the secreted proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases circulating LDL cholesterol (LDL-C) levels through enhanced degradation of the LDLR, independent 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 receptor 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 human primary hepatocytes via increasing 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] Two monoclonal antibodies (mAbs), alirocumab and evolocumab, which 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 that PCSK9 inhibitors may be an effective treatment for individuals with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and may trigger allergic reactions or other adverse immune responses in the body.

[0005] Unlike infections, which may be temporary, cardiovascular diseases often require lifelong management.Therefore, ease of dosing and administration is an important factor for patient compliance with maintenance drug treatment.There is a need for PCSK9 inhibitors with increased efficacy and easier administration, which can be achieved using small molecule PCSK9 inhibitors.

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

[0007] WO 2020 / 15474(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) A compound having the formula: wherein A is of the following formula:

[0009] [ka] wherein the wavy line indicates the point of attachment to B; X 1 is selected from O, S, or NH; X 2 is either N or CH, X 3 is N or CR A3 Either X 1 is NH and X 2 If is CH, then X 3 is CR A3 and X 1 If is NH, R A1 is X 4 and R A2 is X 5 and X 2 is N and X 1 is O or S, R A1 is X 4 and R A2 is X 5 and X 2 is CH and X 1 If S, then R A1 is X 4 and R A2 is X 5 and X 2 is CH and X 1 If is O, then R A1 is X 5 and R A2 is X 4 and X 4 teeth, (i) H, (ii) halo, (iii) CN, (iv) C1 alkyl optionally substituted with one or more OH, CN, or one or more halo groups; (v) C alkoxy optionally substituted with one or more halo groups; X 5 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Alkyl acyl, C 1~6 C optionally substituted with alkoxy or one or more halo groups; 1~6 hydrocarbons, (v) C 1~6 Alkylamide, C 1~6 alkylphosphonyl, or C optionally substituted with one or more halo groups; 1~6 Alkoxy, (vi) C 1~6 alkylamino, (vii)C 1~6 thioalkyl, (viii)C 1~6 alkylphosphinyl, or (ix) C 1~6 alkylphosphonyl; 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, C(=O)OH, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Acylamide, C 1~6 Alkylsulfinyl, C 1~6 C optionally substituted with alkylsulfonyl or one or more halo groups 1~6 hydrocarbons, (v) C optionally substituted by NH, C heterocyclyl, and one or more halo groups. 1~6 Alkoxy, (vi) C4 heterocyclyl, (vii) C optionally substituted by CN, OH, C heterocyclyl 1~6 alkylamino, (viii) C optionally substituted by -NH 1~6 dialkylamino, or (ix) C optionally substituted by OH or —NH 1~6 thioalkyl; 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 is H, OH, =CHCH2-OH, -OC 1~4 Alkyl, or C 1~4 alkyl, C 1~4 alkyl 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, CHC(=O)NHMe, or C 1~3 is alkyl, R A1 is H or halo, then R B2 is C 1~2 alkyl-OH or CHC(=O)NHMe), C is C 6~10 Carboaryl, C 5~6 Heteroaryl, or C 5~10 heterocyclyl, which groups are selected from the group consisting of: (i) The following groups: a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) one or more 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 optional methyl, OH, or ═O substituents 5~6 heterocyclyl, h)C 1~6 C optionally substituted with alkyl 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, l) P(=O)Me2, m) C(=O)OH or CHC(=O)OH, and / or n) C is optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged Heterocyclyl, Spiro C 6~12 Heterocyclyl or spiro C 6~12 carbocyclyl, (ii) C(=O)OH, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6Alkyl sulfonamides and di-C 1~6 alkylsulfonamide, or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof.

[0012] In some embodiments, X 5 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Alkyl acyl, C 1~6 C optionally substituted with alkoxy or one or more halo groups; 1~6 hydrocarbons, (v) C 1~6 alkylamide or C optionally substituted with one or more halo groups 1~6 Alkoxy, (vi) C 1~6 alkylamino, (vii)C 1~6 thioalkyl, or (viii)C 1~6 alkylphosphinyl.

[0013] A second aspect provides a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable diluent, carrier, or excipient.

[0014] A third aspect provides a compound of the first aspect for use in therapy. 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 to a patient in need thereof a therapeutically effective amount of a compound of the first aspect or a composition according to the second aspect.

[0015] The present disclosure includes combinations of the described aspects and preferred features except where such combinations are expressly not permitted or explicitly avoided. DETAILED DESCRIPTION OF THE INVENTION

[0016] Aspects and embodiments are discussed below. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0017] 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 have higher PCSK9 inhibition, 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 have improved secondary pharmacological profile or improved off-target profile.

[0018] definition substituent As used herein, the phrase "optionally substituted" pertains to a parent group which may be unsubstituted or substituted.

[0019] Unless otherwise specified, the term "substituted," as used herein, refers to a parent group bearing one or more substituents. The term "substituent" is used herein in its conventional sense to refer to a chemical moiety that is covalently attached to, or, where appropriate, fused to, a parent group. A wide variety of substituents are well known, as are methods for their formation and introduction into various parent groups.

[0020] Examples of substituents are described in more detail below.

[0021] Unless otherwise specified, halo is selected from chloro (Cl), fluoro (F), bromo (Br), and iodo (I).

[0022] Cyano (nitrile, carbonitrile): -CN.

[0023] Hydroxy: -OH.

[0024] Oxo: =O (oxygen double bonded to the rest of the molecule).

[0025] C 1~6 Hydrocarbon: As used herein, "C 1~6 The term "hydrocarbon" 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" includes terms such as alkyl, alkenyl, alkynyl, cycloalkyl, etc., which are discussed below.

[0026] C 1~6 Alkyl: As used herein, "C 1~6 The term "alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated, and optionally branched, hydrocarbon compound having 1 to 6 carbon atoms. 1~4 The term "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, which is saturated.

[0027] Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), and hexyl (C6).

[0028] 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).

[0029] Examples of saturated branched alkyl groups include isopropyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), and neopentyl (C5).

[0030] C 2~6 Alkenyl: As used herein, "C 2~6 The term "alkenyl" refers to a hydrocarbon group having one or more carbon-carbon double bonds.

[0031] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH), 1-propenyl (-CH=CH-CH), 2-propenyl (allyl, CHCH=CH), isopropenyl (1-methylvinyl, C(CH)=CH), butenyl (C), pentenyl (C), and hexenyl (C).

[0032] C 2~6 Alkynyl: As used herein, "C 2~6 The term "alkynyl" refers to a hydrocarbon group having one or more carbon-carbon triple bonds.

[0033] Examples of unsaturated alkynyl groups include ethynyl

[0034] [ka] and 2-propynyl (propargyl,

[0035] [ka] ), but are not limited to these.

[0036] 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 1~6Examples of alkoxy groups include, but are not limited to, OMe, OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (iso-propoxy), O(nBu) (n-butoxy), O(sBu) (sec-butoxy), O(iBu) (iso-butoxy), and O(tBu) (tert-butoxy).

[0037] 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.

[0038] Amino:NR 1 R 2 (In the formula, 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 together with the nitrogen atom to which they are attached form a heterocycle having 4 to 6 ring atoms). Amino groups can be primary (-NH2) or secondary (-NHR 1 ) even if it is a third-class (-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.

[0039] C 1~6 Acylamide: Acylamide (acylamino): NR 1 C(=O)R 2 (In the formula, 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 to form 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.

[0040] [ka]

[0041] Carbimidoyl: -C(=NH)NH2.

[0042] Methyl-carbimidoyl: -C(=N-CH3)NH2.

[0043] Carboxyamino: -N(H)(C(=O)OH).

[0044] 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.

[0045] C 1~6 Alkylsulfinyl: C 1~6 The term alkylsulfinyl refers to a group having the structure S(=O)R-, where R is C 1~6 It relates to sulfines (sulfinyl, sulfoxide) having hydrocarbon groups. 1~6 Examples of alkylsulfinyl groups include, but are not limited to, S(=-O)CH3 and S(=-O)CH2CH3.

[0046] 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 C, including alkyl groups 1~6 C- is a hydrocarbon group. 1~6 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).

[0047] C 1~6 Sulfonimodil: C 1~6 The term sulfonimozyl refers to sulfonamides (sulfinamoyl, sulfonic acid amides, sulfonamides or di-C 1~6 Also known as alkylsulfonamide, it has the structure S(=O)NR 1 R 2 (In the formula, R 1 and R 2 are independently amino substituents 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).

[0048] Sulfonamino: NR 1S(=O)2R (in the formula, R 1 is an amino substituent as defined for an amino group, and R is a sulfone amino substituent, e.g., C 1~6 Alkyl group, C 3~20 heterocyclyl group, or C 5~20 Aryl groups, preferably C 1~6 Examples of sulfonamino groups include, but are not limited to, NHS(=O)2CH3 and N(CH3)S(=O)2C6H5.

[0049] C 1~6 Alkylphosphinyl: C 1~6 The term alkylphosphinyl (phosphine oxide) refers to a compound having the structure -P(=O)R, where each R is independently selected from the group consisting of C 1~6 C 1~6 Examples of alkylphosphinyl groups include, but are not limited to, P(=O)Me2, P(=O)(CH2CH3)2, and P(=O)(tBu)2, where each R group can be the same or different.

[0050] C 1~6 Alkylphosphonyl: C 1~6 The term alkylphosphonyl refers to a group having the structure -P(=O)R, where R is C 1~6 C 1~6 Examples of alkylphosphonyl groups include, but are not limited to, P(=O)2(CH3), P(=O)2(CH2CH3), and P(=O)2(tBu).

[0051] Carboxy (carboxylic acid): -C(=O)OH.

[0052] C 1~6 Alkyl ester: C 1~6 The term alkyl ester (carboxylate, carboxylic acid ester, oxycarbonyl) refers to the structure C(=O)OR, where R is C 1~6Examples of ester groups include, but are not limited to, C(=O)OCH3, C(=O)OCH2CH3, and C(=O)OC(CH3)3.

[0053] C 1~6 Alkyl acyl: also known as acyl (keto) C 1~6 The term alkyl acyl refers to a group having the structure C(=O)R, where R is C 1~6 C 1~6 Examples of alkyl acyl groups include, but are not limited to, C(=O)CH3 (acetyl), C(=O)CH2CH3 (propionyl), or C(=O)C(CH3)3 (tert-butyryl).

[0054] C 1~6 Alkylamide: C 1~6 The term alkylamide (also known as carbamoyl, carbamyl, aminocarbonyl, or carboxamide) has the structure C(=O)NR 1 R 2 (In the formula, 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 1~6 Alkylamide or C 1~6 (also called dialkylamide) or in the case of a "cyclic" amide group, R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle having 4 to 6 ring atoms. Examples of amide groups include C(=O)NH, C(=O)NHCH, C(=O)N(CH), C(=O)NHCHCH, and C(=O)N(CHCH), as well as 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, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

[0055] C3~12 Cycloalkyl: As used herein, "C 3~12 The term "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, said moiety having 3 to 7 carbon atoms containing 3 to 7 ring atoms. The carbocyclic ring may be saturated or unsaturated, bridged or unbridged. The ring may be fused or monocyclic.

[0056] Examples of cycloalkyl groups include: Saturated monocyclic hydrocarbon compounds: Cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C6), methylcyclopentane (C6), dimethylcyclopentane (C7) and methylcyclohexane (C7); Unsaturated monocyclic hydrocarbon compounds: Cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (C6), methylcyclopentene (C6), dimethylcyclopentene (C7), and methylcyclohexene (C7); and Saturated polycyclic hydrocarbon compounds: Examples include, but are not limited to, those derived from norcarane (C7), norpinane (C7), and norbornane (C7).

[0057] C 3~10 Heterocyclyl: As used herein, "C 3~10The term "heterocyclyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which 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.

[0058] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0059] In this context, prefixes (e.g., C 3~10 , C 3~7 , C 5~6 etc.) indicates the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, "C 5~6 The term "heterocyclyl," as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.

[0060] Examples of monocyclic heterocyclyl groups include: N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 2,5-dihydro-1H-pyrrole) (C5), 2H-pyrrole or 3H-pyrrole, 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), but are not limited to those derived from

[0061] Examples of bicyclic heterocyclyl groups include, but are not limited to, those derived from:

[0062] [Table 1]

[0063] C 6~10 Carboaryl: As used herein, "C 6~10 The term "carboaryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound (which moiety has 6 to 10 ring atoms, all of which are carbon atoms, as in "carboaryl group"). The rings may be fused or single rings. Examples of carboaryl groups include benzene (i.e., phenyl) (C6), naphthalene (C7), and cyclohexane (C8). 10 ), and azulene (C 10 ) are included, but are not limited to.

[0064] In this context, prefixes (e.g., C 5~7 , C 5~6 , C 5~10 etc.) indicates the number of ring atoms or range of the number of ring atoms. For example, as used herein, "C 5~6 The term "aryl" refers to an aryl group having 5 or 6 ring atoms.

[0065] Examples of carboaryl groups containing fused rings in which at least one is aromatic include indane (e.g., 2,3-dihydro-1H-indene) (C9), indene (C9), isoindene (C9), and tetralin (1,2,3,4-tetrahydronaphthalene) (C 10 ) are included, but are not limited to.

[0066] C 5~10 Heteroaryl: As used herein, "C 5~10 The term "heteroaryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, said 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 ring may be fused or monocyclic.

[0067] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0068] Examples of monocyclic heteroaryl groups include: 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: 1H-imidazole (1,3-diazole) (C5), 1H-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), but is not limited to those derived from

[0069] Examples of heteroaryls containing fused rings include, but are not limited to, C9 heteroaryls (having two fused rings) derived from:

[0070] [Table 2]

[0071] Examples of heteroaryls containing fused rings include C derived from: 10 Includes, but is not limited to, heteroaryl (having two fused rings).

[0072] [Table 3]

[0073] Examples of heteroaryl or heterocyclic compounds include, but are not limited to, those derived from:

[0074] [Table 4]

[0075] Spiro C6~12 Carbocyclyl: As used herein, spiro C 6~12 The term carbocyclyl refers to a moiety having at least two rings with only one common 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 single common atom, as defined above. Spiro C6 12 Carbocyclyl 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, with 3 to 7 ring atoms where the rings share a common atom.

[0076] Spiro C 6~12 Heterocyclyl: As used herein, spiro C 6~12 The term heterocyclyl refers to a moiety having at least two rings with only one common 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 single common atom, as defined by the spiro C. 6~12 Heterocyclyl moiety refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has 8 to 12 ring atoms, of which 1 to 3 are ring heteroatoms with which the rings share a common atom. In certain embodiments, each ring has 9 to 11 ring atoms, of which 1 to 2 are ring heteroatoms. For the avoidance of doubt, substituents on heteroaryl rings may be attached via either a carbon atom or a heteroatom.

[0077] For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may include the same or different substituents from within the given group.

[0078] pharmaceutically acceptable salts The term "pharmaceutically acceptable" is used to specify that an object (e.g., a 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 compounds of formula (I) are, for example, acid addition salts. Acid addition salts of compounds 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 inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts can 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.

[0079] 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 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 salt.

[0080] 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 to the extent that such forms have PCSK9 inhibitory activity, for example, when measured using the test described herein.

[0081] The compounds and salts described herein contain one or more chiral (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) corresponding to that structure or name, as well as any mixture of stereoisomers (e.g., a racemate). In some embodiments, a single stereoisomer is obtained by isolation from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by, for example, direct synthesis from chiral starting materials.

[0082] Certain enantiomers of the compounds described herein may be more active than other enantiomers of the same compound.

[0083] 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.

[0084] 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.

[0085] Isotopes The atoms of the compounds and salts described herein may exist in their isotopes. Compounds of formula (I) include all compounds of formula (I) in which atoms are replaced by one or more of their isotopes (e.g., compounds in which one or more carbon atoms are replaced by one or more of their isotopes). 11 C or 13 C carbon isotope or one or more hydrogen atoms 2 H or 3 H isotope).

[0086] tautomers The compounds and salts described herein may exist as a mixture of tautomers. A "tautomer" is a structural isomer that exists in equilibrium resulting from the migration of a hydrogen atom. The compounds of formula (I) include all tautomers of the compounds of formula (I), particularly to the extent that such tautomers have PCSK9 inhibitory activity.

[0087] Crystal form 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.

[0088] 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) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy, etc. The water content of crystalline materials can be determined by Karl Fischer analysis.

[0089] Therapy, prevention, and related terms The term "therapy" is intended to have its ordinary meaning of treating a disease in order to completely or partially alleviate one, some, or all of the symptoms of the disease, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis," unless specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" are to be construed in corresponding ways.

[0090] The term "prevent" is intended to have its ordinary meaning and can include primary prevention, to prevent the onset of a disease, and secondary prevention, where the disease has already occurred and the patient is protected, either temporarily or permanently, from progression or worsening of the disease or the development of new symptoms associated with the disease.

[0091] The term "treatment" is used synonymously with "therapy." Similarly, the term "treating" can be considered as "applying therapy," as "therapy" is defined herein.

[0092] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female, of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. A preferred subject is a human.

[0093] 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 that is sufficient to improve at least one sign or symptom of the disease being treated.

[0094] 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.

[0095] 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.

[0096] 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; 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 can perform different functions, depending on how much of the excipient is present in the composition and which other excipients are present in the composition.

[0097] 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), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or as suppositories for rectal administration. The compositions may be obtained by conventional procedures well known in the art. Compositions intended for oral use may contain additional ingredients, such as one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0098] A suitable daily dose of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the therapeutic treatment of humans is about 0.0001 to 100 mg / kg body weight.

[0099] The pharmaceutical formulations described herein can be formulated by methods known to those skilled in the art to provide a dose of active compound ranging from 0.1 mg to 1000 mg. The daily dose will necessarily vary depending on the host being treated, the particular route of administration, any co-administered therapy, and the severity of the condition being treated. Accordingly, the physician treating any particular patient can determine the optimal dosage.

[0100] 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.

[0101] 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.

[0102] In one embodiment, a pharmaceutical composition is provided 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, a pharmaceutical composition is provided 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, a pharmaceutical composition is provided 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.

[0103] How to use The compounds described herein can be used in therapy. 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.

[0104] The compounds may be administered alone or in combination with other treatments, either simultaneously or sequentially depending on the condition being treated.

[0105] 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 the 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).

[0106] The compounds described herein are PCSK9 inhibitors. The PCSK9 gene was identified using genetic mapping techniques on DNA from subjects with autosomal dominant hypercholesterolemia (Abifadel 2003). The encoded protein is a serine protease that is primarily expressed in the liver, intestine, kidney, and nervous system and circulates in plasma. While not wishing to be bound by any particular theory, studies of mutations in the gene have shown that its putative role is to reduce 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 an increase in the amount 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). Elevated levels of PCSK9 reduce the abundance of LDLR on the cell surface, so increasing doses 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.

[0107] 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 for 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 for 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 for 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 via inhibition of PCSK9 is described, for example, in Robinson 2015.

[0108] In some embodiments, methods of treating cardiovascular disease are provided, comprising 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), for use in treating cardiovascular disease is provided. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), for the manufacture of a medicament for treating cardiovascular disease is provided.

[0109] Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular disease, 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, hepatic steatosis, metabolic syndrome, and coronary artery disease. In certain embodiments, the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In certain embodiments, the disease is hyperlipidemia. In certain embodiments, the disease is coronary artery disease.

[0110] In certain embodiments, the disclosed therapeutic 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 mutations through inhibition of PCSK9.

[0111] Combination treatment The disclosed compounds and compositions can be administered together with other therapeutic agents, such as other drugs suitable for treating high levels of LDL-C and triglycerides.In certain embodiments, administering one or more additional therapeutic agents together with the compounds described herein provides a synergistic effect.In certain embodiments, administering one or more additional therapeutic agents together provides an additive effect.

[0112] 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 target disorder in an animal patient. In this context, the combined amount is a "therapeutically effective amount" if, when combined, they are sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder; cure the disorder; reverse, completely halt, or slow the progression of the disorder; or reduce the risk of worsening the disorder. Typically, such amounts can be determined by one skilled in the art, for example, by starting from the dosage ranges described herein for the compound or salt, or from the approved or otherwise published dosage ranges for the other pharmaceutically active compound.

[0113] The pharmaceutical compositions herein may, where appropriate, include one or more additional active ingredients; examples of combinations of the compounds herein (or pharmaceutically acceptable salts thereof) with one or more additional active ingredients are described herein.

[0114] The present disclosure further relates to combination therapy in which a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a second active ingredient are administered simultaneously, sequentially, or in admixture 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.

[0115] In one aspect, a compound herein, or a pharmaceutically acceptable salt thereof (e.g., for use as a medicament for the treatment of one of the diseases or conditions enumerated herein, such as cardiovascular disease), and i) statins, ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors, iv) P2Y12 inhibitors, v) citrate lyase inhibitors, and vi) an antihypertensive, and at least one active ingredient selected from:

[0116] In a further aspect herein, a compound herein, or a pharmaceutically acceptable salt thereof, is provided (e.g., for use as a medicament for the treatment of one of the diseases or conditions enumerated herein, such as cardiovascular disease); i) statins, ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors, iv) P2Y12 inhibitors, v) citrate lyase inhibitors, vi) an antihypertensive agent; and at least one active ingredient selected from:

[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 statin, wherein the statin is selected from atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin. In another aspect, the statin is rosuvastatin (Crestor).

[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 a cholesterol absorption inhibitor, wherein the cholesterol absorption inhibitor is selected from ezetimibe (ezetrol).

[0119] 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 (Farxiga or Forxiga).

[0120] In another embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient selected from a P2Y12 inhibitor is provided, wherein the P2Y12 inhibitor is selected from Brilinta (ticagrelor) and clopidogrel (Plavix).

[0121] 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).

[0122] 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.

[0123] 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 antihypertensive drug. In some aspects, the antihypertensive drug is selected from valsartan (Diovan), metoprolol (Lopressor), HCTZ (hydrochlorothiazide), olmesartan (Benicar), lisinopril (Prinivil, Zestril), amlodipine besylate (Norvasc), candesartan, or a calcium channel blocker, or a combination thereof. In another aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 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,

[0124] 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.

[0125] 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 simultaneously, separately, or sequentially with at least one additional active agent, wherein the at least one additional active agent is selected from ezetimibe, rosuvastatin, dapagliflozin, and ticagrelor.

[0126] Further embodiments The following embodiments may be applicable to all aspects described above or may relate to a single aspect. The embodiments may be combined together in any combination.

[0127] A A has the following formula:

[0128] [ka] where the dashed line indicates the point of attachment to B.

[0129] X 1 is selected from O, S, or NH.

[0130] X 2 is either N or CH.

[0131] X 3 is N or CR A3 Either:

[0132] X 1 is NH and X 2 If is CH, then X 3 is CR A3 is.

[0133] X 1 In some embodiments, X 1 is O.

[0134] In some embodiments, X 1 is S.

[0135] In some embodiments, X 1 is NH and X 1 is NH and X 2 If is CH, then X 3 is CR A3 is.

[0136] X 2 In some embodiments, X 2 is N.

[0137] In some embodiments, X 2 is CH.

[0138] X 3 In some embodiments, X 3 is N.

[0139] In some embodiments, X 3 is CR A3 is.

[0140] In some embodiments, A is selected from one of formulas A1-A3 below.

[0141] [Table 5] (In the formula, the wavy line indicates the point of attachment to B.)

[0142] In further embodiments, A is selected from one of the following formulae A4-A14:

[0143] [Table 6-1]

[0144] [Table 6-2]

[0145] X 1 If is NH, R A1 is X 4 and R A2 is X 5 is.

[0146] X 2 is N and X 1 is O or S, R A1 is X 4 and R A2 is X 5 is.

[0147] X 2 is CH and X 1 If S, then R A1 is X 4 and R A2 is X 5 is.

[0148] X 2 is CH and X 1 If is O, then R A1 is X 5 and R A2 is X 4 is.

[0149] X 4 X 4 teeth, (i) H, (ii) Halo (iii) CN, (iv) C1 alkyl optionally substituted with one or more OH, CN, or one or more halo groups; or (v) C1 alkoxy optionally substituted with one or more halo groups.

[0150] In some embodiments, X 4 When X is halo, it is Cl, Br, or F. In some embodiments, X 4 When X is halo, it is Br. 4 When X is an optionally substituted C alkyl, it is methyl, CHOH, CHF, CHF, CHBr, CHBr, CHCl, or CHCl. 4 When is optionally substituted C1 alkoxy, it is OMe, OCHF2, or OCF3.

[0151] In some embodiments, X 4 is selected from H, halo, CN, or methyl optionally substituted with one or more OH groups or one or more halo groups.

[0152] In some embodiments, X 4 is selected from H, CN, CH2OH, Br, or methyl.

[0153] In some embodiments, X 4 is H.

[0154] X 5 In some embodiments, X 5 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Alkyl acyl, C 1~6 C optionally substituted with alkoxy or one or more halo groups; 1~6 hydrocarbons, (v) C 1~6 Alkylamide, C 1~6 alkylphosphonyl, or C optionally substituted with one or more halo groups; 1~6 Alkoxy, (vi) C 1~6 alkylamino, (vii)C 1~6 thioalkyl, (viii)C 1~6 alkylphosphinyl, or (ix) C 1~6 alkylphosphonyl.

[0155] In some embodiments, X 5 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Alkyl acyl, C 1~6 C optionally substituted with alkoxy or one or more halo groups; 1~6 hydrocarbons, (v) C 1~6 alkylamide or C optionally substituted with one or more halo groups 1~6 Alkoxy, (vi) C 1~6 alkylamino, (vii)C 1~6 thioalkyl, or (viii)C 1~6 alkylphosphinyl.

[0156] In some embodiments, X 5 teeth, (i) H, (ii) halo, (iii) C optionally substituted with one or more OH or one or more halo groups. 1~6 Alkyl, (iv) C optionally substituted with one or more halo groups. 1~6 Alkoxy, (v) C 3~5 cycloalkyl, (vi) C 1~6 thioalkyl, or (vii)C 1~6 alkylphosphinyl.

[0157] In some embodiments, X 5 is H.

[0158] In some embodiments, X 5 When is halo, it is F, Cl, or Br.

[0159] In some embodiments, X 5 C with optional substitution 1~6 When it is alkyl, it is methyl, ethyl, propyl, CHOH, CHF, CHF, CF. In further embodiments, it is methyl, ethyl, CHOH, or CF.

[0160] In some embodiments, X 5 C with optional substitution 1~6 When it is alkoxy, it is OMe, O-ethyl, O-propyl, OCF2H, OCF3, OCFH2. In a further embodiment, it is OMe, OCF3, OCF2H.

[0161] In some embodiments, X 5 When is cycloalkyl, it is cyclopropyl or cyclobutyl. In some embodiments, it is cyclopropyl.

[0162] In some embodiments, X 5 C 1~6When it is thioalkyl, it is S-CH3, S-CH2CH3, or S-CH2CH2CH3. In some embodiments, it is S-CH3.

[0163] In some embodiments, X 5 C 1~6 When it is alkylphosphinyl, it is P(=O)Me2, P(=O)(CH2CH2)2, or P(=O)(CH3)(CH2CH2). In some embodiments, it is P(=O)Me2.

[0164] In a further embodiment, X 5 H, CH2OH, OCF2H, OCF 3, Selected from CF3, F, Cl, Br, ethyl, cyclopropyl, methyl, P(=O)Me2, S-CH3, or OMe.

[0165] R A3 In some embodiments, R A3 teeth, (i) H, (ii) Halo (iii) CN, (iv) C optionally substituted by OH or one or more halo groups 1~6 Alkyl, (v) C optionally substituted with OH or one or more halo groups 2~6 alkenyl, (vi) C optionally substituted by OH or one or more halo groups 2~6 alkynyl, or (vii) C optionally substituted with one or more halo groups 1~6 Alkoxy.

[0166] In some embodiments, R A3 is H.

[0167] In some embodiments, R A3 is CN.

[0168] In some embodiments, R A3 When is halo, it is selected from Cl, Br, or F.

[0169] In some embodiments, R A3 C with optional substitution 1~6 When it is alkyl, it is methyl, ethyl, propyl, CF, CFH, CH-CFH, or CH-cyclopropyl. In further embodiments, it is CF, CH-CFH, CFH, or CH-cyclopropyl.

[0170] In some embodiments, R A3 C 2~6 When it is alkenyl, it is CH=CH2, CH=CHCH3, or CH2CH=CH2. In some embodiments, it is CH=CH2.

[0171] In some embodiments, R A3 C 2~6 When it is alkynyl, it is propargyl, acetylene, or 1-butyne. In some embodiments, it is propargyl.

[0172] In some embodiments, R A3 C with optional substitution 1~6 When it is alkoxy, it is OCF3, OCF2H, or OMe.

[0173] In some embodiments, R A3 is selected from H, Cl, Br, OMe, CH=CH, OCF, OCFH, F, CH-CFH, CF, CFH, CN, propargyl, CH-cyclopropyl. A3 is selected from H, Cl, Br, or OMe.

[0174] In some embodiments, A has the following formula:

[0175] [ka] wherein X 2 is selected from N and CH, R A1 is selected from H, CN, CH2OH, OCHF2, methyl, or Br.

[0176] In a further embodiment, A has the formula:

[0177] [ka] wherein R A1 is selected from H, CN, CH2OH, methyl, OCHF2, or Br.

[0178] In some embodiments, A has the following formula:

[0179] [ka] It is of the type.

[0180] In some embodiments, A has the following formula:

[0181] [ka] It is of the type.

[0182] In some embodiments, A has formula (A2):

[0183] [ka] wherein X 2 is selected from N or CH, and X 2 If N, then X 3 is N or CR A3 Either X 2 If is CH, then X 3 is CR A3 or N and R A1 is selected from H, methyl or Br, and R A2is H, CN, or CHOH, and R A3 is H.

[0184] In some embodiments, A has the following formula:

[0185] [ka] wherein R A2 teeth, (i) H, (ii) halo, (iii) C optionally substituted with one or more OH or one or more halo groups. 1~6 Alkyl, (iv) C optionally substituted with one or more halo groups. 1~6 Alkoxy, (v) C 3~5 cycloalkyl, (vi) C 1~6 thioalkyl, (vii)C 1~6 alkylphosphinyl, or (viii) CN.

[0186] In a further embodiment, when A is of the formula above, R A2 are H, Br, CH2OH, C 1~6 alkyl, and CN.

[0187] In a further embodiment, when A is of the formula above, R A2 H, CH2OH, C 1~6 alkyl, and CN.

[0188] In some embodiments, A has the following formula:

[0189] [ka] wherein R A3 is selected from H, halo, or OMe; R A2is selected from H, Br, and CH2OH.

[0190] In some embodiments, A has the following formula:

[0191] [ka] wherein R A3 is selected from H, halo, or OMe.

[0192] In a further embodiment, when A is of the formula above, R A3 is H.

[0193] In some embodiments, A has the following formula:

[0194] [ka] wherein X 2 is N or CH, and X 2 If N, then X 3 is N or CR A3 Either X 2 If is CH, then X 3 is CR A3 and R A3 is selected from H, Cl, Br, or OMe, and R A2 is selected from H, CH2OH, OCH3, OCHF2, OCF3, CF3, F, Cl, Br, ethyl, cyclopropyl, methyl, -P(=O)Me2, or -S-CH3.

[0195] In some embodiments, A has the following formula:

[0196] [ka] wherein X 3 is N or CR A3 and R A3 is selected from H, Cl, Br, or OMe, and R A2is selected from H, CH2OH, OCH3, OCHF2, OCF3, CF3, F, Cl, Br, ethyl, cyclopropyl, methyl, -P(=O)Me2, or -S-CH3.

[0197] In some embodiments, A is selected from any one of the following groups listed in the Table:

[0198] [Table 7-1]

[0199] [Table 7-2] (In the formula, the wavy line indicates the point of attachment to B.)

[0200] B In some embodiments, B is represented by formula (B-1):

[0201] [ka] wherein the wavy lines indicate the points of attachment to A and C, and R B1 is H, OH, -OMe, -O-ethyl, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0202] In other embodiments, R B1 is H, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0203] In other embodiments, R B1 is -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0204] In other embodiments, R B1 is H.

[0205] In another embodiment, B is a group represented by formula (B-1a):

[0206] [ka] It is of the type.

[0207] In a further embodiment, B has the formula (B-1b):

[0208] [ka] It is of the type.

[0209] Thus, in some embodiments, the compound of formula (I) is the S,S-enantiomer.

[0210] In some embodiments, B is represented by formula (B-2):

[0211] [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 is alkyl, R A1 is H or halo, then R B2 is C 1~2 Alkyl-OH or CH2C(=O)NHMe.

[0212] In some of these embodiments, R B2 is C 1~2 Alkyl-OH or C 1~3 It is alkyl.

[0213] In some of these embodiments, R B2 is C 1~2 Alkyl-OH or CH2C(=O)NHMe.

[0214] In some embodiments, X 1 is O or S, and R A1 is H or halo, RB2 is C 1~2 Alkyl-OH or CH2C(=O)NHMe.

[0215] In some embodiments, when B is of formula (B-2), it is of the following formula (B-2a):

[0216] [ka] wherein 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 alkyl, and R A1 is H or halo, R B2 is C 1~2 Alkyl-OH or CH2C(=O)NHMe.

[0217] C C optionally replaced by C 5~6 When 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.

[0218] C optionally replaced by C 5~6 When it is heteroaryl, it is (i) 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 optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 1~6 C optionally substituted with alkyl 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, l) P(=O)Me2, m) C(=O)OH or CHC(=O)OH, and / or n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl, which are themselves optionally substituted by one or more groups selected from the group consisting of: 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl or C 5~10 Bridged Heterocyclyl, Spiro C 6~12 Heterocyclyl or spiro C 6~12 carbocyclyl, (ii) C(=O)OH, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamides and di-C 1~6 alkylsulfonamide.

[0219] C is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 When a heterocyclyl is substituted, it may have several substituents. The substituents are: a) one or two =O groups, b) one or more halo groups, CN, NH2, c) one or more C, each optionally substituted with one or more halo groups 1~6 Alkyl, C 1~6 Alkoxy or C 1~6 Alkyl esters, d) C with optional methyl substituents 5~6 Heterocyclyl or C 5~6 heteroaryl, e) C optionally substituted by one or more halo atoms 6~10 Carboaryl, f) P(=O)Me2, or g) C(=O)OH or CH2C(=O)OH.

[0220] In some embodiments, one substituent on C is in the para position.

[0221] 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.

[0222] C optionally replaced by C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 In other embodiments substituted by heterocyclyl, it may be optionally substituted by optionally substituted phenyl, optionally substituted pyridyl, optionally substituted imidazolidinyl, optionally substituted dihydroquinolinyl, optionally substituted benzimidazolyl, or optionally substituted imidazopyridinyl. These groups themselves may 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 5~6It may be optionally substituted by heterocyclyl (with an optional methyl substituent), phenyl substituted by F at the para position, C(=O)OH, CHC(=O)OH, tetrazolyl, pyrazolyl, triazolyl, or P(=O)Me.

[0223] In other embodiments, when C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, it may have several substituents. The substituents are optionally substituted C 5~10 Heteroaryl or C 5~10 heterocyclyl, which itself may 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 5~6 Heterocyclyl (with optional methyl substituent), phenyl optionally substituted with one or two halo groups, C(=O)OH, CHC(=O)OH, tetrazolyl, pyrazolyl, triazolyl, a pyridine ring, optionally substituted by 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.

[0224] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are: i) a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) one or more 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 1~6Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 1~6 C optionally substituted with alkyl 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, l) P(=O)Me2, m) C(=O)OH, CHC(=O)OH, and / or n) C is optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; 6~10 Carboaryl, C 5~10 Heteroaryl, C 5~10 heterocyclyl, (ii) C(=O)OH, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamides and di-C 1~6 one or more groups selected from alkylsulfonamides.

[0225] 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 themselves are selected from a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) one or more 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 optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 1~6 C optionally substituted with alkyl 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, l) P(=O)Me2, m) C(=O)OH, CHC(=O)OH, and / or n) optionally substituted with one or more groups selected from 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 5~10 Heteroaryl, C 5~10 heterocyclyl, which themselves are selected from a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) one or more 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 1~6C optionally substituted with alkyl 5~6 heteroaryl, and / or g) optionally substituted with one or more groups selected from C(=O)OH, CHC(=O)OH.

[0227] In another embodiment, C is a group represented by formula (C-1):

[0228] [ka] wherein D is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 Heterocyclyls, which themselves may contain one or two =O groups, one or more halo groups, CN, NH, OH, one or more C 1~4 alkyl groups (alkyl optionally substituted with halo), C optionally substituted with halo 1~6 Alkoxy, C 1~6 Alkyl esters, C 5~6 Optionally substituted by heterocyclyl (with optional methyl substituent), C(=O)OH, CHC(=O)OH, P(=O)Me, tetrazolyl, pyrazolyl, or triazolyl. In some embodiments, the optional substituents are ═O, CN, F, Cl, Br, methyl, ethyl, OMe, C(=O)OH, ethoxy, O-CF, OCHF, CHF, CHCF, CF, P(=O)Me, and C 1~2 In a further embodiment, the optional substituents are selected from ═O, methyl, CN, Cl, F, OMe, CF, C(═O)OH, OCF, OCHF, or pyrimidinyl having a methyl substituent.

[0229] When C is (C-1), in some embodiments, D is an optionally substituted pyridin-2(1H)-one. In some embodiments, the optional substituents are selected from OMe, Cl, one or more F groups, methyl, CF, I, OCF, OCHF, C(=O)OH, CN, pyrazolyl, triazolyl, tetrazolyl, phenyl with an optional F substituent in the para position, piperazinyl with a methyl substituent, or pyrimidinyl with a methyl substituent. In some embodiments, the pyridin-2(1H)-one is unsubstituted.

[0230] When C is (C-1), in some embodiments, D is an optionally substituted 6-membered heteroaryl containing one or two N atoms, one of which is attached to the pyridyl in (C-1), which is substituted at the ortho position with =0, and other optional substituents selected from methyl, OMe, piperazine substituted with methyl, pyrimidinyl having a methyl substituent, C(=O)OH, Cl, phenyl substituted with fluoro, CN, CF3, one or more F groups, pyrazolyl, triazolyl, tetrazolyl, OCHF2, or O-CF3.

[0231] In some embodiments, when C is (C-1), D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, one of which is bonded to the pyridyl in (C-1), and the pyridyl is substituted at the ortho position with =0, and the optional substituent is i) one =O group, ii) One or two C's that can branch 1~4 alkyl groups, iii) OMe, iv) piperazinyl or pyrimidinyl optionally substituted with methyl; v) C(=O)OH, vi) Cl, vii) one or more F; viii) phenyl optionally substituted with one or more fluoro; ix) CN, x)CF3, xi) OCF3, xii) OCHF2, xiii) tetrazolyl, pyrazolyl, triazolyl, xiv) NH2, xv) pyridinyl, xvi) CH2OH, xvii) OH, or xviii) P(=O)Me2.

[0232] In some embodiments, when C is (C-1), D is either an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl containing one or two N atoms, one of which is bonded to the pyridyl in (C-1), and the pyridyl is substituted at the ortho position with =0, and the optional substituent is i) methyl, ii) OMe, iii) pyrimidinyl substituted by methyl; iv) C(=O)OH, v) Cl, vi) CN, vii) one or more F groups; viii) CF3, ix) -O-CF3, or x) -OCHF2.

[0233] In some embodiments, C is of formula (C-1) and D is an optionally substituted phenyl or pyridyl, where one or two optional substituents are present selected from =O, methyl, OMe, Cl, CN, one or more F groups, C(=O)OH, CF3, OCF3, OCHF2, or pyrimidinyl substituted with methyl.

[0234] In another embodiment, D has formula (D-1):

[0235] [ka] wherein RD1 , R D2 , R D3 , and R D4 one or two of which are C optionally substituted by 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 heteroaryl, C(=O)OH, =O, halo, NH2, CN, or phenyl optionally substituted with one or more halo atoms; Or R D3 and R D4 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 Or R D1 and R D2 forms an optionally substituted 5- or 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, CN, P(=O)Me2, halo, and C(=O)OH; Or R D1 , R D2 , R D3 , and R D4 are all H.

[0236] In some embodiments, R D2 and R D3 form an optionally substituted 5- or 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being halo, CN, OH, P(=O)Me2, C(=O)OH, C(=O) optionally substituted by one or more halo groups; 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 In further embodiments, the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2, and C(=O)OH.

[0237] In another embodiment, R D1 , R D2 , R D3 , and R D4 one or two of which are C optionally substituted by 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, C(=O)OH, halo, or CN, the remainder being H.

[0238] 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) pyrimidinyl substituted by methyl; iv) tetrazolyl, v) C(=O)OH, vi) halo, vii)CN, viii) CF3, ix) -O-CF3, or x)-OCHF 2, Selected from R D1 , R D2 , R D3 , and R D4 The remainder is H.

[0239] In another embodiment, R D1 , R D2 , R D3 , and R D4 is selected from methyl, OMe, halo, C(=O)OH, CN, CF3, tetrazolyl, methyl-substituted pyrimidinyl, OCF3, and OCHF2; D1 , R D2 , R D3 , and R D4 The remainder is H.

[0240] In one embodiment, R D1 , R D2 , R D3 , and R D4 All of them are H.

[0241] In another embodiment, R D3 is selected from H, methyl, OMe, —C(═O)OH, Cl, CN, OCHF, OCHF, tetrazolyl, and pyrimidinyl optionally substituted with methyl; R D1 , R D2 , and R D4 are all H.

[0242] 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.

[0243] In another embodiment, R D3 and R D4 forms an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being selected from OH, CN, P(=O)Me2, methyl, OMe, halo, and C(=O)OH.

[0244] In some embodiments, R D3 and R D4 forms an optionally substituted phenyl ring or an optionally substituted pyridine ring.

[0245] In some embodiments, R D3 and R D4 forms an unsubstituted phenyl ring or an unsubstituted pyridine ring.

[0246] In another embodiment, R D1 and R D2forms an optionally substituted 5- or 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, CN, and C(═O)OH.

[0247] In some embodiments, R D1 and R D2 form an optionally substituted 5-membered heterocyclic or heteroaromatic ring. In some embodiments, R D1 and R D2 form a 5-membered heterocyclic or heteroaromatic ring containing one sulfur atom. D1 and R D2 forms an unsubstituted thiophene.

[0248] In some embodiments, C is of formula (C-1), D is an optionally substituted phenyl or piperidyl, and one or two optional substituents are present selected from F, OCHF2OCF3, or OMe. In some embodiments, the optionally substituted phenyl is substituted with one or two substituents at the ortho position.

[0249] In some embodiments, D is an optionally substituted 6-membered heterocyclyl or heteroaryl containing two N groups, where the optional substituents are selected from =0, methyl, -OMe, halo, -C(=0)OH, CN, CF, and -OCHF. In some embodiments, the optional substituent is =0. In some embodiments, D is a 6-membered heteroaryl containing two nitrogen atoms with =0 substituents in the ortho positions.

[0250] In some embodiments, C has the following formula:

[0251] [ka] and D is as described in the above embodiment.

[0252] In another embodiment, D is a group represented by formula (D-2):

[0253] [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 either both H or together they are CH2-, R D6a is selected from H, ═O, methyl, CHOH, or C(═O)OH; R D6a If =O, R D6b does not exist, RD7a is selected from H, ═O, methyl, CHOH, or C(═O)OH; R D7b is H and R D7a If =O, R D7b does not exist or Or R D6a and R D7a together form a phenyl ring or a C heteroaromatic ring optionally substituted by CN, P(=O)Me2, or C(=O)OH, and R D6b and R D7b does not exist.

[0254] In some embodiments, C is of formula (C-1), D is of formula (D-2), and X D is NR D5a and R D5a is methyl.

[0255] 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, and R D7b is H or RD7a If =O, R D7b is absent. In a further embodiment, R D7a is =O.

[0256] In some embodiments, C is of formula (C-1), D is of formula (D-2), and X D is NR D5a and R D5a is methyl and R D7a is selected from H and ═O, and R D6a is selected from H and ═O, and R D7a If =O, R D6a and R D6b is H and R D7b does not exist, and R D6a If =O, R D7a and R D7b is H and R D6b does not exist.

[0257] In another embodiment, R D6a and R D7a together form a phenyl ring or a C6 heteroaromatic ring optionally substituted by CN, P(=O)Me2, or -C(=O)OH, and R D6b and R D7b does not exist.

[0258] In some embodiments, R D6a and R D7a form an unsubstituted phenyl 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 does not exist.

[0259] In some embodiments, X D is NR D5a and R D5a is selected from H or methyl, R D6a and R D7a form an unsubstituted phenyl ring, and R D6band R D7b does not exist.

[0260] In some embodiments, X D is NR D5a and R D5a is H or methyl.

[0261] In some embodiments, X D is CR D5a R D5b and R D5a is H or methyl, and R D5b is H. In a further embodiment, R D5a and R D5b is H.

[0262] In some embodiments, R D7a is H, C(=O)OH, -CHOH, or =O. In some embodiments, R D7a is ═O or H. R D7b is H or R D7a If =O, R D7b does not exist.

[0263] In some embodiments, R D6a is H or ═O. In some embodiments, R D6a is =O and R D6b does not exist.

[0264] In some embodiments, R D7a If =O, R D6a and R D6b is H and R D7b does not exist, and R D6a If =O, R D7a and R D7b is H and R D6b does not exist.

[0265] In some embodiments, X D is NR D5a and R D5a is H or methyl, and R D6a and R D7atogether form a pyridine or phenyl ring optionally substituted by -C(=O)OH or CN or P(=O)Me2, and R D6b and R D7b does not exist.

[0266] In some embodiments, C is of formula (C-1) and D is of formula (D-3):

[0267] [ka] wherein R D3a is selected from H and methyl; R D3b and R D3c any of which are independently selected from H, halo, CN, OH, P(=O)Me2, C(=O)OH, C(=O) optionally substituted with one or more halo groups 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 alkyl, or R D3b and R D3c is C 5~6 together form a heteroaryl ring.

[0268] In a further embodiment, R D3a is methyl and R D3b and R D3c is H.

[0269] In another embodiment, R D3a is H and R D3b and R D3c together form a thiophene ring.

[0270] In some embodiments, D is selected from any one of the following groups listed in the Table:

[0271] [Table 8-1]

[0272] [Table 8-2]

[0273] [Table 8-3]

[0274] [Table 8-4]

[0275] [Table 8-5]

[0276] In further embodiments, D is selected from any one of the following groups listed in the Table:

[0277] [Table 9-1]

[0278] [Table 9-2]

[0279] [Table 9-3]

[0280] [Table 9-4]

[0281] In another embodiment, C is a group represented by formula (C-2):

[0282] [ka] wherein R C7 , RC8 , R C9 , and R C10 one or two of R are selected from methyl, OMe, halo, OCHF, C(=O)OH, piperazine or pyrimidinyl (optionally substituted with methyl), optionally substituted phenyl (the optional substituents are methyl or halo), CN, CF, -OCF, tetrazolyl, pyrazolyl, or triazolyl; C7 , R C8 , R C9 , and R C10 The remainder is H or R C9 and R C10 forms an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being 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.

[0283] In one embodiment, C has the formula (C-2), and R C7 , R C8 , R C9 , and R C10 All of them are H.

[0284] In another embodiment, R C7 , R C8 , R C9 , and R C10 one or two of which may be independently is selected from methyl, Cl, OMe, phenyl substituted with F at the para position, -C(=O)OH, CN, OCF3, OCHF2, CF3, F, pyrazolyl, triazolyl, tetrazolyl, pyrimidinyl substituted with methyl, piperazinyl substituted with methyl, and R C7 , R C8 , R C9 , and R C10 The remainder of R is H. In a further embodiment, R C7 , R C8 , R C9 , and RC10 is independently selected from methyl, Cl, OMe, CN, OCF, CF, OCHF, C(=O)OH, or pyrimidinyl substituted by methyl; R C7 , R C8 , R C9 , and R C10 The remainder is H.

[0285] In another embodiment, R C7 and R C9 is independently selected from H, OCHF, methyl, -OMe, Cl, -C(=O)OH, piperazinyl optionally substituted with methyl, pyrimidinyl optionally substituted with methyl, optionally substituted phenyl (the optional substituent is F), CN, CF, -OCF, F, pyrazolyl, triazolyl, or tetrazolyl, and the other is H; C10 and R C8 is H. In another embodiment, R C7 and R C9 one of R is independently selected from H, methyl, Cl, CF, OCHF, OMe, CN, OCF, CN, C(=O)OH, or pyrimidinyl substituted with methyl, and the other is H; C10 and R C8 is H.

[0286] In another embodiment, R C7 is selected from H, methyl, Cl, OMe, CN, OCF3, OCHF2, CF3, and R C8 , R C9 , and R C10 are all H.

[0287] In another embodiment, R C9 is selected from H, CN, OMe, OCHF, Cl, C(=O)OH, tetrazolyl, or pyrimidinyl substituted by methyl; R C7 , R C8 , and R C10 are all H.

[0288] In another embodiment, R C9 and RC10 together form a phenyl or pyridyl ring. C7 and R C8 together form a thiophene ring.

[0289] In another embodiment, C is selected from any one of the following groups listed in the table:

[0290] [Table 10-1]

[0291] [Table 10-2]

[0292] [Table 10-3]

[0293] ABC In other embodiments, the compound of formula ABC has formula (IA):

[0294] [ka] wherein X 1 , X 2 , X 3 , R A1 , R A2 , and C are as defined above.

[0295] In a further embodiment, when the compound of formula ABC is of formula (IA), it is of formula (I-A1), (I-A2), or (I-A3).

[0296] In some embodiments, formula (IA) has formula (I-A1):

[0297] [ka] wherein X 2 is either N or CH, and X 3 is N or CR A3 Either X 2 If is CH, then X 3 is CR A3 is.

[0298] R A1 is X 4 and R A2 is X 5 is.

[0299] In some embodiments, formula (IA) has formula (I-A2):

[0300] [ka] wherein X 2 is either N or CH, and X 2 If is CH, R A1 is X 5 and R A2 is X 4 and X 2 If N, then R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 Either:

[0301] In some embodiments, formula (IA) has formula (I-A3):

[0302] [ka] wherein X 2 is either N or CH, and X 2 If N, then R A1 is X 4 and R A2 is X 5 and X 2 If is CH, R A1is X 4 and R A2 is X 5 X 3 is N or CR A3 Either:

[0303] In some embodiments, when ABC is of formula (IA), (I-A1), (I-A2), or (I-A3), X 4 is selected from the group consisting of H, halo, CN, C alkyl optionally substituted with one or more OH, CN, or one or more halo groups, or C alkoxy optionally substituted with one or more halo groups. 4 is selected from H, CN, CH2OH, Br, or methyl.

[0304] In some embodiments, when ABC is of formula (IA), (I-A1), (I-A2), or (I-A3), X 5 is H, one or more halo groups, CN, optionally OH, CN, C 1~6 Alkyl acyl, C 1~6 C substituted by alkoxy or one or more halo groups 1~6 Hydrocarbons, optionally C 1~6 Alkylamide, C 1~6 alkylphosphonyl, or C substituted by one or more halo groups; 1~6 Alkoxy, C 1~6 Alkylamino, C 1~6 Thioalkyl, C 1~6 Alkylphosphinyl, or C 1~6 In a further embodiment, X is selected from the group consisting of alkylphosphonyl. 5 H, CH2OH, OCF2H, OCF 3、 Selected from CF3, F, Cl, Br, ethyl, cyclopropyl, methyl, P(=O)Me2, S-CH3-CN, or OMe.

[0305] In some embodiments, when ABC is of formula (IA), (I-A1), (I-A2), or (I-A3), X 5is H, one or more halo groups, CN, C 1~6 Hydrocarbons (OH, CN, C 1~6 Alkyl acyl, C 1~6 alkoxy, or optionally substituted with one or more halo groups), C 1~6 Alkoxy (C 1~6 alkylamido or optionally substituted with one or more halo groups), C 1~6 Alkylamino, C 1~6 Thioalkyl, or C 1~6 In a further embodiment, X is selected from the group consisting of alkylphosphinyl. 5 H, CH2OH, OCF2H, OCF 3, CF3, F, Cl, Br, ethyl, cyclopropyl, methyl, P(=O)Me2, S-CH 3- CN, or OMe.

[0306] In some embodiments, when ABC is of formula (IA), (I-A1), (I-A2), or (I-A3), R A3 H, halo, CN, C 1~6 alkyl (optionally substituted with OH or one or more halo groups), C 2~6 alkenyl (optionally substituted with OH or one or more halo groups), C 2~6 alkynyl (optionally substituted with OH or one or more halo groups), or C 1~6 In a further embodiment, R is selected from alkoxy (optionally substituted with one or more halo groups). A3 is selected from H, Cl, Br, OMe, CH=CH, OCF, OCFH, F, CH-CFH, CF, CFH, CN, propargyl, CH-cyclopropyl. A3 is selected from H, Cl, Br, or OMe.

[0307] In some embodiments, when ABC is of formula (IA), (I-A1), (I-A2), or (I-A3), C is C 6~10 Carboaryl, C 5~6Heteroaryl, or C 5~10 heterocyclyl, which groups are selected from the group consisting of: (i) The following groups: a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) one or more 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 optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 1~6 C optionally substituted with alkyl 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, l) P(=O)Me2, m) C(=O)OH or CHC(=O)OH, and / or n) C is optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged heterocycles, spiro C 6~12 Heterocyclyl or spiro C 6~12 carbocyclyl, (ii) C(=O)OH, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamides and di-C 1~6 alkylsulfonamide.

[0308] In other embodiments, ABC has the formula (IB):

[0309] [ka] wherein X 1 , X 2 , X 3 , R A1 , R A2 and D is as defined above.

[0310] In a further embodiment, when ABC is of formula (IB), it is of formula (I-B1):

[0311] [ka] wherein X 2 is either N or CH, and X 3 is N or CR A3 Either X 2 If is CH, then X 3 is CR A3 is.

[0312] R A1 is X 4 and R A2 is X 5 In the formula, R A3 , X 4 and X 5 is as defined above.

[0313] In a further embodiment, when ABC is of formula (IB), it is of formula (I-B2):

[0314] [ka] wherein X 2 is either N or CH, and X 2 If is CH, R A1 is X 5 and R A2 is X 4 and X 2 If N, then R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3 , X 4 and X 5 is as defined above.

[0315] In a further embodiment, when ABC is of formula (IB), it is of formula (I-B3):

[0316] [ka] wherein X 2 is either N or CH, and X 2 If N, then R A1 is X 4 and R A2 is X 5 and X 2 If is CH, R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3 , X 4 and X 5 is as defined above.

[0317] In some embodiments, when ABC is of formula (IB), (I-B1), (I-B2), or (I-B3), D is C 6~10 Carboaryl, C 5~10 Heteroaryl, or C 5~10 heterocyclyl, each of which is itself one or two =O groups, one or two C groups which may be branched 1~4 Optionally substituted by alkyl groups, CHF, CHCF, OCHF, OMe, piperazinyl, or pyrimidinyl optionally substituted with methyl, C(=O)OH, Cl, one or more F, phenyl optionally substituted with one or more fluoro, CN, CF, OCF, tetrazolyl, pyrazolyl, triazolyl, NH, pyridinyl, CHOH, OH, or P(=O)Me. In a further embodiment, D is optionally substituted phenyl or an optionally substituted 6-membered heteroaryl containing one or two N atoms. In a further embodiment, the optional substituents are selected from =O, methyl, OMe, pyrimidinyl substituted with methyl, C(=O)OH, Cl, CN, ethyl, one or more F groups, CF, CHF, OCF, or -OCHF.

[0318] In other embodiments, ABC has the formula (IC):

[0319] [ka] wherein X 1 , X 2 , X 3 , R A1 , R A2 , R D1 , R D2 , R D3 , and R D4 is as defined above.

[0320] In a further embodiment, when ABC is of formula (IC), it is of formula (I-C1):

[0321] [ka] wherein X 2 is either N or CH, and X 3 is N or CR A3 Either X 2 If is CH, then X 3 is CR A3 is.

[0322] R A1 is X 4 and R A2 is X 5 is 。 In the formula, R A3 , X 4 and X 5 is as defined above.

[0323] In a further embodiment, when ABC is of formula (IC), it is of formula (I-C2):

[0324] [ka] wherein X 2 is either N or CH, and X 2 If is CH, R A1 is X 5 and R A2 is X 4 and X 2 If N, then R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3 , X 4 and X 5 is as defined above.

[0325] In a further embodiment, when ABC is of formula (IC), it is of formula (I-C3):

[0326] [ka] wherein X 2 is either N or CH, and X 2 If N, then R A1 is X 4 and R A2 is X 5 and X 2 If is CH, R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3 , X 4 and X 5 is as defined above.

[0327] When ABC is of formula (IC), (I-C1), (I-C2), or (I-C3), in one embodiment, R D1 , R D2 , R D3 , and R D4 one or two of which are optionally substituted by 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, C(=O)OH or CHC(=O)OH, =O, halo, NH or CN, phenyl optionally substituted with one or more halo atoms, the remainder being H; or R D3 and R D4 forms an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, and C(=O)OH; or R D1 and R D2forms an optionally substituted 5- or 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, CN, and C(═O)OH.

[0328] In a further embodiment, R D1 , R D2 , R D3 , and R D4 wherein one or two of are selected from methyl, OMe, pyrimidinyl substituted with methyl, tetrazolyl, C(=O)OH, halo, CF3, CN, OCF3, -OCHF2.

[0329] In some embodiments, R D1 , R D2 , R D3 , and R D4 are all H.

[0330] In some embodiments, R D3 and R D4 forms an unsubstituted phenyl ring or an unsubstituted pyridine ring.

[0331] In some embodiments, R D1 and R D2 form an unsubstituted 5-membered heterocyclic or heteroaromatic ring.

[0332] In some embodiments, ABC has the formula (ID):

[0333] [ka] wherein X 1 , X 2 , X 3 , R A1 , R A2 , X D , R D6a , R D6b , R D7a , and R D7b is as defined above.

[0334] In some embodiments, when ABC is of formula (ID), it is of formula (I-D1):

[0335] [ka] wherein X 2 is either N or CH, and X 3 is N or CR A3 Either X 2 If is CH, then X 3 is CR A3 is.

[0336] R A1 is X 4 and R A2 is X 5 In the formula, R A3 , X 4 and X 5 is as defined above.

[0337] In some embodiments, when ABC is of formula (ID), it is of formula (I-D2):

[0338] [ka] wherein X 2 is either N or CH, and X 2 If is CH, R A1 is X 5 and R A2 is X 4 and X 2 If N, then R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3 , X 4 and X 5 is as defined above.

[0339] In some embodiments, when ABC is of formula (ID), it is of formula (I-D3):

[0340] [ka] wherein X 2 is either N or CH, and X 2 If N, then R A1 is X 4 and R A2 is X 5 and X 2 If is CH, R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3 , X 4 and X 5 is as defined above.

[0341] In some embodiments, when ABC is (I-D), (I-D1), (I-D2), or (I-D3), 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 either both H or together they are -CH2-, and R D6a is selected from H, ═O, methyl, —CHOH, or —C(═O)OH; R D6a If =O, R D6b does not exist, and R D7a is selected from H, ═O, methyl, —CHOH, or —C(═O)OH; R D7b is H or R D7a If =O, R D7b does not exist or R D6a and R D7atogether form a phenyl ring or a C heteroaromatic ring optionally substituted by CN, P(=O)Me2, or C(=O)OH, and R D6b and R D7b does not exist.

[0342] In a further embodiment, R D6a and R D6b If is H, then R D7a is selected from =O, C(=O)OH, or CHOH; R D7a If =O, R D7b does not exist, and R D7a is C(=O)OH or CHOH, R D7b is H. In another embodiment, R D7a If is H, then R D7b is H and R D6a is =O and R D6b does not exist.

[0343] In some embodiments, R D6a and R D7a together form a phenyl ring or a C heteroaromatic ring optionally substituted by CN, C(=O)OH, or P(=O)Me2, and R D6b and R D7b does not exist.

[0344] In some embodiments, R D6a and R D7a form an unsubstituted phenyl ring or an unsubstituted pyridine ring, and R D6b and R D7b does not exist.

[0345] In some embodiments, ABC has the formula (IE):

[0346] [ka] wherein X 1 , X 2 , X 3 , R A1 , R A2 , RD3a , R D3b and R D3c is as defined above.

[0347] In some embodiments, when ABC is of formula (IE), it is of formula (I-E1):

[0348] [ka] wherein X 2 is either N or CH, and X 3 is N or CR A3 Either X 2 If is CH, then X 3 is CR A3 is.

[0349] R A1 is X 4 and R A2 is X 5 In the formula, R A3 , X 4 and X 5 is as defined above.

[0350] In some embodiments, when ABC is of formula (IE), it is of formula (I-E2):

[0351] [ka] wherein X 2 is either N or CH, and X 2 If is CH, R A1 is X 5 and R A2 is X 4 and X 2 If N, then R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3, X 4 and X 5 is as defined above.

[0352] In some embodiments, when ABC is of formula (IE), it is of formula (I-E3):

[0353] [ka] wherein X 2 is either N or CH, and X 2 If N, then R A1 is X 4 and R A2 is X 5 and X 2 If is CH, R A1 is X 4 and R A2 is X 5 X 3 is N or CR A3 In the formula, R A3 , X 4 and X 5 is as defined above.

[0354] In some embodiments, when ABC is (I-E), (I-E1), (I-E2), or (I-E3), R D3a is selected from H and methyl; R D3b and R D3c are independently selected from H, halo, CN, OH, P(=O)Me2, C(=O)OH, C optionally substituted with one or more halo groups. 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 alkyl, or R D3b and R D3c is C 5~6 together form a heteroaryl ring.

[0355] In some embodiments, R D3ais methyl and R D3b and R D3c is H.

[0356] In some embodiments, R D3a is H and R D3b and R D3c But C 5~6 When the heteroaryl rings are taken together, they form a thiophene ring.

[0357] In some embodiments, the compound of formula (I) is selected from the following in Table 1:

[0358] [Table 11-1]

[0359] [Table 11-2]

[0360] [Table 11-3]

[0361] [Table 11-4]

[0362] [Table 11-5]

[0363] [Table 11-6]

[0364] [Table 11-7]

[0365] [Table 11-8]

[0366] [Table 11-9]

[0367] [Table 11-10]

[0368] [Table 11-11]

[0369] [Table 11-12]

[0370] In some embodiments, the compound is selected from 73, 15, 21, 12, 82, and 83.

[0371] general synthesis Compounds of general formula (IB) can be prepared according to the following schemes 1, 2, 3 and 4. The schemes and procedures described below are illustrative of synthetic routes to compounds of general formula (IB), but are not intended to be limiting. It is understood that the order of transformations as illustrated in schemes 1, 2, 3 and 4 can be varied in various ways. Therefore, the order of transformations illustrated in these schemes is not intended to be limiting.

[0372] Routes for the preparation of compounds of general formula (IB) and corresponding intermediates are described in Schemes 1, 2, 3 and 4.

[0373] [ka]

[0374] Scheme 1: A route for the preparation of compounds of general formula (A9) is illustrated in the scheme, where LG is a leaving group, PG is a protecting group, and Y 1 and Y 2 is CH or N (provided that Y 1 If N, then Y 2 (provided that is CH and vice versa), D, X 1 , X 2 , X 3 , R A1 , and R A2 has the meaning as indicated for general formula (IB) (see above).

[0375] Monoarylated diamines of general formula (A3) can be prepared by reacting a monoprotected diamine (A1) or its corresponding salt with a halogen, such as fluorine, chlorine, or bromine, or with -S(O) as shown in Scheme 1. 1~2 Nucleophilic aromatic substitution (S) between heteroaryl (A2) and a leaving group LG such as Me N Ar) or palladium-catalyzed Buchwald-Hartwig amination. LG is a group such as fluorine, chlorine, or -S(O)Me. N In the Ar approach, diamine (A1) can be reacted with (A2) in the presence of an inorganic base such as K2CO3, Na2CO3, or Cs2CO3, or in the presence of an organic base such as TEA or DIPEA, or without additional base in a polar solvent such as DMSO, NMP, nBuOH, or 1,4-dioxane at temperatures between 100 and 130 °C. The reaction time can vary between 1 and 24 hours. In certain instances, it can be beneficial to apply microwave heating.

[0376] Palladium-catalyzed Buchwald-Hartwig amination can be carried out by any method known in the art. For example, diamine (A1) can be reacted with diamine (A2) in the presence of a palladium catalyst such as Pd PEPPSI-IpentCl [CAS 1612891-29-8], Pd2(dba)3, tBuXPhos Pd G3 [CAS 1447963-75-8], or tBuBrettPhos G3 and a base such as Cs2CO3, NaOtBu, or MTBD in an aprotic solvent such as 1,4-dioxane, DMF, toluene, NMP, or DMA at a temperature between room temperature and 130°C, preferably 65-100°C, for 15-24 hours.

[0377] Diamines of general formula (A1) and heteroaryls of general formula (A2) 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.

[0378] Arylated diamines of general formula (A6) can be obtained from (A3) via copper-catalyzed Ullmann coupling with heterocycles (A4) or via 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 examples, DMCDA, TMEDA, N 1 N 2 N,N-dimethylethane-1,2-diamine or N,N-dimethylglycine may be added to the reaction mixture.

[0379] For Suzuki coupling to (A6), any method known in the art can be applied. For example, (A3) can be reacted with boronic acid derivative (A5) in the presence of a palladium catalyst such as Pd(dtbpf)Cl2 [CAS 95408-45-0] or Pd(dppf)Cl2 [CAS 72287-26-4] and a base such as Cs2CO3, K2CO3 or K3PO4 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.

[0380] 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.

[0381] Primary amines of general formula (A7) can be obtained from monoprotected diamines of general formula (A6) via 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, P.G.W. Huts, T.W. Greene, Greene's Protective Groups in Organic Synthesis 4. th ed., J. Wiley & Sons, 2006.

[0382] The final compound of general formula (A9) can be prepared by reacting a primary amine of general formula (A7) with S N A primary amine of general formula (A7) can be synthesized via Ar or palladium-catalyzed Buchwald-Hartwig amination. Primary amines of general formula (A7) can be reacted with heteroaryls of general formula (A8) bearing a halogen, such as chlorine or bromine, or a leaving group, LG, such as -S(O)Me, using procedures similar to those described for the synthesis of (A3) from (A1) and (A2) in Scheme 1. Heteroaryls of general formula (A8) are either commercially available or can be prepared according to procedures available in the public domain.

[0383] An alternative route to compounds of general formula (A9) starts from the deprotection of diamines of general formula (A3) to give primary amines of general formula (A10), as shown in Scheme 1. For deprotection, the same procedure as described for the synthesis of (A7) from (A6) is applied.

[0384] Next, the primary amine of general formula (A10) is reacted with S N Reaction with heteroaryls of general formula (A8) via Ar or palladium catalyzed Buchwald-Hartwig amination can provide aryl iodides of general formula (A11), applying procedures similar to those described for the synthesis of (A3) from (A1) and (A2) in Scheme 1.

[0385] Final compounds of general formula (A9) can be synthesized from aryl iodides of general formula (A11) via copper-catalyzed Ullmann coupling with heterocycles HD (A4) or via 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.

[0386] Yet another approach to compounds of general formula (A9) is to react a monoprotected diamine (A1) or its corresponding salt with a halogen, such as fluorine, chlorine or bromine, or -S(O) 1~2 A preassembled heteroaryl (A12) having a leaving group LG such as Me and S N Starting via Ar or palladium-catalyzed Buchwald-Hartwig amination, arylated diamines of general formula (A6) are obtained. The applicable procedure is similar to that described for the synthesis of (A3) from (A1) and (A2) in Scheme 1. Heteroaryls of general formula (A12) are either commercially available or can be prepared according to procedures available in the public domain (e.g., via Chang-Lam coupling, see, e.g., Adv. Synth. Catal. 2020, 362, 3311-3331).

[0387] An alternative route for preparing compounds of general formula (A9) and intermediates of general formula (A11) is shown in Scheme 2.

[0388] [ka]

[0389] Scheme 2: Routes for the preparation of compounds of general formula (A9) and intermediate (A11) are illustrated in the scheme, where LG is a leaving group, PG is a protecting group, and Y 1 and Y 2 is CH or N (provided that Y 1 If N, then Y 2 (provided that is CH and vice versa), D, X 1 , X 2 , X 3 , R A1 , and R A2 has the meaning as indicated for general formula (IB) (see above).

[0390] Monoarylated diamines of general formula (A13) are prepared by the reaction of a monoprotected diamine (A1) or its corresponding salt with a heteroaryl (A8) bearing a halogen, such as chlorine or bromine, or a leaving group LG, such as -S(O)Me. N A3 can be obtained via Ar or palladium-catalyzed Buchwald-Hartwig amination. The applicable procedure is similar to that described for the synthesis of A3 from A1 and A2 in Scheme 1.

[0391] Deprotection of diamines of general formula (A13) can give primary amines of general formula (A14), which follow the same procedure as described for the synthesis of (A7) from (A6) in Scheme 1.

[0392] The final compound of general formula (A9) is then prepared by reacting a primary amine (A14) or its corresponding salt with a halogen, such as fluorine, chlorine or bromine, or with -S(O) 1~2A preassembled heteroaryl (A12) bearing a leaving group LG such as Me, N It can be synthesized via Ar or palladium-catalyzed Buchwald-Hartwig amination. The applicable procedure is similar to that described for the synthesis of (A6) from (A1) and (A12) in Scheme 1.

[0393] In the synthesis of intermediates of general formula (A11), a primary amine (A14) or its corresponding salt is reacted with S N In Ar or palladium catalyzed Buchwald-Hartwig amination, halogens such as fluorine, chlorine, or bromine, or -S(O) 1~2 The heteroaryl (A2) can be reacted with a leaving group LG, such as Me. The applicable procedures are similar to those described for the synthesis of (A3) from (A1) and (A2) in Scheme 1.

[0394] Final compounds of general formula (A17) can be synthesized according to the route shown in Scheme 3. Primary amines of general formula (A7) or their corresponding salts (prepared according to Scheme 1) can be reacted with one carbon equivalent of a methyl group such as CDI or TCDI in a polar aprotic solvent such as DMF at a temperature between room temperature and the boiling point of the solvent, preferably at 100°C for 1-2 hours, in the presence of an inorganic base such as sodium hydroxide, or an organic base such as TEA or DIPEA, or without any additional base, to give an acylimidazole intermediate. This intermediate can be reacted in situ with 1,2-dianiline (A15) in the presence of a carbodiimide reagent such as EDC at a temperature between room temperature and the boiling point of the solvent, preferably at 100°C for 15-24 hours, to give (A17).

[0395] [ka]

[0396] Scheme 3: Route for the preparation of compounds of general formula (A17), wherein Y 1and Y 2 is CH or N (provided that Y 1 If N, then Y 2 (provided that is CH and vice versa), D, X 2 , X 3 , R A1 , and R A2 has the meaning indicated for general formula (I-B1) (see above).

[0397] Alternatively, the protected intermediate of general formula (A16), prepared according to the route shown in Scheme 1 or 2, may be deprotected to give a compound of general formula (A17). Depending on the protecting group applied, these can be, for example, acidic, basic, oxidative, or hydrogenation methods. Suitable protecting groups can be groups such as para-methoxybenzyl (PMB), 4-methylbenzenesulfonyl (Ts), or benzyl (Bn). For example, deprotection of the PMB group can be achieved by reaction with an acid such as TFA in a solvent such as DCM or without any additional solvent at a temperature between room temperature and the boiling point of the solvent, preferably at 60-100°C for 15 minutes to 18 hours. Deprotection of the Ts group can be carried out by reaction with a base such as K2CO3 or Na2CO3 in a polar protic solvent such as MeOH or EtOH at a temperature between room temperature and the boiling point of the solvent, preferably at 60°C for 1 to 4 hours.

[0398] Another approach to compounds of general formula (A9) is shown in Scheme 4. Aryl bromides of general formula (A18), prepared according to the procedures shown in Schemes 1-3, can be functionalized via post-functionalization using nucleophiles, such as general formula (A19) (see, for example, Angew. Chem. Int. Ed. 2003, 42, 5400-5449), boronic acid derivatives (A20) (see, for example, Chem. Rev. 1995, 95, 2457-2483), or stannanes (A21) (see, for example, ACS Catal. 2015, 5, 3040-3053), under metal or metallaphotoredox catalysis (see, for example, Chem. Rev. 2022, 122, 1485-1542), to obtain final compounds of general formula (A9). All methods known in the art for metal or metallaphotoredox catalysis can be applied.

[0399] Nucleophiles of general formula (A19) and boronic acid derivatives of general formula (A20) and stannanes (A21) are either commercially available or can be prepared according to procedures available in the public domain.

[0400] [ka]

[0401] Scheme 4: Route for the preparation of compounds of general formula (A9), wherein Y 1 and Y 2 is CH or N (provided that Y 1 If N, then Y 2 (provided that is CH and vice versa), D, X 1 , X 2 , X 3 , R A1 , and R A2 has the meaning given for general formula (IB) (see above), with the proviso that R A2 (Provided that the is not a halogen).

[0402] The compound of general formula (B-2) can be prepared according to the following schemes 5 and 6. The schemes and procedures described below illustrate the synthetic route to the compound of general formula (B-2), but are not intended to be limiting. It is understood that the order of the conversions illustrated in schemes 5 and 6 can be changed in various ways. Therefore, the order of the conversions illustrated in these schemes is not intended to be limiting.

[0403] Routes for the preparation of compounds of general formula (B-2) and corresponding intermediates are described in Schemes 5 and 6.

[0404] [ka]

[0405] Scheme 5: A route for the preparation of compounds of general formula (A26) is illustrated in the scheme, where LG is a leaving group, PG is a protecting group, and Y 1 and Y 2 is CH or N (provided that Y 1 If N, then Y 2 (provided that is CH and vice versa), D, X 1 , X 2 , X 3 , R A1 , R A2 , and R B2 has the meaning given for general formula (B-2) (see above).

[0406] For the synthesis of final compounds of general formula (A26), routes and methods corresponding to those described in Schemes 1-4 can be applied. Without intending to be limiting, routes to compounds of general formula (A26) in Schemes 5-6 are presented for further illustration. Diamines of general formula (A22) are commercially available or can be prepared according to procedures available in the public domain.

[0407] [ka]

[0408] Scheme 6: Routes for the preparation of compounds of general formula (A26) and intermediate (A28) are illustrated in the scheme, where LG is a leaving group, PG is a protecting group, and Y 1 and Y 2 is CH or N (provided that Y 1 If N, then Y 2 (provided that is CH and vice versa), D, X 1 , X 2 , X 3 , R A1 , R A2 , and R B2 has the meaning given for general formula (B-2) (see above).

[0409] Additional compounds having different formulas above can be prepared by similar methods.

[0410] Those skilled in the art will recognize that the individual process steps described above may be performed in a different order and / or individual reactions may be performed at different stages in the overall pathway (i.e., substituents may be added to intermediates and / or chemical transformations may be performed other than those described above in connection with a particular reaction) to obtain the compounds of the present disclosure in an alternative, and in some cases more convenient, manner, which may obviate or require the need for protecting groups.

[0411] Those skilled in the art will understand that chiral isomers of the compounds herein may be resolved at any stage in the synthetic process using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatographic methods described in the literature and known to those skilled in the art. Stereocenters may also be introduced by asymmetric synthesis. All stereoisomers are included within the scope of this disclosure.

[0412] Those skilled in the art will appreciate that the starting materials for any of the above processes are, in some cases, commercially available.

[0413] Those skilled in the art will appreciate that the processes for some of the starting materials described above may be found in general common knowledge.

[0414] It will also be understood that some of the compounds described in the above processes may exhibit the phenomenon of tautomerism, and that the above processes include any tautomeric forms.

[0415] All novel intermediates form further aspects of the present disclosure.

[0416] Experimental Section NMR peak forms are given as they appear in the spectra and possible higher order effects have not been taken into account.

[0417] 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.

[0418] [Table 12-1]

[0419] [Table 12-2]

[0420] [Table 12-3]

[0421] [Table 13]

[0422] The various embodiments described in this application are exemplified by the following examples, which are not meant to limit the compounds of formula (I) in any way.

[0423] The exemplary testing experiments described herein serve to illustrate the present embodiments and are not limited to the examples shown.

[0424] Experimental Section - General Part General conditions (i) operations are carried out under an atmosphere of an inert gas such as N2 or Ar, at room temperature (rt), i.e., in the range of 17-28°C, and optionally, reactions are carried out using an MBRAUN UNILab Plus ECO or MBRAUN UNILab SP Eco glovebox workstation, where indicated; (ii) where the reaction is referred to as 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 refilling it with a suitable inert atmosphere (e.g., N2(g) or Ar(g)); (iii) if the reaction refers to the use of a microwave reactor, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer; (iv) the progress of the reaction is generally followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC), usually coupled to a mass spectrometer (LCMS); (v) When necessary, organic solutions were dried over anhydrous MgSO or NaSO, or dried using an ISOLUTE® Phase Separator, and work-up procedures were carried out using conventional phase separation techniques. For example, when using a drying agent such as MgSO or NaSO to dry the organic layer, it is understood that the organic layer will be filtered prior to concentration of that layer. (vi) It is understood that wash solutions used in work-up procedures or reagents used for acidification, such as brine (saturated aqueous NaCl), NaHCO3, NH4Cl, HCl, NaH2PO4, etc., are presumed to be aqueous solutions unless otherwise specified; (vii) evaporation was carried out either by rotary evaporation in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10; (viii) Unless otherwise specified, flash column chromatography was performed on normal-phase silica using either Merck Silica Gel (Art. 9385) or preparatively packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica, 4-330 g), Biotage® Sfar silica HC D cartridges (20 μm, 10-100 g), Interchim puriFlash™ cartridges (25 μm, 4-120 g), Interchim puriFlash™ cartridges (50 μm, 25-330 g), Grace® GraceResolv™ Silica Flash cartridges (4-120 g), or Agela Flash Column Silica-CS cartridges (80-330 g), or on reverse-phase silica, spherical cartridges (20-35 μm, 100 A, 80-330 g) using Agela Technologies C-18. Manually or automatically using the Reveleris® X2 Flash System or similar systems; (ix) Purification using an ion exchange column is performed on a standard ion exchange column, e.g., a Biotage ISOLUTE SCX-2 column; (x) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC equipment, respectively, equipped with either MS and / or UV-triggered fraction collection, using either isocratic or gradient mobile phases as described in the Experimental Section, in the following manner: Preparative method A: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 column (5 μm, 150 × 30 mm ID) using a MeCN gradient in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq.) buffer system as the mobile phase; Preparative Method B: 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) as the mobile phase; Preparative Method C: Compounds were purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250 × 50 mm ID) using a MeCN gradient in a H2O / MeCN / NH3 (95 / 5 / 0.2) buffer system as the mobile phase; Preparative Method D: Compounds were purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 50 mm ID) using a MeCN gradient in a H2O / MeCN / FA (95 / 5 / 0.2) buffer system as the mobile phase; Preparative Method E: Compounds were purified by preparative HPLC on an XBridge™ OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in NH3 / H2O (0.2%) as the mobile phase; Preparative Method F: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using an MeCN gradient in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq.) buffer system as the mobile phase; Preparative Method G: Compounds were purified by preparative HPLC on an XBridge C18 OBD column (5 μm, 150 × 19 mm ID) using a MeCN gradient in a H2O / FA ​​(0.1%) buffer system as the mobile phase; Preparative Method H: Compounds were purified by preparative HPLC on an XBridge™ Shield C18 column (5 μm, 150 × 30 mm ID) using an MeCN gradient in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq) buffer system as the mobile phase; Preparative method I: 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 J: Compounds were purified by preparative HPLC on an Atlantis Prep T3 OBD column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in H O / FA (0.1%) as the mobile phase; Preparative method K: Compounds were purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a MeCN gradient in a H2O / FA ​​(0.1%) buffer system as the mobile phase; Preparative method L: Compounds were purified by preparative HPLC on an XBridge C18 OBD column (5 μm, 150 × 19 mm ID) using a MeCN gradient in a H2O / TFA (0.05%) buffer system as the mobile phase; Preparative Method M: Compounds were purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H O / FA (0.1%) as the mobile phase; Preparative method N: Compounds were purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 150 × 30 mm ID) using a MeCN gradient in a H2O / NH4HCO3 (10 mM) / NH3 buffer system (0.05%, aq.) as the mobile phase; Preparative Method O: Compounds were purified by preparative HPLC on an XBridge™ OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in NH3 / H2O (0.05%) as the mobile phase; Preparative method P: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 column (3 μm, 75 × 30 mm ID) using an MeCN gradient in a H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aq.) buffer system as the mobile phase; Preparative Method Q: Compounds were purified by preparative HPLC on an XBridge™ OBD Phenyl column (5 μm, 150 × 19 mm ID) using a MeOH gradient in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq.) buffer system as the mobile phase; Preparative Method R: Compounds were purified by preparative HPLC on an XBridge™ OBD C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H O as the mobile phase; Preparative method S: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150 × 30 mm ID) using a MeCN gradient in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aq.) buffer system as the mobile phase; Preparative Method T: Compounds were purified by preparative HPLC on an XSelect CSH OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN in H O / FA (0.1%) as the mobile phase; Preparative Method U: Compounds were purified by preparative HPLC on an Atlantis Prep T3 OBD column (10 μm, 150 × 19 mm ID) using a gradient of MeCN in H O (0.1% FA) as the mobile phase; Preparative Method V: 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 HO / FA (10 mM) as the mobile phase; Preparative Method W: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a MeCN gradient in a H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aq.) buffer system as the mobile phase; Preparative Method X: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a 20 mM NaOH + 10% MeCN gradient in a HO / NH4HCO3 (10 mM) / NH3 (0.05%, aq.) buffer system as the mobile phase;

[0425] Relevant fractions were collected, combined, and lyophilized or evaporated to give the purified compound, or relevant fractions were collected, combined, concentrated under reduced pressure, the aqueous layer was extracted with DCM or EtOAc, and the organic layer was dried over Na2SO4 or by using a phase separator, then concentrated under reduced pressure and dried in vacuo if necessary to give the purified compound; (xi) yields, if any, are not necessarily the maximum achievable and, if necessary, 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., monohydrochloride or dihydrochloride), the stoichiometry of the salt was based on the number and nature of basic groups in the compound, and the exact stoichiometry of the salt was not generally determined, e.g., by elemental analysis data; where stated, the salt was treated according to processes known in the literature to generate the corresponding free base before use; (xiii) In general, the structure of the final products of formula (I) was confirmed by NMR and / or mass spectral techniques; 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 provided in ppm with the solvent internally referenced. Protons on heteroatoms, such as NH and OH protons, are reported only if detected in the NMR and may therefore be missing. In certain instances, protons may be masked or partially masked by the solvent peak and therefore either missing and not reported, or reported as a multiplet overlapping with the solvent. The following abbreviations (and their derivatives) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet; h, heptet; dd, doublet of doublets, etc. It is understood that if the NMR spectrum contains residual impurities and / or residual solvent, this will not be reported unless it partially coincides with the peaks of the intermediates and / or structures of formula (I), in which case the peaks of the intermediates and / or structures of formula (I) will be reported as a multiplet partially overlapping with the solvent or impurity, and the integral will be omitted. In some cases, compounds of formula (I) will appear as tautomers in the NMR spectrum, in which case only the peak of the major tautomer will be reported.

[0426] In some cases, compounds of formula (I) appear as more equally related tautomers, and in such cases the peaks of such tautomers are reported as multiplets if the signals of the tautomers overlap with other peaks, or as individual peaks if the signals of the tautomers are well separated. The integrals of such peaks are reported as a proportion of protons and indicate the ratio of tautomers in the mixture.

[0427] (xiv) electrospray mass spectral data are obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar instrument, acquiring both positive and negative ion data, with generally only ions associated with the parent structure being reported; high-resolution electrospray mass spectral data are obtained using a Waters XEVO qToF mass spectrometer or similar instrument, acquiring either positive or negative ion data, with generally only ions associated with the parent structure being reported; (xv) intermediates were not necessarily fully purified, but their structure and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xvi) Examples and intermediate compounds are generally named using PerkinElmer's ChemDraw Professional Version 20.1.1.125 or Version 21.0.0. ChemDraw Professional Version 20.1.1.125 or Version 21.0.0 generates names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules whenever possible when generating chemical names. Stereoisomers are cited by name and distinguished from one another by stereodescriptors assigned according to the CIP rules.

[0428] Intermediates Intermediate 1 tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate

[0429] [ka] 2-Fluoro-5-iodopyridine (2.23 g, 9.99 mmol) was added to tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (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 1 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 75 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-50% EtOAc in PE) to give the title compound (2.70 g, 67%) as a pale yellow solid; MS (ESI) m / z [M+H] + 403.9.

[0430] Intermediate 2 tert-Butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0431] [ka] rel-(1R,2R)-N 1 ,N 2

[0047] To a solution of tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (3.0 g, 7.44 mmol), K2CO3 (3.08 g, 22.3 mmol), and pyridin-2(1H)-one (1.42 g, 14.9 mmol) in 1,4-dioxane (20 mL) was added dimethylcyclohexane-1,2-diamine (0.212 g, 1.49 mmol). The resulting solution was stirred at 110 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (25 mL) and washed successively 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. The solid was collected by filtration and dried in vacuo to give the title compound (2.70 g, 98%) as a yellow solid; MS (ESI) m / z [M+H] +371.2.

[0432] Intermediate 3 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0433] [ka] 2 M HCl in EtO (27 mL, 54 mmol) was slowly added to tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate intermediate 2 (1 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 with a second batch of tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate intermediate 2 (1.7 g, 4.6 mmol). The two batches were combined and concentrated. The crude product was recrystallized from EtOAc:PE (5:1) to give a solid which was collected by filtration and dried in vacuo 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.

[0434] Intermediate 4 tert-Butyl ((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0435] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (500 mg, 1.24 mmol) was added to 3-methoxypyridin-2(1H)-one (776 mg, 6.20 mmol), DMCDA (176 mg, 1.24 mmol), CsCO (2.02 g, 6.20 mmol), and Cu(I)I (236 mg, 1.24 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was diluted with water (150 mL). The aqueous layer was extracted with EtOAc (7 × 150 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:20) to give the title compound (387 mg, 78%) as a brown solid; MS (ESI) m / z [M+H] + 401.3.

[0436] Intermediate 5 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one

[0437] [ka] TFA (2 mL, 25.96 mmol) was added to tert-butyl ((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate intermediate 4 (310 mg, 0.77 mmol) in DCM (8 mL) at 30°C. The resulting mixture was stirred at 30°C for 2 hours. The solvent was removed under reduced pressure to give the TFA salt of the title compound (572 mg, 98%) as a brown gum; MS (ESI) m / z [M+H] + 301.0.

[0438] Intermediate 6 tert-Butyl ((1S,3S)-3-((5-chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0439] [ka] DMCDA (106 mg, 0.74 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 1 (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 washed successively 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.

[0440] Intermediate 7 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one

[0441] [ka] 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 Intermediate 6 (220 mg, 0.54 mmol) in DCM (20 mL) at 25°C. The resulting solution was stirred at 100°C for 18 hours. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound (432 mg, 91%) as a brown gum; MS (ESI) m / z [M+H] + 304.9.

[0442] Intermediate 8 tert-Butyl ((1S,3S)-3-((5-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0443] [ka] DMCDA (52.9 mg, 0.37 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (300 mg, 0.74 mmol), 5-methoxypyridin-2-ol (233 mg, 1.86 mmol), CsCO (727 mg, 2.23 mmol), and CuI (70.8 mg, 0.37 mmol) in 1,4-dioxane (15 mL) at 25 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed successively 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.

[0444] Intermediate 9 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one

[0445] [ka] 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 Intermediate 8 (400 mg, 1.00 mmol) in DCM (15 mL) at 25°C. The resulting suspension was stirred at 25°C for 18 hours. 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.

[0446] Intermediate 10 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0447] [ka] Pyridine (0.808 mL, 9.99 mmol) was added to a mixture of 2-oxo-1,2-dihydropyridine-3-carbonitrile (600 mg, 5.00 mmol), (6-chloropyridin-3-yl)boronic acid (1572 mg, 9.99 mmol), Cu(OAc) (1815 mg, 9.99 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 sparged into the reaction mixture through a drying tube containing CaCl(s). The resulting mixture was stirred at 25 °C for 15 h. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (3 × 10 mL), and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and water (150 mL). The aqueous layer was extracted with EtOAc (5 x 200 mL). The organic layers were combined, washed with saturated brine (5 x 100 mL), dried over Na2SO4, filtered, and evaporated. The dried solid was triturated with DMF (3 x 5 mL), and the filter cake was washed with MTBE (3 x 5 mL). The solid was dried in vacuo to give the title compound (105 mg, 9%) as a gray solid; MS (ESI) m / z [M+H] + 232.1.

[0448] Intermediate 11 tert-Butyl ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0449] [ka] CsCO (1843 mg, 5.66 mmol) was added to 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile intermediate 10 (560 mg, 1.89 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (1133 mg, 5.66 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (79 mg, 0.09 mmol) in DMF (30 mL) at 20 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The mixture was filtered through a Celite pad. The filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated and the residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 10-100% MeCN in water (+0.1% aqueous NH3)) followed by preparative TLC (EtOAc:PE, 3:1) to afford the title compound (174 mg, 23%) as a gray solid; MS (ESI) m / z [M+H] + 396.2.

[0450] Intermediate 12 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0451] [ka] 4M HCl in MeOH (8 mL, 32.0 mmol) was added to a stirred solution of tert-butyl ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Intermediate 11 (865 mg, 2.19 mmol) in MeOH (20 mL) at 25°C. The resulting solution was stirred at 80°C for 2 hours. The solvent was removed under reduced pressure to give the HCl salt of the crude title compound (966 mg, 100%) as a brown gum; MS (ESI) m / z [M+H] + 296.0.

[0452] Intermediate 13 tert-Butyl ((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)carbamate

[0453] [ka] 2-Chlorooxazolo[5,4-b]pyridine (120 mg, 0.78 mmol) was added to tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (156 mg, 0.78 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (32.7 mg, 0.04 mmol), and CsCO (759 mg, 2.33 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3 × 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (EtOAc:PE, 3:1) to give the title compound (200 mg, 81%) as a yellow oil; MS (ESI) m / z [M+H] + 319.2.

[0454] Intermediate 14 (1S,3S)-N 1 -(oxazolo[5,4-b]pyridin-2-yl)cyclopentane-1,3-diamine

[0455] [ka] tert-Butyl ((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)carbamate intermediate 13 (180 mg, 0.57 mmol) was added to TFA (2 mL) and DCM (6 mL). The resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated in vacuo to give the TFA salt of the crude title compound (310 mg, 98%) as a brown oil. MS (ESI) m / z [M+H] + 219.1.

[0456] Intermediate 15 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid methyl ester

[0457] [ka] 6-Chloropyridin-3-amine (1.0 g, 7.8 mmol) was added to a solution of methyl 2-oxo-2H-pyran-5-carboxylate (1.2 g, 7.8 mmol) in EtOH (20 mL) at 15 °C, and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with EtOH (20 mL). The resulting suspension was filtered, and the filter cake was collected to give the crude title compound (1.53 g, 74%) as a purple solid. MS (ESI) m / z [M+H] + 265.2.

[0458] Intermediate 16 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid

[0459] [ka] Methyl 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate intermediate 15 (300 mg, 1.13 mmol) was added to NaOH (91 mg, 2.27 mmol) in THF (8 mL) and water (2 mL) at 20 °C. 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 diluted with water (100 mL) and extracted with EtOAc (3 × 75 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (230 mg, 81%) as a white solid; MS (ESI) m / z [M+H] + 251.

[0460] Intermediate 17 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide

[0461] [ka] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid intermediate 16 (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. The reaction was quenched with saturated brine (100 mL), and the mixture was extracted with EtOAc (3 × 75 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The 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.

[0462] Intermediate 18 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile

[0463] [ka] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide intermediate 17 (700 mg, 2.80 mmol) was added to pyridine (0.680 mL, 8.41 mmol) in DCM (10 mL). TFAA (1.188 mL, 8.41 mmol) was slowly added to the mixture at 0 °C. The resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The synthetic procedure was repeated for a second batch of 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide intermediate 17 (100 mg, 0.40 mmol). The two batches were combined 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.

[0464] Intermediate 19 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0465] [ka] TMEDA (2.59 g, 22.3 mmol) was added to a mixture of (6-chloropyridin-3-yl)boronic acid (2.93 g, 18.6 mmol), 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.11 g, 7.44 mmol), and Cu(OTf) (4.04 g, 11.2 mmol) in dioxane (100 mL), and the resulting solution was stirred at 100 °C for 16 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (300 mL) and water (50 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (5 × 150 mL). The combined organic layers were washed with water (3 x 50 mL), dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by reverse-phase flash chromatography on a C18 column (gradient: 5-40% MeCN in water (0.1% NH3, aq.)) to give the title compound (0.235 g, 12%) as a white solid; MS (ESI) m / z [M+H] + 261.

[0466] Intermediate 20 tert-Butyl ((1S,3S)-3-((5-(1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0467] [ka] 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 19 (200 mg, 0.77 mmol) was added to tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (307 mg, 1.53 mmol), CsCO (750 mg, 2.30 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (32 mg, 0.04 mmol) in 1,4-dioxane (10 mL) at 30 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (8 × 30 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc) to give the title compound (233 mg, 71%) as a yellow solid; MS (ESI) m / z [M+H] + 425.1.

[0468] Intermediate 21 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0469] [ka] TFA (2 mL, 25.96 mmol) was added to tert-butyl ((1S,3S)-3-((5-(1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 20 (220 mg, 0.52 mmol) in DCM (8 mL) at 30° C. The resulting mixture was stirred at 30° C. for 2 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound (347 mg, 100%) as a brown gum; MS (ESI) m / z [M+H] + 325.0.

[0470] Intermediate 22 tert-Butyl ((1S,3S)-3-((3-methyl-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0471] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 1 (400 mg, 0.99 mmol) was added to 3-methylpyridin-2(1H)-one (1082 mg, 9.92 mmol), DMCDA (282 mg, 1.98 mmol), CsCO (3232 mg, 9.92 mmol), and Cu(I)I (378 mg, 1.98 mmol) in 1,4-dioxane (15 mL) at 20° C. under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 15 hours. The reaction mixture was diluted with saturated brine (150 mL), and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:15) to give the title compound (375 mg, 98%) as a yellow solid; MS (ESI) m / z [M+H] + 385.3.

[0472] Intermediate 23 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one

[0473] [ka] tert-Butyl ((1S,3S)-3-((3-methyl-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate intermediate 22 (360 mg, 0.94 mmol) was added to 4 M HCl in MeOH (10 mL, 40.0 mmol) in MeOH (15 mL). The resulting solution was stirred at 60°C for 2 hours. The solvent was removed under reduced pressure to give the HCl salt of the crude title compound (356 mg, 97%) as a yellow solid. MS (ESI) m / z [M+H] + 285.2.

[0474] Intermediate 24 3-chloro-6'-fluoro-2H-[1,3'-bipyridin]-2-one

[0475] [ka] DMCDA (357 mg, 2.51 mmol) was added to 2-fluoro-5-iodopyridine (560 mg, 2.51 mmol), 3-chloropyridin-2(1H)-one (651 mg, 5.02 mmol), Cu(I)I (478 mg, 2.51 mmol), and KPO (1.60 g, 7.53 mmol) in 1,4-dioxane (60 mL) at 25° C. The solution was stirred at 100° C. under a nitrogen atmosphere for 18 hours. The reaction mixture was poured into saturated brine (350 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3×250 mL). The organic layer was dried over NaSO, filtered, and evaporated. The crude product was purified by flash chromatography on silica (gradient: 0-30% EtOAc in PE) to give the title compound (258 mg, 45%) as a pale yellow solid; MS (ESI) m / z [M+H] + 224.9.

[0476] Intermediate 25 tert-Butyl ((1S,3S)-3-((3-chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0477] [ka] tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (467 mg, 2.33 mmol) was added to 3-chloro-6'-fluoro-2H-[1,3'-bipyridin]-2-one intermediate 24 (262 mg, 1.17 mmol) and Na2CO3 (371 mg, 3.50 mmol) in DMSO (20 mL) at 25 °C. The resulting mixture was stirred at 120 °C for 15 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL), and washed with saturated brine (4 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 2:1) to give the title compound (456 mg, 97%) as a white solid; MS (ESI) m / z [M+H] + 404.9.

[0478] Intermediate 26 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-chloro-2H-[1,3'-bipyridin]-2-one

[0479] [ka] 4M HCl in dioxane (2 mL, 8.00 mmol) was added to tert-butyl ((1S,3S)-3-((3-chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Intermediate 25 (425 mg, 1.05 mmol) in MeOH (20 mL) at 30°C. The resulting solution was stirred at 30°C for 2 hours. The solvent was removed under reduced pressure to give the HCl salt of the crude title compound (329 mg, 83%) as a yellow oil. MS (ESI) m / z [M+H] + 305.0.

[0480] Intermediate 27 tert-Butyl ((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)carbamate

[0481] [ka] 2-Bromothiazolo[5,4-b]pyridine (200 mg, 0.93 mmol) was added to tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (186 mg, 0.93 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (39.1 mg, 0.05 mmol), and CsCO (909 mg, 2.79 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 15 hours. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3×20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE, 2:1) to give the title compound (220 mg, 70%) as a yellow oil. MS(ESI) m / z[M+H] + 335.0.

[0482] Intermediate 28 (1S,3S)-N 1 -(thiazolo[5,4-b]pyridin-2-yl)cyclopentane-1,3-diamine

[0483] [ka] tert-Butyl ((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)carbamate intermediate 27 (200 mg, 0.60 mmol) was added to TFA (2 mL) and DCM (6 mL). The resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give the TFA salt of the crude title compound (370 mg, 90%) as a brown oil. MS (ESI) m / z [M+H] + 235.0.

[0484] Intermediate 29 tert-Butyl ((1S,3S)-3-((5-(6-oxopyridazin-1(6H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0485] [ka] Cs2CO3 (606 mg, 1.86 mmol) was dissolved in 1,4-dioxane (5 mL) with tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (250 mg, 0.62 mmol), pyridazin-3(2H)-one (119 mg, 1.24 mmol), Cu(I)I (59 mg, 0.31 mmol), and N 1 ,N 2 To the resulting suspension was added 27.3 mg (0.31 mmol) of dimethylethane-1,2-diamine (27.3 mg, 0.31 mmol) at 25° C. The resulting suspension was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The solvent was removed under reduced pressure. The residue was poured into water (50 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:30) to give the title compound (173 mg, 75%) as a brown solid; MS (ESI) m / z [M+H] + 372.0.

[0486] Intermediate 30 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[0487] [ka] 4M HCl in MeOH (5.0 mL, 20.00 mmol) was added to tert-butyl ((1S,3S)-3-((5-(6-oxopyridazin-1(6H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 29 (168 mg, 0.45 mmol) in MeOH (5 mL) at 25° C. The resulting solution was stirred at 60° C. for 3 h. The solvent was removed under reduced pressure to give the HCl salt of the crude title compound (156 mg, 100%) as a brown solid. MS (ESI) m / z [M+H] + 272.0.

[0488] Intermediate 31 tert-Butyl ((1S,3S)-3-((5-(6-oxopyrimidin-1(6H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0489] [ka] Cs2CO3 (727 mg, 2.23 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 1 (300 mg, 0.74 mmol), pyrimidin-4(3H)-one (214 mg, 2.23 mmol), CuI (71 mg, 0.37 mmol), and DMCDA (53 mg, 0.37 mmol) in 1,4-dioxane (5 mL) at 15 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 2 h. The solvent was removed under reduced pressure. The residue was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:30) and then by flash chromatography on silica (gradient: 7-10% MeOH in DCM) to give the title compound (165 mg, 59%) as a brown solid; MS (ESI) m / z [M+H] + 372.0.

[0490] Intermediate 32 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one

[0491] [ka] tert-Butyl ((1S,3S)-3-((5-(6-oxopyrimidin-1(6H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 31 (155 mg, 0.42 mmol) was added to TFA (5 mL) at 25° C. The resulting solution was stirred at 60° C. for 2 hours. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound (356 mg, 99%) as a brown gum; MS (ESI) m / z [M+H] + 271.9.

[0492] Intermediate 33 6'-chloro-3-fluoro-2,3'-bipyridine

[0493] [ka] 2-Bromo-3-fluoropyridine (500 mg, 2.84 mmol) was added to (6-chloropyridin-3-yl)boronic acid (581 mg, 3.69 mmol), K2CO3 (1.18 g, 8.52 mmol), and Pd(dtbpf)Cl2 (185 mg, 0.28 mmol) in 1,4-dioxane (4 mL) and water (1 mL) at room temperature under a nitrogen atmosphere, and the resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash chromatography on silica (gradient: 0 to 100% EtOAc in PE) to give the crude title compound (750 mg) as a brown solid, which was used without further purification; MS (ESI) m / z [M+H] + 209.

[0494] Intermediate 34 tert-Butyl ((1S,3S)-3-((3-fluoro-[2,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0495] [ka] Cs2CO3 (937 mg, 2.88 mmol) was added to 6'-chloro-3-fluoro-2,3'-bipyridine intermediate 33 (200 mg, 0.96 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (288 mg, 1.44 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (64 mg, 0.08 mmol) in 1,4-dioxane (5 mL) at room temperature, and the resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed successively with brine (2 × 25 mL), dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:30) to give the title compound (314 mg, 88%) as a brown gum; MS (ESI): m / z [M+H] + 373.

[0496] Intermediate 35 (1S,3S)-N 1 -(3-Fluoro-[2,3'-bipyridin]-6'-yl)cyclopentane-1,3-diamine

[0497] [ka] 4M HCl in MeOH (1.11 mL, 4.44 mmol) was added to tert-butyl ((1S,3S)-3-((3-fluoro-[2,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Intermediate 34 (331 mg, 0.89 mmol) in MeOH (5 mL) at room temperature, and the resulting solution was stirred for 16 hours and then at 50°C for 1 hour. The solvent was removed under reduced pressure to give the HCl salt of the title compound (390 mg, 100%) as a yellow gum, which was used without further purification: MS (ESI) m / z [M+H] + 273.

[0498] Intermediate 36 tert-Butyl ((1S,3S)-3-((5-iodopyrimidin-2-yl)amino)cyclopentyl)carbamate

[0499] [ka] K2CO3 (690 mg, 4.99 mmol) was added to 2-chloro-5-iodopyrimidine (900 mg, 3.74 mmol) and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (500 mg, 2.50 mmol) in DMSO (2 mL) at 20 °C. The resulting suspension was stirred at 100 °C for 3 h. The reaction mixture was poured into saturated brine (200 mL) and extracted with EtOAc (3 × 150 mL). The organic layers were combined, washed with saturated brine (3 × 100 mL), dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash chromatography (gradient: 2-30% EtOAc in PE) to give the title compound (950 mg, 94%) as a pale yellow solid; MS (ESI) m / z [M+H] + 404.9.

[0500] Intermediate 37 tert-Butyl ((1S,3S)-3-((5-(6-oxopyridazin-1(6H-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate

[0501] [ka] DMCDA (44.0 mg, 0.31 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyrimidin-2-yl)amino)cyclopentyl)carbamate intermediate 36 (250 mg, 0.62 mmol), pyridazin-3-ol (178 mg, 1.86 mmol), Cu(I)I (59 mg, 0.31 mmol), and CsCO (403 mg, 1.24 mmol) in 1,4-dioxane (15 mL) at 20 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was poured into saturated brine (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc) to give the title compound (190 mg, 82%) as a pale yellow oil that solidified upon standing. MS (ESI) m / z [M+H] + 373.3.

[0502] Intermediate 38 2-(2-(((1S,3S)-3-aminocyclopentyl)amino)pyrimidin-5-yl)pyridazin-3(2H)-one

[0503] [ka] 4M HCl in MeOH (0.114 mL, 0.46 mmol) was added to tert-butyl ((1S,3S)-3-((5-(6-oxopyridazin-1(6H)-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate Intermediate 37 (170 mg, 0.46 mmol) in MeOH (15 mL) at 20° C. The resulting solution was stirred at 60° C. for 6 h. The solvent was removed under reduced pressure to give the HCl salt of the crude title compound (150 mg, 95%) as a yellow gum; MS (ESI) m / z [M+H] + 272.9.

[0504] Intermediate 39 2-Chloro-3-tosyl-3H-imidazo[4,5-b]pyridine *

[0505] [ka] 4-Methylbenzenesulfonyl chloride (1.290 g, 6.77 mmol) was added to 2-chloro-3H-imidazo[4,5-b]pyridine (0.990 g, 6.45 mmol), DMAP (0.079 g, 0.64 mmol), and DIPEA (3.38 mL, 19.3 mmol) in DCE (35 mL) at 20 °C. The resulting solution was stirred at 60 °C for 15 h. The reaction mixture was poured into saturated brine (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with saturated brine (3 × 100 mL), dried over NaSO, filtered, and evaporated. The crude product was purified by flash chromatography (gradient: 5–30% EtOAc in PE) to give the title compound (1.7 g, 86%) as a white solid. MS (ESI) m / z [M+H] + 307.9. ( * (Regiochemistry not confirmed)

[0506] Intermediate 40 2-(2-(((1S,3S)-3-((3-tosyl-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)pyridazin-3(2H-one *

[0507] [ka] 2-(2-(((1S,3S)-3-aminocyclopentyl)amino)pyrimidin-5-yl)pyridazin-3(2H)-one·2HCl intermediate 38 (130 mg, 0.38 mmol) was dissolved in 2-chloro-3-tosyl-3H-imidazo[4,5-b]pyridine in 1,4-dioxane (10 mL). *Intermediate 39 (232 mg, 0.75 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (16 mg, 0.02 mmol), and CsCO (613 mg, 1.88 mmol) were added. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 hours. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH:DCM, 1:10) to give the title compound (110 mg, 53%) as a red solid; MS (ESI) m / z [M+H] + 544.1. ( * (Regiochemistry not confirmed)

[0508] Intermediate 41 2-chloro-5-(2-(difluoromethoxy)-6-fluorophenyl)pyridine

[0509] [ka] Na2CO3 (202 mg, 1.91 mmol) was added to (6-chloropyridin-3-yl)boronic acid (100 mg, 0.64 mmol), 1-(difluoromethoxy)-3-fluoro-2-iodobenzene (366 mg, 1.27 mmol), XPhos Pd G2 (50 mg, 0.06 mmol), and XPhos (30 mg, 0.06 mmol) in 1,4-dioxane (2 mL) and water (2 mL) at room temperature, and the resulting suspension was heated in a microwave reactor at 120 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water (100 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative TLC (EtOAc:PE, 1:4) to give the title compound (119 mg, 68%) as a brown solid; MS (ESI): m / z [M+H] + 274.

[0510] Intermediate 42 tert-Butyl ((1S,3S)-3-((5-(2-(difluoromethoxy)-6-fluorophenyl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0511] [ka] Cs2CO3 (389 mg, 1.20 mmol) was added to 2-chloro-5-(2-(difluoromethoxy)-6-fluorophenyl)pyridine intermediate 41 (109 mg, 0.40 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (120 mg, 0.60 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (27 mg, 0.03 mmol) in 1,4-dioxane (3 mL) at room temperature, and the resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:30) to give the title compound (88 mg, 51%) as a brown solid; MS (ESI): m / z [M+H] + 438.

[0512] Intermediate 43 (1S,3S)-N 1 -(5-(2-(difluoromethoxy)-6-fluorophenyl)pyridin-2-yl)cyclopentane-1,3-diamine

[0513] [ka] 4M HCl in MeOH (0.24 mL, 0.96 mmol) was added to tert-butyl ((1S,3S)-3-((5-(2-(difluoromethoxy)-6-fluorophenyl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 42 (85 mg, 0.19 mmol) in MeOH (3 mL) at room temperature, and the resulting solution was stirred at 60° C. for 2 h. The reaction mixture was poured into water (50 mL) and extracted with 7M NH in MeOH:DCM (2×25 mL). The organic layers were combined, washed with saturated NaHCO (aq., 2×25 mL), dried over NaSO, filtered, and evaporated to give (65 mg, 99%) of the title compound as a brown gum, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 338.

[0514] Intermediate 44 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one

[0515] [ka] TMEDA (1.20 g, 10.3 mmol) was added to a mixture of (6-chloropyridin-3-yl)boronic acid (1.63 g, 10.3 mmol), quinolin-2(1H)-one (500 mg, 3.44 mmol), and Cu(OTf) (2.49 g, 6.89 mmol) in 1,4-dioxane (20 mL), and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with water (3 × 300 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 5-46% MeCN in water (0.1% aqueous NH3)) to give the title compound (211 mg, 24%) as a green solid. MS (ESI) m / z [M+H] + 256.95.

[0516] Intermediate 45 tert-Butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0517] [ka] Cs2CO3 (571 mg, 1.75 mmol) was added to a mixture of 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one intermediate 44 (90 mg, 0.35 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (211 mg, 1.05 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (29 mg, 0.04 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated brine (2 × 10 mL) and water (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (MeOH:DCM, 1:40) to give the title compound (122 mg, 83%) as a white solid; MS (ESI) m / z [M+H] + 421.00.

[0518] Intermediate 46 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[0519] [ka] 4M HCl in MeOH (5.0 mL, 20 mmol) was added to a solution of tert-butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 45 (110 mg, 0.26 mmol) in MeOH (10 mL), and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the HCl salt of the title compound (90 mg, 96%) as a brown gum. MS (ESI) m / z [M+H]+ 321.00.

[0520] Intermediate 47 2-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 2-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine

[0521] [ka] K2CO3 (297 mg, 2.15 mmol) was added to a solution of 2-chloro-3H-imidazo[4,5-b]pyridine (220 mg, 1.43 mmol) and 1-(chloromethyl)-4-methoxybenzene (673 mg, 4.30 mmol) in DMF (5 mL), and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with EtOAc (25 mL) and washed with water (3 × 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (EtOAc:PE, 1:1) to give the regioisomeric title compounds (150 mg, 38%) as yellow solids; MS (ESI) m / z [M+H] + 273.8.

[0522] Intermediate 48 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one and 1-(6-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[0523] [ka] tBuBrettPhos G3 (20 mg, 0.02 mmol) was added to a mixture of 2-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 2-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine intermediate 47 (174 mg, 0.64 mmol), 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one·2HCl intermediate 46 (100 mg, 0.25 mmol), and NaOtBu (122 mg, 1.27 mmol) in DMA (5 mL). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (3 × 25 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (MeOH:DCM, 1:20) to give the regioisomeric title compounds (100 mg, 70%) as yellow solids; MS (ESI) m / z [M+H] + 558.30.

[0524] Intermediate 49 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0525] [ka] TMEDA (1.43 g, 12.32 mmol) was added to a solution of (6-chloropyridin-3-yl)boronic acid (1.29 g, 8.21 mmol), 1,8-naphthyridin-2(1H)-one (600 mg, 4.11 mmol), and Cu(OTf) (1.78 g, 4.93 mmol) in 1,4-dioxane (10 mL) at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was partitioned between EtOAc (200 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with water (3 × 50 mL). The organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 5-43% MeCN in water (0.1% aqueous NH3)) to give the title compound (252 mg, 23%) as a pale yellow solid. MS (ESI): m / z [M+H] + 257.9.

[0526] Intermediate 50 tert-Butyl ((1S,3S)-3-((5-(2-oxo-1,8-naphthyridin-1(2H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0527] [ka] Pd-PEPPSI-IpentCl 2-methylpyridine (33 mg, 0.04 mmol) was added to 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one intermediate 49 (100 mg, 0.39 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (117 mg, 0.58 mmol), and CsCO (379 mg, 1.16 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (3×15 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (MeOH:DCM, 1:30) to give the title compound (140 mg, 86%) as a pale yellow solid; MS m / z (ES + ), [M+H] + 422.10.

[0528] Intermediate 51 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0529] [ka] 4M HCl in MeOH (5 mL, 20.0 mmol) was added to tert-butyl ((1S,3S)-3-((5-(2-oxo-1,8-naphthyridin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 50 (130 mg, 0.31 mmol) in MeOH (5 mL). The resulting solution was stirred at 80° C. for 2 hours. The solvent was removed under reduced pressure to give the HCl salt of the title compound (105 mg, 95%) as a light brown solid. MS m / z (ES+), [M+H] + 322.0.

[0530] Intermediate 52 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one and 1-(6-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0531] [ka] Pd-PEPPSI-IpentCl 2-methylpyridine (26 mg, 0.03 mmol) was added to a mixture of 2-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 2-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine intermediate 47 (111 mg, 0.40 mmol), 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one)HCl intermediate 51 (100 mg, 0.31 mmol), and NaOtBu (60 mg, 0.62 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (3 × 25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc:PE, 1:1) to give the regioisomeric title compounds (120 mg, 69%) as yellow solids; MS m / z (ES+), [M+H] + 559.

[0532] Intermediate 53 3-(4-Methoxybenzyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine *

[0533] [ka] 1-(Chloromethyl)-4-methoxybenzene (4.45 g, 28.40 mmol) was added to a mixture of 2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine (3.5 g, 17.8 mmol) and DIPEA (9.3 mL, 53 mmol) in THF (60 mL), and the reaction mixture was stirred at 60 °C for 18 h. The solvent was removed under reduced pressure. The crude product was purified by normal-phase flash chromatography on silica (gradient: 1-5% MeOH in DCM) to give the title compound (5.30 g, 94%) as a brown gum and a single regioisomer; MS (ESI) m / z [M+H] + 317.9. ( * (Regiochemistry not confirmed)

[0534] Intermediate 54 tert-Butyl ((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)carbamate *

[0535] [ka] tert-Butyl ((1S,3S)-3-aminocyclopentyl)carbamate (3.03 g, 15.12 mmol) was dissolved in 3-(4-methoxybenzyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine in n-BuOH (50 mL). * Intermediate 53 (4.0 g, 12.60 mmol) was added to the mixture, and the reaction mixture was stirred at 120 °C for 18 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on deactivated alumina (gradient: 0 to 5% MeOH in DCM) to give the title compound (5.20 g, 94%) as a brown gum and a single regioisomer; MS (ESI) m / z [M+H] + 438.1. ( * (Regiochemistry not confirmed)

[0536] Intermediate 55 (1S,3S)-N 1-(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *

[0537] [ka] TFA (15 mL, 194.70 mmol) was dissolved in DCM (50 mL) to prepare tert-butyl ((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)carbamate * Intermediate 54 (5.2 g, 11.9 mmol) was added and the reaction mixture was stirred at 20° C. for 18 hours. The solvent was removed under reduced pressure to give the TFA salt of the title compound (6.0 g, 89%) as a brown gum and a single regioisomer. MS (ESI) m / z [M+H] + 338.05. ( * (Regiochemistry not confirmed)

[0538] Intermediate 56 (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *

[0539] [ka] 2-Fluoro-5-iodopyridine (2.162 g, 9.70 mmol) was dissolved in DMSO (30 mL) in (1S,3S)-N 1-(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine·5TFA Intermediate 55 (4.0 g, 4.41 mmol) and K2CO3 (6.09 g, 44.08 mmol) were added, and the reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was poured into saturated brine (350 mL) and extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with saturated brine (3 × 200 mL). The organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by normal-phase flash chromatography on silica (gradient: 0–1% MeOH (7 M NH3) in DCM) to give the title compound (2.0 g, 84%) as a yellow gum and a single regioisomer; MS (ESI) m / z [M+H] + 541. ( * (Regiochemistry not confirmed)

[0540] Intermediate 57 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one *

[0541] [ka] DMCDA (26 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL) containing 1,3-dihydro-2H-benzo[d]imidazol-2-one (149 mg, 1.11 mmol), (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *Intermediate 56 (200 mg, 0.37 mmol), CuI (35 mg, 0.19 mmol), and CsCO (362 mg, 1.11 mmol) were added to a mixture, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (3 × 35 mL) and saturated brine (3 × 25 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (7 M NH in MeOH:DCM, 1:20) to give the title compound (80 mg, 39%) as a brown solid and a single regioisomer; MS (ESI) m / z [M+H] + 547. ( * (Regiochemistry not confirmed)

[0542] Intermediate 58 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one *

[0543] [ka] DMCDA (26 mg, 0.19 mmol) was dissolved in 1,4-dioxane (3 mL) containing 1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (41 mg, 0.28 mmol), (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *Intermediate 56 (50 mg, 0.09 mmol), CuI (35 mg, 0.19 mmol), and CsCO (90 mg, 0.28 mmol) were added to a mixture, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (3 × 25 mL) and saturated brine (3 × 10 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (MeOH: EtOAc, 1:10) to give the title compound (40 mg, 77%) as a brown solid and a single regioisomer; MS (ESI) m / z [M+H] + 441.2. ( * (Regiochemistry not confirmed)

[0544] Intermediate 59 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methylimidazolidine-2,4-dione *

[0545] [ka] DMCDA (39 mg, 0.28 mmol) was dissolved in 1,4-dioxane (5 mL) in (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *A mixture of intermediate 56 (300 mg, 0.56 mmol), 3-methylimidazolidine-2,4-dione (127 mg, 1.11 mmol), CuI (53 mg, 0.28 mmol), and CsCO (543 mg, 1.67 mmol) was added, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (3 × 25 mL) and saturated brine (3 × 20 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (7 M NH in MeOH:DCM, 1:20) to give the title compound (165 mg, 56%) as a brown solid and a single regioisomer; MS (ESI) m / z [M+H] + 527.30. ( * (Regiochemistry not confirmed)

[0546] Intermediate 60 (1S,3S)-N 1 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *

[0547] [ka] 4M HCl in MeOH (4 mL, 16.00 mmol) was dissolved in tert-butyl ((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)carbamate in MeOH (10 mL). * A solution of Intermediate 54 (1.5 g, 3.43 mmol) was added and the reaction mixture was stirred at 60° C. for 18 hours. The solvent was removed under reduced pressure to give the HCl salt of the title compound (1.0 g, 86%) as a brown gum and a single regioisomer. MS (ESI) m / z [M+H] + 338.05. ( * (Regiochemistry not confirmed)

[0548] Intermediate 61 4-Nitrophenyl(6-chloropyridin-3-yl)carbamate

[0549] [ka] 4-Nitrophenyl carbonochloridate (1.73 g, 8.56 mmol) was added to a solution of 6-chloropyridin-3-amine (1 g, 7.78 mmol) in MeCN (20 mL), and the reaction mixture was stirred for 30 minutes at 20° C. The reaction mixture was diluted with MeCN (200 mL), filtered through an organic phase filter, and concentrated to give the crude title compound (2.18 g, 96%) as a purple solid; MS (ESI): m / z [M+H] + 293.9.

[0550] Intermediate 62 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione

[0551] [ka] DIPEA (3.90 mL, 22.32 mmol) was added to a suspension of methyl methylglycinate HCl (1.04 g, 7.44 mmol) in MeCN (20 mL), and the reaction mixture was stirred at 20 °C for 15 min. 4-Nitrophenyl (6-chloropyridin-3-yl)carbamate Intermediate 61 (2.18 g, 7.44 mmol) was added, and the reaction mixture was stirred at 20 °C for 10 min. The solvent was removed under reduced pressure. The crude product was purified by normal-phase flash chromatography on silica (gradient: 65-70% EtOAc in PE) to give the title compound (1.55 g, 92%) as a white solid. MS (ESI): m / z [M+H] + 225.8.

[0552] Intermediate 63 3-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methylimidazolidine-2,4-dione *

[0553] [ka]

[0554] 2.5 M NaOtBu in THF (2.66 mL, 6.65 mmol) was dissolved in DMA (5.00 mL) and the (1S,3S)-N 1 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine * To a mixture of HCl intermediate 60 (829 mg, 2.22 mmol), 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione intermediate 62 (250 mg, 1.11 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (93 mg, 0.11 mmol) was added at 20 °C. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with saturated brine (3 × 25 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by reverse-phase flash chromatography on a C18-column (gradient: 40–55% MeCN in water) to afford the title compound (243 mg, 42%) as a single regioisomer and a brown oil that solidified upon standing. MS(ESI) m / z[M+H] + 527.2. ( * (Regiochemistry not confirmed)

[0555] Intermediate 64 (1S,3S)-N 1 -(5-bromopyrimidin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *

[0556] [ka] (1S,3S)-N 1 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine* HCl intermediate 60 (500 mg, 1.48 mmol) was added to 5-bromo-2-chloropyrimidine (430 mg, 2.22 mmol) and CsCO (966 mg, 2.96 mmol) in DMSO (10 mL) at 20 °C. The resulting mixture was stirred at 100 °C for 15 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (5 × 150 mL). The organic layers were combined, washed with saturated brine (3 × 100 mL), dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 3:7) followed by reverse-phase flash chromatography on a C18 column (gradient: 0–73% MeCN in water) to give the title compound (237 mg, 32%) as an orange solid; MS (ESI) m / z [M+H] + 494.0 and 496.0 (Br isotope pattern). * (Regiochemistry not confirmed)

[0557] Intermediate 65 3-(2-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)-1-methylpyridin-2(1H-one *

[0558] [ka] (1S,3S)-N 1 -(5-bromopyrimidin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *Intermediate 64 (200 mg, 0.40 mmol) was added to (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (390 mg, 2.55 mmol), K2CO3 (168 mg, 1.21 mmol), and Pd(dtbpf)Cl2 (39.5 mg, 0.06 mmol) in 1,4-dioxane (4 mL) and water (1 mL) at 20 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (4 × 125 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:15) followed by reverse-phase flash chromatography on a C18 column (gradient: 0-51% MeOH in water) to give the title compound (76 mg, 35%) as a brown solid; MS (ESI) m / z [M+H] + 523.3. ( * (Regiochemistry not confirmed)

[0559] Intermediate 66 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one *

[0560] [ka] K3PO4 (236 mg, 1.11 mmol) was dissolved in 1,4-dioxane (5.0 mL) in (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *To a suspension of intermediate 56 (200 mg, 0.37 mmol), 3-methylpyridin-2-ol (121 mg, 1.11 mmol), CuI (35 mg, 0.19 mmol), and DMCDA (26 mg, 0.19 mmol) was added, and the reaction mixture was heated at 100 °C under a nitrogen atmosphere for 16 h. The solvent was removed under reduced pressure. The residue was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE, 1:3) to give the title compound (101 mg, 52%) as a brown solid and a single regioisomer; MS (ESI) m / z [M+H] + 522.45. ( * (Regiochemistry not confirmed)

[0561] Intermediate 67 3-Methoxy-6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one *

[0562] [ka] Cs2CO3 (543 mg, 1.67 mmol) was dissolved in 1,4-dioxane (5.0 mL) in (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *To a suspension of intermediate 56 (300 mg, 0.56 mmol), 3-methoxypyridin-2-ol (208 mg, 1.67 mmol), CuI (53 mg, 0.28 mmol), and DMCDA (39 mg, 0.28 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. The solvent was removed under reduced pressure. The residue was poured into water (100 mL) and extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over Na SO , filtered, and concentrated. The residue was purified by preparative TLC (7 M NH in MeOH:DCM, 1:20) to give the title compound (86 mg, 29%) as a brown solid and a single regioisomer; MS (ESI) m / z [M+H] + 538.20. ( * (Regiochemistry not confirmed)

[0563] Intermediate 68 3-chloro-6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one *

[0564] [ka] DMCDA (26 mg, 0.19 mmol) was dissolved in 1,4-dioxane (8 mL) in (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *To a mixture of intermediate 56 (200 mg, 0.37 mmol), 3-chloropyridin-2-ol (96 mg, 0.74 mmol), CsCO (362 mg, 1.11 mmol), and CuI (35 mg, 0.19 mmol) was added, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (3 × 25 mL) and saturated brine (3 × 15 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (MeOH:DCM, 15:1) to give the title compound (95 mg, 47%) as a brown solid and a single regioisomer; MS (ESI) m / z [M+H] + 541. ( * (Regiochemistry not confirmed)

[0565] Intermediate 69 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile *

[0566] [ka] Cs2CO3 (2258 mg, 6.93 mmol) was reacted with 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile intermediate 18 (321 mg, 1.39 mmol), (1S,3S)-N in DMA (5.0 mL). 1 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *HCl intermediate 60 (674 mg, 1.80 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (117 mg, 0.14 mmol) were added, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with saturated brine (3 × 25 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 40–55% MeCN in water). Pure fractions were evaporated to dryness, and the product was purified by preparative HPLC, Prep Method K (gradient: 25–35%) to give the title compound (57 mg, 8%) as a beige solid and a single regioisomer. MS (ESI) m / z [M+H] + 533.35. ( * (Regiochemistry not confirmed)

[0567] Intermediate 70 6'-(((1S,3S)-3-((3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid methyl ester *

[0568] [ka] Cs2CO3 (724 mg, 2.22 mmol) was dissolved in 1,4-dioxane (10 mL) in (1S,3S)-N 1 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *To a mixture of TFA intermediate 55 (500 mg, 0.74 mmol), methyl 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate intermediate 15 (392 mg, 1.48 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (50 mg, 0.06 mmol) was added, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The solvent was removed under reduced pressure. The residue was poured into water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (2:1 EtOAc:PE) followed by reverse-phase flash chromatography on a C18 column (gradient: 30–50% MeCN in water) to afford the title compound (86 mg, 21%) as a brown solid and a single regioisomer. MS(ESI) m / z[M+H] + 566.40. ( * (Regiochemistry not confirmed)

[0569] Intermediate 71 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid methyl ester

[0570] [ka] Methyl 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate in TFA (5.0 mL) * A mixture of Intermediate 70 (81 mg, 0.14 mmol) was stirred at 80° C. under a nitrogen atmosphere for 16 hours. The solvent was removed under reduced pressure to give the TFA salt of the title compound (104 mg, 99%) as a yellow solid. The product was used directly in the next step without further purification; * (Regiochemistry not confirmed)

[0571] Intermediate 72 3-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one *

[0572] [ka] Sodium 2,2-dimethylpropan-1-olate (121 mg, 1.09 mmol) was dissolved in DMA (3 mL) to prepare 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 19 (47 mg, 0.18 mmol), (1S,3S)-N 1 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine * The mixture of HCl intermediate 60 (80 mg, 0.24 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (12 mg, 0.01 mmol) was added, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 0 to 67% MeCN in water) to give the title compound (65 mg, 64%) as a brown solid and a single regioisomer; MS (ESI) m / z [M+H] + 562. ( * (Regiochemistry not confirmed)

[0573] Intermediate 73 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0574] [ka] 1-(Chloromethyl)-4-methoxybenzene (117 mg, 0.75 mmol) was added to 2-chloro-1H-imidazo[4,5-b]pyridine (125 mg, 0.81 mmol) and MTBD (300 mg, 1.96 mmol) in DMA (4 mL) at 20 °C, and the resulting solution was stirred at 20 °C for 18 h under a nitrogen atmosphere. Pd-PEPPSI-IpentCl 2-methylpyridine (27.4 mg, 0.03 mmol) and 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl Intermediate 3 (100 mg, 0.33 mmol) were added, and the resulting suspension was stirred at 100 °C for 16 h. The crude reaction mixture was directly purified by reverse-phase flash chromatography on a C18 column (gradient: 5-30% MeCN in water) to afford a mixture of regioisomeric title compounds (120 mg, 73%) as a yellow gum. MS (ESI) m / z [M+H] + 508.35.

[0575] Intermediate 74 2-Chloro-6-fluoro-3H-imidazo[4,5-b]pyridine

[0576] [ka] POCl3 (6.0 mL, 64 mmol) was added to 6-fluoro-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (130 mg, 0.85 mmol) in an oven-dried microwave vial. Pyridine (0.68 mL, 8.5 mmol) was slowly added to the reaction mixture at room temperature, and the reaction mixture was then heated at 120 °C for 90 min. Tetrabutylammonium chloride (1.18 g, 4.25 mmol) was added, and the reaction mixture was heated at 120 °C for 5 h. The volatiles were removed in vacuo, the resulting oil was taken up in EtOAc, and the mixture was sonicated with 7.5% aqueous NaHCO3. The phases were separated, and the aqueous layer was extracted with EtOAc (x2). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was purified by flash chromatography on silica (gradient: 15-100% EtOAc in heptane) to give 2-chloro-6-fluoro-3H-imidazo[4,5-b]pyridine (89 mg, 61%) as a white solid. MS (ESI) m / z [M+H] + 172.0 and 174.0 (Cl isotope pattern); 1 H NMR (500MHz, DMSO-d6) δ7.98 (1H, dd), 8.37 (1H, dd).

[0577] Intermediate 75 6-Bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 6-Bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine

[0578] [ka] NaH (1.17 g, 29.3 mmol) was added to an ice-cold solution of 6-bromo-3H-imidazo[4,5-b]pyridine (3.87 g, 19.5 mmol) in DMF (95 mL), and the reaction mixture was stirred at 0 °C for 10 min. 1-(Chloromethyl)-4-methoxybenzene (2.78 ml, 20.52 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 17 h. The reaction was quenched with 10% NH Cl (aq), diluted with water, and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (gradient: 40 to 100% EtOAc in heptane) to give a mixture of 6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 6-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine (5.21 g, 84%) as a yellow oil. MS (ESI) m / z [M+H] + 318.0 and 320.11 (Br isotope pattern).

[0579] Intermediate 76 6-Bromo-2-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 6-Bromo-2-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine

[0580] [ka] A mixture of 6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 6-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine intermediate 75 (1.00 g, 3.14 mmol) was dissolved in THF (17 mL) under an argon atmosphere, and the solution was cooled to −78 °C. A 1 M solution of lithium bis(trimethylsilyl)amide in THF (4.09 mL, 4.09 mmol) was added, and the reaction mixture was stirred at −78 °C for 2 h. A solution of 1-chloropyrrolidine-2,5-dione (0.839 g, 6.29 mmol) in THF (17 mL) was added to the reaction mixture, and the reaction mixture was cooled and allowed to warm to room temperature over 15 min. The reaction was quenched with 10% NH4Cl (aq). The mixture was extracted with EtOAc (x2), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (gradient: 20-50% EtOAc in heptane) to give 6-bromo-2-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine. and A mixture of 6-bromo-2-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridines (0.376 g, 34%) was obtained as a white solid; MS (ESI) m / z [M+H] + 352.1 and 354.1 and 355.9 (Br / Cl isotope pattern); 1 H NMR (500MHz, DMSO-d6) δ3.71(3H,d),5.39-5.49(2H,m),6.87-6.94(2H,m),7.21-7.27(2H,m),8.38-8.56(2H,m).

[0581] Intermediate 77 5-(6-Methoxypyridin-3-yl)-2-methylpyrimidine

[0582] [ka] 5-Bromo-2-methylpyrimidine (257 mg, 1.48 mmol), (6-methoxypyridin-3-yl)boronic acid (227 mg, 1.48 mmol), and Pd(PPh3)4 (86 mg, 0.07 mmol) were combined in a sealed reactor, which was then evacuated and refilled with Ar(g). DME (5.94 mL) and 2 M Na2CO3 (aqueous, 1.48 mL, 2.97 mmol) were added, and the reaction mixture was stirred at 80 °C for 1 h 30 min. The reaction mixture was cooled to room temperature, EtOAc was added, and the mixture was washed with 10% NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography on silica (gradient: 30-60% EtOAc in heptane) to give the title compound (217 mg, 73%) as a pale yellow solid; MS (ESI) m / z [M+H] + 202.18.

[0583] Intermediate 78 5-(2-methylpyrimidin-5-yl)pyridin-2-ol

[0584] [ka] A solution of 5-(6-methoxypyridin-3-yl)-2-methylpyrimidine intermediate 77 (217 mg, 1.08 mmol) and 48% HBr in water (5 mL, 45 mmol) in EtOH (2.5 mL) was stirred at 80° C. for 6 h, then at room temperature for 64 h, and then at 80° C. for 6 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was precipitated from THF, and the beige precipitate was filtered, washed with THF, and dried to give the HBr salt of the title compound (277 mg, 74%). MS (ESI) m / z [M+H] + 188.0.

[0585] Intermediate 79 tert-Butyl ((1S,3S)-3-((5-(2-methylpyrimidin-5-yl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0586] [ka] A solution of 5-(2-methylpyrimidin-5-yl)pyridin-2-ol Intermediate 78 (217 mg, 0.62 mmol) and DIPEA (344 μL, 1.97 mmol) in 1,4-dioxane (2 mL) in a sealed tube was stirred under an Ar(g) atmosphere for 5 minutes. tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 1 (199 mg, 0.49 mmol), CuI (19 mg, 0.10 mmol), KCO (273 mg, 1.97 mmol), and DMCDA (16 μL, 0.10 mmol) were added, and the reaction vessel was evacuated and refilled with Ar(g) (×3), then stirred at 90 °C for 4 hours. DMSO (696 μL) was added, and the reaction mixture was stirred at 90 °C for 23 hours. The reaction mixture was cooled to room temperature. EtOAc was added and the mixture was washed with 10% NH4Cl (aq), 10% NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with heptane:EtOAc (4:1), and the resulting beige solid was filtered off and washed with heptane:EtOAc (1:4) to give the title compound (176 mg, 77%); MS (ESI) m / z [M+H] + 463.4.

[0587] Intermediate 80 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)-2H-[1,3'-bipyridin]-2-one

[0588] [ka] 4M HCl in 1,4-dioxane (3.79 mL, 15.2 mmol) was added to a suspension of tert-butyl ((1S,3S)-3-((5-(2-methylpyrimidin-5-yl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Intermediate 79 (175 mg, 0.38 mmol) in MeOH (1 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed to give the HCl salt of the title compound (264 mg, crude) as a brown solid; MS (ESI) m / z [M+H] + 363.3.

[0589] Intermediate 81 6'-(((1S,3S)-3-((6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((6-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)-2H-[1,3'-bipyridin]-2-one

[0590] [ka] A mixture of 6-bromo-2-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 6-bromo-2-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine Intermediate 76 (120 mg, 0.34 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)-2H-[1,3'-bipyridin]-2-one HCl Intermediate 80 (68.9 mg, 0.19 mmol), and DIPEA (331 μL, 1.90 mmol) in NMP (1.57 mL) in a sealed vial was stirred at 130° C. for 24 hours. KF (22 mg, 0.38 mmol) was added, and the reaction mixture was stirred at 130° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by normal phase flash chromatography on silica (gradient: 0-20% MeOH in DCM). Fractions containing the two regioisomers were combined and concentrated to give the title compound (95 mg, 74%) as a brown solid. MS (ESI) m / z [M+H] + 678 and 680.3 (Br isotope pattern).

[0591] Intermediate 82 6'-(((1S,3S)-3-((6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((6-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0592] [ka] A solution of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl (Intermediate 3, 109 mg, 0.40 mmol) in NMP (2.5 mL) was added to a sealed reactor containing a mixture of 6-bromo-2-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine and 6-bromo-2-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine (Intermediate 76, 157 mg, 0.45 mmol) in NMP (2.5 mL) at room temperature. DIPEA (262 mg, 2.02 mmol) was added, and the reaction mixture was stirred at 120 °C for 22 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica (gradient: 0-20% MeOH in DCM) to give a mixture of regioisomeric title compounds (78 mg, 33%) as a brown solid; MS (ESI) m / z [M+H] + 586.3 and 588.3 (Br isotope pattern). 1 H NMR(500MHz,DMSO-d6)δ1.44-1.72(2H,m),1.85-2.12(3H,m),2.12-2.29(3H,m),3. 69(3H,d),4.37(1H,s),4.44-4.54(1H,m),5.25(2H,s),6.27(1H,t),6.41-6.47(1H ,m),6.47-6.56(1H,m),6.84-6.93(2H,m),6.94-7.02(1H,m),7.13-7.2(2H,m),7.2 5-7.43(2H,m),7.44-7.51(1H,m),7.58-7.69(2H,m),7.9-7.95(1H,m),8.01(1H,d).

[0593] Intermediate 83 6'-(((1S,3S)-3-((6-hydroxy-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((6-hydroxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0594] [ka] A sealed vial containing 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (57 mg, 0.22 mmol), Pd(dppf)Cl₂·DCM (6.1 mg, 7.4 μmol), and KOAc (29 mg, 0.30 mmol) was evacuated and backfilled with Ar(g). A solution of 6'-(((1S,3S)-3-((6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((6-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Intermediate 82 (87 mg, 0.15 mmol) in dioxane (1.6 mL) was added and the reaction mixture was stirred at 80 °C for 17 h. The mixture was cooled to room temperature, diluted with EtOAc, and the organic layer was washed with 10% NaHCO (aq) and brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (0.4 mL), treated with AcOH (0.043 mL, 0.74 mmol) and 30% HO (0.34 mL, 0.30 mmol), and stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica (gradient: 0-20% MeOH in DCM) to afford the mixture of regioisomeric title compounds (20 mg, 26%) as a brown solid. MS (ESI) m / z [M+H] + 524.51.

[0595] Intermediate 84 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-6-((methoxymethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((1-(4-methoxybenzyl)-6-((methoxymethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0596] [ka] Tributyl((methoxymethoxy)methyl)stannane (148 mg, 0.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.7 mg, 4.1 μmol) were added to a mixture of 6′-(((1S,3S)-3-((6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one and 6′-(((1S,3S)-3-((6-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3′-bipyridin]-2-one Intermediate 82 (48 mg, 0.08 mmol) in DMF (0.8 mL) in a sealed reactor. The reaction mixture was evacuated and backfilled with Ar(g), then stirred at 110° C. for 16 h. The mixture was cooled to room temperature, diluted with EtOAc, and the organic layer was washed with 10% NaHCO (aq) and brine. The organic layer was dried over NaSO, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography on silica (gradient: 0-10% MeOH in DCM) to give a mixture of regioisomeric title compounds (5.2 mg, 11%) as a brown solid. MS (ESI) m / z [M+H] + 582.3.

[0597] Intermediate 85 3-(4-Methoxybenzyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine *

[0598] [ka] NaH (70.5 mg, 1.76 mmol) was added to a solution of 6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine (220 mg, 1.18 mmol) in DMF (4.5 mL), and the mixture was stirred at room temperature for 5 minutes. 1-(Bromomethyl)-4-methoxybenzene (0.169 mL, 1.18 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with 10% NH4Cl (aq) and diluted with water. The mixture was extracted with EtOAc (x3), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (gradient: 20-50% EtOAc in heptane) to afford the title compound (97 mg, 27%) as a beige solid. Only one of the resulting two regioisomers was isolated; the second was lost during purification. MS (ESI) m / z [M+H] + 308.0. ( * (Regiochemistry not confirmed)

[0599] Intermediate 86 2-chloro-3-(4-methoxybenzyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine *

[0600] [ka] 3-(4-Methoxybenzyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine *Intermediate 85 (97 mg, 0.31 mmol) was dissolved in THF (2 mL) under an argon atmosphere, and the solution was cooled to −78° C. Lithium bis(trimethylsilyl)amide (0.41 mL, 0.41 mmol) was added, and the reaction mixture was stirred at −78° C. for 1.5 h. A solution of 1-chloropyrrolidine-2,5-dione (84 mg, 0.63 mmol) in THF (2 mL) was added, and the reaction mixture was stirred at −78° C. for 1 h and then warmed to room temperature. The reaction was quenched with 10% NH4Cl (aq), and the mixture was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (gradient: 0 to 30% EtOAc in heptane) to afford the title compound (63 mg, 59%) as a white solid and a single regioisomer. MS(ESI) m / z[M+H] + 342.1. 1 H NMR(500MHz,DMSO-d6)δ3.71(3H,d),5.49(2H,s),6.87-6.93(2H,m),7.24-7.3(2H,m),8.57(1H,d),8.82-8.86(1H,m).( * (Regiochemistry not confirmed)

[0601] Intermediate 87 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one *

[0602] [ka] DIPEA (92 mg, 0.71 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one x HCl intermediate 3 (64 mg, 0.24 mmol) and 2-chloro-3-(4-methoxybenzyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine in NMP (1 mL) in a sealed reactor. *A solution of intermediate 86 (63 mg, 0.19 mmol) was added at room temperature, and the reaction mixture was subsequently stirred at 120 °C for 17 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Preparative Method B, gradient: 45-95%). The fractions containing the desired product were combined and concentrated under reduced pressure. The resulting aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (42 mg, 31%) as a yellow oil. MS (ESI) m / z [M+H] + 576.5. ( * (Regiochemistry not confirmed)

[0603] Intermediate 88 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-3-(trifluoromethoxy)-2H-[1,3'-bipyridin]-2-one *

[0604] [ka] DMCDA (17 mg, 0.12 mmol) was dissolved in 1,4-dioxane (5 mL) in (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *To a mixture of intermediate 56 (130 mg, 0.24 mmol), 3-(trifluoromethoxy)pyridin-2-ol (129 mg, 0.72 mmol), Cu(I)I (23 mg, 0.12 mmol), and CsCO (235 mg, 0.72 mmol) was added at room temperature, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (3 × 25 mL) and brine (3 × 25 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (7 M NH in MeOH:DCM, 1:20) to give the title compound (413 mg, 55% purity) containing residual impurities as a brown solid and a single regioisomer; MS (ESI) m / z [M-CHFNO+H] + 415. ( * (Regiochemistry not confirmed)

[0605] Intermediate 89 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-3-(trifluoromethyl)-2H-[1,3'-bipyridin]-2-one *

[0606] [ka] DMCDA (68 mg, 0.48 mmol) was dissolved in 1,4-dioxane (3 mL) in (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *To a mixture of Intermediate 56 (130 mg, 0.24 mmol), 3-(trifluoromethyl)pyridin-2-ol (157 mg, 0.96 mmol), Cu(I)I (92 mg, 0.48 mmol), and CsCO (235 mg, 0.72 mmol) was added at room temperature, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (3 × 25 mL) and saturated brine (3 × 20 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by flash chromatography on silica (gradient: 0–18% MeOH in DCM) to give the title compound (97 mg, 70%) as a brown gum and a single regioisomer. MS (ESI) m / z [M+H] + 576; 1 H NMR(300MHz,DMSO-d6)δ1.44-1.65(2H,m),1.85-2.04(2H,m),2.11-2.21(2H,m),3.70(3H,s),4.28-4.45(2H,m),5.48(2H,s),6.41(1H,t), 6.55(1H,d),6.73-6.79(1H,m),6.87-6.91(2H,m),7.02(1H,d),7.25- 7.27(1H,m),7.37-7.46(4H,m),7.61-7.65(1H,m),7.95-8.01(3H,m); 19 F NMR(282MHz,DMSO-d6)δ-74.07(3F,s). ( * (Regiochemistry not confirmed)

[0607] Intermediate 90 6-Bromo-2-(methylthio)thiazolo[5,4-b]pyridine

[0608] [ka] tert-Butyl nitrite (0.807 g, 7.82 mmol) was added dropwise to 6-bromothiazolo[5,4-b]pyridin-2-amine (CAS reg. no. 1160791-13-8) (0.30 g, 1.30 mmol) and 1,2-dimethyldisulfane (1.16 mL, 13.0 mmol) in MeCN (30 mL) at 20 °C. The resulting solution was stirred at 20 °C for 15 h. The reaction mixture was poured into saturated brine (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na SO , filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:5) to give the title compound (0.3 g, 88%) as a pale yellow solid; MS (ESI): m / z [M+H], respectively + 260.8 and 262.8 (Br isotope pattern).

[0609] Intermediate 91 6-Bromo-2-(methylsulfonyl)thiazolo[5,4-b]pyridine

[0610] [ka] mCPBA (80% wt, 816 mg, 3.78 mmol) was added dropwise to 6-bromo-2-(methylthio)thiazolo[5,4-b]pyridine intermediate 90 (395 mg, 1.51 mmol) in DCM (8 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 15 h. The reaction mixture was diluted with DCM (100 mL) and washed sequentially with water (3 × 100 mL). The organic layer was dried over Na SO , filtered, and evaporated. The residue was purified by preparative TLC (PE: EtOAc, 2:1) to give the title compound (440 mg, 99%) as a yellow solid; MS (ESI): m / z [M+H] + 294.8 (Br isotope pattern).

[0611] Intermediate 92 tert-Butyl ((1S,3S)-3-((5-(7-oxothieno[2,3-c]pyridin-6(7H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0612] [ka] DMCDA (71 mg, 0.50 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (200 mg, 0.50 mmol), thieno[2,3-c]pyridin-7(6H)-one (CAS Registry Number 28981-13-7) (225 mg, 1.49 mmol), CuI (94 mg, 0.50 mmol), and CsCO (485 mg, 1.49 mmol) in 1,4-dioxane (10 mL) at 20 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed successively with water (2 x 150 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc) and then by C18-flash chromatography (gradient: 10-100% MeCN in water) to give the title compound (176 mg, 83%) as a pale yellow solid. MS (ESI) m / z [M+H] + 426.9.

[0613] Intermediate 93 6-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)thieno[2,3-c]pyridin-7(6H)-one

[0614] [ka] 4M HCl in MeOH (2 mL, 8.00 mmol) was added to tert-butyl ((1S,3S)-3-((5-(7-oxothieno[2,3-c]pyridin-6(7H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 92 (160 mg, 0.38 mmol) in MeOH (5 mL) at 20° C. The resulting solution was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure to give the crude unspecified HCl salt of the title compound (160 mg, 98%) as a pale yellow solid; MS (ESI) m / z [M+H] +327.0.

[0615] Intermediate 94 6-(6-chloropyridin-3-yl)thieno[2,3-c]pyridin-7(6H)-one

[0616] [ka] Dimethylglycine HCl (175 mg, 1.25 mmol) was dissolved in 2-chloro-5-iodopyridine (CAS Registry Number 69045-79-0) (300 mg, 1.25 mmol), thieno[2,3-c]pyridin-7(6H-one) (CAS Registry Number 28981-13-7) (379 mg, 2.51 mmol), CuI (239 mg, 1.25 mmol), and KCO (519 mg, 3.76 mmol) in DMF (5 mL). l) at 30°C. The resulting suspension was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with EtOAc (75 mL) and washed successively with saturated brine (3 x 250 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound (214 mg, 64%) as a white solid; MS (ESI) m / z [M+H] + 262.9.

[0617] Intermediate 95 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)imidazolidine-2,4-dione *

[0618] [ka] tBuBrettphos Pd G3 (60.6 mg, 0.07 mmol) was added to 1-(6-chloropyridin-3-yl)imidazolidine-2,4-dione intermediate 96 (150 mg, 0.71 mmol), (1S,3S)-N1-(1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine·HCl intermediate 55 (345 mg, 0.92 mmol), and sodium tert-pentoxide (2.5 M) in THF (1.70 mL, 4.25 mmol) in DMA (8 mL) at room temperature. The resulting suspension was stirred at 100 °C under nitrogen for 16 h. The crude product was purified by preparative method A (gradient: 21–41%) to afford the title compound (58 mg, 16%) as a pale yellow gum. MS(ESI) m / z[M+H] + 513.4. ( * (Regiochemistry not confirmed)

[0619] Intermediate 96 1-(6-chloropyridin-3-yl)imidazolidine-2,4-dione

[0620] [ka] 2-Chloroacetyl isocyanate (0.93 g, 7.78 mmol) was added dropwise to 6-chloropyridin-3-amine (1.0 g, 7.78 mmol) in 1,4-dioxane (30 mL) cooled to 0 °C under nitrogen. The resulting solution was stirred at room temperature for 2 h. DBU (2.93 mL, 19.5 mmol) was added, and the resulting solution was stirred at room temperature for 15 h. The reaction mixture was poured into 0.1 M HCl (200 mL) and extracted with EtOAc (3 × 125 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product as an orange solid. The crude solid was triturated with petroleum ether:EtOAc (1:1, 30 mL) to give a solid that was collected by filtration and dried under vacuum to give the title compound (1.1 g, 67%) as an orange solid. MS (ESI) m / z [M+H] + 211.8.

[0621] Intermediate 97 (1S,3S)-N 1 -(5-(2-methoxyphenyl)pyridin-2-yl)-N3-(3-tosyl-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *

[0622] [ka] (1S,3S)-N 1 -(5-(2-Methoxyphenyl)pyridin-2-yl)cyclopentane-1,3-diamine·3HCl Intermediate 98 (170 mg, 0.43 mmol) was dissolved in 1,4-dioxane (10 mL) to give 2-chloro-3-tosyl-3H-imidazo[4,5-b]pyridine. * Intermediate 39 (266 mg, 0.87 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (18 mg, 0.02 mmol), and CsCO (705 mg, 2.16 mmol) were added, and the mixture was stirred under nitrogen at 100 °C for 16 h. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3 × 20 mL), and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound (160 mg, 67%) as a red solid; MS (ESI) m / z [M+H] + 555.0. ( * (Regiochemistry not confirmed)

[0623] Intermediate 98 (1S,3S)-N 1 -(5-(2-Methoxyphenyl)pyridin-2-yl)cyclopentane-1,3-diamine 3HCl

[0624] [ka] tert-Butyl ((1S,3S)-3-((5-(2-methoxyphenyl)pyridin-2-yl)amino)cyclopentyl)carbamate intermediate 99 (180 mg, 0.47 mmol) was added to 4 M HCl in MeOH (5 ml, 20.00 mmol). The reaction mixture was stirred at 60° C. for 2 hours. The organic solvent was removed by evaporation to give the title compound (180 mg, 98%) as a brown solid, which was used directly in the next step without further purification. MS (ESI) m / z [M+H] + 284.1.

[0625] Intermediate 99 tert-Butyl ((1S,3S)-3-((5-(2-methoxyphenyl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0626] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (250 mg, 0.62 mmol) was added to (2-methoxyphenyl)boronic acid (CAS Registry Number 5720-06-9) (283 mg, 1.86 mmol), Pd(dppf)Cl·DCM (51 mg, 0.06 mmol), and KPO (395 mg, 1.86 mmol) in water (2 mL) and 1,4-dioxane (6.00 mL). The resulting mixture was stirred at 80 °C under nitrogen for 3 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (3×100 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product, which was purified by preparative TLC (EtOAc:petroleum ether=2:1) ​​to give (190 mg, 80%) of the title compound as a yellow solid. MS (ESI) m / z [M+H] + 384.2.

[0627] Intermediate 100 (1S,3S)-N 1 -(3H-imidazo[4,5-b]pyridin-2-yl)-N 3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0628] [ka] In a microwave vial, add 2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (CAS reg. no. 57159-81-6) (250 mg, 1.27 mmol), (1S,3S)-N 1 -(5-Iodopyridin-2-yl)cyclopentane-1,3-diamine (CAS Registry Number 2272129-95-8) (730 mg, 2.41 mmol) and n-butanol (4 mL) were added. The vial was capped and heated to 160 °C in a microwave reactor for 2 h. The solvent was removed under reduced pressure, and the crude product was purified by Preparative Method R (gradient 20-45%) to give the title compound (70 mg, 13%) as a colorless gum. MS (ESI) m / z [M+H] + 420.9.

[0629] Intermediate 101 (1S,3S)-N 1 -(5-(2,6-difluorophenyl)pyridin-2-yl)-N 3 -(3-Tosyl-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *

[0630] [ka] (1S,3S)-N 1 -(5-(2,6-difluorophenyl)pyridin-2-yl)cyclopentane-1,3-diamine·3HCl Intermediate 102 (140 mg, 0.35 mmol) was dissolved in 1,4-dioxane (10 mL) to give 2-chloro-3-tosyl-3H-imidazo[4,5-b]pyridine. *Intermediate 39 (216 mg, 0.70 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (15 mg, 0.02 mmol), and CsCO (572 mg, 1.76 mmol) were added. The resulting mixture was stirred under nitrogen at 100 °C for 16 h. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3 × 20 mL), and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound (154 mg, 78%) as a red solid; MS (ESI) m / z [M+H] + 561.0. ( * (Regiochemistry not confirmed)

[0631] Intermediate 102 (1S,3S)-N 1 -(5-(2,6-difluorophenyl)pyridin-2-yl)cyclopentane-1,3-diamine 3HCl

[0632] [ka] tert-Butyl ((1S,3S)-3-((5-(2,6-difluorophenyl)pyridin-2-yl)amino)cyclopentyl)carbamate intermediate 103 (160 mg, 0.41 mmol) was added to 4 M HCl in MeOH (6 mL, 24 mmol). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was evaporated to dryness to give (160 mg, 98%) of the title compound as a red oil, which was used without further purification. MS (ESI) m / z [M+H] + 290.0.

[0633] Intermediate 103 tert-Butyl ((1S,3S)-3-((5-(2,6-difluorophenyl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0634] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (200 mg, 0.50 mmol) was added to (2,6-difluorophenyl)boronic acid (235 mg, 1.49 mmol), KPO (316 mg, 1.49 mmol), and Pd(dppf)Cl·DCM (40 mg, 0.05 mmol) in water (2 mL) and 1,4-dioxane (6 mL). The resulting mixture was stirred at 80 °C under nitrogen for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by preparative TLC (MeOH:DCM=1:10) to give (187 mg, 97%) of the title compound as a white solid. MS (ESI) m / z [M+H] + 390.2.

[0635] Intermediate 104 (1S,3S)-N 1 -(5-(2-fluorophenyl)pyridin-2-yl)cyclopentane-1,3-diamine·3.5HCl

[0636] [ka] 4M HCl in MeOH (0.555 mL, 2.22 mmol) was added to tert-butyl ((1S,3S)-3-((5-(2-fluorophenyl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 105 (165 mg, 0.44 mmol) in MeOH (1.0 mL) at room temperature. The resulting solution was stirred at 60° C. for 3 hours. The solvent was removed under reduced pressure to give the title compound (177 mg, 100%) as a brown gum, which was used directly in the next step without further purification. MS (ESI) m / z [M+H] + 272.0.

[0637] Intermediate 105 tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate

[0638] [ka] Cs2CO3 (485 mg, 1.49 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (200 mg, 0.50 mmol), 2-fluorophenylboronic acid, pinacol ester (110 mg, 0.50 mmol), and Pd(dtbpf)Cl2 (32 mg, 0.05 mmol) in 1,4-dioxane (5 mL) at room temperature. The resulting suspension was stirred under nitrogen at 100 °C for 2 h. The solvent was removed under reduced pressure. The residue was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The residue was purified by preparative TLC (EtOAc:PE = 1:2) to give the title compound (168 mg, 91%) as a brown solid. MS(ESI) m / z[M+H] + 372.0.

[0639] Intermediate 106 (1S,3S)-N 1 -(5-(2-fluoro-6-(trifluoromethoxy)phenyl)pyridin-2-yl)cyclopentane-1,3-diamine·HCl

[0640] [ka] 4M HCl in MeOH (1.0 mL, 4.0 mmol) was added to tert-butyl ((1S,3S)-3-((5-(2-fluoro-6-(trifluoromethoxy)phenyl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 107 (80 mg, 0.18 mmol) in MeOH (2.5 mL) at room temperature, and the resulting mixture was stirred at 60° C. for 2 hours. The resulting mixture was evaporated to dryness to give the crude product, which was used without further purification. MS (ESI) m / z [M+H] + 356.0.

[0641] Intermediate 107 tert-Butyl ((1S,3S)-3-((5-(2-fluoro-6-(trifluoromethoxy)phenyl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0642] [ka] CataCXium A Pd G3 (56 mg, 0.08 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 1 (310 mg, 0.77 mmol), (2-fluoro-6-(trifluoromethoxy)phenyl)boronic acid (310 mg, 1.38 mmol), and CsF (350 mg, 2.31 mmol) in 1,4-dioxane (16 mL) and water (4 mL) at room temperature, and the resulting solution was stirred at 100° C. under nitrogen for 15 hours. The reaction mixture was filtered through a Celite pad. The filter cake was washed with DCM (4×100 mL). The resulting filtrate was evaporated to dryness to give the crude product. The residue was purified by preparative TLC (EtOAc:petroleum ether=1:2) to give (87 mg, 25%) of the title compound as a pale yellow oil; MS (ESI) m / z [M+H] + 456.0.

[0643] Intermediate 108 5-chloro-6'-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one *

[0644] [ka] DMCDA (26 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL) with 5-chloropyridin-2-ol (CAS Registry Number 4214-79-3) (144 mg, 1.11 mmol), (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3-(3-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine * Intermediate 56 (200 mg, 0.37 mmol), CuI (35 mg, 0.19 mmol), and CsCO (362 mg, 1.11 mmol) were added under nitrogen at room temperature. The resulting solution was stirred at 100 °C for 20 h. The reaction mixture was diluted with EtOAc (75 mL) and washed successively with water (3 × 25 mL) and saturated brine (3 × 20 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound (188 mg, 94%) as a brownish-green solid; MS (ESI) m / z [M+H] + 542. ( * The regiochemistry of the PMB group was not confirmed.

[0645] Intermediate 109 5-Methoxy-6'-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one *

[0646] [ka] DMCDA (26 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL) with 5-methoxypyridin-2(1H-one (CAS Registry Number 61941-79-5) (139 mg, 1.11 mmol), (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(1-(4-Methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine *Intermediate 56 (200 mg, 0.37 mmol), CuI (35 mg, 0.19 mmol), and CsCO (362 mg, 1.11 mmol) were added at room temperature, and the resulting solution was stirred at 100 °C under nitrogen for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and washed successively with water (3 × 25 mL) and saturated brine (2 × 20 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by preparative TLC (NH in MeOH:DCM = 1:20) to give the title compound (70 mg, 35%) as a white solid; MS (ESI) m / z [M+H] + 418. ( * The regiochemistry of the PMB group was not confirmed.

[0647] Intermediate 110 1-(4-(((1S,3S)-3-((3-tosyl-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)phenyl)pyridin-2(1H)-one *

[0648] [ka] 1-(4-(((1S,3S)-3-aminocyclopentyl)amino)phenyl)pyridin-2(1H)-one·2HCl intermediate 111 (100 mg, 0.29 mmol) was treated with CsCO (286 mg, 0.88 mmol), Pd-PEPPSI-IpentCl, 2-methylpyridine (12 mg, 0.01 mmol), and 2-chloro-3-tosyl-3H-imidazo[4,5-b]pyridine in 1,4-dioxane (10 mL). * Intermediate 39 (117 mg, 0.38 mmol) was added to the resulting mixture. The resulting mixture was stirred under nitrogen at 100° C. for 15 hours. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3×20 mL), and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (MeOH:DCM=1:10) to give the title compound (80 mg, 51%) as a brown solid; MS (ESI) m / z [M+H] + 541.2. ( *(Regiochemistry not confirmed)

[0649] Intermediate 111 1-(4-(((1S,3S)-3-aminocyclopentyl)amino)phenyl)pyridin-2(1H)-one·HCl

[0650] [ka] 4M HCl in MeOH (2.0 mL, 8.0 mmol) was added to tert-butyl ((1S,3S)-3-((4-(2-oxopyridin-1(2H-yl)phenyl)amino)cyclopentyl)carbamate Intermediate 112 (200 mg, 0.54 mmol) in MeOH (10 mL) at room temperature, and the resulting solution was stirred at 60° C. for 15 hours. The solvent was removed under reduced pressure to give (180 mg, 97%) of the title compound as a pale yellow oil that solidified upon standing. The product was used directly in the next step without further purification; MS (ESI) m / z [M+H] + 270.1.

[0651] Intermediate 112 tert-Butyl ((1S,3S)-3-((4-(2-oxopyridin-1(2H-yl)phenyl)amino)cyclopentyl)carbamate

[0652] [ka] Pd-PEPPSI-IpentCl 2-methylpyridine (30 mg, 0.04 mmol) was added to 1-(4-iodophenyl)pyridin-2(1H)-one (CAS Registry Number 766556-75-6) (300 mg, 1.01 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 655400-44-8) (202 mg, 1.01 mmol), and CsCO (494 mg, 1.51 mmol) in 1,4-dioxane (15 mL) at room temperature, and the resulting suspension was stirred at 100 °C under nitrogen for 15 h. The reaction mixture was filtered through silica. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc:petroleum ether, 2:1) to give (220 mg, 59%) of the title compound as a pale yellow oil that solidified upon standing. MS (ESI) m / z [M+H] + 370.2.

[0653] Intermediate 113 3-(5-(((1S,3S)-3-aminocyclopentyl)amino)pyrazin-2-yl)-1-methylpyridin-2(1H)-one HCl

[0654] [ka] 4M HCl in MeOH (5.0 mL, 20 mmol) was added to a stirred solution of tert-butyl ((1S,3S)-3-((5-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrazin-2-yl)amino)cyclopentyl)carbamate Intermediate 114 (70 mg, 0.18 mmol) in MeOH (5 mL) at room temperature, and the resulting solution was stirred at 60° C. for 2 hours. The solvent was removed under reduced pressure to give (68 mg, 98%) of the title compound as a yellow solid, which was used directly in the next step without further purification. MS (ESI) m / z [M+H] + 286.0.

[0655] Intermediate 114 tert-Butyl ((1S,3S)-3-((5-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrazin-2-yl)amino)cyclopentyl)carbamate

[0656] [ka] Cs2CO3 (147 mg, 0.45 mmol) was added to 3-(5-bromopyrazin-2-yl)-1-methylpyridin-2(1H)-one intermediate 115 (60 mg, 0.23 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 655400-44-8) (68 mg, 0.34 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (10 mg, 0.01 mmol) in 1,4-dioxane (3 mL) at room temperature. The resulting suspension was stirred under nitrogen at 100 °C for 15 h. The reaction mixture was diluted with EtOAc (200 mL) and washed successively with saturated brine (2 × 15 mL) and water (2 × 15 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The residue was purified by preparative TLC (EtOAc) to give (82 mg, 94%) of the title compound as a yellow solid: MS (ESI) m / z [M+H] + 386.0.

[0657] Intermediate 115 3-(5-bromopyrazin-2-yl)-1-methylpyridin-2(1H)-one

[0658] [ka] 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 Pd(dppf)Cl·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 at 100 °C under nitrogen 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 and evaporated and the resulting material was purified by flash chromatography on silica (gradient: 0-100% EtOAc in n-heptane) to give (360 mg, 69%) of the title compound as a brown solid; MS (ESI): m / z [M+H] + 265.8 / 267.8 (Br isotope pattern).

[0659] Intermediate 116 tert-Butyl ((1S,3S)-3-((5-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0660] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (600 mg, 1.49 mmol) was dissolved in 1-methyluracil (CAS Registry Number 615-77-0) (563 mg, 4.46 mmol), K2CO3 (617 mg, 4.46 mmol), Cu(I)I (576 mg, 2.98 mmol) and rel-(1R,2R)-N 1 ,N 2The mixture was then stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and diluted with saturated brine (150 mL). It was extracted with EtOAc (3×100 mL), and the combined organic layers were dried (NaSO), filtered, and evaporated. The resulting material was purified by preparative TLC (MeOH:DCM=1:15) to give the title compound (262 mg, 44%) as a yellow solid; MS (ESI): m / z [M+H] + 402.2.

[0661] Intermediate 117 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1-methylpyrimidine-2,4(1H,3H)-dione

[0662] [ka] tert-Butyl ((1S,3S)-3-((5-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 116 (80 mg, 0.20 mmol) was treated with TFA (1 mL) in DCM (3 mL) at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the unspecified TFA salt of the title compound (120 mg, 94%) as a brown gum. MS (ESI): m / z [M+H] + 302.2.

[0663] Intermediate 118 tert-Butyl ((1S,3S)-3-((5-(difluoromethoxy)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0664] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (600 mg, 1.49 mmol) was dissolved in 1,4-dioxane (15 mL) with 5-(difluoromethoxy)-2(1H)-pyridinone (CAS reg. no. 130318-75-1) (360 mg, 2.23 mmol), CsCO (1.45 g, 4.46 mmol), Cu(I)I (283 mg, 1.49 mmol) and rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (212 mg, 1.49 mmol) was added at room temperature, and the mixture was then stirred at 100 °C under nitrogen for 18 h. The reaction mixture was cooled to room temperature, combined with another crude reaction mixture of equivalent size (starting from 500 mg of Intermediate 1), and diluted with EtOAc (150 mL). The organic layer was washed with water (3 × 125 mL), dried (NaSO), filtered, evaporated, and the resulting material purified by flash chromatography on silica (gradient: 0 to 100% EtOAc in PE) to give the title compound (887 mg, 74%) as a brown gum; MS (ESI): m / z [M+H] + 437; 19 F NMR(282MHz,DMSO-d6)δ-82.30.

[0665] Intermediate 119 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-(difluoromethoxy)-2H-[1,3'-bipyridin]-2-one

[0666] [ka] tert-Butyl ((1S,3S)-3-((5-(difluoromethoxy)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Intermediate 118 (867 mg, 1.99 mmol) was treated with TFA (0.5 mL, 6.5 mmol) in DCM (20 mL) at 40°C for 1 h. The reaction mixture was concentrated under reduced pressure to give the unspecified TFA salt of the title compound (1.43 g, 91%) as a brown gum. MS (ESI): m / z [M+H] + 337.1; 19 F NMR (282MHz, DMSO-d6) δ-82.3.

[0667] Intermediate 120 tert-Butyl ((1S,3S)-3-((3-(difluoromethoxy)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0668] [ka] rel-(1R,2R)-N 1 ,N 2

[0043] 1,4-Dimethylcyclohexane-1,2-diamine (88 mg, 0.62 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 1 (250 mg, 0.62 mmol), 3-(difluoromethoxy)-2(1H)-pyridinone (CAS Registry Number 1241752-48-6) (150 mg, 0.93 mmol), CsCO (606 mg, 1.86 mmol), and Cu(I)I (118 mg, 0.62 mmol) in 1,4-dioxane (15 mL) at room temperature, and the mixture was then stirred at 100 °C under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, combined with another crude reaction mixture of the same size (starting from 250 mg of Intermediate 1), and diluted with water (125 mL). It was extracted with EtOAc (4 x 100 mL), and the combined organic layers were dried (NaSO), filtered, and evaporated. The resulting material was purified by preparative TLC (7M NH in MeOH:DCM, 1:20) to give the title compound (428 mg, 79%) as a brown solid; MS (ESI): m / z [M+H] + 437.2; 19 F NMR(282MHz,DMSO-d6)δ-82.30.

[0669] Intermediate 121 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-(difluoromethoxy)-2H-[1,3'-bipyridin]-2-one

[0670] [ka] tert-Butyl ((1S,3S)-3-((3-(difluoromethoxy)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Intermediate 120 (410 mg, 0.94 mmol) in MeOH (8 mL) was treated with 4 M HCl in MeOH (2.0 mL, 8.0 mmol) and stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the unspecified HCl salt of the title compound (398 mg, 100%) as a yellow solid. MS (ESI): m / z [M+H] +337; 19 F NMR (282MHz, DMSO-d6) δ-82.3.

[0671] Intermediate 122 tert-Butyl ((1S,3S)-3-((5-(2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0672] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 1 (300 mg, 0.74 mmol) was dissolved in DMF (15 mL) to prepare rel-(1R,2R)-N 1 ,N 2 To a mixture of 1,2-dimethylcyclohexane-1,2-diamine (53 mg, 0.37 mmol), thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (CAS reg. no. 16233-51-5) (375 mg, 2.23 mmol), K2CO3 (308 mg, 2.23 mmol), and Cu(I)I (71 mg, 0.37 mmol) was added at room temperature, and the mixture was then stirred at 100 °C under nitrogen for 15 h. The reaction mixture was cooled to room temperature and diluted with saturated brine (125 mL). It was extracted with EtOAc (4 × 75 mL), and the combined organic layers were dried (Na2SO4), filtered, and evaporated. The resulting material was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound (230 mg, 70%) as a yellow solid; MS (ESI): m / z [M+H] + 443.9.

[0673] Intermediate 123 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

[0674] [ka] tert-Butyl ((1S,3S)-3-((5-(2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Intermediate 122 (190 mg, 0.43 mmol) was treated with TFA (2 mL) in DCM (6 mL) at 20° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give the unspecified TFA salt of the title compound (263 mg, 90%) as a brown oil; MS (ESI): m / z [M+H] + 343.9.

[0675] Intermediate 124 6'-(((1S,3S)-3-((5-bromobenzo[d]thiazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0676] [ka] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (408 mg, 1.51 mmol) was added to a mixture of 5-bromo-2-chlorobenzothiazole (CAS Registry Number 824403-26-1) (250 mg, 1.01 mmol) and K2CO3 (417 mg, 3.02 mmol) in DMSO (10 mL) at room temperature, and the resulting mixture was stirred at 120 °C for 18 h. The reaction mixture was diluted with water (75 mL) and extracted with EtOAc (5 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated, and the resulting material was purified by preparative TLC (EtOAc) to give the title compound (359 mg, 74%) as a yellow solid; MS (ESI): m / z [M+H] + 481.8 / 483.8 (Br isotope pattern).

[0677] Intermediate 125 tert-Butyl ((1S,3S)-3-((6-bromobenzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate

[0678] [ka] Na2CO3 (318 mg, 3.00 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (200 mg, 1.00 mmol) and 6-bromo-2-chlorobenzoxazole (CAS Registry Number 1260643-15-9) (464 mg, 2.00 mmol) in DMSO (3 mL) at room temperature, and the resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, evaporated, and the resulting material was purified by preparative TLC (7 M NH3 in MeOH:DCM, 1:30) to give the title compound (383 mg, 97%) as a brown solid; MS (ESI): m / z [M+H] + 395.9 / 397.9 (Br isotope pattern).

[0679] Intermediate 126 tert-Butyl ((1S,3S)-3-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate

[0680] [ka] KOAc (223 mg, 2.27 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((6-bromobenzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate intermediate 125 (300 mg, 0.76 mmol), bis(pinacolato)diboron (CAS Registry Number 73183-34-3) (384 mg, 1.51 mmol), and Pd(dppf)Cl·DCM (40 mg, 0.05 mmol) in 1,4-dioxane (1 mL) at 20 °C, and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:20) to give the title compound (360 mg, 100%) as a brown solid; MS (ESI) m / z [M+H] + 444.1.

[0681] Intermediate 127 tert-Butyl ((1S,3S)-3-((6-hydroxybenzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate

[0682] [ka] Sodium perborate tetrahydrate (CAS Registry Number 10486-00-7) was added to tert-butyl ((1S,3S)-3-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate Intermediate 126 (350 mg, 0.77 mmol) in a mixture of THF (6 mL) and water (3 mL) at 30° C., and the resulting mixture was stirred at this temperature for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:20) to give the title compound (168 mg, 64%) as a pale yellow solid; MS (ESI) m / z [M+H]+ 334.

[0683] Intermediate 128 tert-Butyl ((1S,3S)-3-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate

[0684] [ka] KOH (6 M in water) was added to a mixture of tert-butyl ((1S,3S)-3-((6-hydroxybenzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate Intermediate 127 (153 mg, 0.46 mmol) and diethyl (bromodifluoromethyl)phosphonate (CAS Registry Number 65094-22-6) (367 mg, 1.37 mmol) in MeCN (2 mL) at 30 °C, and the resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over NaSO, filtered, and evaporated to give the crude product, which was analyzed by preparative TLC (7 M in MeOH). NH3:DCM, 1:30) to give the title compound (52 mg, 30%) as a brown gum; MS (ESI) m / z [M+H] + 383.8.

[0685] Intermediate 129 (1S,3S)-N 1 -(6-(difluoromethoxy)benzo[d]oxazol-2-yl)cyclopentane-1,3-diamine

[0686] [ka] tert-Butyl ((1S,3S)-3-((6-(difluoromethoxy)benzo[d]oxazol-2-yl)amino)cyclopentyl)carbamate Intermediate 128 (42 mg, 0.11 mmol) was treated with TFA (1 mL) in DCM (1 mL) at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give the unspecified TFA salt of the title compound (51 mg, 100%); MS (ESI): m / z [M+H] + 283.9. 19 F NMR (282MHz, DMSO-d6) δ-81.46.

[0687] Intermediate 130 6'-chloro-5-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0688] [ka] Bis(4-nitrophenyl)phosphorazidate (CAS reg. no. 51250-91-0) (880 mg, 2.4 mmol) was added to a solution of 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide intermediate 17 (300 mg, 1.20 mmol) in pyridine (5 mL) under air. The resulting mixture was stirred at 90 °C for 16 h, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18-flash chromatography (gradient: 0-20% MeCN in water) to afford the title compound (210 mg, 64%) as a white solid. MS (ESI): m / z [M+H] + 275.0.

[0689] Intermediate 131 6'-chloro-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0690] [ka] 4-Methoxybenzyl chloride (CAS Registry Number 824-94-2) (690 mg, 4.4 mmol) was added to a mixture of 6'-chloro-5-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one intermediate 130 (810 mg, 2.95 mmol) and K2CO3 (815 mg, 5.90 mmol) in DMF (15 mL), and the resulting suspension was stirred at 80 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated, and the crude material was purified by C18-flash chromatography (gradient: 30-40% MeCN in water) to give the title compound (1000 mg, 86%) as a white solid. MS (ESI): m / z [M+H] + 395.1.

[0691] Intermediate 132 tert-Butyl ((1S,3S)-3-((5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0692] [ka] Pd-PEPPSI-IPentCl 2-methylpyridine (0.179 g, 0.21 mmol) was added to a mixture of 6'-chloro-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one intermediate 131 (0.84 g, 2.13 mmol), CsCO (1.37 g, 4.26 mmol), and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (0.43 g, 2.13 mmol) in DMF (13 mL), which was stirred at 100 °C for 18 h under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by flash chromatography on silica (gradient: 0-10% MeOH in DCM) to give (0.70 g, 59%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 559.3.

[0693] Intermediate 133 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0694] [ka] TFA (3 mL, 39 mmol) was added to tert-butyl ((1S,3S)-3-((5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Intermediate 132 (690 mg, 1.24 mmol) in DCM (10 mL) at room temperature, which was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure to give the unspecified TFA salt of the title compound (600 mg, 85%) as an orange gum, which was used without further purification. MS (ESI): m / z [M+H] + 459.0.

[0695] Intermediate 134 5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0696] [ka] 1-(Chloromethyl)-4-methoxybenzene (27 mg, 0.17 mmol) was added to 2-chloro-1H-imidazo[4,5-b]pyridine (20 mg, 0.13 mmol) and KCO (54 mg, 0.39 mmol) in DMA (3 mL), and the resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. Pd-PEPPSI-IpentCl 2-methylpyridine (11 mg, 0.01 mmol) and 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one Intermediate 133 (60 mg, 0.13 mmol) were added at 20 °C, and the resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with EtOAc (50 mL). The combined filtrates were concentrated under reduced pressure, and the resulting material was purified by reverse-phase flash chromatography on a C18 column (gradient: 30-40% MeCN in water) to give the crude mixture of regioisomeric title compounds (80 mg, 88%) as a brown gum; MS (ESI) m / z [M+H] + 696.3.

[0697] Intermediate 135 6'-Fluoro-2H-[1,3'-bipyridin]-2-one

[0698] [ka] rel-(1R,2R)-N 1 ,N 2 1.50 g (10.5 mmol) of 1,2-dimethylcyclohexanediamine was added to 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), 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 flash chromatography on silica (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) δppm 6.36 (1H, dt), 6.52 (1H, d), 7.36 (1H, dd), 7.54 (1H, dd), 7.73 (1H, dd), 8.14 (1H, ddd), 8.35 (1H, dd). [Example]

[0699] Example 1 6'-(((1S,3S)-3-(benzo[d]oxazol-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 1

[0700] [ka] 2-Chlorobenzo[d]oxazole (100 mg, 0.65 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (100 mg, 0.33 mmol) and Na2CO3 (104 mg, 0.98 mmol) in DMSO (10 mL) at room temperature, and the resulting solution was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (3 × 125 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC, Prep Method F (gradient 20-50%) to give the title compound (31 mg, 25%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 22 Calculated value for N5O2: 388.1768, Measured value: 388.1782; 1 H NMR(300MHz,DMSO-d6)δ1.37-1.77(2H,m),1.84-2.11(2H,m),2.11-2.36(2H,m),4.30(2H,dp),6.28(1H,td),6.38-6.50(1H,m),6. 56(1H,d),6.85-7.06(2H,m),7.11(1H,td),7.25(1H,dd),7.33(1H,dd),7.39-7.52(2H,m),7.61(1H,dd),7.94(1H,d),8.03(1H,d).

[0701] Example 2 6'-(((1S,3S)-3-((6-methylbenzo[d]oxazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one-compound 2

[0702] [ka] 2-Chloro-6-methylbenzo[d]oxazole (43.7 mg, 0.26 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl Intermediate 3 (100 mg, 0.33 mmol) and Na2CO3 (104 mg, 0.98 mmol) in DMSO (10 mL) at room temperature, and the resulting solution was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (3 × 35 mL). The organic layer was dried (Na2SO4), filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method F (gradient 22–52%) to give the title compound (60 mg, 46%) as a white solid. 1 H-NMR(300MHz,DMSO-d6)δ1.42-1.75(2H,m),1.81-2.05(2H,m),2.16(2H,ddd),2.31(3H,s),4.27(2H,dq),6.25(1H,td),6.43(1H, ddd),6.52(1H,dd),6.86-7.00(2H,m),7.04-7.17(2H,m),7.30-7.51(2H,m),7.59(1H,ddd),7.80-7.98(2H,m).HRMS(ESI)m / z[M+H] + C 23 H 24 Calculated value for N5O2: 402.1924, Measured value: 402.1936.

[0703] Example 3 6'-(((1S,3S)-3-((6-bromobenzo[d]oxazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 3

[0704] [ka] 6-Bromo-2-chlorobenzo[d]oxazole (68 mg, 0.29 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (100 mg, 0.33 mmol) and Na2CO3 (104 mg, 0.98 mmol) in DMSO (5 mL) at room temperature, and the resulting solution was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated brine (3 × 35 mL). The organic layer was dried (Na2SO4), filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method H (gradient 22-59%) to give the title compound (65 mg, 43%) as a white solid. HRMS (ESI) m / z [M+H] + C 22 H 21 Calculated for BrN5O2: 466.0874, Found: 466.0884. 1 H NMR(300MHz,DMSO-d6)δ1.47-1.69(2H,m),1.88-2.25(4H,m),4.19-4.41(2H,m),6.27(1H,td),6.44(1H,d),6.54(1H, d),6.97(1H,d),7.19(1H,d),7.27(1H,dd),7.41(1H,dd),7.48(1H,ddd),7.59-7.64(2H,m),7.94(1H,d),8.23(1H,d).

[0705] Example 4 6'-(((1S,3S)-3-((6-(hydroxymethyl)benzo[d]oxazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 4

[0706] [ka] (Tributylstannyl)methanol (207 mg, 0.64 mmol) was added to 6'-(((1S,3S)-3-((6-bromobenzo[d]oxazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 3 (200 mg, 0.43 mmol) and Pd(PPh3)4 (25 mg, 0.02 mmol) in 1,4-dioxane (3 mL) at room temperature, and the resulting suspension was stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2 x 5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method K (gradient: 2-19%) to give (8 mg, 4%) of the title compound as a white solid. HRMS (ESI) m / z [M+H] + C 23 H 24 Calculated value for N5O3: 418.1874, Measured value: 418.1880; 1 H NMR(300MHz,CD3OD)δ1.57-1.82(2H,m),1.98-2.23(2H,m),2.23-2.42(2H,m),4.24-4.48(2H,m),4.64 (2H,s),6.48(1H,td),6.64(2H,ddd),7.08-7.4(3H,m),7.47(1H,dd),7.55-7.69(2H,m),7.97(1H,d).

[0707] Example 5 2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)benzo[d]oxazole-6-carbonitrile - Compound 5

[0708] [ka] Zn(s) (26 mg, 0.40 mmol) was added to 6'-(((1S,3S)-3-((6-bromobenzo[d]oxazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 3 (318 mg, 0.40 mmol), Zn(CN) (95 mg, 0.81 mmol), dppf (45 mg, 0.08 mmol), and Pd(dba) (37 mg, 0.04 mmol) in DMF (5 mL) at room temperature, and the resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was dried (NaSO), filtered, and evaporated. The crude product was purified by reversed-phase mobile phase flash chromatography on a C18 column (gradient: 50-75% MeCN in water) to give (30 mg, 18%) of the title compound as a pale grey solid. HRMS (ESI) m / z [M+H] + C 23 H 21 Calculated value for N6O2: 413.1720, Measured value: 413.1716; 1 H NMR(300MHz,DMSO-d6)δ1.44-1.71(2H,m),1.87-2.11(2H,m),2.14-2.26(2H,m),4.23-4.43(2H,m),6.28(1H,td ),6.45(1H,dd),6.54(1H,d),7.00(1H,d),7.27-7.54(3H,m),7.54-7.75(2H,m),7.88-7.97(2H,m),8.66(1H,d).

[0709] Example 6 6'-(((1S,3S)-3-((6-bromobenzo[d]thiazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 6

[0710] [ka] 6-Bromo-2-chlorobenzo[d]thiazole (81 mg, 0.33 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (100 mg, 0.33 mmol) and Na2CO3 (104 mg, 0.98 mmol) in DMSO (10 mL) at room temperature, and the resulting solution was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with brine (3 × 125 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method A (gradient 38-68%) to give the title compound (65 mg, 41%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 21 Calculated for BrN5OS: 482.0644, Found: 482.0694; 1 H NMR(300MHz,DMSO-d6)δ1.48-1.65(2H,m),1.88-2.04(2H,m),2.11-2.27(2H,m),4.35(2H,br d),6.28(1H,t),6.45(1H,d),6.54(1H,d),6.98(1H,d),7.28-7.51(4H,m),7.61(1H,dd),7.92(2H,dd),8.28(1H,d).

[0711] Example 7 6'-(((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 7

[0712] [ka] 2-Chlorobenzo[d]thiazole (55 mg, 0.33 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (100 mg, 0.33 mmol) and Na2CO3 (104 mg, 0.98 mmol) in DMSO (10 mL) at room temperature, and the resulting solution was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (3 × 25 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product, which was purified by preparative HPLC, Prep Method F (gradient 25-55%) to give the title compound (51 mg, 39%) as a white solid; MS (ESI) m / z [M+H] + 404 1 H NMR(300MHz,DMSO-d6)δ1.48-1.65(2H,m),1.89-2.03(2H,m),2.08-2.28(2H,m),4.30-4.41(2H,m),6.27(1H,td),6.45(1H, d),6.54(1H,d),6.96-7.04(2H,m),7.21(1H,td),7.36-7.51(3H,m),7.61(1H,dd),7.66(1H,dd),7.94(1H,d),8.13(1H,d).

[0713] Example 8 6'-(((1S,3S)-3-((6-methylbenzo[d]thiazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 8

[0714] [ka] 2-Chloro-6-methylbenzo[d]thiazole (100 mg, 0.54 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl Intermediate 3 (251 mg, 0.82 mmol) and Na2CO3 (173 mg, 1.63 mmol) in DMSO (10 mL) at room temperature, and the resulting solution was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (3 × 35 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method A (gradient: 33–63%) to give the title compound (52 mg, 23%) as a white solid; HRMS (ESI) m / z [M+H] + C 23 H 24 Calculated value for N5OS: 418.1696, Measured value: 418.1704; 1 H NMR(300MHz,DMSO-d6)δ1.42-1.69(2H,m),1.83-2.04(2H,m),2.08-2.25(2H,m),2.29(3H,s),4.32(2H,hept),6.25(1H,td), 6.43(1H,dt),6.48-6.59(1H,m),6.87-7.05(2H,m),7.25(1H,d),7.34-7.52(3H,m),7.59(1H,ddd),7.92(1H,d),7.99(1H,d).

[0715] Example 9 2-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)benzo[d]thiazole-5-carbonitrile - Compound 9

[0716] [ka] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (100 mg, 0.33 mmol) was added to 2-chlorobenzo[d]thiazole-5-carbonitrile (63 mg, 0.33 mmol) and Na2CO3 (104 mg, 0.98 mmol) in DMSO (4 mL) at room temperature, and the resulting solution was stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (3 × 25 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC, Prep Method A (gradient 29-59%) to give the title compound (69 mg, 49%) as a white solid; HRMS (ESI) m / z [M+H] + C 23 H 21 Calculated value for N6OS: 429.1492, Measured value: 429.1504; 1 H-NMR(300MHz,DMSO-d6)δ1.50-1.66(2H,m),1.90-2.04(2H,m),2.14-2.29(2H,m),4.32-4.44(2H,m),6.28(1H,td),6.4 5(1H,d),6.54(1H,d),7.00(1H,d),7.38-7.52(3H,m),7.61(1H,d),7.77(1H,d),7.90(1H,d),7.94(1H,d),8.52(1H,d).

[0717] Example 10 6'-(((1S,3S)-3-((1H-benzo[d]imidazol-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 10

[0718] [ka] tBuBrettPhos G3 (4.3 mg, 5.00 μmol) and 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·3HCl intermediate 3 (19 mg, 0.05 mmol) were added as a stock solution in NMP (180 μL) to a vial containing 2-bromo-1H-benzo[d]imidazole (9.9 mg, 0.05 mmol) in a glovebox, followed by MTBD (32 μL, 0.22 mmol). The vial was sealed, and the reaction mixture was stirred at room temperature for 16 h. SiliaMetS thiol (SH) metal scavenger was added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with MeOH and loaded onto an SCX-2 column (500 mg / 6 mL) and eluted with 2 M NH3 in MeOH (5 mL). The volatiles were removed in vacuo and the sample was diluted with DMSO and purified by preparative HPLC, Prep Method E (gradient: 5-95%) to give the title compound (3.6 mg, 18%); HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N6O: 387.1928, Measured value: 387.1526; 1 H NMR(600MHz,DMSO-d6)δ1.47-1.61(2H,m),1.88-2.01(2H,m),2.18(2H,qt),4.26(1H,h),4.35(1H,q),6.27(1H,td),6.45(1H,dt),6.54(1H,dd ),6.68(1H,d),6.82(1H,td),6.88(1H,td),6.96(1H,d),7.12(2H,dd), 7.41(1H,dd),7.48(1H,ddd),7.61(1H,ddd),7.93(1H,d),10.61(1H,s).

[0719] Example 11 6'-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 11

[0720] [ka] 2-Chlorooxazolo[5,4-b]pyridine (17.15 mg, 0.11 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl Intermediate 3 (30 mg, 0.11 mmol), and NMP (0.5 mL) were added to a vial, followed by DIPEA (0.097 mL, 0.55 mmol). The vial was sealed and heated at 130 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with DMSO (1.5 mL), and purified by preparative HPLC, Prep Method C (gradient: 15-55%) to give the title compound (6 mg, 13%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated value for N6O2: 389.1720, Measured value: 389.1706; 1 H NMR(500MHz,CD3OD)δ1.57-1.86(2H,m),1.99-2.1(1H,m),2.1-2.22(1H,m),2.22-2.45(2H,m),4.23-4.48(2H, m),6.47(1H,td),6.58-6.69(2H,m),7.21(1H,dd),7.45(1H,dd),7.56-7.67(3H,m),7.87(1H,dd),7.95(1H,d).

[0721] Example 12 3-Methoxy-6'-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 12

[0722] [ka] 2-Chlorooxazolo[5,4-b]pyridine (100 mg, 0.65 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one·4.2TFA intermediate 5 (756 mg, 0.97 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (27 mg, 0.03 mmol), and CsCO (1054 mg, 3.24 mmol) in 1,4-dioxane (10 mL) at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was poured into saturated brine (150 mL) and extracted with EtOAc (4 × 100 mL). The organic layers were combined, washed with saturated brine (3 × 100 mL), dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:15) and then by preparative HPLC, Prep Method F (gradient: 10-40%) to give the title compound (135 mg, 49%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N6O3: 419.1826, Measured value: 419.1832; 1 H NMR(300MHz,DMSO-d6)δ1.45-1.71(2H,m),1.95(2H,m),2.17(2H,m),3.70(3H,s),4.30(2H,m),6.17 (1H,m),6.53(1H,d),6.90(2H,m),7.14(2H,m),7.38(1H,m),7.56(1H,d),7.86(2H,m),8.40(1H,d).

[0723] Example 13 5-Chloro-6'-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 13

[0724] [ka] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one·5TFA intermediate 7 (396 mg, 0.45 mmol) was added to 2-chlorooxazolo[5,4-b]pyridine (100 mg, 0.65 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (27 mg, 0.03 mmol), and CsCO (1.05 g, 3.24 mmol) in 1,4-dioxane (10 mL) at 25 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was concentrated, diluted with EtOAc (125 mL), and washed sequentially with water (3 × 50 mL) and saturated brine (3 × 35 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:15) and then by preparative HPLC, Prep Method F (gradient: 16-46%) to give the title compound (123 mg, 45%) as a white solid; HRMS (ESI) m / z [M+H] + C 21 H 20 Calculated for ClN6O2: 423.1330, Found: 423.1370; 1 H NMR(300MHz,DMSO-d6)δppm1.45-1.74(2H,m)1.87-2.07(2H,m)2.11-2.28(2H,m)4.20-4.45(2H,m)6.51(2 H,dd)7.02(1H,d)7.17(1H,dd)7.43(1H,dd)7.50-7.64(2H,m)7.84(1H,dd)7.94(2H,dd)8.37-8.47(1H,m).

[0725] Example 14 5-Methoxy-6'-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 14

[0726] [ka] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one·7TFA intermediate 9 (498 mg, 0.45 mmol) was added to 2-chlorooxazolo[5,4-b]pyridine (100 mg, 0.65 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (27.2 mg, 0.03 mmol), and CsCO (1054 mg, 3.24 mmol) in 1,4-dioxane (5 mL) at 25 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was concentrated, diluted with EtOAc (125 mL), and washed sequentially with water (3 × 50 mL) and saturated brine (3 × 35 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:15) and then by preparative HPLC, Prep Method F (gradient: 11-41%) to give the title compound (180 mg, 66%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N6O3: 419.1826, Measured value: 419.1806; 1 H NMR(300MHz,DMSO-d6)δppm1.46-1.74(2H,m)1.88-2.07(2H,m)2.11-2.31(2H,m)3.64(3H,s)4.19-4.47(2H,m)6.43(1H, d)6.55(1H,d)6.96(1H,d)7.11-7.26(2H,m)7.36(1H,dd)7.44(1H,dd)7.58(1H,dd)7.84(1H,dd)7.99(1H,d)8.42(1H,d).

[0727] Example 15 6'-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile - Compound 15

[0728] [ka] Cs2CO3 (517 mg, 1.59 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile·4HCl intermediate 12 (140 mg, 0.32 mmol), 2-chlorooxazolo[5,4-b]pyridine (49.0 mg, 0.32 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (13.35 mg, 0.02 mmol) in DMF (5 mL) at 20 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (4 × 100 mL). The organic layers were combined and washed with brine (5 × 150 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc) and then by preparative HPLC, Prep Method A (gradient: 20-50%) to give the title compound (50 mg, 38%) as a pale yellow solid; HRMS (ESI) m / z [M+H] + C 22 H 20 Calculated value for N7O2: 414.1672, Measured value: 414.1642; 1 H NMR(300MHz,DMSO-d6)δ1.45-1.72(2H,m),1.98(2H,m),2.18(2H,tt),4.31(2H,m),6.47(1H,m),6.56(1H,d),7.1 1(1H,d),7.17(1H,m),7.48(1H,m),7.59(1H,m),7.84(1H,m),8.00(1H,d),8.06(1H,m),8.23(1H,m),8.42(1H,d).

[0729] Example 16 3-Chloro-6'-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 16

[0730] [ka] 2-Chlorooxazolo[5,4-b]pyridine (108 mg, 0.70 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-chloro-2H-[1,3'-bipyridin]-2-one intermediate 26 (178 mg, 0.58 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (24.56 mg, 0.03 mmol) and CsCO (951 mg, 2.92 mmol) in 1,4-dioxane (20 mL) at 30 °C. The resulting solution was stirred at 100 °C for 15 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed with saturated brine (3 × 75 mL). The organic layer was dried over NaSO, filtered and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:15) and then by preparative HPLC, Prep Method A (gradient: 27-47%) to give the title compound (49.5 mg, 20%) as a white solid; HRMS (ESI) m / z [M+H] + C 21 H 20 Calculated for ClN6O2: 423.1330, Found: 423.1324; 1 H NMR(300MHz,DMSO-d6)δ1.60(2H,m),1.99(2H,m),2.18(2H,m),4.32(2H,m),6.31(1H,m),6.55(1H,d),7.0 5(1H,d),7.17(1H,m),7.45(1H,m),7.59(1H,m),7.67(1H,m),7.79-7.86(2H,m),7.98(1H,d),8.42(1H,d).

[0731] Example 17 6'-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile - Compound 17

[0732] [ka] (1S,3S)-N 1To the 3TFA intermediate 14 (194 mg, 0.35 mmol) was added 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile intermediate 18 (80 mg, 0.35 mmol), CsCO (338 mg, 1.04 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (14.5 mg, 0.02 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3 × 20 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by preparative TLC (MeOH:DCM, 1:10) and then by preparative HPLC, Prep Method K (gradient 3-14%) to give the title compound (27 mg, 18%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 20 Calculated value for N7O2: 414.1672, Measured value: 414.1676; 1 H NMR(300MHz,CD3CD)δppm1.58-1.86(2H,m)1.99-2.24(2H,m)2.24-2.45(2H,m)4.25-4.52(2H,m)6.57-6.7 2(2H,m)7.23(1H,dd)7.48(1H,dd)7.61(1H,dd)7.71(1H,dd)7.89(1H,dd)7.97-8.05(1H,m)8.37(1H,dd).

[0733] Example 18 1-Methyl-3-(6-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one - Compound 18

[0734] [ka] 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one·3TFA Intermediate 21 (250 mg, 0.38 mmol) was added to 2-chlorooxazolo[5,4-b]pyridine (58.0 mg, 0.38 mmol), CsCO (611 mg, 1.88 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (15.78 mg, 0.02 mmol) in 1,4-dioxane (10 mL) at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was poured into saturated brine (150 mL) and extracted with EtOAc (4 × 100 mL). The organic layers were combined, washed with saturated brine (3 x 100 mL), dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (7M NH in MeOH:DCM, 1:15) and then by preparative HPLC, Prep Method F (gradient: 18-38%) to give the title compound (81 mg, 48%) as a white solid; HRMS (ESI) m / z [M+H] + C 23 H 23 Calculated value for N8O2: 443.1938, Measured value: 443.1912; 1 H NMR (300 MHz, DMSO-d6) δ ppm: 1.48-1.74 (2H, m), 1.93-2.11 (2H, m), 2.14-2.36 (2H, m), 3.41 (3H, s partially overlapped with solvent peak), 4.21-4.46 (2H, m), 6.60 (1H, d), 6.97 (1H, d), 7.06-7.25 (2H, m), 7.48-7.64 (3H, m), 7.84 (1H, dd), 7.94 (1H, dd), 8.11 (1H, d), 8.42 (1H, d).

[0735] Example 19 6'-(((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 19

[0736] [ka] 2-Chlorothiazolo[5,4-b]pyridine (30 mg, 0.18 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl Intermediate 3 (40 mg, 0.15 mmol), and NMP (0.35 mL) were added to a vial, followed by DIPEA (0.129 mL, 0.74 mmol). The vial was sealed and heated at 130 °C for 20 h. The mixture was diluted with EtOAc and washed with 1 M NaHCO. The aqueous phase was separated and extracted with EtOAc (×2). The combined organic layers were dried over NaSO, filtered, and evaporated. The residue was diluted with DMSO and purified by preparative HPLC, Prep Method D (gradient 5-50%) to give the title compound (15 mg, 25%) as a white solid; HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated value for N6OS: 405.1492, Measured value: 405.1452; 1 H NMR(500MHz,CD3OD)δ1.57-1.82(2H,m),2.01-2.2(2H,m),2.23-2.44(2H,m),4.32-4.53(2H,m),6.41-6.52(1H,m) ,6.58-6.68(2H,m),7.29(1H,dd),7.45(1H,dd),7.54-7.66(2H,m),7.70(1H,dd),7.96(1H,d),8.05-8.15(1H,m).

[0737] Example 20 6'-(((1S,3S)-3-(thiazolo[4,5-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 20

[0738] [ka] 2-Chlorothiazolo[4,5-b]pyridine (30 mg, 0.18 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (50 mg, 0.16 mmol), and NMP (0.35 mL) were added to a vial, followed by DIPEA (0.2 mL, 1.15 mmol). The vial was sealed and heated at 130 °C for 24 h. The mixture was diluted to 4 mL with DMSO / MeCN (2:1) and purified by preparative HPLC, Method D (gradient: 5-50%) to give the title compound (48 mg, 72%) as a beige solid. 1 By HNMR, the sample contained 0.65 mol equivalents of NMP; HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated value for N6OS: 405.1492, measured value: 405.1458. 1 H NMR(500MHz,CD3OD)δ1.59-1.78(2H,m),2.07-2.17(2H,m),2.22-2.35(2H,m),4.33-4.44(1H,m),4.44-4.56(1H,m),6. 47(1H,td),6.59-6.66(2H,m),7.02(1H,dd),7.45(1H,dd),7.56-7.65(2H,m),7.95(1H,d),8.00(1H,dd),8.22(1H,dd).

[0739] Example 21 3-Methoxy-6'-(((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 21

[0740] [ka] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one·4TFA intermediate 5 (300 mg, 0.40 mmol) was added to 2-bromothiazolo[5,4-b]pyridine (85 mg, 0.40 mmol), CsCO (646 mg, 1.98 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (33.4 mg, 0.04 mmol) in 1,4-dioxane (10 mL) at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was poured into saturated brine (150 mL) and extracted with EtOAc (4 × 100 mL). The organic layers were combined, washed with saturated brine (3 × 100 mL), dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:10) and then by preparative HPLC, Prep Method A (gradient: 19-49%) to give the title compound (40 mg, 23%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N6O2S: 435.1598, Measured value: 435.1594; 1 H NMR(300MHz,DMSO-d6)δ1.44-1.67(2H,m),1.98(2H,m),2.10-2.29(2H,m),3.72(3H,s),4.37(2H,m),6.20(1H,m),6.54(1H,d ),6.86(1H,m),6.98(1H,d),7.17(1H,m),7.24(1H,m),7.39(1H,m),7.60-7.74(1H,m),7.92(1H,d),8.09(1H,m),8.47(1H,d).

[0741] Example 22 3-Methyl-6'-(((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 22

[0742] [ka] Cs2CO3 (1490 mg, 4.57 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one intermediate 23 (260 mg, 0.91 mmol), 2-bromothiazolo[5,4-b]pyridine (236 mg, 1.10 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (38.5 mg, 0.05 mmol) in 1,4-dioxane (10 mL) at 25 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC, Prep Method L (gradient 15-19%) to give the title compound (81 mg, 21%) as a yellow gum; HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N6OS: 419.1648, measured value: 419.1632. 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.73 (2H, m) 2.04 (3H, s) 2.06-2.13 (2H, m) 2.15-2.36 (2H, m) 4.19-4.65 (3H, m, partially overlapped with solvent) 6.27 (1H, t) 6.97 (1H, d) 7.26 (1H, dd) 7.37-7.57 (2H, m)

[0743] Example 23 2-Oxo-6'-(((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-3-carbonitrile - Compound 23

[0744] [ka] Cs2CO3 (502 mg, 1.54 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile·4HCl intermediate 12 (136 mg, 0.31 mmol), 2-bromothiazolo[5,4-b]pyridine (133 mg, 0.62 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (12.96 mg, 0.02 mmol) in DMF (7 mL) at 20 °C. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was diluted with water (90 mL) and extracted with EtOAc (5 × 150 mL). The organic layers were combined, washed with saturated brine (5 × 300 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc) and then by preparative HPLC, Prep Method A (gradient: 29-44%) to give the title compound (35 mg, 26%) as a yellow solid; HRMS (ESI) m / z [M+H] + C 22 H 20 Calculated value for N7OS: 430.1444, measured value: 430.1460. 1 H NMR(300MHz,DMSO-d6)δ1.47-1.68(2H,m),1.98(2H,m),2.19(2H,d),4.31-4.48(2H,m),6.47(1H,m),6.56(1H ,d),7.11(1H,d),7.25(1H,m),7.48(1H,m),7.67(1H,m),8.00(1H,d),8.08(2H,m),8.23(1H,m),8.47(1H,d).

[0745] Example 24 3-Chloro-6'-(((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 24

[0746] [ka] 2-Bromothiazolo[5,4-b]pyridine (96 mg, 0.45 mmol) was added to CsCO (336 mg, 1.03 mmol) and 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-chloro-2H-[1,3'-bipyridin]-2-one·2HCl Intermediate 26 (130 mg, 0.34 mmol) in 1,4-dioxane (20 mL) at 30 °C. The resulting solution was stirred at 100 °C for 18 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL), and washed with water (3 × 75 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE, 1:10) and then by preparative HPLC, Prep Method F (gradient: 35-50%) to give the title compound (26 mg, 17%) as a white solid; HRMS (ESI) m / z [M+H] + C 21 H 20 Calculated for ClN6OS: 439.1102, Found: 439.1106. 1 H NMR(300MHz,DMSO-d6)δ1.55(2H,m),1.88-2.02(2H,m),2.10-2.30(2H,m),4.37(2H,m),6.29(1H,m),6.53(1H,d ),7.04(1H,d),7.23(1H,m),7.43(1H,m),7.59-7.72(2H,m),7.80(1H,m),7.96(1H,d),8.07(1H,m),8.45(1H,d).

[0747] Example 25 5-Methoxy-6'-(((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 25

[0748] [ka] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one·7TFA intermediate 9 (300 mg, 0.27 mmol) was added to 2-bromothiazolo[5,4-b]pyridine (88 mg, 0.41 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (11.49 mg, 0.01 mmol), and CsCO (623 mg, 1.91 mmol) in 1,4-dioxane (8 mL) at 25 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was concentrated, diluted with EtOAc (100 mL), and washed successively with water (3 × 45 mL) and saturated brine (3 × 35 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (7M NH3 in MeOH:DCM, 1:15) and then by preparative HPLC, Prep Method F (gradient: 23-43%) to give the title compound (39 mg, 32%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value for N6O2S: 435.1598, Measured value: 435.1560; 1 H NMR(300MHz,DMSO-d6)δ1.43-1.73(2H,m),1.89-2.06(2H,m),2.1-2.33(2H,m),3.64(3H,s),4.25-4.52(2H,m),6.43(1H, d),6.54(1H,d),6.97(1H,d),7.12-7.31(2H,m),7.31-7.51(2H,m),7.67(1H,dd),7.98(1H,d),8.09(1H,dd),8.47(1H,d).

[0749] Example 26 2-Oxo-6'-(((1S,3S)-3-(thiazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-5-carbonitrile - Compound 26

[0750] [ka] (1S,3S)-N1 -(Thiazolo[5,4-b]pyridin-2-yl)cyclopentane-1,3-diamine·4TFA intermediate 28 (209 mg, 0.30 mmol) was added to 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile intermediate 18 (70 mg, 0.30 mmol), CsCO (295 mg, 0.91 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (12.71 mg, 0.02 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE, 5:1) and then by preparative HPLC, Prep Method K (gradient: 3-14%) to give the title compound (18.4 mg, 14%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 20 Calculated value for N7OS: 430.1444, measured value: 430.1418. 1 H NMR(300MHz,CD3CD)δppm1.57-1.83(2H,m)2.00-2.18(2H,m)2.22-2.42(2H,m)4.31-4.53(2H,m)6. 57-6.68(2H,m)7.29(1H,dd)7.46(1H,dd)7.66-7.73(2H,m)7.99(1H,d)8.10(1H,dd)8.35(1H,dd).

[0751] Example 27 6'-(((1S,3S)-3-((7-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 27

[0752] [ka] TCDI (235 mg, 1.32 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·3HCl intermediate 3 (250 mg, 0.66 mmol) and NaOH (158 mg, 3.95 mmol) in DMF (1 mL) at room temperature, and the resulting solution was stirred at 100 °C for 2 h. After the reaction was cooled to room temperature, 4-methoxypyridine-2,3-diamine (101 mg, 0.72 mmol) and EDC (252 mg, 1.32 mmol) were added. The resulting solution was then stirred at 100 °C for 15 h. The mixture was filtered through a Celite pad, and the filter cake was washed with DCM (3 × 5 mL). The filtrate was concentrated and initially purified by reverse-phase chromatography on a C18-column (gradient: 5-22% MeCN in water / 0.1% NH) to give the crude product (300 mg), which was further purified by preparative TLC (7M NH in MeOH:DCM, 1:20) to give the crude product (80 mg). Final purification was achieved by preparative HPLC, preparative method F (gradient 10-30%) to give the title compound (30 mg, 11%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 24 Calculated value for N7O2: 418.1986, Measured value: 418.1990; 1 H NMR(300MHz,DMSO-d6)1.44-1.63(2H,m),1.86-2.02(2H,m),2.08-2.24(2H,m),3.94(3H ,s),4.26-4.39(2H,m),6.27(1H,td),6.44(1H,d),6.54(1H,d),6.60(1H,d),6.71(1H,br d),6.94(1H,d),7.38-7.51(2H,m),7.61(1H,dd),7.75(1H,br s),7.93(1H,d),11.17(1H,d)

[0753] Example 28 2-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H-one - Compound 28

[0754] [ka]

[0755] TEA (0.344 mL, 2.47 mmol) was added to 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one·2.5HCl Intermediate 30 (179 mg, 0.49 mmol) and TCDI (176 mg, 0.99 mmol) in DMF (5 mL) at 25° C. The resulting suspension was stirred at 100° C. for 2 hours under a nitrogen atmosphere. EDC (189 mg, 0.99 mmol) and pyridine-2,3-diamine (54 mg, 0.49 mmol) were added to the mixture at 25° C. The resulting suspension was stirred at 100° C. for 16 hours under a nitrogen atmosphere. The crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 45-60% MeCN in water) followed by preparative HPLC, Prep Method J (gradient: 6-21%) to give the title compound (51 mg, 26%) as a yellow solid. HRMS (ESI) m / z [M+H] + C 20 H 21 Calculated value for N8O: 389.1832, Measured value: 389.1836; 1 H NMR(300MHz,DMSO-d6)δppm1.43-1.73(2H,m)1.83-2.09(2H,m)2.10-2.34(2H,m)4.14-4.51(2H,m)6.54(1H,d) 6.85(1H,dd)6.92-7.08(2H,m)7.13-7.27(1H,m)7.32-7.62(3H,m)7.87(1H,dd)8.02(1H,dd)8.09-8.26(2H,m).

[0756] Example 29 3-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one - Compound 29

[0757] [ka] TEA (0.279 mL, 2.00 mmol) was added to TCDI (143 mg, 0.80 mmol) and 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)pyrimidin-4(3H)-one·5.2TFA Intermediate 32 (346 mg, 0.40 mmol) in DMF (5 mL) at 20 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 2 h. EDC (153 mg, 0.80 mmol) and pyridine-2,3-diamine (44 mg, 0.40 mmol) were added to the mixture at 20 °C. The resulting suspension was stirred at 100 °C under a nitrogen atmosphere for 16 h. The crude product was purified by reverse-phase flash chromatography on a C18 column (gradient: 40-50% MeCN in water) followed by preparative HPLC, Prep Method J (gradient: 2-17%) to give the title compound (26 mg, 16%) as a purple solid. HRMS (ESI) m / z [M+H] + C 20 H 21 Calculated value for N8O: 389.1832, Measured value: 389.1822; 1 H NMR(300MHz,DMSO-d6)δ1.38-1.67(2H,m),1.81-2.06(2H,m),2.06-2.24(2H,m),4.17-4.43(2H,m),6.42-6.6(2H,m),6 .82(1H,dd),7.01-7.18(2H,m),7.35(1H,dd),7.44(1H,dd),7.84(1H,d),7.91-8.01(2H,m),8.18(1H,s),8.39(1H,s).

[0758] Example 30 (1S,3S)-N 1 -(3-fluoro-[2,3'-bipyridin]-6'-yl)-N 3 -(3H-Imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine - Compound 30

[0759] [ka] 2-(Methylsulfonyl)-3H-imidazo[4,5-b]pyridine (134 mg, 0.68 mmol) was dissolved in n-BuOH (5 mL) in a microwave vial and then cooled to room temperature. 1 -(3-Fluoro-[2,3'-bipyridin]-6'-yl)cyclopentane-1,3-diamine·4.6HCl (300 mg, 0.68 mmol) was added to intermediate 35 at room temperature, and the resulting solution was stirred at 160 °C for 2 h in a microwave reactor. The crude product was pre-purified by reverse-phase flash chromatography on a C18 column (gradient: 40-65% MeCN in water) to give the crude product (70 mg), which was further purified by preparative HPLC, Prep Method F (gradient: 44-56%) to give the title compound (10 mg, 4%) as a pale yellow solid; HRMS (ESI) m / z [M+H] + C 21 H 21 FN7 calculated value: 390.1836, measured value: 390.1842; 1 H-NMR(300MHz,DMSO-d6)1.51-1.65(2H,m),1.90-2.05(2H,m),2.12-2.25(2H,m),4.22-4.49(2H,m),6.59(1H,d),6.81-6.91(1H,m), 7.09(1H,d),7.18(1H,s),7.30-7.45(2H,m),7.70-7.80(1H,m),7.87(1H,d),7.93-8.00(1H,m),8.45-8.50(1H,m),8.59-8.61(1H,m).

[0760] Example 31 2-(2-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)pyridazin-3(2H-one - Compound 31

[0761] [ka] 2-(2-(((1S,3S)-3-((3-tosyl-3H-imidazo[4,5-b](pyridin-2-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)pyridazin-3(2H)-one* Intermediate 40 (80 mg, 0.15 mmol) was added to K2CO3 (41 mg, 0.29 mmol) in MeOH (5 mL). The resulting mixture was stirred at 60 °C for 3 h. The reaction mixture was filtered through filter paper. The filter cake was washed with MeOH (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (MeOH:DCM, 1:10) and then by preparative HPLC, Prep Method F (gradient: 5-30%) to give the title compound (10 mg, 17%) as a white solid; HRMS (ESI) m / z [M+H] + C 19 H 20 Calculated value for N9O: 390.1786, Measured value: 390.1758; 1 H NMR(300MHz,DMSO-d6)δppm1.45-1.74(2H,m)1.92-2.05(2H,m)2.09-2.28(2H,m)4.13-4.59(2H,m)6.70-6.93(1H,m)7.07(1H,dd)7.1 0-7.28(1H,m)7.30-7.42(1H,m)7.50(1H,dd)7.65-7.76(1H,m)7.77-7.96(1H,m)7.98-8.14(1H,m)8.49(2H,s)10.45-11.83(1H,m).( * (Regiochemistry not confirmed)

[0762] Example 32 (1S,3S)-N 1 -(5-(2-(difluoromethoxy)-6-fluorophenyl)pyridin-2-yl)-N 3 -(3H-Imidazo[4,5-b]pyridin-2-yl)cyclopentane-1,3-diamine - Compound 32

[0763] [ka] Cs2CO3 (174 mg, 0.53 mmol) was dissolved in 1,4-dioxane (3 mL) in (1S,3S)-N 1-(5-(2-(difluoromethoxy)-6-fluorophenyl)pyridin-2-yl)cyclopentane-1,3-diamine Intermediate 43 (60 mg, 0.18 mmol), 2-chloro-3-tosyl-3H-imidazo[4,5-b]pyridine * Intermediate 39 (109 mg, 0.36 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (12 mg, 0.01 mmol) were added at room temperature, and the resulting suspension was stirred at 100° C. for 16 hours under a nitrogen atmosphere. A solution of KCO (74 mg, 0.53 mmol) in MeOH (1 mL) was added to the mixture at room temperature, and the resulting suspension was stirred at 60° C. for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with DCM (2×50 mL). The organic layers were combined and washed with saturated brine (2×50 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was first purified by preparative TLC (7M NH3 in MeOH:DCM, 1:20) to give the crude product (51 mg), which was further purified by preparative HPLC, Prep Method F (gradient: 50-68%) to give the title compound (5 mg, 6%) as a white solid; HRMS (ESI) m / z [M+H] + C 23 H 22 Calculated value for F3N6O: 455.1802, Measured value: 455.1814; 1 H-NMR(300MHz,DMSO-d6)δppm1.45-1.65(2H,m),1.88-2.05(2H,m),2.12-2.25(2H,m),4.23-4.44(2H,m),6.55 (1H,d),6.75-6.98(3H,m),7.12-7.27(3H,m),7.33-7.48(3H,m),7.78-7.95(1H,d),7.97(1H,s),11.06(1H,d); 19 F-NMR (282MHz, DMSO-d6) δppm -113.761, -81.749. ( * (Regiochemistry not confirmed)

[0764] Example 33 1-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)quinolin-2(1H-one - Compound 33

[0765] [ka] A solution of 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one and 1-(6-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one intermediate 48 (60 mg, 0.11 mmol) in TFA (2 mL) was stirred at 60° C. for 5 h. The reaction mixture was concentrated and the crude product was purified by preparative HPLC, Prep Method I (gradient: 5-20%) to give the title compound (15 mg, 32%) as a yellow solid; HRMS (ESI) m / z [M+H] + C 25 H 24 Calculated value for N7O: 438.2036, Measured value: 438.2056; 1 H NMR(300MHz,DMSO-d6)δ1.58-1.74(m,2H),2.06(br s,2H),2.32(br s,2H),4.42(d,2H),6.70(ddd,3H),7.19-7.29(m,3H),7.34-7.51(m,2H),7.75-7.84(m,2H),7.89(d,1H),8.04(t,2H),8.99(s,1H),12.26(br s,1H).

[0766] Example 34 1-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H-one - Compound 34

[0767] [ka] TFA (2 mL) was added to a mixture of 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one and 1-(6-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one Intermediate 52 (100 mg, 0.18 mmol), and the reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC, Prep Method J (gradient 6-18%) to give the title compound (19 mg, 24%) as a white solid; MS (ESI) m / z [M+H] + 439.2: 1 H NMR(300MHz,DMSO-d6)δ1.53-1.70(m,2H),1.94-2.14(m,2H),2.15-2.33(m,2H),4.26-4.46(m,2H),6.58(d,1H),6.74(d,1H),6.88(d,1 H),7.04(dd,1H),7.23-7.32(m,2H),7.62(dd,1H),7.81(dd,1H),7.96(dd,1H),8.03(d,1H),8.11-8.23(m,2H),8.42(dd,1H),12.79(br s,1H).

[0768] Example 35 1-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one - Compound 35

[0769] [ka] 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one * Intermediate 57 (75 mg, 0.14 mmol) was suspended in TFA (5 mL) and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2 × 5 mL) and the combined filtrates were concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method J (gradient 12-17%) to give the title compound (25 mg, 41%) as a white solid; HRMS (ESI) m / z [M+H] + C 23 H 23 Calculated value for N8O: 427.1990, measured value: 427.1992; 1 H NMR(300MHz,DMSO-d6)d1.46-1.72(2H,m),1.90-2.10(2H,m),2.13-2.31(2H,m),4.24-4.45(2H,m),6.58-6.67(1H, m),6.83(1H,d),6.88-7.09(6H,m),7.42-7.57(3H,m),7.91(1H,dd),8.05(1H,d),8.11-8.17(1H,m),11.05(1H,s). ( * (Regiochemistry not confirmed)

[0770] Example 36 1-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one - Compound 36

[0771] [ka] 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one in TFA (2 mL) * A solution of intermediate 58 (30 mg, 0.05 mmol) was stirred at 80 °C for 16 h. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2 × 5 mL), and the combined filtrates were concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method F (gradient 25-55%) to give the title compound (12 mg, 51%) as a white solid; HRMS (ESI) m / z [M+H] + C 24 H 25 Calculated value for N8O: 441.2146, Measured value: 441.2170; 1 H NMR(300MHz,DMSO-d6)1.36-1.71(2H,m),1.88-2.09(2H,m),2.12-2.13(2H,m),3.37(3H,s),4.22-4.25(2 H,m),6.60(1H,d),6.71-7.27(7H,m),7.36(1H,t),7.47(1H,dd),7.85(1H,d),8.04(1H,d),10.77(0.5H,br s),11.36(0.4H,br s). Mixture of tautomers approximately 1:1.

[0772] Example 37 1-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methylimidazolidine-2,4-dione - Compound 37

[0773] [ka] 1-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methylimidazolidine-2,4-dione *Intermediate 59 (155 mg, 0.29 mmol) was dissolved in TFA (5 mL), and the reaction mixture was stirred at 80° C. for 4 h. The reaction mixture was filtered through Celite. The filter cake was washed with DCM (2×5 mL), and the combined filtrates were concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method J (gradient 8-17%), to give the title compound (74 mg, 62%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 23 Calculated value for N8O2: 407.1938, Measured value: 407.1940; 1 H NMR(300MHz,DMSO-d6)1.46-1.71(2H,m),1.90-2.08(2H,m),2.11-2.28(2H ,m),2.90(3H,s),4.25-4.31(2H,m),4.37(2H,s),6.53(1H,d),6.75(1H,br s),7.17(1H,dd),7.66(1H,dd),7.78(1H,dd),8.03(1H,dd),8.09-8.13(1H,m),8.91(1H,d),13.21(1H,br s). ( * (Regiochemistry not confirmed)

[0774] Example 38 3-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methylimidazolidine-2,4-dione - Compound 38

[0775] [ka] 3-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methylimidazolidine-2,4-dione in TFA (5.0 mL) *A solution of Intermediate 63 (236 mg, 0.45 mmol) was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC, Preparative Method A (gradient: 8-38%) to give the title compound (26 mg, 14%) as a white solid; HRMS (ESI) m / z [M+H] + C 20 H 23 Calculated value for N8O2: 407.1938, Measured value: 407.1914; 1 H NMR(300MHz,DMSO-d6)1.42-1.63(2H,m),1.85-2.02(2H,m),2.09-2.23(2H,m),2.90(3H,s),4.06(2H,s),4.24-4.34(2H,m),6.51(1H,d), 6.76(0.5H,dd),6.85-6.93(2H,m),7.16(0.5H,d),7.27(1H,dd),7.35(1H,dd),7.78(0.5H,d),7.85(1H,d),7.91(0.5H,d),10.74(0.5H,br s),11.34(0.5H,br s). Mixture of tautomers approximately 1:1. ( * (Regiochemistry not confirmed)

[0776] Example 39 3-(2-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)-1-methylpyridin-2(1H-one - Compound 39

[0777] [ka] 3-(2-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)-1-methylpyridin-2(1H-one *Intermediate 65 (69 mg, 0.13 mmol) was added to TFA (5 mL, 64.90 mmol) at 20° C. The resulting mixture was stirred at 80° C. for 3 hours. The solvent was removed under reduced pressure. The synthetic procedure was repeated to obtain 3-(2-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyrimidin-5-yl)-1-methylpyridin-2(1H)-one. * The procedure was repeated for a second batch using Intermediate 65 (40 mg, 0.08 mmol). The two batches were combined and purified by preparative HPLC, Prep Method A (gradient 16-31%) to give the title compound (25 mg, 29%) as a white solid; HRMS (ESI) m / z [M+H]+ C 21 H 23 Calculated value for N8O: 403.1990, measured value: 403.1986; 1 H NMR(300MHz,DMSO-d6)δ1.48-1.71(2H,m),1.89-2.05(2H,m),2.1-2.25(2H,m),3.50(3H,s),4.17-4.59(2H,m),6.30(1H,t), 6.72-6.94(1H,m),6.94-7.26(1H,m),7.29-7.48(2H,m),7.67(2H,ddd),7.76-7.98(1H,m),8.65(2H,s),10.63-11.54(1H,m). ( * (Regiochemistry not confirmed)

[0778] Example 40 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one - Compound 40

[0779] [ka] A solution of 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one intermediate 66 (91 mg, 0.17 mmol) in TFA (5.0 mL) was stirred at 80 °C for 2 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, Prep Method A (gradient 15-35%) to give the title compound (18 mg, 25%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 24 Calculated value for N7O: 402.2036, Measured value: 402.2046; 1 H NMR(300MHz,DMSO-d6)1.46-1.66(2H,m),1.89-2.06(5H,m),2.12-2.25(2H,m),4.25-4.39(2H,m),6. 18(1H,t),6.53(1H,d),6.90-6.98(2H,m),7.34-7.40(2H,m),7.44(1H,dd),7.49(1H,dd),7.69(1H,br d),7.89-7.91(2H,m),12.09(1H,br s). ( * (Regiochemistry not confirmed)

[0780] Example 41 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one - Compound 41

[0781] [ka] 3-Methoxy-6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one *A solution of intermediate 67 (84 mg, 0.16 mmol) in TFA (5.0 mL) was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC, Prep Method K (gradient: 2-20%) to give the title compound (8 mg, 13%) as a brown solid. HRMS (ESI) m / z [M+H] + C 22 H 24 Calculated value for NO2: 418.1986, Measured value: 418.1986. 1 H NMR(300MHz,DMSO-d6)1.52-1.74(2H,m),1.96-2.12(2H,m),2.15-2.31(2H,m),3.71(3H,s),4.27-4.39(2H,m),6.21(1 H,t),6.63(1H,d),6.87(1H,dd),7.11-7.41(3H,m),7.49(1H,dd),7.81(1H,dd),7.97(1H,d),8.04(1H,d),9.03(1H,br s),12.44(1H,br s). ( * (Regiochemistry not confirmed)

[0782] Example 42 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-3-chloro-2H-[1,3'-bipyridin]-2-one - Compound 42

[0783] [ka] 3-Chloro-6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one in TFA (3 mL) *A mixture of Intermediate 68 (90 mg, 0.17 mmol) was stirred at 80° C. for 3 hours. The reaction mixture was filtered through Celite, and the filter cake was washed with DCM (2×5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method H (gradient: 11-41%) to give the title compound (45 mg, 64%) as a white solid; HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated for ClNO: 422.1490, Found: 422.1508; 1 H NMR(300MHz,DMSO-d6)δ1.46-1.64(2H,m),1.87-2.03(2H,m),2.11-2.22(2H,m),4.25-4.35(2H,m),6.29(1H,t),6.54(1H,d),6.74-6.78(0.5H, m),6.87-7.03(2H,m),7.17(0.5H,d),7.36(1H,dd),7.43(1H,dd),7.65( 1H,d),7.77-7.81(1.5H,m),7.91(0.5H,d),7.96(1H,d),10.73(0.5H,br s),11.34(0.5H,br s). A mixture of tautomers, approximately 1:1. * (Regiochemistry not confirmed)

[0784] Example 43 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile - Compound 43

[0785] [ka] 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile in TFA (4.0 mL) *The mixture of intermediate 69 (55 mg, 0.10 mmol) was stirred at 80° C. for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, Preparative Method F (gradient: 7-32%) to give the title compound (5 mg, 12%) as a white solid: HRMS (ESI) m / z [M+H] + C 22 H 21 Calculated N8O value: 413.1832, Measured value: 413.1826; 1 H NMR(300MHz,DMSO-d6)δ1.45-1.65(2H,m),1.85-2.00(2H,m),2.10-2.30(2H,m),4.25-4.51(2H,m),6.49-6.62(2H,m),6.76-7.18(3H,m) ,7.28-7.42(1H,m),7.45-7.55(1H,m),7.65-7.83(1H,m),7.86-7.96(1H,m),7.99(1H,d),8.57(1H,s),10.74(0.5H,s),11.35(0.5H,s). Mixture of tautomers approximately 1:1. ( * (Regiochemistry not confirmed)

[0786] Example 44 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid - Compound 44

[0787] [ka] NaOH (54 mg, 1.36 mmol) was added to a solution of methyl 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate·2.5TFA Intermediate 71 (99 mg, 0.14 mmol) in MeOH (6 mL) and water (2 mL), and the reaction mixture was stirred at 20 °C under a nitrogen atmosphere for 16 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL), and the pH was adjusted to 3 with 1 M HCl (aq). The reaction mixture was poured into water (50 mL), extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method J (gradient 6-21%) to give the title compound (16 mg, 27%) as a white solid; HRMS (ESI) m / z [M+H] + C 22 H 22 Calculated value for N7O3: 432.1778, Measured value: 432.1778; 1 H NMR(300MHz,DMSO-d6)δppm1.42-1.71(m,2H)1.84-2.08(m,2H)2.09-2.36(m,2H)4.18-4.51(m,2H)6.35-6.67(m,2H)6.75-6.93 (m,1H)6.94-7.05(m,1H)7.07-7.23(m,1H)7.33-7.41(m,1H)7.45(dd,1H)7.74-7.94(m,2H)7.96-8.04(m,1H)8.09-8.25(m,1H).

[0788] Example 45 3-(6-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one - Compound 45

[0789] [ka] 3-(6-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one in TFA (1 mL) * A solution of intermediate 72 (50 mg, 0.09 mmol) was stirred at 80° C. for 18 hours. The reaction mixture was filtered through Celite, and the filter cake was washed with DCM (2×5 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC, Prep Method F (gradient: 15-35%) to give the title compound (10 mg, 25%) as a white solid; HRMS (ESI) m / z [M+H] + C 23 H 24 Calculated value for N9O: 442.2098, Measured value: 442.2092; 1 H NMR(300MHz,DMSO-d6)δppm1.46-1.71(m,2H)1.87-2.10(m,2H),2.12-2.35(m,2H)3.42(s,3H)4.14-4.53(m,2H)6.57-6.65(m,1H)6.8 1-6.91(m,1H)6.91-6.98(m,1H)7.09-7.19(m,1H)7.40(dd,1H)7.48-7.62(m,2H)7.84-7.91(m,1H)7.94(dd,1H)8.11(d,1H),11.32(br s,1H). ( * (Regiochemistry not confirmed)

[0790] Example 46 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 46

[0791] [ka] A mixture of 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Intermediate 73 (100 mg, 0.20 mmol) was treated with TFA (3 mL) at 20 °C, and the resulting solution was stirred at 80 °C under a nitrogen atmosphere for 18 h. The reaction mixture was cooled to room temperature, filtered through Celite, and the filter cake was washed with DCM (2 × 5 mL). The combined filtrates were concentrated under reduced pressure and the resulting residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 0-29% MeCN in water (1% TFA)) followed by preparative HPLC, Prep Method A (gradient: 12-42%) to afford the title compound (10 mg, 13%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 22 Calculated value for N7O: 388.1880, Measured value: 388.1896. 1 H NMR(300MHz,Methanol-d4)1.55-1.74(2H,m),2.04-2.13(2H,m),2.22-2.42(2H,m),4.38(2H,h),6.4 6(1H,td),6.57-6.67(2H,m),6.96(1H,dd),7.39-7.54(2H,m),7.54-7.68(2H,m),7.82-8.00(2H,m).

[0792] Example 47 6'-(((1S,3S)-3-((6-chloro-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 47

[0793] [ka] 2,6-Dichloro-3H-imidazo[4,5-b]pyridine (23.9 mg, 0.13 mmol) and 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one intermediate 3 (31 mg, 0.12 mmol) were added to a sealed vial, followed by NMP (0.4 mL) and TEA (32 μL, 0.23 mmol). The mixture was heated at 110°C under air atmosphere for 24 h. Another amount of TEA (32 μL, 0.23 mmol) was added, and the reaction mixture was stirred at 110°C for an additional 20 h. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC (Preparative Method B, gradient: 15-55%) to give the title compound (18 mg, 37%) as an off-white solid; HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated for ClNO: 422.1490, Found: 422.1502; 1 H NMR(500MHz,DMSO-d6)δ1.46-1.64(2H,m),1.95(2H,dt),2.17(2H,s),4.31(2H,dq),6.27(1H,td),6.4 4(1H,dt),6.53(1H,d),6.96(1H,dd),7.25-7.49(4H,m),7.60(1H,d),7.77-7.95(2H,m),11.27(1H,d).

[0794] Examples 48 to 50 The following examples were synthesized and purified similarly as described for Example 47, starting from 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one intermediate 3 and commercially available starting materials, unless otherwise stated. The reaction time was 20 hours.

[0795] [Table 14]

[0796] Example 51 6'-(((1S,3S)-3-((6-(trifluoromethoxy)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 51

[0797] [ka] 1,1'-Thiocarbonyldiimidazole (55 mg, 0.31 mmol) was added to a solution of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one·HCl intermediate 3 (42 mg, 0.16 mmol) in DMF (1 mL), and the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, and a solution of 5-(trifluoromethoxy)pyridine-2,3-diamine (32 mg, 0.16 mmol), TEA (0.043 mL, 0.31 mmol), and EDC (60 mg, 0.31 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at 100 °C for 17 h, cooled to room temperature, and poured into water. The aqueous layer was extracted with EtOAc (×2), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Preparative Method B, gradient: 10-50%), and the fractions containing the desired product were combined and concentrated under reduced pressure. The resulting aqueous layer was extracted with EtOAc (×2), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (14 mg, 19%) as a yellow solid; HRMS (ESI) m / z [M+H] + C 22 H 21 Calculated value for F3N7O2: 472.1704, Measured value: 472.1692; 1H NMR(500MHz,DMSO-d6)δ1.43-1.66(2H,m),1.85-2.06(2H,m),2.1-2.27(2H,m),4.22-4.43(2H,m),6.23-6.3(1H,m),6 .44(1H,d),6.53(1H,dd),6.95(1H,dd),7.29-7.51(4H,m),7.56-7.63(1H,m),7.79-7.98(2H,m),10.72-11.89(1H,m).

[0798] Example 52 6-(((1S,3S)-3-((6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)-2H-[1,3'-bipyridin]-2-one - Compound 52

[0799] [ka] A mixture of 6'-(((1S,3S)-3-((6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)-2H-[1,3'-bipyridin]-2-one and 6'-(((1S,3S)-3-((6-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)-2H-[1,3'-bipyridin]-2-one Intermediate 81 (95 mg, 0.14 mmol) in TFA (2 mL) was stirred at 100° C. for 1 h in a sealed reactor. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC, Preparative Method B (gradient: 10-50%). The compound-containing fractions were combined, and the organic solvent was removed under reduced pressure. The aqueous layer was extracted twice with a mixture of EtOAc:MeOH (9:1). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (31 mg, 39%); HRMS (ESI) m / z [M+H] + C 26 H 25Calculated for BrNO: 558.1360, Found: 558.1362; 1 H NMR(500MHz,DMSO-d6)δ1.46-1.69(2H,m),1.87-2.07(2H,m),2.18(2H,s),2.62(3H,s),4.24-4.42(2H,m),6.56(1H,d),6.60(1H,d),6.9 9(1H,s),7.18-7.45(1H,m),7.46-7.6(2H,m),7.8-8.01(2H,m),8.04(1H,d),8.19(1H,d),8.97(2H,s),10.87(0.5H,s),11.61(0.5H,s). Mixture of tautomers approximately 1:1.

[0800] Example 53 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-5-(2-methylpyrimidin-5-yl)...

Claims

1. Formula (I): A-B-C (I) A compound of the formula wherein A is of the following formula: 【Chemistry 1】 wherein the wavy line indicates the point of attachment to B; X １ is selected from O, S, or NH; X ２ is either N or C—H, X ３ is N or C-R Ａ３ Either X １ is NH, and X ２ is C—H, then X ３ is C-R Ａ３ and X １ When is NH, R Ａ１ is X ４ and R Ａ２ is X ５ and X ２ is N and X １ is O or S, R Ａ１ is X ４ and R Ａ２ is X ５ and X ２ is CH and X １ If S, then R Ａ１ is X ４ and R Ａ２ is X ５ and X ２ is CH and X １ is O, then R Ａ１ is X ５ and R Ａ２ is X ４ and X ４ teeth, (i) H, (ii) halo, (iii) CN, (iv) C optionally substituted by one or more OH, CN, or one or more halo groups. １ alkyl, or (v) C optionally substituted with one or more halo groups. １ alkoxy; X ５ teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C １～６ Alkyl acyl, C １～６ C optionally substituted with alkoxy or one or more halo groups; １～６ hydrocarbons, (v) C １～６ Alkylamide, C １～６ alkylphosphonyl, or C optionally substituted with one or more halo groups; １～６ Alkoxy, (vi) C １～６ alkylamino, (vii) C １～６ thioalkyl, (viii) C １～６ alkylphosphinyl, or (ix) C １～６ alkylphosphonyl; 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, C(=O)OH, C １～６ Alkyl esters, C １～６ Alkylamino, —C(═O)NH ２ , C １～６ Alkylamide, C １～６ Acylamide, C １～６ Alkylsulfinyl, C １～６ C optionally substituted with alkylsulfonyl or one or more halo groups; １～６ hydrocarbons, (v) NH ２ , C ４ C optionally substituted with heterocyclyl and one or more halo groups; １～６ Alkoxy, (vi) C ４ heterocyclyl, (vii) CN, OH, C ４ C optionally substituted by heterocyclyl １～６ alkylamino, (viii) -NH ２ C optionally substituted by １～６ dialkylamino, or (ix) OH or —NH ２ C optionally substituted by １～６ thioalkyl; B is a group represented by the formula (B-1) or (B-2) i) 【Chemistry 2】 (wherein 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 alkyl optionally substituted with OH or OMe); (ii) 【Transformation 3】 (wherein the wavy lines indicate the points of attachment to A and C, R Ｂ２ is C １～２ Alkyl-OH, CH ２ C(═O)NHMe, or C １～３ is alkyl, R Ａ１ is H or halo, then R Ｂ２ is C １～２ Alkyl-OH or CH ２ C(═O)NHMe), C is C ６～１０ Carboaryl, C ５～６ Heteroaryl, or C ５～１０ heterocyclyl, wherein these groups are selected from the group consisting of: (i) 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, 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 １～６ C optionally substituted with alkyl 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) C(=O)OH or CH ２ C(=O)OH, and / or n) tetrazolyl, CH ２ -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, spiro C ６～１２ Heterocyclyl or spiro C ６～１２ carbocyclyl, (ii) C(=O)OH, CN, halo, nitro, C １～６ Alkyl, C １～６ Thioalkyl, C １～６ Alkoxy, C １～６ Alkyl acyl, C １～６ Alkylamide, di-C １～６ Alkylamide, C １～６ Alkyl sulfonamides, and di-C １～６ 1. A compound, or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof, optionally substituted with one or more groups selected from alkylsulfonamide.

2. A is represented by the following formulae A1 to A3: Table 1 wherein the wavy line indicates the point of attachment to B; ２ , X ３ , R Ａ１ , and R Ａ２ is as defined in claim 1, and optionally A is one of the following formulae A4 to A14: Table 2-1 Table 2-2 wherein the wavy line indicates the point of attachment to B, and R Ａ１ , R Ａ２ , and R Ａ３ 2. The compound of claim 1, wherein:

3. X ４ but, (i) H, (ii) halo, (iii) CN, or (iv) C optionally substituted with one or more OH groups or one or more halo groups. １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

4. X ５ but, (i) H, (ii) halo, (iii) C optionally substituted with one or more OH or one or more halo groups; １～６ Alkyl, (iv) C optionally substituted with one or more halo groups. １～６ Alkoxy, (v) C ３～５ cycloalkyl, (vi) C １～６ thioalkyl, or (vii) C １～６ 4. The compound of claim 1, wherein the compound is selected from the group consisting of alkylphosphinyl, alkylphenylphosphinyl, and alkylphenylphosphinyl.

5. The compound of claim 1, wherein the compound is selected from the group consisting of alkylphosphinyl, alkylphenyl ...

5. R Ａ３ but, (i) H, (ii) halo, (iii) CN, (iv) C optionally substituted with OH or one or more halo groups; １～６ Alkyl, (v) C optionally substituted with OH or one or more halo groups. ２～６ alkenyl, (vi) C optionally substituted with OH or one or more halo groups ２～６ alkynyl, or (vii) C optionally substituted with one or more halo groups; １～６ 5. The compound of claim 1, wherein the compound is selected from the group consisting of alkoxy, or a pharmaceutically acceptable salt thereof.

6. A is of the formula: a) 【Chemistry 4】 (In the formula, X ２ is selected from N and C—H; R Ａ１ are H, CN, CH ２ OH, OCHF ２ , methyl, or Br), b) 【Transformation 5】 (In the formula, R Ａ１ are H, CN, CH ２ OH, methyl, OCHF ２ or Br), c) 【Transformation 6】 d) 【Transformation 7】 (In the formula, X ２ is selected from N or C—H, X ２ If N, then X ３ is N or C-R Ａ３ Either X ２ is C—H, then X ３ is C-R Ａ３ or N, R Ａ１ is selected from H, methyl, or Br; R Ａ２ is H, CN, or CH ２ OH, R Ａ３ is H), e) 【Transformation 8】 (In the formula, R Ａ２ teeth, (i) H, (ii) halo, (iii) C optionally substituted with one or more OH or one or more halo groups; １～６ Alkyl, (iv) C optionally substituted with one or more halo groups. １～６ Alkoxy, (v) C ３～５ cycloalkyl, (vi) C １～６ thioalkyl, (vii) C １～６ alkylphosphinyl, or (viii) CN, f) 【Chemistry 9】 (In the formula, R Ａ３ is selected from H, halo, or OMe; R Ａ２ is H, Br, and CH ２ OH), (g) 【Chemistry 10】 (In the formula, X ２ is N or C—H, X ２ If N, then X ３ is N or C-R Ａ３ Either X ２ is C—H, then X ３ is C-R Ａ３ and R Ａ３ is selected from H, Cl, Br, or OMe; R Ａ２ is H, CH ２ OH, OCH ３ , OCHF ２ , OCF ３ , C.F. ３ , F, Cl, Br, ethyl, cyclopropyl, methyl, -P(=O)Me ２ , or -S-CH ３ selected from h) 【Chemistry 11】 (In the formula, X ３ is N or C-R Ａ３ and R Ａ３ is selected from H, Cl, Br, or OMe; R Ａ２ is H, CH ２ OH, OCH ３ , OCHF ２ , OCF ３ , C.F. ３ , F, Cl, Br, ethyl, cyclopropyl, methyl, -P(=O)Me ２ , or -S-CH ３ 6. The compound of claim 1, wherein the compound is selected from one of the following:

7. A is the following compound: Table 3-1 Table 3-2 7. The compound of claim 1, wherein the wavy line indicates the point of attachment to B, or a pharmaceutically acceptable salt thereof.

8. B is represented by the following formula (B-1a): 【Chemistry 12】 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is

9. C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, and 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, spiro C ６～１２ Heterocyclyl or spiro C ６～１２ carbocyclyl, which themselves may be 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, 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 １～６ C optionally substituted with alkyl 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) C(=O)OH or CH ２ C(=O)OH, and / or n) tetrazolyl, CH ２ 9. The compound of claim 1, wherein the compound is optionally substituted with one or more of the following: -tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl, or a pharmaceutically acceptable salt thereof.

10. C is a compound represented by formula (C-1): 【Chemistry 13】 wherein D is C ６～１０ Carboaryl, C ５～１０ Heteroaryl, or C ５～１０ heterocyclyl, each of which may itself be i) one or two =O groups; ii) one or two C which may be branched １～４ alkyl groups, iii) OMe; iv) piperazinyl or pyrimidinyl optionally substituted with methyl; v) C(=O)OH, vi) Cl, vii) one or more F; viii) phenyl optionally substituted with one or more fluoro; ix) CN, x)CF ３ 、 xi)OCF ３ 、 x｡｡｡)OCHF ２ 、 xiii) tetrazolyl, pyrazolyl, triazolyl, xiv)NH ２ 、 xv) pyridinyl, xvi)CH ２ OH、 xvii) OH, xviii)P(=O)Me ２ 、 xix) CHF ２ , or xx) CH ２ CF ３ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted by:

11. D is a compound represented by formula (D-1): 【Chemistry 14】 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) 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) C(=O)OH or CH ２ C(=O)OH, 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 forms an optionally substituted 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, and C(═O)OH; or R Ｄ１ and R Ｄ２ forms an optionally substituted 5- or 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, and C(═O)OH; or R Ｄ２ and R Ｄ３ form an optionally substituted 5- or 6-membered carboaromatic, heterocyclic, or heteroaromatic ring, the optional substituents being halo, CN, OH, P(═O)Me, ２ , C(═O)OH, C optionally substituted by one or more halo groups １～６ C optionally substituted with alkoxy or one or more halo groups １～６ alkyl, or R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ are all H, or a pharmaceutically acceptable salt thereof.

12. a) R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ One or two of the i) methyl, ii) OMe, iii) pyrimidinyl substituted by methyl; iv) tetrazolyl, v) C(=O)OH, vi) halo, vii) CF ３ , viii) C.N.; ix)O-CF ３ 、 x) -OCHF ２ , selected from R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ The remainder is H, or b) R Ｄ１ , R Ｄ２ , R Ｄ３ , and R Ｄ４ is H or c) R Ｄ３ is H, OMe, C(=O)OH, Cl, CN, OCH ２ pyrimidinyl optionally substituted with F, tetrazolyl, or methyl; R Ｄ１ , R Ｄ２ , and R Ｄ４ Are all H? d) R Ｄ１ H, methyl, OMe, Cl, OCF ３ , C.F. ３ , OCHF ２ , and CN; R Ｄ２ , R Ｄ３ , and R Ｄ４ Are all H? e) R Ｄ３ and R Ｄ４ form an unsubstituted phenyl ring or an unsubstituted pyridine ring, or f) R Ｄ１ and R Ｄ２ form an unsubstituted 5-membered heterocyclic or heteroaromatic ring, or g) R Ｄ１ and R Ｄ２ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein:

13. D is a compound represented by formula (D-2): 【Chemistry 15】 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 they are -CH ２ - or R Ｄ６ａ is H, ═O, methyl, CH ２ OH, or C(═O)OH; R Ｄ６ａ When =O, R Ｄ６ｂ does not exist, R Ｄ７ａ is H, ═O, methyl, CH ２ OH, or C(═O)OH; R Ｄ７ｂ is H and R Ｄ７ａ When =O, R Ｄ７ｂ does not exist or Or, R Ｄ６ａ and R Ｄ７ａ is CN, P(=O)Me ２ or a phenyl ring optionally substituted by C(═O)OH or C ６ together form a heteroaromatic ring, R Ｄ６ｂ and R Ｄ７ｂ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: is not present.

14. D is a compound represented by formula (D-3): 【Chemistry 16】 wherein R Ｄ３ａ is selected from H and methyl; R Ｄ３ｂ and R Ｄ３ｃ are independently H, halo, CN, OH, P(=O)Me ２ , C(═O)OH, C optionally substituted by one or more halo groups １～６ C optionally substituted with alkoxy or one or more halo groups １～６ alkyl; or R Ｄ３ｂ and R Ｄ３ｃ is C ５～６ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein either together form a heteroaryl ring.

15. 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein D is selected from the following group: Table 4-1 Table 4-2 Table 4-3 Table 4-4

16. C is a compound represented by formula (C-2): 【Chemistry 17】 wherein R Ｃ７ , R Ｃ８ , R Ｃ９ , and R Ｃ１０ is methyl, OMe, piperazinyl or pyrimidinyl optionally substituted with methyl, C(═O)OH, Cl, F, pyrazolyl, triazolyl, tetrazole, optionally substituted phenyl (the optional substituents are methyl or halo), CN, CF ３ , OCHF ２ , O-CF ３ and R Ｃ７ , R Ｃ８ , R Ｃ９ , and R Ｃ１０ the remainder are H, or R Ｃ９ and R Ｃ１０ form a phenyl or 6-membered heteroaromatic ring optionally substituted by methyl, 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 9, or a pharmaceutically acceptable salt thereof, wherein all of

17. a) R Ｃ７ , R Ｃ８ , R Ｃ９ , and R Ｃ１０ are all H, or b) R Ｃ９ H, CN, OMe, Cl, OCHF ２ , tetrazolyl, pyrimidinyl substituted by methyl, C(═O)OH; R Ｃ７ , R Ｃ８ , and R Ｃ１０ are all H, or c) R Ｃ７ H, methyl, Cl, OMe, CN, CF ３ , OCHF ２ , OCF ３ and R Ｃ８ , R Ｃ９ , and R Ｃ１０ are all H, or a pharmaceutically acceptable salt thereof.

18. 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of: Table 5-1 Table 5-2 Table 5-3

19. ABC is a formula (IA), (I-A1), (I-A2), (I-A3), (IB), (I-B1), (I-B2), (I-B3), (IC), (I-C 1), (I-C2), (I-C3), (ID), (ID1), (ID2), (ID3), (IE), (I-E1), (I-E2), or (I-E3): [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 wherein X １ , X ２ , X ３ , R Ａ１ , R Ａ２ , R Ａ３ , C., D., R. Ｄ１ , R Ｄ２ , R Ｄ３ , R Ｄ４ , R Ｄ６ａ , R Ｄ６ｂ , R Ｄ７ａ , R Ｄ７ｂ , X Ｄ R Ｄ３ａ , R Ｄ３ｂ , and R Ｄ３ｃ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

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

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

23. 23. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, for use in the treatment of cardiovascular disease, optionally wherein the cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular disease, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure, or congestive heart failure.

24. The compound is vii) statins; viii) cholesterol absorption inhibitors; ix) SGLT2 inhibitors; x) P2Y12 inhibitors, xi) a citrate lyase inhibitor, and 24. The compound for use according to claim 23, administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of: xii) antihypertensive drugs.

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