PCSK9 inhibitors and methods of use thereof

Abstract

A compound having the formula (I): ABC, wherein A is of the following formula (II): 1 But, CR A1 wherein B is of formula (B-1) or (B-2) and C is optionally substituted C 6~10 Carboaryl, C 5~6 Heteroaryl and C 5~10 1. Compounds selected from the group consisting of heterocyclyls, and their use as PCSK9 inhibitors. [Case 1] JPEG2025532671000369.jpg67128

Description

[Technical Field]

[0001] The present disclosure relates to compounds that inhibit PCSK9 and their use in methods of treatment. This application claims the benefit of priority to U.S. Patent Application No. 63 / 376,791, filed September 23, 2022, U.S. Patent Application No. 63 / 483,797, filed February 8, 2023, Pakistan Patent Application No. 581 / 2023, filed August 31, 2023, and U.S. Patent Application No. 63 / 580,507, filed September 5, 2023, which are incorporated herein by reference in their entireties. [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 recycling and instead targets the LDLR for lysosomal degradation. Genetic association studies have shown 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 fails 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 suggests 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 therapy.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 / 150474(A1) relates to inhibitor pharmacophores of PCSK9 and heteroaryl compounds that bind to the PCSK9 protein. Summary of the Invention

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

[0009] [ka] where the wavy line indicates the point of attachment to B; X 1 But, CR A1 and R A1 but, (i) H, (ii) halo, (iii) CN, (iv) one or more of OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v) OH, one or more halo groups, C 1~6 C optionally substituted with alkylamide 1~6 Alkoxy, (vi) C 1~6 Alkyl esters, (vii)C 1~6 alkyl acyls, and (viii) selected from the group consisting of OH; R A2 but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups;1~6 hydrocarbons, (v) OH, C 1~6 C optionally substituted with alkylamido or one or more halo groups 1~6 Alkoxy, (vi) C 1~6 acylamides (wherein acyl is optionally substituted by H or methyl); (vii)C 1~6 C optionally substituted with alkyl esters 1~6 thioalkyl, (viii)C 1~6 Alkyl esters, (ix) C 1~6 alkyl acyls, (x)C 4~5 heterocyclyl, (xi) C5 heteroaryl, (xii)C 1~3 Alkylamide, CN, OH, C 2~3 Alkynyl, C 4~6 Heterocyclyl, C 1~3 C optionally substituted with alkyl 1~6 Alkyl amides, such as C 1~3 C, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 alkylamides, and (xiii) selected from the group consisting of OH; R A3 but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6C optionally substituted with alkylsulfonyl or one or more halo groups 1~6 hydrocarbons, (v)OH, (vi) C optionally substituted by OH, NH, C heterocyclyl, or one or more halo groups. 1~6 Alkoxy, (vii)C 1~6 acyloxy, (viii) C4 heterocyclyl, (ix) NH2, (x) C optionally substituted by CN, OH, C heterocyclyl 1~6 alkylamino, (xi) C optionally substituted by -NH 1~6 Dialkylamino, (xii)C 1~6 acylamides (wherein the acyl substituent is H or Me); (xiii) carbimidoyl or methyl-carbimidoyl, (xiv) carboxyamino, (xv) C optionally substituted by OH or NH 1~6 thioalkyl, (xvi)C 1~6 alkylsulfinyl, (xvii) C optionally substituted with one or more halo groups 1~6 alkylsulfonyl, (xviii)C 1~6 sulfonimodil, (xix)C 1~6 alkylphosphinyl, (xx) carboxy, (xxi) C(=O)NH2, (xxii)C 1~6 Alkyl esters, (xxiii) C optionally substituted with one or more halo groups 1~6 alkyl acyls, (xxiv)C 1~6 alkylamides; or RA3 and R A2 together with the carbon atoms to which they are attached, (i) optionally substituted C 5~7 heterocycles, (ii) optionally substituted C 5~7 heteroaromatic rings, (iii) an optionally substituted C6 carboaromatic ring; (iv) optionally substituted C 5~7 forming a carbocyclic ring, The optional substituents are C 1~6 Alkyl, Halo, C 1~6 Alkoxy, NH2, C 1~6 selected from alkylamino, OH, and CN; B is of formula (B-1) or (B-2), (i)

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

[0011] [ka] where the wavy lines indicate the points of attachment to A and C; R B2 But C 1~2 Alkyl-OH, CH2CONHMe or C 1~3 is alkyl, C is C 6~10 Carboaryl, C 5~6 Heteroaryl and C 5~10 heterocyclyl, wherein these groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged heterocycles, spiro C 6~12 Heterocyclyl or spiro C 6~12 A group selected from carbocyclyl (These are themselves the following groups: a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) OH, C, including branched and cyclic 1~6 one or more C with optional substituents selected from alkylsulfonyl or one or more halo groups; 1~6 alkyl groups, e) C with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h) C optionally substituted with methyl 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) P(=O)Me2, m) carboxy or CH2-carboxy, and / or n) optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; and / or (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C1~6 Alkylamide, C 1~6 Alkyl sulfonamides and di-C 1~6 Provided are compounds having the formula (I), or pharmaceutically acceptable salts thereof, and tautomeric forms or stereoisomers thereof, optionally substituted with one or more groups selected from alkylsulfonamides.

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

[0013] A third aspect provides a compound of the first aspect for use in a method of therapy. The third aspect also provides the use of a compound of the first aspect in the manufacture of a medicament for treating cardiovascular disease. The third aspect also provides a compound of the first aspect for use in treating cardiovascular disease. The third aspect also provides a method of treating cardiovascular disease, comprising administering a therapeutically effective amount of a compound of the first aspect or a composition according to the second aspect to a patient in need thereof.

[0014] The present disclosure includes combinations of the described aspects and features except where such combinations are expressly disallowed or explicitly avoided. DETAILED DESCRIPTION OF THE INVENTION

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

[0016] The compounds of formula (I) and their use in the treatment of cardiovascular disease are described herein.The compounds disclosed herein are PCSK9 inhibitors.These 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.These compounds may have improved secondary pharmacological profile or improved off-target profile.

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

[0018] Unless otherwise specified, as used herein, the term "substituted" 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 their methods of formation and introduction into various parent groups.

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

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

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

[0022] Hydroxy: -OH.

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

[0024] C 1~6 Hydrocarbon: As used herein, "C1~6 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 branched. Thus, the term "hydrocarbon" includes terms such as alkyl, alkenyl, alkynyl, cycloalkyl, etc., which are discussed below.

[0025] 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 hydrocarbon compound having 1 to 6 carbon atoms, which may be saturated and branched. 1~4 The term "alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having 1 to 4 carbon atoms.

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

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

[0028] Examples of saturated branched alkyl groups include iso-propyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), and neo-pentyl (C5).

[0029] 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.

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

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

[0032] Examples of unsaturated alkynyl groups include ethynyl

[0033] [ka] and 2-propynyl (propargyl,

[0034] [ka] ), but are not limited to these.

[0035] C 1~6 Alkoxy: As used herein, C 1~6 The term alkoxy refers to when R is C 1~6 It relates to the hydrocarbon group OR. 16 Examples of alkoxy groups include, but are not limited to, OMe, OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), O(nBu) (n-butoxy), O(sBu) (sec-butoxy), O(iBu) (isobutoxy), and O(tBu) (tert-butoxy).

[0036] C 1~6 Acyloxy: As used herein, C 1~6The 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.

[0037] Amino:-NR 1 R 2 , where R 1 and R 2 are independently an amino substituent, e.g., hydrogen, C 1~6 Hydrocarbon group (C 1~6 Alkylamino or C 1~6 (also called dialkylamino) or, in the case of a "cyclic" amino group, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 6 ring atoms. Amino groups can be primary (-NH2), secondary (-NHR 1 ), or 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.

[0038] C 1~6 Acylamide: Acylamide (acylamino): NR 1 C(=O)R 2 , where R 1 is an amide substituent, e.g., hydrogen or C 1~6 is a hydrocarbon group, R 2 is an acyl substituent, e.g., C 1~6Examples 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 be taken together to form a cyclic or bicyclic structure or 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.

[0039] [ka]

[0040] Carbimidoyl: -C(=NH)(NH2).

[0041] Methyl-carbimidoyl: -C(=N-CH3)NH2.

[0042] Carboxyamino: -N(H)(C(=O)OH).

[0043] C 1~6 Thioalkyl: As used herein, C 1~6 The term thioalkyl refers to -SR, where R is C 1~6 It is a hydrocarbon group. 1~6 Examples of alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3.

[0044] C 1~6 Alkyl sulfinyl: C 1~6 The term alkylsulfinyl refers to a sulfine (sulfinyl, sulfoxide) having the structure -S(=O)R, where R is C 1~6 It is a hydrocarbon group. 1~6Examples of alkylsulfinyl groups include, but are not limited to, -S(=O)CH3 and -S(=O)CH2CH3.

[0045] 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 containing alkyl groups 1~6 It is a hydrocarbon group. 1~6 Examples of alkylsulfonyl groups include, but are not limited to, -S(=O)2CH3 (methanesulfonyl, mesyl), -S(=O)2CF3 (triflyl), -S(=O)2CH2CH3 (esyl), -S(=O)2C4F9 (nonaflyl), and -S(=O)2CH2CF3 (tresyl).

[0046] C 1~6 Sulfonimodil: C 1~6 The term sulfonimodil, also known as sulfonamide (sulfinamoyl, sulfonic acid amide, sulfonamide), has the structure -S(=O)NR 1 R 2 wherein R 1 and R 2 are independently an amino substituent as defined for an amino group. Examples of sulfonamide groups include, but are not limited to, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3), -S(=O)2NH(CH2CH3), and -S(=O)2N(CH2CH3).

[0047] C 1~6 Alkylphosphinyl: C 1~6 The term alkylphosphinyl (phosphine oxide) has the structure -P(=O)R, where each R is independently C 1~6 It is a hydrocarbon group. 1~6Examples of alkylphosphinyl groups include, but are not limited to, P(=O)(CH), P(=O)(CHCH), and P(=O)(tBu), where each R group can be the same or different.

[0048] Carboxy (carboxylic acid): -C(=O)OH.

[0049] C 1~6 Alkyl ester: C 1~6 The term alkyl ester (carboxylate, carboxylic acid ester, oxycarbonyl) has the structure -C(=O)OR, where R is C 1~6 Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, and -C(=O)OC(CH3)3.

[0050] C 1~6 Alkyl acyl: also known as acyl (keto) C 1~6 The term alkyl acyl has the structure -C(=O)R, where R is C 1~6 It is a hydrocarbon group. 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 (t-butyryl).

[0051] C 1~6 Alkylamide: C 1~6 The term alkylamide (also known as carbamoyl, carbamyl, aminocarbonyl, or carboxamide) refers to a compound with the structure -C(=O)NR 1 R 2 wherein 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, R1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring 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 but are not limited to amide groups which, together with the nitrogen atom to which they are attached, form a heterocyclic ring structure such as found in piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

[0052] C 3~12 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, the 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.

[0053] Examples of cycloalkyl groups include, but are not limited to, those derived from: Saturated monocyclic hydrocarbon compounds: Cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (C6), cycloheptane (C7), methylcyclopropane (C4), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C6), methylcyclopentane (C6), dimethylcyclopentane (C7) and methylcyclohexane (C7); Unsaturated monocyclic hydrocarbon compounds: Cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (C6), methylcyclopentene (C6), dimethylcyclopentene (C7), and methylcyclohexene (C7); and Saturated polycyclic hydrocarbon compounds: Norkarane (C7), norpinane (C7), norbornane (C7).

[0054] C 3~10 Heterocyclyl: As used herein, "C 3~10 The 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.

[0055] In this context, the term "heteroatom" means O, S, N, Si or B (boron).

[0056] 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.

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

[0058] N1: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepin (C7); S1: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiane (tetrahydrothiopyran) (C6), thiepane (C7); O2: dioxolane (C5), dioxane (C6), and dioxepane (C7); O3: Trioxane (C6); N2: Imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6); N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6); N2O1: oxadiazine (C6); O1S1: oxathiols (C5) and oxathianes (thioxanes) (C6); and N1O1S1: Oxathiazine (C6).

[0059] Examples of bicyclic heterocyclyl groups include, but are not limited to, those derived from:

[0060] [Table 1]

[0061] 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.

[0062] 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 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.

[0063] 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.

[0064] C 5~10 Heteroaryl: As used herein, "C 5~10The term "heteroaryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has 5 to 10 ring atoms, of which 1 to 5 are ring heteroatoms. In certain embodiments, each ring has 5 to 7 ring atoms, of which 1 to 4 are ring heteroatoms. For the avoidance of doubt, substituents on a heteroaryl ring may be attached via either a carbon atom or a heteroatom. The rings may be fused or monocyclic.

[0065] In this context, the term "heteroatom" means O, S, N, Si or B (boron).

[0066] Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:

[0067] N1: pyrrole (azole) (C5), pyridine (azine) (C6); O1: furan (oxol) (C5); S1: thiophene (thiol) (C5); N1O1: oxazole (C5), isoxazole (C5), isoxazine (C6); N2O1: oxadiazole (furazan) (C5); N3O1: oxatriazole (C5); N1S1: Thiazole (C5), Isothiazole (C5); N2: imidazole (1,3-diazole) (C5), pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6); N3: Triazoles (C5), triazines (C6); and N4: tetrazole (C5).

[0068] Examples of heteroaryls containing fused rings include, but are not limited to, C9 (having two fused rings) derived from:

[0069] [Table 2-1]

[0070] [Table 2-2]

[0071] Examples of heteroaryls containing fused rings include C derived from: 10 (having two fused rings).

[0072] [Table 3]

[0073] Spiro C 6~12 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 linked through a single common atom that defines the two rings. Spiro C 6~12 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, including 3 to 7 ring atoms, and the rings share a common atom.

[0074] Spiro C 6~12 Heterocyclyl: As used herein, a 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 linked through a single common atom that defines the two rings. Spiro C6~12 A 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, and 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.

[0075] 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.

[0076] 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 the compound of formula (I) are, for example, acid addition salts. Acid addition salts of the compound of formula (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art. Acid addition salts can be formed, for example, using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts may also be formed using organic acids selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, and para-toluenesulfonic acid.

[0077] 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. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a methanesulfonate salt. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mono-methanesulfonate salt, i.e., the stoichiometry of the compound of formula (I) to methanesulfonic acid is 1:1.

[0078] Other forms The compounds and salts described herein can exist in solvated and unsolvated forms. For example, the solvated form may be a hydrated form such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate, or an amount 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 kinase inhibitory activity, as measured, for example, using the tests described herein.

[0079] 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 chemical name is intended to encompass any single stereoisomer (i.e., any single chiral isomer) corresponding to that structure or chemical name, as well as any mixture of stereoisomers (e.g., a racemate). In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained, for example, by direct synthesis from chiral starting materials.

[0080] Certain enantiomers of the compounds described herein may be more active than other enantiomers of the same compound.

[0081] 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. Conveniently, the single enantiomer is present in an enantiomeric excess (ee%) of 99% or more.

[0082] 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 greater, 98% or greater, or 99% or greater, together with one or more pharmaceutically acceptable excipients. Advantageously, the single enantiomer is present in an enantiomeric excess (ee%) of 99% or greater.

[0083] 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).

[0084] 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.

[0085] For example, R A1 Tautomeric forms of some of the exemplified compounds where is OH can be depicted as follows:

[0086] [ka]

[0087] Crystalline morphology The compounds and salts described herein may be crystalline or 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 dealing with a disease in order to completely or partially alleviate one, some, or all of the symptoms of the disease, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis," unless specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

[0090] The term "prevention" is intended to have its ordinary meaning and includes primary prevention, to prevent the onset of disease, and secondary prevention, where the disease has already occurred and the patient is temporarily or permanently protected from progression or worsening of the disease or the onset 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 adults, middle-aged adults, 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 sufficient to ameliorate at least one sign or symptom of the disease being treated.

[0094] Pharmaceutical Composition The compounds of formula (I), and pharmaceutically acceptable salts thereof, 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 alternative 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 doses of active compound ranging from 0.1 mg to 1000 mg. The daily dose will necessarily vary depending on the host treated, the particular route of administration, any co-administered therapy, and the severity of the disease being treated. Accordingly, the physician treating any particular patient may determine the optimum 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, there is provided a pharmaceutical composition for use in the treatment of a disease in which inhibition of PCSK9 is beneficial, the pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In one embodiment, there is provided a pharmaceutical composition for use in the treatment of a cardiovascular disease in which inhibition of PCSK9 is beneficial, the pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In one embodiment, there is provided a pharmaceutical composition for use in the treatment of a cardiovascular disease in which inhibition of PCSK9 is beneficial, the pharmaceutical composition 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 therapeutic methods. Also provided is a method of treatment, comprising administering a therapeutically effective amount of a compound of formula I to a subject in need of treatment. The term "therapeutically effective amount" refers to an amount sufficient to show benefit to the patient. Such benefit may be at least an improvement in at least one symptom. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of what is being treated. Prescribing treatment, for example, 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 a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), for the manufacture of a medicament. In another embodiment, there is provided a method of treatment comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I).

[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 expressed primarily 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 presumed 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 increased levels of circulating low-density lipoprotein (LDL). PCSK9 is upregulated by statins, SREBP-1a and SREBP-2, LXR agonists, and insulin, but downregulated by dietary cholesterol, glucagon, ethinylestradiol, chenodeoxycholic acid, and bile acid-activated farnesoid X receptor (FXR) (Maxwell 2003; Persson 2009; Langhi 2008). Because elevated PCSK9 levels reduce the abundance of LDLR on the cell surface, increasing the dose of statins cannot achieve proportional LDL-C lowering results. Therefore, methods for treating a wide range of cardiovascular diseases and conditions that benefit from inhibiting PCSK9 and thereby lowering LDL-C are disclosed herein.

[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 by inhibiting 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 dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, heart failure, or congestive heart failure. In certain embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipidemia, atherosclerosis, 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 by 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 may be administered together with other therapeutic agents, such as other agents 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 amounts of the compounds or salts described herein and the amounts of the other pharmaceutically active agent, when combined, are therapeutically effective to treat the target disorder in an animal patient. In this context, the combined amounts are "therapeutically effective" if, when combined, they are sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder, cure the disorder, reverse, completely halt, or slow the progression of the disorder, or reduce the risk of the disorder worsening. Typically, such amounts can be determined by one of ordinary skill in the art, for example, by starting from the dosage ranges described herein for the compounds or salts and approved or otherwise published dosage ranges for the other pharmaceutically active compound.

[0113] The pharmaceutical compositions herein may optionally contain one or more additional active ingredients, and 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 of the present invention, or a pharmaceutically acceptable salt thereof, and i) statins, ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors, iv) P2Y12 inhibitors, v) citrate lyase inhibitors, and vi) at least one active ingredient selected from an antihypertensive agent; and vi) at least one active ingredient selected from an antihypertensive agent.

[0116] In a further aspect herein, a compound of the present invention, or a pharmaceutically acceptable salt thereof, and i) statins, ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors, iv) P2Y12 inhibitors, v) citrate lyase inhibitors, vi) at least one active ingredient selected from an antihypertensive drug.

[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 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, 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) There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with 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 ingredient 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 and simultaneously, separately or sequentially administering at least one additional active substance, wherein the at least one additional active substance is selected from ezetimibe, rosuvastatin, dapagliflozin and ticagrelor.

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

[0127] X 1 X 1 is CR A1 is.

[0128] R A1 In some embodiments, R A1 teeth, (i) H, (ii) halo, (iii) CN, (iv) one or more of OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v) OH, one or more halo groups, C 1~6 C optionally substituted with alkylamide 1~6 Alkoxy, (vi) C 1~6 Alkyl esters, (vii)C 1~6 alkyl acyls, and (viii) is selected from the group consisting of OH.

[0129] In some embodiments, R A1 teeth, (i) H, (ii) halo, (iii) CN, (iv) one or more of OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, and (v) OH, halo or C 1~6 C optionally substituted with alkylamide 1~6 alkoxy is selected from the group consisting of:

[0130] In some embodiments, R A1 teeth, (i) H, (ii) halo, (iii) CN, (iv) one or more of OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v) OH, one or more halo groups, or C 1~6 C optionally substituted with alkylamide 1~6 Alkoxy, and (vi) OH.

[0131] R A1 is optionally substituted C 1~6 If it is a hydrocarbon, it may be an optionally substituted C 1~6 In some embodiments, it is optionally substituted methyl or optionally substituted ethyl. In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl.

[0132] R A1 is optionally substituted C 1~6 When alkyl, in some embodiments, the optional substituents are selected from OH, CN, or one or more halo groups. In further embodiments, the optional substituents are selected from OH, F, and Br.

[0133] RA1 is optionally substituted C 1~6 When R is alkoxy, in some embodiments it is optionally substituted OMe or ethoxy. A1 is unsubstituted OMe.

[0134] R A1 is optionally substituted C 1~6 When alkoxy, in some embodiments, the optional substituents are selected from alkylamido or one or more halo groups, hi other embodiments, the optional substituents are selected from 1, 2, or 3 F atoms.

[0135] R A1 When is halo, in some embodiments it is F, Br, or Cl. In other embodiments, it is Br or Cl.

[0136] In some embodiments, R A1 is OH.

[0137] In some embodiments, R A1 is CN.

[0138] In some embodiments, R A1 is methyl.

[0139] In some embodiments, R A1 is -OCF2H.

[0140] In some embodiments, R A1 is selected from H, Br, Cl, CN, OMe, ethoxy, methyl, or ethyl. A1 is selected from H, —OCF2H, Br and Cl. In a further embodiment, R A1 is selected from H, Br, or Cl. In other embodiments, R A1 is H or -OCF2H.

[0141] In some embodiments, RA1 is selected from the group consisting of H, OH, Br, Cl, CN, OCFH, OMe, ethoxy, methyl, and ethyl. In some embodiments, R A1 is selected from the group consisting of H, Br, Cl, CN, OCFH, OMe, ethoxy, methyl, and ethyl. In some embodiments, R A1 is selected from the group consisting of H, OH, —OCFH, Br, and Cl. In some embodiments, R A1 is selected from the group consisting of H, —OCF2H, Br and Cl.

[0142] In some embodiments, R A1 is H.

[0143] In some embodiments, R A1 is OH or H.

[0144] R A2 In some embodiments, R A2 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v) C optionally substituted with OH, alkylamido, or one or more halo groups. 1~6 Alkoxy, (vi) C 1~6 acylamides (wherein acyl is optionally substituted by H or methyl); (vii)C 1~6 C optionally substituted with alkyl esters 1~6 thioalkyl, (viii)C 1~6 Alkyl esters, (ix) C 1~6 alkyl acyls, (x)C 4~5 heterocyclyl, (xi) C5 heteroaryl, (xii)C 1~3 Alkylamide, CN, OH, C 2~3 Alkynyl, C 4~6 Heterocyclyl, C 1~3 C optionally substituted with alkyl 1~6 Alkylamides, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 alkylamides, and (xiii) is selected from the group consisting of OH.

[0145] In some embodiments, R A2 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v) C optionally substituted with OH, alkylamido, or one or more halo groups. 1~6 Alkoxy, (vi) C 1~6 acylamides (wherein acyl is optionally substituted by H or methyl); (vii)C 1~6 thioalkyl, (viii)C 1~6 Alkyl esters, (ix) C 1~6 alkyl acyls, (x)C 4~5 heterocyclyl, (xi) C5 heteroaryl, (xii)C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl, C 1~3 C optionally substituted with alkyl 1~6 Alkylamides, wherein the alkyl is optionally substituted with one or more halo or OH groups;1~6 alkylamides, and (xiii) is selected from the group consisting of OH.

[0146] In a further embodiment, R A2 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v) OH, C 1~6 alkylamide, or C optionally substituted with one or more halo groups; 1~6 Alkoxy, (vi) C 1~6 thioalkyl, (viii)C 1~6 alkyl esters, and (ix) C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl, or C 1~3 C optionally substituted with alkyl 1~6 Alkylamides, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 alkylamides.

[0147] In a further embodiment, R A2 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v)OH, (vi) OH, C 1~6 alkylamide, or C optionally substituted with one or more halo groups; 1~6Alkoxy, (vii)C 1~6 Alkyl esters, (viii)C 1~6 alkyl acyls, and (ix) C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl, or C 1~3 C optionally substituted with alkyl 1~6 Alkylamides, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 alkylamides.

[0148] In some embodiments, R A2 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v)OH, (vi) OH, C 1~6 alkylamide, or C optionally substituted with one or more halo groups; 1~6 Alkoxy, (vii)C 1~6 Alkyl esters, (viii)C 1~6 alkyl acyls, (ix) C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl, or C 1~3 C optionally substituted with alkyl 1~6 Alkylamides, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 alkylamides, and (x)C 1~6 C optionally substituted with alkyl esters 1~6thioalkyl.

[0149] In some embodiments, R A2 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups; 1~6 hydrocarbons, (v) C optionally substituted with OH, alkylamido, or one or more halo groups. 1~6 Alkoxy, (vi) C 1~6 C optionally substituted with alkyl esters 1~6 thioalkyl, (vii)C 1~6 alkyl esters, or (viii)C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl or C 1~3 C optionally substituted with alkyl 1~6 Alkyl amides, such as C 1~3 C, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 alkylamides.

[0150] In some embodiments, R A2 teeth, (i) H, (ii) halo, (iii) CN, (iv) C 1~6 Alkyl, (v) cyclopropyl, (vi) C optionally substituted with one or more halo groups. 1~6 Alkoxy, (vii)C 1~6 Alkyl esters, (viii)C 1~6 alkylamides, (ix) C 1~6 C optionally substituted with alkyl esters 1~6 thioalkyl, or (x) is selected from OH.

[0151] In a further embodiment, R A2 teeth, (i) H, (ii) Cl, (iii) CN, (iv) methyl, (v) cyclopropyl, (vii) C optionally substituted with two or three fluoro groups 1~2 Alkoxy, (viii)C 1~3 C optionally substituted with alkyl esters 1~3 thioalkyl, (viii) C(=O)CH3, or (ix) C(=O)NH(CH3).

[0152] R A2 When is halo, in some embodiments it is Br or Cl. In further embodiments it is Cl.

[0153] In some embodiments, R A2 is CN, Cl, OMe, methyl, cyclopropyl, -OCF2H, -OCF3 and optionally substituted C 1~6 alkylamides.

[0154] In some embodiments, R A2 is CN.

[0155] In some embodiments, R A2 is H.

[0156] In some embodiments, R A2 is OH.

[0157] In some embodiments, R A2 is -C(=O)CH3.

[0158] In some embodiments, R A2 is -OCF2H.

[0159] In some embodiments, R A2 is cyclopropyl.

[0160] In some embodiments, R A2 is Cl.

[0161] In some embodiments, R A2 is methyl.

[0162] In some embodiments, R A2 is -S-CH3.

[0163] In some embodiments, R A2 is -S-CH2CH3.

[0164] In some embodiments, R A2 is -S-CH2-C(=O)-O-CH3.

[0165] In some embodiments, R A2 is C(=O)NH(CH)3.

[0166] R A2 C 1~6 If it is a hydrocarbon, it may be an optionally substituted C 1~6 In some embodiments, it is optionally substituted methyl, optionally substituted ethyl, or optionally substituted cyclopropyl. In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl. In other embodiments, it is unsubstituted cyclopropyl.

[0167] R A2 is optionally substituted C1~6 When alkyl, in some embodiments, the optional substituents are selected from OH, CN, or one or more halo groups. In further embodiments, the optional substituents are selected from OH, F, and Br.

[0168] R A2 is optionally substituted C 1~6 When alkoxy, in some embodiments it is optionally substituted OMe or ethoxy.

[0169] R A2 is optionally substituted C 1~6 When alkoxy, in some embodiments, the optional substituents are selected from alkylamido or one or more halo groups. In other embodiments, the optional substituents are selected from one or more F. R A2 is optionally substituted C 1~6 In another embodiment where it is alkoxy, it is difluoromethoxy (OCHF2).

[0170] R A2 C 1~6 When it is an alkyl ester, in some embodiments it is -C(=O)OCH2CH3.

[0171] R A2 C 1~6 When R is an alkylamide, in some embodiments, the optional substituents are selected from one or more methyl groups, an oxetane ring, a C alkylamide, and ethyl, where the ethyl is optionally substituted with OH or one or more halo groups. A2 C 1~6 When it is an alkylamide, it is C(=O)NHCH2C(=O)NH2, C(=O)NHCH2CHCH, -C(=O)NH-oxetane, C(=O)NHCH2CHF2, C(=O)NHCH2CH2OH, C(=O)NHCH2CH3, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2. R A2 C 1~6When an alkylamide, in some embodiments the optional substituent is OH.

[0172] R A2 C 1~6 When thioalkyl, in some embodiments the optional substituents are C 1~6 It is an alkyl ester. A2 C 1~6 When thioalkyl, in some embodiments, the optional substituents are selected from C(=O)-O-CH3 or C(=O)-O-CH2CH3. In some embodiments, the thioalkyl is unsubstituted and is -S-CH3 or -S-CH2CH3. In some embodiments, R A2 is optionally substituted C 1~6 When it is thioalkyl, it is —S—CH 3 , —S—CH 2 CH 3 or —S—CH 2 —C(═O)—O—CH 3 .

[0173] In other embodiments, R A2 is selected from -OCHF, Cl, -OMe, methyl, C(=O)CH, CN, -CHOH, H, and cyclopropyl. A2 is selected from methyl, —OCHF2, Cl, —CH2OH, H, CN, —C(═O)CH3, —OMe.

[0174] In a further embodiment, R A2 is selected from methyl, —OCHF2, Cl and cyclopropyl.

[0175] In a further embodiment, R A2 is selected from H, -COOH, -CHOH, methyl, CN, cyclopropyl, -C(=O)CH, -OCFH, Cl, -C(=O)OCHCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -C(=O)NHCHC(=O)NH, -C(=O)NHCHCH, -C(=O)NH-oxetane, -C(=O)NHCHCHF, -C(=O)NHCHCHOH, -C(=O)NHCHCH.

[0176] In a further embodiment, R A2 is selected from the group consisting of -CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCF2H, H, -OMe, and -OCF3.

[0177] In a further embodiment, R A2 is selected from CN, methyl, Cl, —C(═O)CH3, —OCHF2, cyclopropyl, —OCF3, —OCH3, H, —C(═O)NH(CH3), —S—CH3, —S—CH2CH3 or —S—CH2-C(═O)—O—CH3.

[0178] In some embodiments, R A2 is selected from CN, methyl, Cl, -C(=O)CH, -C(C=O)OCHCH, cyclopropyl, -C(=O)NHCHC(=O)NH, -C(=O)NHCHCHCH, -C(=O)NH-oxetane, -C(=O)NHCHCHF, -C(=O)NHCHCHOH, -C(=O)NHCHCH, -C(=O)NH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -OCFH, H, -OMe, -OCF. These groups are as shown in the table below.

[0179] [Table 4]

[0180] In some embodiments, R A2 is selected from the following group:

[0181] [Table 5]

[0182] In some embodiments, R A2 is selected from the following group:

[0183] [Table 6] R A3 In some embodiments, R A3 teeth, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 alkylsulfonyl, or C optionally substituted with one or more halo groups 1~6 hydrocarbons, (v)OH, (vi) C optionally substituted by OH, NH, C heterocyclyl or one or more halo groups 1~6 alkoxy is selected from the group consisting of:

[0184] R A3 When is halo, in some embodiments it is Br or Cl. In some embodiments it is Cl. In further embodiments, R A3 is Br.

[0185] R A3 C 1~6 If it is a hydrocarbon, it may be an optionally substituted C 1~6In some embodiments, it is optionally substituted methyl or optionally substituted ethyl. In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl.

[0186] R A3 is optionally substituted C 1~6 When alkyl, in some embodiments, the optional substituents are selected from OH, CN, or one or more halo groups. In further embodiments, the optional substituents are selected from OH, F, and Br.

[0187] In some embodiments, R A3 is OH.

[0188] R A3 is optionally substituted C 1~6 When alkoxy, in some embodiments it is optionally substituted OMe or ethoxy, in further embodiments it is OMe.

[0189] R A3 is optionally substituted C 1~6 When alkoxy, in some embodiments the optional substituents are selected from alkylamido or one or more halo groups, hi other embodiments the optional substituents are selected from one or more F.

[0190] In some embodiments, R A3 are H, CF3, CN, and C 1~2 In another embodiment, R A3 is selected from H, methyl, CN and Cl.

[0191] In some embodiments, R A3 H, OMe, CF3, CN, C 1~2 It is selected from alkyl, NH2 and halo.

[0192] In some embodiments, RA3 is CN.

[0193] In some embodiments, R A3 is H.

[0194] In some embodiments, R A3 is methyl.

[0195] In some embodiments, R A3 is OMe.

[0196] In some embodiments, R A3 is selected from methyl, H and CN.

[0197] R A2 and R A3 R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 When heteroaromatic rings are formed, they form an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0198] R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 When forming a heteroaromatic ring, the optional substituents are NH, C 1~6 Alkyl, C 1~6 In another embodiment, the optional substituents are selected from methyl, ethyl, OMe, NH, F, Cl, and Br. In another embodiment, the optional substituents are selected from methyl, NH, Cl, F, and OMe. In another embodiment, the optional substituent is methyl.

[0199] In one embodiment, R A2 and R A3 together with the carbon atoms to which they are attached, optionally substituted C5~7 When heteroaromatic rings are formed, they form an optionally substituted pyridine. In some embodiments, the optional substituent is NH. In other embodiments, R A2 and R A3 together with the carbon atoms to which they are attached form an unsubstituted pyridine. A2 and R A3 taken together form an optionally substituted pyrazole, an optionally substituted pyrrole, or an optionally substituted thiazole. In some embodiments, the optional substituent is methyl.

[0200] R A3 and R A2 together with the carbon atoms to which they are attached, optionally substituted C 5~7 When forming a heteroaromatic ring, the optional substituents are C 1~6 Alkyl, C 1~6 In other embodiments, the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH and halo. In other embodiments, the optional substituents are selected from NH and methyl.

[0201] R A3 and R A2 together with the carbon atoms to which they are attached, optionally substituted C 5~7 When forming a heterocycle, they form a 5-membered ring containing one or two atoms selected from N, O, and S. In some embodiments, the 5-membered ring contains one N and one S. In other embodiments, the 5-membered ring contains one N. In other embodiments, the 5-membered ring contains one N and one O. In other embodiments, the 5-membered ring contains two N. In some embodiments, R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted pyrrole or pyrazole.

[0202] R A3 and RA2 together with the carbon atoms to which they are attached, optionally substituted C 5~7 When forming a heterocycle, the optional substituents are NH, C 1~6 Alkyl, C 1~6 In another embodiment, the optional substituent is selected from methyl, ethyl, OMe, ethoxy, NH, F, Cl, and Br. In another embodiment, the optional substituent is methyl.

[0203] In other embodiments, R A2 and R A3 together with the carbon atoms to which they are attached, (i) an optionally substituted C6 heteroaromatic ring, wherein the optional substituent is NH2; (ii) an optionally substituted C6 carboaromatic ring, wherein the optional substituents are F, OMe, Cl; (iii) An optionally substituted C5 heteroaromatic or C5 heterocyclic ring, wherein the optional substituent is methyl.

[0204] In some embodiments, R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 forming a heteroaromatic ring, and the optional substituents are C 1~6 It is selected from alkyl and halo.

[0205] In some embodiments, R A2 and R A3 taken together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted by methyl, a pyridine optionally substituted by NH2, or a phenyl optionally substituted by Cl, F, or OMe.

[0206] In some embodiments, RA2 and R A3 are taken together to form a ring selected from:

[0207] [Table 7]

[0208] B In some embodiments, B is of formula (B-1):

[0209] [ka] where 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.

[0210] In other embodiments, R B1 is H, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0211] In other embodiments, R B1 is -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0212] In other embodiments, R B1 is H.

[0213] In another embodiment, B is a group represented by formula (B-1a):

[0214] [ka] It is of the type.

[0215] In a further embodiment, B has the formula (B-1b):

[0216] [ka] It is of the type.

[0217] Thus, in some embodiments, the compound of formula (I) is the S,S-enantiomer.

[0218] In some embodiments, B is of formula (B-2):

[0219] [ka] where the wavy lines indicate the points of attachment to A and C; R B2 But C 1~2 Alkyl-OH, CH2CONHMe or C 1~3 It is alkyl.

[0220] In some of these embodiments, R B2 is C 1~2 Alkyl-OH or C 1~3 It is alkyl.

[0221] In some embodiments, when B is of formula (B-2), it is of formula (B-2a) below, where the wavy lines indicate the points of attachment to A and C, and R B2 But C 1~2 Alkyl-OH, CH2CONHMe or C 1~2 It is alkyl.

[0222] [ka]

[0223] C C is C 6~10 Carboaryl, C 5~6 Heteroaryl and C 5~10 heterocyclyl, wherein these groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl, or C 5~10 Bridged heterocycles, spiro C6~12 Heterocyclyl or spiro C 6~12 Carbocyclyl (These are themselves the following groups: a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) OH, C, including branched and cyclic 1~6 one or more C groups optionally substituted with alkylsulfonyl or one or more halo groups; 1~6 alkyl groups, e) C with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h) C with optional methyl substituents 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) P(=O)Me2, m) carboxy or CH2-carboxy, n) optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamides and di-C 1~6 alkylsulfonamides.

[0224] In some embodiments, C is C 6~10 Carboaryl, C 5~6 Heteroaryl and C 5~10 heterocyclyl, which groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl, or C 5~10 Bridged heterocycles, spiro C 6~12 Heterocyclyl or spiro C 6~12 Carbocyclyl (These are themselves 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 with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) P(=O)Me2, m) carboxy or CH2-carboxy, and / or n) optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) Carboxy, CN, halo, nitro, C 1~6Alkyl, 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 alkylsulfonamides.

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

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

[0227] C is optionally substituted 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.

[0228] C is optionally substituted C 5~6 When it is heteroaryl, it is (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, or C 5~10 Bridged Heterocyclyl, Spiro C 6~12 Heterocyclyl or spiro C 6~12 Carbocyclyl (These are themselves a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) OH, C, including branched and cyclic 1~6 C, with optional substituents selected from alkylsulfonyl or one or more halo groups; 1~6 alkyl groups, e) C with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h) C with optional methyl substituents 5~6 heteroaryl, i) C with optional methyl or ═O substituents4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) P(=O)Me2, m) carboxy or CH2-carboxy, and / or n) optionally substituted by one or more groups selected from tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamides and di-C 1~6 It may be optionally substituted with one or more groups selected from alkylsulfonamides.

[0229] C is C 6~10 Carboaryl, C 5~10 Heteroaryl or C 5~10 When substituted by a heterocyclyl, it may have multiple substituents. a) one or two =O groups, b) one or more halo groups, CN, NH2, c) (CH3)2, C 1~6 Alkoxy or C 1~6 One or more C containing alkyl esters 1~6 one or more C alkyl, each optionally substituted with one or more halo groups; 1~6 Alkyl, 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) selected from carboxy or CH2-carboxy.

[0230] C is C 6~10 Carboaryl, C 5~10 Heteroaryl or C 5~10 When substituted by a heterocyclyl, it may have multiple substituents. a) one or two =O groups, b) one or more halo groups, CN or NH2; c) one or more C 1~6 Alkyl group, C 1~6 Alkoxy or C 1~6 alkyl esters, each group optionally substituted with one or more halo groups; 1~6 Alkyl group, 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) carboxy or CH2-carboxy, or g) selected from tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0231] C is C 6~10 Carboaryl, C 5~10 Heteroaryl or C 5~10 When substituted by a heterocyclyl, it may have multiple substituents. a) one or two =O groups, b) one or more halo groups; c)CN, d) one or more halo groups or C 1~6 one or more C optionally substituted by alkylsulfonyl 1~6Alkyl, e) C optionally substituted with one or more halo groups 1~6 Alkoxy, f) C with optional methyl substituents 5~6 Heterocyclyl or C 5~6 heteroaryl, g) C6 carboaryl optionally substituted with one or more halo atoms, or h) carboxy.

[0232] 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. In some embodiments, C is C 6~10 Carboaryl, C 5~6 Heteroaryl, and C 5~10 heterocyclyl, each group being substituted by methyl.

[0233] In some embodiments, one substituent on C is in the para position.

[0234] C is optionally substituted C 6~10 Carboaryl, C 5~10 Heteroaryl or C 5~10 In other embodiments substituted by heterocyclyl, it may be substituted by optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyridazine, optionally substituted imidazolidinyl, optionally substituted pyrrolidine, optionally substituted dihydroquinolinyl, optionally substituted naphthyridine, optionally substituted 2,3-dihydro-1H-imidazo[4,5-b]pyridine, optionally substituted 3H-imidazo[4,5-b]pyridine, optionally substituted benzimidazolyl, or optionally substituted imidazopyridinyl. 6~10Carboaryl, C 5~10 Heteroaryl or C 5~10 In other embodiments substituted by heterocyclyl, it may be substituted by optionally substituted phenyl, optionally substituted pyridyl, optionally substituted imidazolidinyl, optionally substituted dihydroquinolinyl, optionally substituted benzimidazolyl, or optionally substituted imidazopyridinyl. 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 5~6 Heterocyclyl (with optional methyl substituent), phenyl substituted at the para position by F, carboxy, CH2-carboxy, tetrazolyl, pyrazolyl, triazolyl, or P(=O)Me2 may be optionally substituted. In other embodiments, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted imidazolidinyl, optionally substituted dihydroquinolinyl, optionally substituted benzimidazolyl, or optionally substituted imidazopyridinyl may contain one or two =O groups, halo, CN, one or more halo groups, or C 1~6 one or more C optionally substituted by alkylsulfonyl 1~6 alkyl, C optionally substituted with one or more halo groups 1~6 Alkoxy, C 5~6 heterocyclyl (with optional methyl substituents), C 5~6 It may be substituted by heteroaryl (with optional methyl substituents), F or phenyl substituted by carboxy.

[0235] 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 and C 5~10heterocyclyl, 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 substituents), phenyl optionally substituted with one or two halo groups, carboxy, CH2-carboxy, tetrazolyl, pyrazolyl, triazolyl, pyridine ring, optionally substituted by NH2 or OH. In other embodiments, optionally substituted C 5~10 Heteroaryl and C 5~10 Heterocyclyl is a heterocyclic group containing one or two =O groups, halo, CN, one or more halo groups or C 1~6 one or more C optionally substituted by alkylsulfonyl 1~6 alkyl, C optionally substituted with one or more halo groups 1~6 Alkoxy, C 5~6 heterocyclyl (with optional methyl substituents), C 5~6It may be optionally substituted by heteroaryl (with an optional methyl substituent), F, or phenyl substituted by carboxy. 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. In some embodiments, the substituents are optionally substituted pyridyl, optionally substituted pyridazine, optionally substituted imidazolidinyl, optionally substituted pyrrolidinyl, optionally substituted dihydroquinolinyl, optionally substituted naphthyridine, optionally substituted benzimidazolyl, optionally substituted 2,3-dihydro-1H-imidazo[4,5-b]pyridine, optionally substituted 3H-imidazo[4,5-b]pyridine, and optionally substituted 3-azabicyclo[3.1.0]hexane or optionally substituted 2,3,3a,4,5,6,7,7a-octahydrofuro[2,3-c]pyridine.

[0236] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl, wherein the optional substituents are: I C 6~10 Carboaryl, C 5~10 Heteroaryl, C 5~10 Heterocyclyls (which themselves can be substituted with the following groups: a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) OH, C, including branched and cyclic 1~6 one or more C with optional substituents selected from alkylsulfonyl or one or more halo groups; 1~6 alkyl groups, e) C with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) P(=O)Me2, m) carboxy, CH2-carboxy, and / or n) optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamides and di-C 1~6 alkylsulfonamides.

[0237] 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 the following: 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 with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) P(=O)Me2, m) carboxy, CH2-carboxy, and / or n) optionally substituted with one or more groups selected from tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0238] In some embodiments, C is an optionally substituted pyridinyl, and the optional substituents are C 6~10 Carboaryl, C 5~10 Heteroaryl, C 5~10 heterocyclyl, which themselves are selected from the following: a) one or two =O groups, b) one or more halo groups; c)CN, d) one or more C optionally substituted by sulfonyl or one or more halo groups 1~6 Alkyl, e) C optionally substituted with one or more halo groups 1~6 Alkoxy, f) the C group has an optional methyl substituent; 5~6 Heterocyclyl or C 5~6 heteroaryl, g) C6 carboaryl optionally substituted with one or more halo atoms, or h) optionally substituted with one or more groups selected from carboxy.

[0239] In another embodiment, C is of formula (C-1):

[0240] [ka] In the formula, D is C 6~10 Carboaryl, C 5~10 Heteroaryl or C 5~10 Heterocyclyl, which themselves may be substituted with ═O, halo, CN, NH, OH, one or more C 1~6 Alkyl group (wherein the alkyl group is halo or C 1~6 C optionally substituted by halo), 1~6 Alkoxy, C 1~6 Alkyl esters, C 5~6 Optionally substituted by heterocyclyl (with optional methyl substituent), carboxy, CH2-carboxy, P(=O)Me2, tetrazolyl, pyrazolyl optionally substituted by methyl, or triazolyl. In some embodiments, the optional substituents are ═O, CN, F, Cl, Br, methyl, ethyl, OMe, ethoxy, O-CF3, OMe, CF3, P(=O)Me2, and C 1~2 In some embodiments, the optional substituents are selected from: ═O, OMe, carboxy, Cl, methyl optionally substituted with —S(═O)CH, CN, phenyl substituted with F, piperazinyl substituted with methyl, CF, OCF, pyrazolyl optionally substituted with methyl, tetrazolyl, or triazolyl.

[0241] In some embodiments, C is of formula (C-1):

[0242] [ka] In the formula, D is C 6~10 Carboaryl, C 5~10 Heteroaryl or C 5~10heterocyclyl, each of which may itself be i) one or two =O groups, ii) one or two C's which may be branched 1~4 alkyl groups, i) OMe, ii) piperazinyl optionally substituted with methyl; iii) C(=O)OH (carboxy), iv) Cl, v) F, vi) phenyl optionally substituted with one or more fluoro; vii)CN, viii) CF3, ix) O-CF3, x)OMe, xi) tetrazolyl, pyrazolyl, triazolyl, xii) NH2, xiii) (CH3)2, xiv) pyridinyl, xv) CH2OH, xvi) OH, or xvii) optionally substituted by P(=O)Me2.

[0243] In some embodiments, C is of formula (C-1):

[0244] [ka] In the formula, 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 optionally branched C groups optionally substituted by S(=O)2CH3 1~4 alkyl groups, i) OMe, ii) piperazinyl optionally substituted with methyl; iii) C(=O)OH (carboxy), iv) Cl, v) F, vi) phenyl optionally substituted with one or more fluoro; vii)CN, viii) CF3, ix) O-CF3, x)OMe, xi) tetrazolyl, pyrazolyl optionally substituted with methyl, triazolyl; xii) NH2, xiii) pyridinyl, xiv) CH2OH, xv) OH, or xvi) optionally substituted by P(=O)Me2.

[0245] When C is (C-1), in some embodiments, D is an optionally substituted pyridin-2-one. In some embodiments, the optional substituents are selected from OMe, Cl, F, methyl, trifluoromethyl, OCF, —C(═O)OH (carboxy), CN, pyrazolyl, triazolyl, tetrazolyl, phenyl with an optional F substituent at the para position, or piperazinyl with a methyl substituent. In some embodiments, the pyridin-2-one is unsubstituted. In some embodiments, the optional substituents are selected from OMe, carboxy, Cl, methyl optionally substituted with —S(═O)CH, CN, phenyl substituted with F, piperazinyl substituted with methyl, CF, OCF, pyrazolyl, tetrazolyl, or triazolyl optionally substituted with methyl. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0246] 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 (C-1) and is substituted at the ortho position with =0, and other optional substituents are selected from methyl, OMe, piperazine substituted with methyl, -C(=O)OH (carboxy), Cl, phenyl substituted with fluoro, CN, CF, F, pyrazolyl, triazolyl, tetrazolyl, or O-CF. In some embodiments, the optional substituents are selected from OMe, -C(=O)OH (carboxy), Cl, methyl optionally substituted with -S(=O)CH, CN, phenyl substituted with F, piperazinyl substituted with methyl, CF, OCF, pyrazolyl, tetrazolyl, or triazolyl optionally substituted with methyl.

[0247] In some embodiments, when C is (C-1), D is an optionally substituted 6-membered heteroaryl containing one or two N atoms, one of which is attached to (C-1), and substituted in the ortho position with =0, and the optional substituents are i) methyl, ii) OMe, iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy), v) Cl, vi) F, vii) phenyl substituted by fluoro; viii) CN, ix) CF3, x) O-CF3, xi) selected from pyrazole, triazole, and tetrazole.

[0248] In some embodiments, when C is (C-1), D is an optionally substituted 6-membered heteroaryl containing one or two N atoms, one of which is attached to (C-1), and substituted in the ortho position with =0, and the optional substituents are i) methyl optionally substituted with —S(═O)2CH3; ii) OMe, iii) piperazinyl substituted by methyl; iv) C(=O)OH (carboxy), v) Cl, vi) phenyl substituted by fluoro; vii)CN, viii) CF3, ix) O-CF3, x) selected from pyrazole, triazole or tetrazole optionally substituted by methyl.

[0249] In further embodiments, C is of formula (C-1) and D is optionally substituted with optionally substituted pyridyl, phenyl, or pyridazinyl optionally substituted with methyl (wherein the methyl is optionally substituted with -S(=O)CH), OMe, piperazinyl substituted with methyl, C(=O)OH (carboxy), Cl, phenyl substituted with fluoro, CN, CF, O-CF, pyrazole, triazole, or tetrazole optionally substituted with methyl. In some embodiments, D is optionally substituted pyridyl or pyridazinyl.

[0250] In some embodiments, C is of formula (C-1), D is an optionally substituted phenyl or piperidyl, and there are one or two optional substituents selected from F, OMe, and CN.

[0251] In some embodiments, C is of formula (C-1) and D is optionally substituted C 10In some embodiments, D is an optionally substituted 1,2,3,4-tetrahydro-1,8-naphthyridine or 1,2,3,4-tetrahydroquinoline, and the optional substituent is an =O group. In some embodiments, D is 3,4-dihydro-1H-1,8-naphthyridin-2-one (2-oxo-3,4-dihydro-1,8-naphthyridin-1-yl) or 3,4-dihydro-1H-quinolin-2-one (2-oxo-3,4-dihydroquinolin-1-yl). In some embodiments, D is an optionally substituted 1,2-dihydro-1,8-naphthyridine or 1,2-dihydroquinoline, and the optional substituent is an =O group. In some embodiments, D is 1H-1,8-naphthyridin-2-one (2-oxo-1,8-naphthyridin-1-yl) or 1H-quinolin-2-one (2-oxo-1-quinolyl).

[0252] In another embodiment, D is of formula (D-1):

[0253] [ka] In the formula, R D1 , R D2 , R D3 and R D4 One or two of the following are C 1~6 C optionally substituted with alkylsulfonyl or 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; R D3 and R D4form an optionally substituted 6-membered carboaromatic, heterocyclic or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, CN, P(=O)Me2, and C(=O)OH; or Or R D1 , R D2 , R D3 and R D4 But they're all H.

[0254] In another embodiment, D is of formula (D-1):

[0255] [ka] In the formula, R D1 , R D2 , R D3 and R D4 C, 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 heteroaryl, C(=O)OH, =O, halo, NH2, CN, or phenyl optionally substituted with one or more halo atoms; R D3 and R D4 form an optionally substituted 6-membered carboaromatic, heterocyclic or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, CN, P(=O)Me2, and C(=O)OH; or Or R D1 , R D2 , R D3 and R D4 But they're all H.

[0256] In some embodiments, D is of formula (D-1):

[0257] [ka] In the formula, R D1 , R D2 , R D3 and R D4 One or two of the i) C optionally substituted with one or more halo groups 1~6 Alkyl, ii) C optionally substituted with one or more halo groups 1~6 Alkoxy, iii) the C group has an optional methyl substituent 5~6 Heterocyclyl or C 5~6 heteroaryl, iv) C(=O)OH or CH2-C(=O)OH, v) =O, halo, NH2 or CN, vi) phenyl optionally substituted with one or more halo atoms; The remainder is H, or R D3 and R D4 form an optionally substituted 6-membered carboaromatic, heterocyclic or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo and C(═O)OH; or or R D1 , R D2 , R D3 and R D4 But they're all H.

[0258] In another embodiment, R D1 , R D2 , R D3 and R D4 one or two of which are -S(=O)2CH3 or 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, CN, or phenyl optionally substituted with one or more halo atoms, the remainder being H.

[0259] In some embodiments, D is of formula (D-1), and R D1 , R D2 , R D3 and R D4 One or two of the i) methyl, ii) OMe, iii) methyl-substituted piperazines; iv) C(=O)OH (carboxy), v) Cl, vi) phenyl substituted by fluoro; vii)CN, viii) CF3, ix) F, x) pyrazolyl, triazolyl, tetrazolyl, xi) O-CF3; R D1 , R D2 , R D3 and R D4 The remainder is H.

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

[0261] In some embodiments, D is of formula (D-1), and R D1 , R D2 , R D3 and R D4 One or two of the i) methyl optionally substituted with —S(═O)2CH3; ii) OMe, iii) methyl-substituted piperazines; iv) C(=O)OH (carboxy), v) Cl, vi) phenyl substituted by fluoro; vii)CN, viii) CF3, ix) pyrazolyl, triazolyl, tetrazolyl optionally substituted by methyl; x) O-CF3; R D1 , R D2 , R D3 and R D4 The remainder is H.

[0262] In another embodiment, R D1 , R D2 , R D3 and R D4 one or two of R are selected from methyl, -OMe, halo, -C(=O)OH, CN, CF3, -OCF3, -OCHF2; D1 , R D2 , R D3 and R D4 The remainder of R D1 , R D2 , R D3 and R D4 one or two of R are selected from methyl optionally substituted with -S(=O)2CH3, -OMe, halo, -C(=O)OH, CN, CF3, -OCF3, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, phenyl substituted with fluoro, piperazine substituted with methyl; D1 , RD2 , R D3 and R D4 The remainder is H.

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

[0264] In some embodiments, R D3 is selected from the group consisting of H; optionally substituted phenyl, wherein the optional substituents are halo, methyl, OMe, C(═O)OH, Cl, CN; or piperazinyl optionally substituted with methyl; or pyrazolyl, triazolyl, or tetrazolyl, and R D1 , R D2 and R D4 are all H. In another embodiment, R D3 is selected from the group consisting of H; optionally substituted phenyl, wherein the optional substituents are halo, methyl optionally substituted with -S(=O)CH, OMe, C(=O)OH, Cl, CN; or piperazinyl optionally substituted with methyl; or pyrazolyl, triazolyl, or tetrazolyl optionally substituted with methyl, and R D1 , R D2 and R D4 are all H. In another embodiment, R D3 is selected from H, optionally substituted phenyl (the optional substituent is halo), methyl, OMe, —C(═O)OH, —OCHF, Cl, CN, and piperazinyl optionally substituted with methyl; R D1 , R D2 and R D4 are all H. In another embodiment, R D3is selected from H, methyl optionally substituted with -S(=O)2CH3, OMe, -C(=O)OH, Cl, CN, phenyl optionally substituted with F, piperazine substituted with methyl, pyrazolyl, triazolyl or tetrazolyl optionally substituted with methyl.

[0265] In other embodiments, R D1 is selected from H, methyl, OMe, Cl, CF3, OCF3, OCHF2 and CN; R D2 , R D3 and R D4 are all H. In another embodiment, R D1 is selected from H, methyl, OMe, Cl, F, CF3, OCF3, and CN; R D2 , R D3 and R D4 are all H. In other embodiments, R D1 is selected from H, methyl, OMe, Cl, CF3, OCF3, pyrazolyl optionally substituted with methyl, triazolyl and CN; R D2 , R D3 and R D4 are all H.

[0266] In another embodiment, R D3 and R D4 form 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.

[0267] In some embodiments, R D3 and R D4 forms an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0268] In some embodiments, R D3 and R D4 forms an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0269] In another embodiment, D is of formula (D-2):

[0270] [ka] In the formula, X D But NR D5a or CR D5a R D5b and R D5a is selected from H or methyl; R D5b and R D6b are either both H or together are -CH2-, R D6a is selected from H, ═O, methyl, —CHOH, or —C(═O)OH; R D6a If =O, then R D6b does not exist, R D7a is selected from H, ═O, methyl, —CHOH, or —C(═O)OH; R D7b is H and R D7a If =O, then R D7b does not exist or or R D6a and R D7a together form a benzene ring or a C6 heteroaromatic ring optionally substituted by CN, P(=O)Me2 or carboxy, and R D6b and R D7b does not exist.

[0271] In some embodiments, C is of formula (C-1), D is of formula (D-2), and X D is N and R D5a is methyl.

[0272] 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 D7ais selected from =O, -CHOH or -C(=O)OH, R D7b is H or R D7a If =O, R D7b does not exist.

[0273] In some embodiments, C is of formula (C-1), D is of formula (D-2), and X D is N and R D5a is methyl and R D7a is selected from H and ═O, and R D6a is H and =O, R D7a If =O, R D6a and R D6b is H and R D6a is =O and R D7a is H and R D6b does not exist, and R D7b is H or R D7a If =O, R D7b does not exist.

[0274] In some embodiments, C is of formula (C-1), D is of formula (D-2), and R D7a is =O and X D is C and R D5b and R D6b together form -CH2-, and R D6a and R D5a is methyl.

[0275] In another embodiment, R D6a and R D7a together form a benzene ring or a C6 heteroaromatic ring optionally substituted by CN, P(=O)Me2 or -C(=O)OH, R D6b and R D7b is absent. In some embodiments, R D6a and R D7a together form a benzene or pyridyl ring optionally substituted with CN.

[0276] In some embodiments, R D6aand R D7a forms an unsubstituted benzene ring, and R D6b and R D7b is absent. In some embodiments, R D6a and R D7a forms an unsubstituted pyridine ring, and R D6b and R D7b does not exist.

[0277] In some embodiments, X D is N and R D5a is H or methyl.

[0278] In some embodiments, X D is C and R D5a is H or methyl, and R D5b is H. In a further embodiment, R D5a and R D5b are both H.

[0279] In some embodiments, R D7a is carboxy, —CHOH, or ═O. In some embodiments, R D7a is =O. R D7b is H or R D7a If =O, R D7b does not exist.

[0280] In some embodiments, R D6a is H or ═O. In some embodiments, R D6a is =O and R D6b does not exist.

[0281] 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 D6a does not exist.

[0282] In some embodiments, X D is N and R D5a is H or methyl, and R D6b is H and R D6a and R D7a together form a pyridine or benzene ring optionally substituted by —C(═O)OH or —CN or —P(═O)Me, and R D6b and R D7b does not exist.

[0283] In some embodiments, X D is CR D5a R D5b and R D5a and R D6a is methyl and R D7a is =O and R D7b does not exist, and R D6b and R D5b together form a three-membered ring.

[0284] In some embodiments, D is (7-oxo-2,3,3a,4,5,7a-hexahydrofuro[2,3-c]pyridin-6-yl). In some embodiments, D is [(1R,5S)-1,5-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl].

[0285] In some embodiments, D is selected from the following table:

[0286] [Table 8-1]

[0287] [Table 8-2]

[0288] [Table 8-3]

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

[0290] [Table 9]

[0291] In some embodiments, D is selected from the following table:

[0292] [Table 10-1]

[0293] [Table 10-2]

[0294] In another embodiment, C has the formula (C-2):

[0295] [ka] In the formula, R C7 , R C8 , R C9 and R C10 one or two of are selected from methyl optionally substituted with -S(=O)2CH3, OMe, halo, -C(=O)OH, piperazine optionally substituted with methyl, optionally substituted phenyl (the optional substituents are methyl or halo), CN, CF3, -O-CF3, tetrazolyl, pyrazolyl optionally substituted with methyl, or triazolyl; R C7 , R C8 , R C9 and R C10 the remainder are H or R C9 and R C10 forms an optionally substituted 6-membered carbocyclic aromatic, heterocyclic or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, CN, P(=O)Me2 or C(=O)OH, or RC7 , R C8 , R C9 and R C10 are all H.

[0296] In some embodiments, R C7 , R C8 , R C9 and R C10 one of which is selected from the group consisting of methyl; OMe; piperazinyl optionally substituted with methyl; —C(═O)OH (carboxy); Cl; F; pyrazolyl; triazolyl; tetrazole; optionally substituted phenyl (the optional substituents are methyl or halo); CN; CF3; O—CF3; C7 , R C8 , R C9 and R C10 the remainder are H, or R C9 and R C10 forms a benzene or six-membered heteroaromatic ring, and R C7 and R C8 are both H or R C7 , R C8 , R C9 and R C10 are all H. In other embodiments, R C7 , R C8 , R C9 and R C10 one of which is selected from the group consisting of methyl optionally substituted with -S(=O)2CH3; OMe; piperazinyl optionally substituted with methyl; -C(=O)OH (carboxy); Cl; F; pyrazolyl optionally substituted with methyl; triazolyl; tetrazole; optionally substituted phenyl (the optional substituents are methyl or halo); CN; CF3; O-CF3; C7 , R C8 , R C9 and R C10 The remainder of the groups are H or R C9 and R C10 forms a benzene or six-membered heteroaromatic ring, and R C7 and R C8 are both H or RC7 , R C8 , R C9 and R C10 But they're all H.

[0297] In some embodiments, R C7 , R C8 , R C9 and R C10 one or two of are selected from methyl optionally substituted with -S(=O)2CH3, OMe, halo, C(=O)OH, piperazine optionally substituted with methyl, optionally substituted phenyl (the optional substituents are methyl or halo), CN, CF3, -O-CF3, tetrazolyl, pyrazolyl optionally substituted with methyl, or triazolyl; R C7 , R C8 , R C9 and R C10 the remainder are H or R C9 and R C10 forms an optionally substituted 6-membered carbocyclic aromatic, 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.

[0298] In one embodiment, C has the formula (C-1), and R C7 , R C8 , R C9 and R C10 All of them are H.

[0299] In another embodiment, R C7 , R C8 , R C9 and R C10 One or two of the methyl, Cl, OMe, phenyl substituted with F at the para position, -C(=O)OH, CN, OCF3, CF3, F, pyrazolyl, triazolyl, tetrazolyl, piperazinyl substituted with methyl; R C7, R C8 , R C9 and R C10 and the remainder of R C7 , R C8 , R C9 and R C10 One or two of the methyl optionally substituted with -S(=O)2CH3, Cl, OMe, phenyl substituted in the para position with F, -C(=O)OH, CN, OCF3, CF3, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, piperazinyl substituted with methyl; R C7 , R C8 , R C9 and R C10 The remainder is H.

[0300] In another embodiment, R C7 and R C9 is independently selected from methyl, -OMe, Cl, -C(=O)OH, piperazinyl optionally substituted with methyl, optionally substituted phenyl (the optional substituent is F), CN, CF, -O-CF, F, pyrazolyl, triazolyl, or tetrazolyl, and the others are H; C10 and R C8 is H. In another embodiment, R C7 and R C9 is independently selected from methyl optionally substituted with -S(=O)2CH3, Cl, OMe, phenyl substituted in the para position with F, -C(=O)OH, CN, OCF3, CF3, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, piperazinyl optionally substituted with methyl, and R C8 and R C10 is H.

[0301] In another embodiment, R C9is selected from H, optionally substituted phenyl (the optional substituent is halo), methyl, OMe, C(═O)OH, Cl, CN, pyrazolyl, triazolyl, tetrazolyl, and piperazinyl optionally substituted with methyl; R C7 , R C8 and R C10 are all H. In another embodiment, R C9 is selected from H, methyl optionally substituted with -S(=O)2CH3, OMe, -C(=O)OH, Cl, CN, phenyl optionally substituted with F, piperazine substituted with methyl, pyrazolyl, triazolyl or tetrazolyl optionally substituted with methyl.

[0302] In other embodiments, R C7 is selected from H, methyl, OMe, Cl, F, CF3, -OCF3 and CN; R C8 , R C9 and R C10 are all H. In other embodiments, R C7 is selected from H, methyl, OMe, Cl, CF3, OCF3, pyrazolyl optionally substituted with methyl, triazolyl and CN; R C8 , R C9 and R C10 are all H.

[0303] In some embodiments a)R C7 , R C8 , R C9 and R C10 are all H, or b)R C9 is selected from H, optionally substituted phenyl (the optional substituent is F), methyl optionally substituted with —S(═O)CH, OMe, C(═O)OH, Cl, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, CN, and piperazinyl optionally substituted with methyl; R C7 , R C8 and R C10 are all H, or c)RC7 is selected from H, methyl, OMe, O—CF, CF, Cl, pyrazolyl optionally substituted with methyl, triazolyl and CN; R C8 , R C9 and R C10 are all H.

[0304] In other embodiments a)R C7 , R C8 , R C9 and R C10 are all H, or b)R C9 is selected from H, optionally substituted phenyl (the optional substituent is F), methyl, OMe, C(═O)OH, Cl, F, pyrazolyl, triazolyl, tetrazolyl, CN, and piperazinyl optionally substituted with methyl; R C7 , R C8 and R C10 are all H, or c)R C7 is selected from H, methyl, OMe, O-CF3, CF3, Cl, F, pyrazolyl, and CN; R C8 , R C9 and R C10 But they're all H.

[0305] In another embodiment, C is selected from the group consisting of groups 1-48 listed in the table below.

[0306] [Table 11-1]

[0307] [Table 11-2]

[0308] In another embodiment, C is selected from the group consisting of the groups listed in the table below.

[0309] [Table 12]

[0310] In another embodiment, C is selected from the group consisting of the groups listed in the table below.

[0311] [Table 13-1]

[0312] [Table 13-2]

[0313] ABC In other embodiments, the compound of formula ABC is of formula (IA):

[0314] [ka] In the formula, X 1 But, CR A1 is.

[0315] In some embodiments, R A1 is H, OH, CN, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl, or ethyl, where the optional substituents on the -OMe, -O-ethyl, methyl, or ethyl group are selected from OH, CN, or one or more halo groups. A1 is H, CN, OH, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl or ethyl, where the optional substituents on the -OMe, -O-ethyl, methyl or ethyl groups are selected from OH, CN, or one or more halo groups. A1 is optionally substituted O-methyl, the optional substituents being one or more F groups. In a further embodiment, R A1 is H. In a further embodiment, R A1 is OH.

[0316] In some embodiments, R A2 is Br, Cl, CN, H, -C(=O)CH3, C 1~6 Alkylamide (This alkylamide is C 1~3 optionally substituted by alkylamide), C 1~3 Thioalkyl optionally substituted with alkyl esters, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl, C 1~3 In some embodiments, R is selected from the group consisting of alkyl (wherein the alkyl is optionally substituted with one or more halo or OH groups), optionally substituted methoxy, methyl, ethyl, or cyclopropyl, where the optional substituents are selected from OH, CN, or one or more halo groups, optionally substituted methoxy or ethoxy, and the optional substituents are selected from alkylamido or one or more halo groups. A2 is Br, Cl, CN, H, -C(=O)CH3, C 1~6 Alkylamide (This alkylamide is C 1~3 optionally substituted with alkylamide), CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl, C 1~3 In a further embodiment, R is selected from the group consisting of alkyl (wherein the alkyl is optionally substituted with one or more halo or OH groups), optionally substituted methoxy, methyl, ethyl, or cyclopropyl, where the optional substituents are selected from OH, CN, or one or more halo groups, optionally substituted methoxy or ethoxy, where the optional substituents are selected from alkylamido or one or more halo groups. A2is selected from CN, methyl, Cl, -C(=O)CH, -C(=O)OCHCH, cyclopropyl, -C(=O)NHCHC(=O)NH, -C(=O)NHCHCHCH, -C(=O)NH-oxetane, -C(=O)NHCHCHF, -C(=O)NHCHCHOH, -C(=O)NHCHCH, -C(=O)NH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -OCFH, H, -OMe, -OCF. In some embodiments, R A2 is selected from the group consisting of CN, methyl, Cl, -C(=O)CH3, OCHF2, cyclopropyl, OCF3, OCH3, H, -C(=O)NH(CH3), S-CH3, -S-CH2CH3 or -S-CH2-C(=O)-O-CH3.

[0317] In some embodiments, R A3 are CN, Br, Cl, OH, H, CF3, C 1~2 Alkyl, C 1~2 In a further embodiment, R A3 is selected from H, methyl and CN.

[0318] In other embodiments, R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carboaromatic ring or C 5~7 Forms a heteroaromatic ring, and the optional substituents are NH, C 1~6 Alkyl, C 1~6 In other embodiments, the optional substituents are selected from NH, methyl, ethyl, OMe, F, Cl, and Br.

[0319] Some embodiments include R A3 and R A2 taken together with the carbon atoms to which they are attached form an optionally substituted pyridine, an optionally substituted benzene, a pyrrole, or a pyrazole. A2 and R A3together form unsubstituted 2-pyrazole, 2-pyrrole substituted by methyl, pyridine optionally substituted by NH2, or benzene optionally substituted by Cl, F, or OMe.

[0320] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the optional substituents are: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, or C 5~10 Bridged heterocycles, spiro C 6~12 Heterocyclyl or spiro C 6~12 Carbocyclyls (which themselves are a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) OH, C, including branched and cyclic 1~6 one or more C with optional substituents selected from alkylsulfonyl or one or more halo groups; 1~6 alkyl groups, e) C with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h) C with optional methyl substituents 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, k) carboxy, CH2-carboxy; l) optionally substituted with one or more groups selected from P(=O)Me (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamide, di-C 1~6 alkylsulfonamides.

[0321] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the optional substituents are: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 5~10 Heterocyclyl, or C 5~10 Bridged heterocycles, spiro C 6~12 Heterocyclyl or spiro C 6~12 Carbocyclyls (which themselves are 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 with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, k) carboxy, CH2-carboxy; l) optionally substituted with one or more groups selected from P(=O)Me (ii) Carboxy, CN, halo, nitro, C 1~6 Alkyl, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C 1~6 Alkylamide, di-C 1~6 Alkylamide, C 1~6 Alkyl sulfonamide, di-C 1~6 alkylsulfonamides.

[0322] In other embodiments, the compound of formula ABC is of formula (IB):

[0323] [ka] In the formula, X 1 , R A2 and R A3 is as defined in (IA).

[0324] In some embodiments, formula (IB) can be formula (I-Ba) or (I-Bb) shown below.

[0325] [ka]

[0326] In some embodiments, D is C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl or C 5~10 heterocyclyl, which themselves are: a) one or two =O groups, b) one or more halo groups; c) CN, NH2, OH, d) OH, C, including branched and cyclic 1~6 one or more C with optional substituents selected from alkylsulfonyl or one or more halo groups; 1~6 alkyl groups, e) C with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h) C optionally substituted by methyl 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) carboxy, CH2-carboxy, m) optionally substituted with one or more groups selected from P(=O)Me2.

[0327] In some embodiments, D is C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl or C 5~10 heterocyclyl, which themselves are: 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 with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) carboxy, CH2-carboxy, m) optionally substituted with one or more groups selected from P(=O)Me2.

[0328] In some embodiments, D is an optionally substituted pyridin-2-one. In some embodiments, the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF), OCF, carboxy (C(=O)OH), CN, phenyl with an optional F substituent at the para position, or piperazine with a methyl substituent. In some embodiments, the pyridin-2-one is unsubstituted. In some embodiments, the optional substituents are selected from OMe, carboxy, Cl, methyl optionally substituted with —S(=O)CH, CN, phenyl substituted with F, piperazinyl substituted with methyl, CF, OCF, pyrazolyl, tetrazolyl, or triazolyl optionally substituted with methyl. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0329] In some embodiments, D is an optionally substituted 6-membered heteroaryl containing one or two N atoms, one of which is attached to a C substituted in the ortho position with =0, and the other optional substituents are selected from methyl, OMe, piperazinyl substituted with methyl, C(=O)OH(carboxy), Cl, F, pyrazolyl, triazolyl, tetrazolyl, phenyl substituted with fluoro, CN, CF3, or O-CF3. In some embodiments, the other optional substituents are selected from methyl optionally substituted with -S(=O)2CH3, OMe, piperazinyl substituted with methyl, C(=O)OH(carboxy), Cl, phenyl substituted with fluoro, CN, CF3, O-CF3, pyrazole, triazole, or tetrazole optionally substituted with methyl.

[0330] In other embodiments, the compound of formula ABC is of formula (IC):

[0331] [ka] In the formula, X 1 , R A2 and R A3 is as defined in (IA).

[0332] In some embodiments, 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 heteroaryl, carboxy, =O, halo, NH, CN, or phenyl optionally substituted with one or more halo atoms, or C 1~6 C optionally substituted by alkylsulfonyl 1~6 alkyl; or R D3 and R D4 form an optionally substituted 6-membered carboaromatic, heterocyclic or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, CN, P(=O)Me2, and C(=O)OH; or or R D1 , R D2 , R D3 and R D4 But they're all H.

[0333] In some embodiments, R D1 , R D2 , R D3 and R D4 one or two of which are C optionally substituted by one or more halo groups or S(=O)2CH3 1~6 alkyl; C optionally substituted with one or more halo groups 1~6 Alkoxy, C with optional methyl substituents 5~6 Heterocyclyl or C 5~6 selected from heteroaryl, carboxy, =O, halo, NH2, CN, or phenyl optionally substituted with one or more halo atoms; R D3 and R D4 form an optionally substituted 6-membered carboaromatic, heterocyclic or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo, C(=O)OH.

[0334] In another embodiment, R D1 , R D2 , R D3 and R D4 wherein one or two of R are selected from methyl, OMe, halo, C(=O)OH, CN, CF, OCF, OCHF, pyrazolyl, triazolyl, tetrazolyl, and the remainder are H. In another embodiment, R D1 , R D2 , R D3 and R D4one or two of R are selected from methyl optionally substituted with —S(═O)2CH3, OMe, halo, C(═O)OH, CN, CF3, OCF3, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, phenyl substituted with fluoro, piperazine substituted with methyl; D1 , R D2 , R D3 and R D4 The remainder is H.

[0335] In one embodiment, R D1 , R D2 , R D3 and R D4 All of them are H.

[0336] In some embodiments, R D3 and R D4 forms an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0337] In other embodiments, the compound of formula ABC has the formula (ID):

[0338] [ka] (ID).

[0339] In some embodiments, X 1 , R A2 and R A3 is as defined as (IA).

[0340] In some embodiments, X D is NR D5a or CR D5a R D5b and R D5a is selected from H or methyl; R D5b and R D6b are either both H or together are -CH2-, R D6ais selected from H, ═O, methyl, —CHOH, or C(═O)OH; R D7a is selected from H, ═O, methyl, —CHOH, or C(═O)OH; R D7b is H and R D7a If =O, then R D7b does not exist or or R D6a and R D7a together form a benzene ring or a C6 heteroaromatic ring optionally substituted by CN, P(=O)Me2 or carboxy, and R D6b and R D7b does not exist.

[0341] In some embodiments, the compound is of formula (I) ABC(I) or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof; wherein A is:

[0342] [ka] where the wavy line indicates the point of attachment to B; X 1 But, CR A1 and R A1 but, (i) H, (ii) halo, (iii) CN, (iv) one or more of OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups 1~6 hydrocarbons, (v) OH, one or more halo groups, C 1~6 C optionally substituted with alkylamide 1~6 Alkoxy, (vi) C 1~6 Alkyl esters, (vii)C 1~6alkyl acyls, and (viii) selected from the group consisting of OH; R A2 but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Achill, C 1~6 C optionally substituted with alkoxy or one or more halo groups; 1~6 hydrocarbons, (v) C optionally substituted with OH, alkylamido, or one or more halo groups. 1~6 Alkoxy, (vi) C 1~6 acylamides (wherein acyl is optionally substituted by H or methyl); (vii)C 1~6 thioalkyl, (viii)C 1~6 Alkyl esters, (ix) C 1~6 alkyl acyls, (x)C 4~5 heterocyclyl, (xi) C5 heteroaryl, (xii)C 1~3 Alkylamide, CN, C 2~3 Alkynyl, C 4~6 Heterocyclyl or C 1~3 C optionally substituted with alkyl 1~6 Alkyl amides, such as C 1~3 C, wherein the alkyl is optionally substituted with one or more halo or OH groups; 1~6 alkylamides, and (xiii) selected from the group consisting of OH; R A3 but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C 1~6 Thioalkyl, C 1~6 Alkoxy, C 1~6 Alkyl acyl, C1~6 Acyloxy, carboxy, C 1~6 Alkyl esters, C 1~6 Alkylamino, -C(=O)NH2, C 1~6 Alkylamide, C 1~6 Alkyl acylamido, C 1~6 Alkylsulfinyl, C 1~6 C optionally substituted with alkylsulfonyl or one or more halo groups; 1~6 hydrocarbons, (v)OH, (vi) C optionally substituted by OH, NH, C heterocyclyl, or one or more halo groups. 1~6 Alkoxy, (vii)C 1~6 acyloxy, (viii) C4 heterocyclyl, (ix) -NH2, (x) C optionally substituted by CN, OH, or C heterocyclyl 1~6 alkylamino, (xi) C optionally substituted by -NH 1~6 Dialkylamino, (xii)C 1~6 acylamides (wherein the acyl substituent is H or Me); (xiii) carbimidoyl or methyl-carbimidoyl, (xiv) carboxyamino, (xv) C optionally substituted by OH or NH 1~6 thioalkyl, (xvi)C 1~6 alkylsulfinyl, (xvi) C optionally substituted with one or more halo groups 1~6 alkylsulfonyl, (xvii)C 1~6 sulfonimodil, (xviii)C 1~6 alkylphosphinyl, (xix) carboxy, (xx)C(=O)NH2, (xxi)C 1~6 Alkyl esters, (xxii) C optionally substituted with one or more halo groups 1~6 alkyl acyls, and (xxiii)C 1~6 alkylamides; or R A3 and R A2 together with the carbon atoms to which they are attached, (i) optionally substituted C 5~7 heterocycles, (ii) optionally substituted C 5~7 heteroaromatic rings, (iii) an optionally substituted C6 carboaromatic ring; (iv) optionally substituted C 5~7 forming a carbocyclic ring, The optional substituents are C 1~6 Alkyl, Halo, C 1~6 Alkoxy, NH2, C 1~6 selected from alkylamino, OH, and CN; B is of formula (B-1) or (B-2), i)

[0343] [ka] where 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 is optionally substituted with OH or OMe; (ii)

[0344] [ka] where the wavy lines indicate the points of attachment to A and C; R B2 But C 1~2 Alkyl-OH, CH2CONHMe or C1~3 is alkyl, C is C 6~10 Carboaryl, C 5~6 Heteroaryl and C 5~10 heterocyclyl, wherein these groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl, or C 5~10 Bridged heterocycles, spiro C 6~12 Heterocyclyl or spiro C 6~12 Carbocyclyl (These are themselves 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 with optional substitution of one or more halo groups. 1~6 Alkoxy, f)C 1~6 Alkyl esters, g) C with optional methyl, OH or ═O substituents 5~6 heterocyclyl, h)C 5~6 heteroaryl, i) C with optional methyl or ═O substituents 4~10 carbocyclyl, j) C having one or more halo optional substituents; 6~10 Carboaryl, l) P(=O)Me2, m) carboxy or CH2-carboxy, and / or n) optionally substituted by one or more of tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl; (ii) Carboxy, CN, halo, nitro, C 1~6Alkyl, 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 alkylsulfonamides.

[0345] In some embodiments, the compound is of formula (I) ABC(I) or a pharmaceutically acceptable salt, tautomeric form, or stereoisomer thereof; wherein A is:

[0346] [ka] where the wavy line indicates the point of attachment to B; R A2 But C 1~6 C substituted by alkyl ester 1~6 thioalkyl or alkylamide substituted by OH, C is C 6~10 Carboaryl, C 5~6 Heteroaryl and C 5~10 heterocyclyl, wherein these groups are selected from the group consisting of: (I C 6~10 Carboaryl, C 4~10 Carbocyclyl, C 5~10 Heteroaryl, C 4~10 Heterocyclyl or C 5~10 Bridged heterocycles, spiro C 6~12 Heterocyclyl or spiro C 6~12 A group selected from carbocyclyl (These are themselves the following groups: C 1~6 C substituted with alkylsulfonyl substituent or methyl 5~6 Heteroaryl containing one or more C 1~6optionally substituted by one or more of the following alkyl groups: X 1 , R A3 and B is as defined above.

[0347] In some embodiments, the compound of formula (I) is selected from Table 1 below.

[0348] [Table 14-1]

[0349] [Table 14-2]

[0350] [Table 14-3]

[0351] [Table 14-4]

[0352] [Table 14-5]

[0353] [Table 14-6]

[0354] Further compounds are shown in Table 2.

[0355] [Table 15-1]

[0356] [Table 15-2]

[0357] [Table 15-3]

[0358] [Table 15-4]

[0359] [Table 15-5]

[0360] In some embodiments, the compound is selected from 36, 47, and 103. In some embodiments, the compound is 36.

[0361] Further compounds are shown in Table 2a.

[0362] [Table 16-1]

[0363] [Table 16-2]

[0364] [Table 16-3]

[0365] [Table 16-4]

[0366] [Table 16-5]

[0367] general synthesis Compounds according to general formula (IB) can be prepared according to the following schemes 1, 2, or 3. 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 clear that the order of the transformations illustrated in schemes 1, 2, or 3 can be varied in various ways. Therefore, the order of the transformations illustrated in these schemes is not intended to be limiting.

[0368] Routes for preparing compounds of general formula (IB) and corresponding intermediates are described in Schemes 1, 2 or 3.

[0369] [ka]

[0370] Scheme 1: X is a leaving group, PG is a protecting group, and D, X 1 , R A2 and R A3 has the meaning as given for general formula (IB) above.

[0371] Monoarylated diamines of general formula (A3) are prepared by nucleophilic aromatic substitution (S) between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A2a) where X is a halogen or a leaving group such as -S(O)Me, as shown in Scheme 1. N X can be obtained via a palladium-catalyzed Buchwald-Hartwig amination or via a S(O)Me group, where X is for example fluorine or a group such as -S(O)Me. NIn the Ar approach, diamine (A1) can be reacted with (A2a) in the presence of an inorganic base such as K2CO3 or Na2CO3, or in the presence of an organic base such as triethylamine or DIPEA, or without additional base in a polar solvent such as DMSO, NMP, or nBuOH 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.

[0372] For the palladium-catalyzed Buchwald-Hartwig amination, any method known in the art can be applied. For example, diamine (A1) can be reacted with (A2a) in the presence of a palladium catalyst such as Pd PEPPSI-IpentCl [CAS 1612891-29-8], Pd2(dba)3, or tBuXPhos Pd G3 [1447963-75-8] and a base such as Cs2CO3 or NaOtBu in an aprotic solvent such as 1,4-dioxane, DMF, toluene, or DMA at room temperature to 130°C, preferably 65 to 100°C, for 15 to 24 hours.

[0373] Diamines of general formula (A1) and heteroaryls of general formula (A2a) are commercially available or can be prepared according to procedures available in the public domain. For the synthesis of diamines (A1), see, for example, WO 2004 / 004726 and the references therein.

[0374] Arylated diamines of general formula (A6) can be obtained from (A3) via copper-catalyzed Ullmann coupling with heterocycles (A4) or 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 instances, N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine, TMEDA, N 1 ,N 2 A ligand such as N,N-dimethylethane-1,2-diamine, or N,N-dimethylglycine may be added to the reaction mixture.

[0375] For the Suzuki coupling to (A6), any method known in the art can be applied. For example, (A3) can be reacted with a boronic acid derivative (A5) in the presence of a palladium catalyst such as 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride [CAS 95408-45-0] or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride [CAS 72287-26-4] and a base such as CsCO, KCO, or KPO in a polar solvent such as 1,4-dioxane, THF, and water or a mixture thereof at a temperature between room temperature and 120°C for 2 to 15 hours.

[0376] 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.

[0377] Primary amines of general formula (A7) can be obtained from monoprotected diamines of general formula (A6) by deprotection methods. Depending on the protecting group used, these can be, for example, acidic, basic, oxidative, or hydrogenation methods. Suitable protecting moieties for amino groups and their introduction and cleavage are well known in the art. For an overview of protecting group chemistry, see, for example, Wuts 2014.

[0378] Final compounds of general formula (IB) can be prepared from primary amines of general formula (A7) by nucleophilic aromatic substitution (S N

[0042] Primary amines 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), where X is a leaving group such as chlorine or a halogen, such as -S(O)Me, applying procedures similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A8) are either commercially available or can be prepared according to procedures available in the public domain.

[0379] An alternative route to compounds of general formula (IB) starts from the deprotection of diamines of general formula (A3) to give primary amines of general formula (A9), as shown in Scheme 1. For deprotection, the same procedure applies as described for the synthesis of (A7) from (A6).

[0380] Applying a procedure similar to that described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1, primary amines of general formula (A9) can then be converted to nucleophilic aromatic substitution (S N Ar) or palladium catalyzed Buchwald-Hartwig amination with heteroaryls of general formula (A8) to provide aryl iodides of general formula (A10).

[0381] Applying procedures similar to those described for the synthesis of compound (A6) from (A3) in Scheme 1, final compounds of general formula (IB) can be synthesized from aryl iodides of general formula (10) via copper-catalyzed Ullmann coupling with heterocycles HD (A4) or via palladium-catalyzed Suzuki coupling with boronic acid derivatives (A5).

[0382] Yet another approach to compounds of general formula (IB) is to start from a monoprotected diamine (1) or its corresponding salt and a pre-constructed heteroaryl (A11a) where X is a halogen or a leaving group such as -S(O)Me, followed by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination to obtain arylated diamines of general formula (A6). Applicable procedures are similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. Heteroaryls of general formula (A11a) are commercially available or can be prepared according to procedures available in the public domain (e.g., via Chan-Lam coupling). Specific examples of (A11a) are described in the following paragraphs.

[0383] An alternative route for preparing compounds of general formula (IB) and intermediates of general formula (A10) is shown in Scheme 2.

[0384] [ka]

[0385] Scheme 2: X is a leaving group, PG is a protecting group, and D, X 1 , R A2 and R A3 has the meaning given above for general formula (IB), and a route for the preparation of compounds of general formula (IB) and intermediate (A10).

[0386] Monoarylated diamines of general formula (A12) are prepared by nucleophilic aromatic substitution (S) between monoprotected diamines (A1) or their corresponding salts and heteroaryls (A8) where X is a halogen or a leaving group such as -S(O)Me. N Ar) or palladium-catalyzed Buchwald-Hartwig amination. The applicable procedures are similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

[0387] Deprotection of diamines of general formula (A12) can give primary amines of general formula (A13), for which the same procedure as described for the synthesis of (A7) from (A6) in Scheme 1 applies.

[0388] The final compound of general formula (IB) is then reacted with a nucleophilic aromatic substitution (S N A6 can be synthesized from a primary amine (A13) or its corresponding salt and a pre-constructed heteroaryl (A11a) in which X is a halogen or a leaving group such as -S(O)Me via Ar or palladium-catalyzed Buchwald-Hartwig amination. The applicable procedures are similar to those described for the synthesis of A6 from A1 and A11a in Scheme 1.

[0389] For the synthesis of intermediates of general formula (A10), primary amines (A13) or their corresponding salts are substituted by nucleophilic aromatic substitution (S N In a palladium-catalyzed Buchwald-Hartwig amination, X can be reacted with heteroaryl (A2a) where X is a halogen or a leaving group such as -S(O)Me. The applicable procedures are similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1.

[0390] Carboxylic acid derivatives of general formula (A21) can be synthesized according to the route shown in Scheme 3. Nitro compounds of general formula (A15) can be synthesized by nucleophilic aromatic substitution (S NThe nitroaryls of general formula (A14) can be obtained by reacting monoprotected diamines (A1) or their corresponding salts with nitroaryls (A14) in which X is a leaving group such as chlorine, in the presence of an inorganic base such as K2CO3, in a polar solvent such as DMSO, at a temperature between room temperature and the boiling point of the solvent, for 2-12 hours. Nitroaryls of general formula (A14) are commercially available or can be prepared according to procedures available in the public domain.

[0391] Anilines of general formula (A16) can be obtained from nitro compounds of general formula (A15) by reduction. Any method known in the art can be applied for the reduction. For example, nitro compounds of general formula (A15) can be reacted in the presence of a metal catalyst such as palladium on charcoal under an atmosphere of hydrogen gas (1-5 bar) in a polar protic solvent such as methanol or ethanol at a temperature between 0°C and the boiling point of the solvent for 15-24 hours.

[0392] [ka]

[0393] Scheme 3: X is a leaving group, PG is a protecting group, Alk is methyl or ethyl, and X 1 , R A2 and R A3 A route for preparing compounds of general formula (A21), wherein (IB) has the meaning as given above.

[0394] Pyridones of general formula (A18) can be obtained from anilines (A16) by condensation with oxo-pyrans of general formula (A17), in which Alk is methyl or ethyl, in a polar protic solvent such as ethanol at a temperature between room temperature and the boiling point of the solvent for 2-12 hours. Oxo-pyrans of general formula (A17) are commercially available or can be prepared according to procedures available in the public domain.

[0395] Primary amines of general formula (A19) can be synthesized from (A18) via removal of the protecting group, for which the same procedure as described for the synthesis of (A7) from (A6) in Scheme 1 applies.

[0396] Carboxylic acid esters of general formula (A20) can be prepared by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination from primary amines (A19) and heteroaryls (A8).

[0397] The carboxylic acid derivative of general formula (A21) can be synthesized from the carboxylic acid ester of general formula (A20) by ester hydrolysis. Any method known in the art for saponification can be applied. For example, the ester (A20) can be reacted with a base such as sodium hydroxide in a polar protic solvent such as methanol, water, or a mixture thereof at a temperature between 0°C and the boiling point of the solvent for 0.5 to 2 hours.

[0398] For the synthesis of final compounds of general formula (B-2), routes and methods comparable to those described in Schemes 1-3 can be applied. Without intending to be limiting, routes to compounds of general formula (A43) in Schemes 6-7 are provided for further illustration. Diamines of general formula (A39) are commercially available or can be prepared according to procedures available in the public domain.

[0399] [ka]

[0400] Scheme 6: X is a leaving group, PG is a protecting group, and D, X 1 , R A2 , R A3 and R B2has the meaning as given above for general formulas (IB) and (B-2), a route for the preparation of compounds of general formula (A43).

[0401] [ka]

[0402] Scheme 7: X is a leaving group, PG is a protecting group, and D, X 1 , R A2 , R A3 and R B2 has the meaning as given above for general formulas (IB) and (B-2), and a route for the preparation of compounds of general formula (A43) and intermediate (A45).

[0403] Additional compounds having different formulas above can be prepared by similar methods.

[0404] Experimental Section NMR peak forms are given as they appear in the spectra and possible higher order effects have not been taken into account.

[0405] 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.

[0406] [Table 17-1]

[0407] [Table 17-2]

[0408] [Table 18]

[0409] The various embodiments described in this application are illustrated by the following examples, which are not meant to limit the compounds of formula (I) in any way.

[0410] The exemplary test experiments described herein serve to illustrate the present embodiments and are not limited to the examples given.

[0411] Experimental Section - General Part General conditions (i) The operation was carried out at room temperature (rt), i.e., in the range of 17-28°C, and required an atmosphere of an inert gas such as N2; (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 backfilling it with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g)); (iii) Where a reaction refers to the use of a microwave reactor, one of the following microwave reactors was used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer; (iv) Generally, the course of reactions was followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC), usually coupled to a mass spectrometer (LCMS); (v) To remove excess water, the organic solution was dried over anhydrous MgSO4 or Na2SO4 or using an ISOLUTE® phase separator, followed by work-up procedures using traditional phase separation techniques; (vi) evaporation was performed in a rotary evaporator vacuum or on either a Genevac™ HT-4 / EZ-2 or Biotage® V10; (vii) Unless otherwise stated, flash column chromatography was performed on normal-phase silica using either Merck Silica Gel (Art. 9385) or 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. performed manually or automated using the Reveleris® X2 Flash System or similar system; (viii) 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 instruments, using either isocratic or gradient mobile phases as described in the Experimental Section; The relevant fractions were collected, combined, lyophilized or evaporated to give the purified compound, or the relevant fractions were collected, combined, concentrated under reduced pressure, extracted with DCM or EtOAc, the organic phase was dried either over Na2SO4 or by using a phase separator, and then concentrated under reduced pressure to give the purified compound; (ix) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC equipment, respectively, using either isocratic or gradient runs with mobile phases as described in the Experimental Section; (x) Preparative thin layer chromatography (TLC) was performed using TLC glass plates and applying appropriate solvents or mixtures of solvents; (xi) yields, if any, are not necessarily the maximum achievable, and some reactions were repeated when larger amounts of reaction product were required; (xii) When a particular compound was obtained as an acid addition salt, e.g., a monohydrochloride or dihydrochloride, the 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 generally not determined, e.g., by elemental analysis data. Where noted, the salt was treated according to methods known in the literature to generate the corresponding free base prior to use; (xiii) In general, the structure of the final product of formula (I) was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; proton NMR chemical shift values ​​were 300, 400, 500 and 600 MHz, respectively. 1Measurements were made on a Bruker Avance III 300, 400, 500, and 600 spectrometer operating at H frequencies on the delta scale. Experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as the internal standard. 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, e.g., dd, doublet of doublet, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar instrument, acquiring both positive and negative ion data, generally only ions associated with the parent structure being reported; high-resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar instrument, acquiring either positive or negative ion data, generally only ions associated with the parent structure being reported; (xiv) intermediates were in certain cases not fully purified, but their structure and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xv) Certain intermediates were isolated as TFA salts and may contain excess TFA. The excess can be calculated from the weight of the crude sample. Where indicated, the salts were treated according to literature methods to generate the corresponding free bases before use; (xvi) Unless otherwise specified, compounds containing asymmetric carbon and / or sulfur atoms were not resolved; (xvii) In general, the examples and intermediate compounds are named using ChemDraw Professional version 21.0.0.28 from PerkinElmer. ChemDraw Professional version 21.0.0.28 generates names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules whenever possible when generating chemical names. Stereoisomers are cited by name and distinguished from one another by stereodescriptors assigned according to the CIP rules.

[0412] Where applicable, ChemDraw optionally uses indicators in the graphical representation of stereocenters, such as "&" and "or", to describe the configuration of stereochemical centers present in a structure. Numbers following the "&" and "or" flags are assigned to each stereocenter present.

[0413] In some cases, the above purification methods can provide compounds of formula (I) having sufficiently basic or acidic functional groups in the form of a salt, such as a trifluoroacetate or formate salt for compounds of formula (I) that are sufficiently basic, or an ammonium salt for compounds of formula (I) that are sufficiently acidic. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known in the art, or can be used as salts in subsequent biological assays. It should be understood that the particular form (e.g., salt, free base, etc.) of a compound of formula (I) isolated and described herein is not necessarily the only form in which the compound can be applied to a biological assay to quantify a particular biological activity.

[0414] Purification method Preparative HPLC method: Preparative Method A: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeOH (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative method B: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method C: Compounds were purified by preparative HPLC on an XBridge™ Shield RP18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method D: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method E: Compounds were purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) buffer system as the mobile phase; Preparative Method F: Compounds were purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN in a H2O / MeCN / NH3 (95 / 5 / 0.2) buffer system as the mobile phase; Preparative method G: Compounds were purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) buffer system as the mobile phase; Preparative Method H: Compounds were purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in a H2O / MeCN / NH3 (95 / 5 / 0.2) buffer system as the mobile phase; Preparative Method I: Compounds were purified by preparative HPLC on an XBridge™ C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H 2 O / NH 4 HCO 3 (10 mM, pH 9) buffer system as the mobile phase. Preparative Method J: Compounds were purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%) in H2O / FA ​​as the mobile phase; Preparative method K: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.05%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method L: Compounds were purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative method M: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method N: Compounds were purified by preparative HPLC on an XBridge™ OBD phenyl column (5 μm, 150 × 19 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative method O: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.05%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method P: Compounds were purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O as the mobile phase; Preparative Method Q: Compounds were purified by preparative HPLC on an XBridge™ Shield RP18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN (0.05%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method R: Compounds were purified by preparative HPLC on a Waters™ Sunfire™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(10 mM) as the mobile phase; Preparative Method S: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) buffer system as the mobile phase; Preparative Method T: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of 20 mM NaOH + 10% MeCN (0.05%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method U: Compounds were purified by preparative HPLC on an XBridge™ OBD phenyl column (5 μm, 250 × 19 mm ID) using a gradient of MeCN (0.05%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method V: Compounds were purified by preparative HPLC on an XBridge™ OBD phenyl column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in a H O / TFA (0.05%) buffer system as the mobile phase; Preparative method X: Compounds were purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.05%, aq.) in H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method Y: Compounds were purified by preparative HPLC on an XBridge™ Shield RP18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN (0.05%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative method Z: Compounds were purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H2O / FA ​​(0.1%) buffer system as the mobile phase; Preparative method Z1: Compounds were purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative method Z2: Compounds were purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150 × 30 mm ID) using a gradient of MeCN (0.05%, aq.) in H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative method Z3: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN (0.05%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method Z4: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeCN in a H2O / TFA (0.005%) buffer system as the mobile phase; Preparative method Z5: Compounds were purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 250 × 19 mm ID) using a gradient of MeOH (0.05%, aq.) in H2O / NH4HCO3 (10 mM) / NH3 buffer system as mobile phase; Preparative method Z6: Compounds were purified by preparative HPLC on an XBridge™ Shield RP18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative method Z7: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 100 × 50 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase; Preparative Method Z8: Compounds were purified by preparative HPLC on an XBridge™ RP18 OBD column (5 μm, 100 × 30 mm ID) using a gradient of MeCN (0.1%, aq.) in a H2O / NH4HCO3 (10 mM) / NH3 buffer system as the mobile phase. Preparative Method Z9: Compounds were purified by preparative HPLC on an XBridge™ C8 column (5 μm, 250 × 20 mm ID) using a gradient of MeCN in a H2O / MeCN / NH3 (95 / 5 / 0.2) buffer system as the mobile phase; Preparative Method Z10: Compounds were purified by preparative HPLC on an XBridge™ C8 column (5 μm, 250×50 mm ID) using a gradient of MeCN in a H 2 O / MeCN / NH 3 (95 / 5 / 0.2) buffer system as the mobile phase.

[0415] Preparative SFC method: Preparative method SFC-A: Compounds were purified by preparative SFC on a Waters™ BEH (5 μm, 250 × 30 mm ID) using MeOH / H O (NH , 50 mM) (97 / 3) in CO as mobile phase; Preparative method SFC-B: Compounds were purified by preparative SFC on a Phenomenex Luna Hilic (3.5 μm, 100 × 3 mm ID) using MeOH / NH 3 (20 mM) in CO 2 as the mobile phase; Preparative method SFC-C: Compounds were purified by preparative SFC on a Waters™ Acquity UPC2 BEH (3.5 μm, 100×3 mm ID) using MeOH / H 2 O(NH 3 , 50 mM) (97 / 3) in CO 2 as the mobile phase. Preparative method SFC-D: Compounds were purified by preparative SFC on a Waters™ BEH (5 μm, 250 × 30 mm ID) using MeOH / NH (20 mM) in CO as the mobile phase; Preparative method SFC-E: Compounds were purified by preparative SFC on a Phenomenex Luna Hilic (5 μm, 250×30 mm ID) using MeOH / NH 3 (20 mM) in CO 2 as the mobile phase.

[0416] Preparative HPLC method for parallel experimental setup: Preparative Method Parallel A: Compounds were purified by preparative HPLC on a Waters™ XBridge™ C18 column (5 μm, 100 × 10 mm ID) using a gradient of MeCN (2-94%) in a H2O / NH3 (pH 10) buffer system as the mobile phase; Preparative Method Parallel B: Compounds were purified by preparative HPLC on a Waters™ Xselect™ CSH Fluoro Phenyl column (5 μm, 100 × 10 mm ID) using a gradient of MeCN (2-94%) in a HO / FA (pH 3) buffer system as the mobile phase. Preparative Method Parallel C: Compounds were purified by preparative HPLC on a Waters™ XBridge™ C18 OBD column (5 μm, 150 × 19 mm ID) using a gradient of MeCN (5–95%) in a H2O / MeCN / NH3 (95 / 5 / 0.2) (pH 10) buffer system as the mobile phase; Preparative Method Parallel D: Compounds were purified by preparative HPLC on an XBridge™ C18 OBD column (5 μm, 150 × 19 mm ID) using a gradient of MeCN (5-95%) in a HO / NH4HCO3 (10 mM, pH 9) buffer system as the mobile phase.

[0417] Synthesis method General Method 1 (GM1): Nucleophilic aromatic substitution (S N Ar) Condition A (GM1A): Conventional heating To a solution of the respective amine nucleophile or its salt (1 equivalent) in DMSO (or alternatively NMP, n-BuOH, or 1,4-dioxane) is added a base (1-7 equivalents) and the respective heteroaryl electrophile (0.9-2 equivalents) at room temperature, and the resulting mixture is stirred under heating (100-130°C) until TLC and / or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is concentrated under reduced pressure, and the resulting crude material is subjected to chromatography or preparative TLC and / or preparative HPLC to afford the desired aniline product.

[0418] In another aqueous workup, the reaction mixture was poured into saturated brine or water and extracted with EtOAc. The combined organic layers were washed with water or brine, dried over Na2SO4, filtered, evaporated, and the resulting crude material was chromatographed on silica to give the desired aniline product.

[0419] Condition B (GM1B): Microwave heating To a mixture of the respective amine nucleophile or its salt (1 equivalent) and the respective heteroaryl electrophile (1-1.5 equivalents) in a microwave vial, NMP and base (1-3 equivalents) are added, the vial is capped, and heated under microwave irradiation until TLC and / or LCMS indicate consumption of the starting material (typically 0.5-2 hours). The reaction mixture is concentrated under reduced pressure, and the resulting crude material is subjected to preparative separation. HPLC affords the desired aniline product.

[0420] General Method 2 (GM2): Buchwald-Hartwig amination A solution of the respective amine nucleophile or its salt (1 equiv.) in 1,4-dioxane is treated with the respective heteroaryl electrophile (0.5–4 equiv.), CsCO (1.2–5 equiv.), and Pd PEPPSI-IpentCl [CAS 1612891-29-8] (3–7 mol%) at room temperature under nitrogen. The reaction mixture is stirred under heating (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is filtered through a pad of Celite or silica, the filter cake is washed with EtOAc, and the combined filtrates are concentrated under reduced pressure. The resulting crude material is either triturated with PE / EtOAc or subjected to preparative TLC and / or preparative HPLC to afford the desired aniline product.

[0421] In another aqueous workup, the reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and water. The phases are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with water and / or brine, dried over Na2SO4, filtered, evaporated, and the resulting crude material is subjected to preparative TLC and / or preparative HPLC to give the desired aniline product.

[0422] General Method 3 (GM3): Ullmann Coupling A solution of each aryl halide (1 equiv.) in 1,4-dioxane was treated at room temperature under nitrogen with the respective heteroatom nucleophile HD(A4) (1–10 equiv.), Cs2CO3 (3–6 equiv.), Cu(I)I (0.2–2 equiv.), and rel-(1R,2R)-N 1 ,N 2The resulting mixture is treated with 1,2-dimethylcyclohexane-1,2-diamine [CAS 67579-81-1] (0.2–2 equiv.), and the reaction mixture is stirred under heat (80–100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically 15–18 h). The reaction mixture is diluted with EtOAc and washed sequentially with water and brine. Alternatively, the reaction mixture is diluted with water or brine, and the aqueous layer is extracted with EtOAc. The organic layer is dried over Na2SO4, filtered, and evaporated. The resulting crude material is triturated with PE / EtOAc or subjected to preparative TLC and / or preparative HPLC to afford the desired coupling product.

[0423] In an alternative non-aqueous workup, the reaction mixture is filtered through a pad of Celite, the filter cake is washed with DCM, and the combined filtrates are concentrated under reduced pressure. The resulting crude material is subjected to preparative TLC and / or preparative HPLC to afford the desired coupled product.

[0424] Condition A (GM3A): Parallel experimental setup A mixture of each heteroatom nucleophile HD(A4) (50 μmol, 2 equiv.) and a premix of Cu(I)I (1.9 mg, 10 μmol, 0.40 equiv.) and KCO (10.4 mg, 75.0 μmol, 3.0 equiv.) was added to the (1S,3S)-N in DMSO (100 μL) under argon. 1 -(5-(difluoromethoxy)pyrazin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine (Intermediate 19), compound i-19d (11 mg, 25 μmol, 1.0 equiv.), and rel-(1R,2R)-N 1 ,N 2A stock solution of 2.8 mg of dimethylcyclohexane-1,2-diamine [CAS 67579-81-1] (20 μmol, 0.80 equiv.) was added. The reaction mixture was stirred at 120 °C for 17–22 h and then diluted with 500 μL of DMSO. SiliaMetS™ imidazole metal scavenger (42 mg, 50 μmol, loading: 1.20 mmol / mg) in 200 μL of DMSO was added to each vial, and the mixture was shaken overnight at 800 rpm and 25 °C on a Bioshake® microplate shaker. The reaction mixture was transferred to a 24-well filter plate and filtered into a 4 mL high-recovery vial using a Biotage® Pressure+ manifold. The vial was rinsed with 1 mL of DMSO, and the solution was passed through the filter plate. The filtered solution was concentrated in a Genevac™ centrifugal concentrator, reconstituted in DMSO (300 μL), and purified by preparative HPLC to give the desired coupled product.

[0425] General Method 4 (GM4): Suzuki Coupling Condition A (GM4A): Coupling with boronic acid derivatives A solution of the respective aryl halide (1 equiv.) in a mixture of 1,4-dioxane and water was treated with the respective boronic acid derivative (A5) (1.5-2 equiv.) or (A26) (10 equiv.), CsCO (3 equiv.), KCO (3 equiv.), or KPO (2-3 equiv.), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride [CAS 95408-45-0] (5-10 mol%) or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride [CAS 72287-26-4] (10 mol%) at room temperature under nitrogen. The reaction mixture was stirred at 80-100 °C until TLC and / or LCMS indicated complete consumption of the starting material (2-18 h). The reaction mixture is filtered through a pad of Celite, the filter cake is washed with DCM, and the combined filtrates are concentrated under reduced pressure. The resulting crude material is subjected to preparative TLC and / or preparative HPLC to afford the desired coupled product.

[0426] In another aqueous workup, the reaction mixture is diluted with water, the phases are separated, and the aqueous phase is extracted with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and evaporated, and the resulting crude material is subjected to preparative TLC and / or C18-flash chromatography or preparative HPLC to give the desired coupling product.

[0427] Condition B (GM4B): Coupling with trifluoroborate A solution of each aryl halide (1 equivalent) in 1,4-dioxane is treated with the respective potassium trifluoroborate (A25) (4 equivalents), CsCO (4 equivalents), and CataCXium A Pd G3 [CAS 1651823-59-4] (20 mol%) at room temperature under nitrogen. The reaction mixture is stirred under heating (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically 15 h). The reaction mixture is filtered through a pad of Celite, the filter cake is washed with DCM, and the combined filtrate is concentrated under reduced pressure. The resulting crude material is subjected to preparative TLC and / or preparative HPLC to obtain the desired coupling product.

[0428] General Method 5 (GM5): Chan-Lam Coupling A mixture of the respective heteroatom nucleophile HD(A4) (1 equivalent) in 1,4-dioxane is treated with the respective boronic acid (2-3 equivalents), TMEDA (3 equivalents), and Cu(OTf)2 (1.2-2 equivalents) at room temperature. The reaction mixture is stirred under heating (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (typically 16 h). The reaction mixture is filtered through a pad of Celite, the filtrate is concentrated under reduced pressure, and the residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc, and the combined organic layers are washed with water, dried over Na2SO4, filtered, and evaporated. The resulting crude material is subjected to C18-flash chromatography to yield the desired coupling product.

[0429] General method 6 (GM6): Boc deprotection Condition A (GM6A): Deprotection with HCl A solution of each Boc-protected amine (1 equiv.) in MeOH at room temperature was treated with 4 M HCl in MeOH (13–77 equiv.), and the reaction mixture was stirred under heating (60–80° C.) until TLC and / or LCMS indicated complete consumption of the starting material (typically 2–3 h). The reaction mixture was concentrated under reduced pressure to give the desired amine as the (unspecified) HCl salt.

[0430] Condition B (GM6B): Deprotection with TFA A solution of the respective Boc-protected amine (1 equiv.) in DCM at room temperature is treated with TFA (11-190 equiv.), and the reaction mixture is stirred at room temperature until TLC and / or LCMS indicate complete consumption of the starting material (3-16 h). The reaction mixture is concentrated under reduced pressure to give the desired amine as an (unspecified) TFA salt.

[0431] General Method 7 (GM7): Amide Formation In a microwave vial, a solution of the respective ester (A35) in MeOH is treated at room temperature with the respective amine or its salt (A36) (4-100 equivalents, either neat or as a solution in THF) and, if applicable, DIPEA (4-8 equivalents). The vial is capped and the reaction mixture is stirred at room temperature or with heating (60-70 °C) until TLC and / or LCMS indicate complete consumption of the starting material (3 hours to 5 days). The reaction mixture is concentrated under reduced pressure, and the resulting crude material is subjected to preparative HPLC to afford the desired amide.

[0432] General Method 8 (GM8): Methyl-thioether oxidation A solution of the methyl thioether (1 equiv.) in DCM was cooled to 0 °C and slowly treated with 3-chlorobenzoperoxoic acid (m-CPBA) [CAS 937-14-4] (0.9-1.2 equiv.), and the resulting mixture was stirred at room temperature until TLC and / or LCMS indicated complete consumption of the starting material (0.5-2 h). The reaction mixture was used directly in the next step.

[0433] Alternatively, the reaction mixture is concentrated under reduced pressure and the resulting crude material is subjected to flash chromatography on silica to give the desired oxidation product.

[0434] Intermediates Intermediate 1 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Process Ai-1a tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate

[0435] [ka] According to GM1A, 2-fluoro-5-iodopyridine (CAS Registry Number 171197-80-1) (2.23 g, 9.99 mmol) was added to tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (2.00 g, 9.99 mmol) and K2CO3 (2.76 g, 20 mmol) in DMSO (30 mL). The resulting solution was stirred at 125 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 × 75 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude 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.

[0436] Process Bi-1b tert-Butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0437] [ka] In a slight modification of GM3, rel-(1R,2R)-N1 ,N 2 1-Dimethylcyclohexane-1,2-diamine (CAS Registry Number 67579-81-1) (0.212 g, 1.49 mmol) and Cu(I)I (0.283 g, 1.49 mmol) were added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Compound i-1a (3.0 g, 7.44 mmol), KCO (3.08 g, 22.3 mmol), and pyridin-2(1H)-one (CAS Registry Number 142-08-5) (1.42 g, 14.9 mmol) in 1,4-dioxane (20 mL). The resulting solution was stirred at 110 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with water (3 × 25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude material was triturated with EtOAc:PE (5:1) to give a solid which was collected by filtration and dried under vacuum to give the title compound (2.70 g, 98%) as a yellow solid. MS (ESI): m / z [M+H] + 371.2.

[0438] Process Ci-1c 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0439] [ka] In the modification of GM6A, HCl (2 M in diethyl ether, 27 mL, 54 mmol) was slowly added to tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-1b (1.0 g, 2.70 mmol) in DCM (10 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 3 hours. This synthesis procedure was repeated for a second batch of tert-butyl ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-1b (1.7 g, 4.6 mmol). The two batches were combined and concentrated. The crude product was recrystallized from EtOAc:PE (5:1) to give a solid that was collected by filtration and dried under vacuum to give the unidentified HCl salt of the title compound (2.5 g, 100%) as a yellow solid. MS (ESI): m / z [M+H] + 270.9.

[0440] Intermediate 2 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one x 3TFA Process Ai-2a tert-Butyl ((1S,3S)-3-((5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0441] [ka] According to GM3, rel-(1R,2R)-N 1 ,N 2-dimethylcyclohexane-1,2-diamine (88 mg, 0.62 mmol), tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (250 mg, 0.62 mmol), 1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CAS Registry Number 1849-01- 0) (184 mg, 1.24 mmol), CsCO (606 mg, 1.86 mmol), and Cu(I)I (118 mg, 0.62 mmol) were reacted in 1,4-dioxane (1 mL) at 100 °C for 18 h to give the title compound (172 mg, 65%) as a brown gum after aqueous workup and preparative TLC (7 M NH in MeOH:DCM = 1:20). MS (ESI): m / z [M+H] + 424.

[0442] Process Bi-2b 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one x 3TFA

[0443] [ka] In a slight modification of GM6B, tert-butyl ((1S,3S)-3-((5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamate compound i-2a (165 mg, 0.39 mmol) was reacted with TFA (2 mL, 26 mmol) in DCM (4 mL) at 25° C. for 3 hours, and the reaction mixture was filtered through Celite. The filter cake was washed with DCM (2×5 mL), and the filtrate was concentrated under reduced pressure to give the title compound (216 mg, 83%) as a brown gum. MS (ESI): m / z [M+H] + 324.

[0444] Intermediate 3 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one x 2HCl Process Ai-3a tert-Butyl ((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0445] [ka] According to GM3, tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (500 mg, 1.24 mmol), 3-methoxypyridin-2(1H)-one (CAS Registry Number 20928-63-6) (776 mg, 6.20 mmol), rel-(1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (176 mg, 1.24 mmol), CsCO (2020 mg, 6.20 mmol), and Cu(I)I (236 mg, 1.24 mmol) were reacted in 1,4-dioxane (5 mL) at 100 °C for 15 h to give the title compound (387 mg, 78%) as a brown solid after aqueous workup and preparative TLC (MeOH:DCM = 1:20). MS (ESI): m / z [M+H] + 401.3.

[0446] Process Bi-3b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one x 2HCl

[0447] [ka] According to GM6A3, tert-butyl ((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-3a (370 mg, 0.92 mmol) was reacted with 4 M HCl in MeOH (10 mL, 40 mmol) in MeOH (15 mL) at 60°C for 2 hours to give the crude title compound (340 mg, 99%) as a brown solid. MS (ESI): m / z [M+H] + 301.1.

[0448] Intermediate 4 Methyl 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate Process Ai-4a tert-Butyl ((1S,3S)-3-((5-nitropyridin-2-yl)amino)cyclopentyl)carbamate

[0449] [ka] According to GM1A, K2CO3 (4.14 g, 29.96 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (3.0 g, 14.98 mmol), and 2-chloro-5-nitropyridine (CAS Registry Number 4548-45-2) (2.375 g, 14.98 mmol) were reacted in DMSO (50 mL) at 100 °C for 3 h. The crude gum obtained during aqueous workup was triturated with PE:EtOAc (2:1, 20 mL) to give a solid that was collected by filtration and dried under vacuum to give the title compound (4.0 g, 83%) as a brown solid. MS (ESI): m / z [M+H] + 323.1.

[0450] Process Bi-4b tert-Butyl ((1S,3S)-3-((5-aminopyridin-2-yl)amino)cyclopentyl)carbamate

[0451] [ka] tert-Butyl ((1S,3S)-3-((5-nitropyridin-2-yl)amino)cyclopentyl)carbamate Compound i-4a (1.6 g, 4.96 mmol) and Pd—C (5% wet, 0.53 g, 0.25 mmol) in MeOH (40 mL) were stirred under H (g, 2 atm) at 20° C. for 15 h. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure to give the crude title compound (1.4 g, 96%) as a dark oil that solidified upon standing. MS (ESI): m / z [M+H] + 293.0.

[0452] Process Ci-4c Methyl 6'-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate

[0453] [ka] Methyl 2-oxo-2H-pyran-5-carboxylate (CAS Registry Number 6018-41-3) (506 mg, 3.28 mmol) was added to tert-butyl ((1S,3S)-3-((5-aminopyridin-2-yl)amino)cyclopentyl)carbamate Compound i-4b (800 mg, 2.74 mmol) in EtOH (20 mL) at 20 °C. The resulting solution was stirred at 80 °C for 5 h, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica (gradient: 2-30% EtOAc in PE) to afford the title compound (800 mg, 68%) as a yellow oil that solidified upon standing. MS (ESI): m / z [M+H] + 429.1.

[0454] Process Di-4d Methyl 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate

[0455] [ka] According to GM6A, methyl 6'-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate compound i-4c (800 mg, 1.87 mmol) was reacted with HCl (4 M in MeOH, 6.0 ml, 24 mmol) in MeOH (6 mL) at 60 °C for 2 h to afford the unidentified HCl salt of the title compound (661 mg, 97%) as a brown solid. MS (ESI): m / z [M+H] + 329.0.

[0456] Process Ei-4e Methyl 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate

[0457] [ka] According to GM2, CsCO (893 mg, 2.74 mmol) was added to methyl 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate compound i-4d (300 mg, 0.91 mmol), 5-chloro-2,3-dimethylpyrazine (CAS Registry Number 59489-32-6) (261 mg, 1.83 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (38 mg, 0.05 mmol) in 1,4-dioxane (5 mL) at 25 °C. The resulting suspension was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over Na2SO4, filtered, evaporated, and the resulting material was purified by preparative TLC (7M NH3 in MeOH:DCM = 1:30) to give the title compound (68 mg, 17%) as a brown solid. MS (ESI): m / z [M+H] + 435.1.

[0458] Intermediate 5 (1S,3S)-N 1 -(5,6-dimethylpyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Process Ai-5a tert-Butyl ((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)carbamate

[0459] [ka] The reaction was carried out in three parallel batches. According to GM2, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (430 mg, 2.15 mmol), 5-chloro-2,3-dimethylpyrazine (CAS Registry Number 59489-32-6) (306 mg, 2.15 mmol), CsCO (1049 mg, 3.22 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (54 mg, 0.06 mmol) were reacted in 1,4-dioxane (20 mL) at 100 °C for 15 hours. The batches were combined, subjected to nonaqueous workup, triturated (PE: EtOAc = 5:1, 25 mL), and the solid was collected by filtration and dried under vacuum to give the title compound (1.5 g, 75%) as a pale yellow solid. MS(ESI):m / z[M+H] + 307.1.

[0460] Process Bi-5b (1S,3S)-N 1 -(5,6-dimethylpyrazin-2-yl)cyclopentane-1,3-diamine x 5TFA

[0461] [ka] According to GM6B, tert-butyl ((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)carbamate compound i-5a (1.5 g, 4.9 mmol) was reacted with TFA (4 mL, 52 mmol) in DCM (20 mL) at 20° C. for 15 hours to give the crude title compound (3.80 g, 100%) as a yellow gum. MS (ESI): m / z [M+H] + 207.2.

[0462] Process Ci-5c (1S,3S)-N 1 -(5,6-dimethylpyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0463] [ka] According to GM1A, (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)cyclopentane-1,3-diamine × 5TFA Compound i-5b (3.80 g, 4.89 mmol), 2-fluoro-5-iodopyridine (CAS reg. no. 171197-80-1) (2.18 g, 9.79 mmol), and K2CO3 (3.38 g, 24.5 mmol) were reacted in DMSO (20 mL) at 120 °C for 15 h. After aqueous workup, purification by flash chromatography on silica (gradient: 2-25% EtOAc in PE) afforded the title compound (1.6 g, 80%) as a pale yellow oil that solidified upon standing. MS (ESI): m / z [M+H] + 410.0.

[0464] Intermediate 6 i-6a 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0465] [ka] According to GM5, (6-chloropyridin-3-yl)boronic acid (CAS Registry Number 444120-91-6) (1.29 g, 8.21 mmol), 1,8-naphthyridin-2(1H)-one (CAS Registry Number 15936-09-1) (600 mg, 4.11 mmol), N 1 ,N 1 ,N 2 ,N 2 -Tetramethylethane-1,2-diamine (1431 mg, 12.32 mmol) and Cu(OTf)2 (1782 mg, 4.93 mmol) were reacted in 1,4-dioxane (10 mL) at 100 °C for 16 h to afford the title compound (252 mg, 23%) as a pale yellow solid, which was purified by C18-flash chromatography (gradient: 5-43% MeCN in water + 0.1% NH3 (aq)). MS (ESI): m / z [M+H] + 257.9.

[0466] Intermediate 7 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione Process Ai-7a 4-Nitrophenyl(6-chloropyridin-3-yl)carbamate

[0467] [ka] 4-Nitrophenyl carbonochloridate (CAS Registry Number 7693-46-1) (1.73 g, 8.56 mmol) was added to 6-chloropyridin-3-amine (CAS Registry Number 5350-93-6) (1.0 g, 7.8 mmol) in MeCN (20 mL) at 20 °C, and the resulting solution was stirred at this temperature for 30 minutes. The reaction mixture was diluted with MeCN (200 mL), filtered through an organic phase filter, and evaporated to give the crude title compound (2.18 g, 96%) as a purple solid. MS (ESI): m / z [M+H] + 293.9.

[0468] Process Bi-7b 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione

[0469] [ka] DIPEA (3.90 mL, 22.3 mmol) was added to methyl methylglycinate HCl (CAS Registry Number 13515-93-0) (1.04 g, 7.44 mmol) in MeCN (20 mL) at 20 °C. The resulting suspension was stirred at 20 °C for 15 min, at which time 4-nitrophenyl (6-chloropyridin-3-yl)carbamate Compound i-7a (2.18 g, 7.44 mmol) was added and stirring was continued at 20 °C for 10 min. The mixture was concentrated under reduced pressure, and the resulting crude material was purified by flash chromatography on silica (gradient: 65-70% EtOAc in PE) to afford the title compound (1.55 g, 92%) as a white solid. MS (ESI): m / z [M+H] + 225.8.

[0470] Intermediate 8 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile Process Ai-8a Methyl 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate

[0471] [ka] 6-Chloropyridin-3-amine (CAS Registry Number 5350-93-6) (1.0 g, 7.8 mmol) was added to a solution of methyl 2-oxo-2H-pyran-5-carboxylate (CAS Registry Number 6018-41-3) (1.2 g, 7.8 mmol) in EtOH (20 mL) at 15° C., which was stirred at 80° C. for 16 hours. The reaction mixture was diluted with EtOH (20 mL), filtered through an organic phase filter, and evaporated to give the crude title compound (1.53 g, 74%) as a purple solid. MS (ESI): m / z [M+H] + 265.2.

[0472] Process Bi-8b 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid

[0473] [ka] Methyl 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate compound i-8a (300 mg, 1.13 mmol) was added to NaOH (91 mg, 2.3 mmol) in a mixture of THF (8 mL) and water (2 mL) at 20 °C, and the resulting solution was stirred at 20 °C for 15 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (5 mL), and the pH was adjusted to pH < 7 with 1 M HCl. The mixture was further diluted with water (100 mL) and extracted with EtOAc (3 × 75 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude title compound (230 mg, 81%) as a white solid. MS (ESI): m / z [M+H] +251.

[0474] Process Ci-8c 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide

[0475] [ka] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid compound i-8b (160 mg, 0.64 mmol) was added to HATU (485 mg, 1.28 mmol), TEA (0.712 mL, 5.11 mmol), and NH4Cl (137 mg, 2.55 mmol) in DMF (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 3 h, then cooled to room temperature, quenched with saturated brine (100 mL), and extracted with EtOAc (3 × 75 mL). The organic layer was dried over Na2SO4, filtered, and evaporated, and the resulting residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (130 mg, 82%) as a white solid. MS (ESI): m / z [M+H] + 250.

[0476] Process Di-8d 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile

[0477] [ka] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide compound i-8c (700 mg, 2.80 mmol) was added to a solution of pyridine (0.68 mL, 8.4 mmol) in DCM (10 mL). TFAA (1.19 mL, 8.41 mmol) was slowly added to the mixture at 0 °C, which was stirred at 20 °C for 1 hour. The synthesis procedure was repeated with a second batch of 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide compound i-8c (100 mg, 0.40 mmol). The two batches were combined, concentrated under reduced pressure, and purified by preparative TLC (EtOAc:PE = 3:1) to give the title compound (540 mg, 72%) as a white solid. MS (ESI): m / z [M+H] + 232.1.

[0478] Intermediate 9 3-(trifluoromethoxy)pyridin-2-ol Process Ai-9a 2-((4-methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine

[0479] [ka] KOtBu (682 mg, 6.07 mmol) was added to (4-methoxyphenyl)methanol (CAS Registry Number 105-13-5) (629 mg, 4.56 mmol) in 1,4-dioxane (2 mL) at 20 °C, which was stirred at 20 °C for 2 hours. 2-Chloro-3-(trifluoromethoxy)pyridine (CAS Registry Number 1206980-39-3) (600 mg, 3.04 mmol) was added to the reaction mixture, and the resulting suspension was stirred at 100 °C for 15 hours. The reaction mixture was poured into saturated brine (125 mL) and extracted with EtOAc (3 × 75 mL). The organic layer was dried over NaSO, filtered, and evaporated, and the resulting residue was purified by preparative TLC (EtOAc:PE = 1:5) to give the title compound (600 mg, 66%) as a pale yellow liquid. MS (ESI): m / z [M+H] + 300.0.

[0480] Process Bi-9b 3-(trifluoromethoxy)pyridin-2-ol

[0481] [ka] 2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine Compound i-9a (500 mg, 1.67 mmol) was added to TFA (10 mL) at 25° C., which was then warmed to 60° C., and the resulting solution was stirred at this temperature for 15 hours. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (150 mg, 50%) as a pale yellow solid. MS (ESI): m / z [M+H] + 180.0.

[0482] Intermediate 10 i-10a 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[0483] [ka] In a variation of GM5, pyridine (0.81 mL, 10 mmol) was added to a mixture of 2-oxo-1,2-dihydropyridine-3-carbonitrile (CAS Registry Number 20577-27-9) (600 mg, 5.00 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry Number 444120-91-6) (1.57 g, 10 mmol), Cu(OAc) (1.82 g, 10 mmol), and 5 Å molecular sieves (500 mg, dried at 200 °C for 24 h) in DCM (100 mL) and DMF (15 mL) at 25 °C. Air was sparged into the reaction mixture via a CaCl tube. The resulting mixture was stirred at 25 °C for 15 h and then filtered through Celite. The filter cake was washed with DCM (3 x 10 mL), the combined filtrates were concentrated under reduced pressure, and the residue was partitioned between EtOAc (400 mL) and water (150 mL). The aqueous layer was extracted with EtOAc (5 x 200 mL), and the combined organic layers were 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), the solid was filtered off, and the filter cake was washed with MTBE (3 x 5 mL). The solid was dried under vacuum to give the title compound (105 mg, 9%) as a gray solid. MS (ESI): m / z [M+H] + 232.1.

[0484] Intermediate 13 i-13a 3-chloro-6'-fluoro-2H-[1,3'-bipyridin]-2-one

[0485] [ka] In a slight variation of GM3, 2-fluoro-5-iodopyridine (CAS Registry Number 171197-80-1) (560 mg, 2.51 mmol), 3-chloropyridin-2(1H)-one (CAS Registry Number 13466-35-8) (651 mg, 5.02 mmol), potassium phosphate tribasic (1.60 g, 7.53 mmol), Cu(I)I (478 mg, 2.51 mmol), and rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (357 mg, 2.51 mmol) was reacted in 1,4-dioxane (60 mL) at 100 °C for 18 hours. The reaction mixture was poured into saturated brine (350 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3 x 250 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated. The crude material was purified by flash chromatography on silica (gradient: 0-30% EtOAc in PE) to give the title compound (258 mg, 45%) as a pale yellow solid. MS (ESI): m / z [M+H] + 224.9.

[0486] Intermediate 15 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one x 3HCl Process Ai-15a tert-Butyl ((1S,3S)-3-((3-methyl-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0487] [ka] According to GM3, tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (400 mg, 0.99 mmol), 3-methylpyridin-2(1H)-one (CAS Registry Number 1003-56-1) (1.08 g, 9.92 mmol), CsCO (3.23 g, 9.92 mmol), Cu(I)I (378 mg, 1.98 mmol), and rel-(1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (282 mg, 1.98 mmol) was reacted in 1,4-dioxane (15 mL) at 100 °C for 15 h to give the title compound (375 mg, 98%) as a yellow solid after aqueous workup and preparative TLC (MeOH:DCM = 1:15). MS (ESI): m / z [M+H] + 385.30.

[0488] Process Bi-15b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one x 3HCl

[0489] [ka] According to GM6A, tert-butyl ((1S,3S)-3-((3-methyl-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-15a (360 mg, 0.94 mmol) was reacted with HCl in MeOH (4 M, 10 mL, 40 mmol) in MeOH (15 mL) at 60 °C for 2 hours to give the title compound (356 mg, 97%) as a yellow solid. MS (ESI): m / z [M+H] + 285.20.

[0490] Intermediate 16 2-(6-(((1S,3S-3-aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one Process Ai-16a tert-Butyl ((1S,3S)-3-((5-(6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0491] [ka] In a slight modification of GM3, tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (250 mg, 0.62 mmol), pyridazin-3(2H)-one (CAS Registry Number 504-30-3) (119 mg, 1.24 mmol), CsCO (606 mg, 1.86 mmol), Cu(I)I (59 mg, 0.31 mmol), and N 1 ,N 2-Dimethylethane-1,2-diamine (27 mg, 0.31 mmol) was reacted in 1,4-dioxane (5 mL) at 100 °C for 16 h to give the title compound (173 mg, 75%) as a brown solid after aqueous workup and preparative TLC (NH3 in MeOH (7 M):DCM = 1:30). MS (ESI): m / z (ESI), [M+H] + 372.0.

[0492] Process Bi-16b 2-(6-(((1S,3S-3-aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[0493] [ka] According to GM6A, tert-butyl ((1S,3S)-3-((5-(6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate compound i-16a (168 mg, 0.45 mmol) was reacted with HCl in MeOH (4 M, 5.0 mL, 20 mmol) in MeOH (5 mL) at 60° C. for 3 hours to give the unidentified HCl salt of the title compound (156 mg, 100%) as a brown solid. MS (ESI): m / z [M+H] + 272.00.

[0494] Intermediate 17 (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Process Ai-17a (1S,3S)-N 1 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine x 3HCl

[0495] [ka] According to GM6A, tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (Intermediate 1, Step A) (1.29 g, 3.19 mmol) was reacted with HCl in MeOH (4 M, 10 mL, 40 mmol) in MeOH (20 mL) at 80° C. for 2 hours to give the title compound (1.27 g, 96%) as a beige solid. MS (ESI): m / z [M+H] + 303.90.

[0496] Process Bi-17b (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0497] [ka] According to GM1A, (1S,3S)-N 1 -(5-Iodopyridin-2-yl)cyclopentane-1,3-diamine Compound i-17a (1.26 g, 3.05 mmol), 2,5-dichloropyrazine (CAS reg. no. 19745-07-4) (0.910 g, 6.11 mmol), and Na2CO3 (1.62 g, 15.3 mmol) were reacted in DMSO (25 mL) at 120 °C for 15 h. The mixture was filtered through a Celite pad, and the filtrate was purified by flash C18-flash chromatography (gradient: 10-61% MeCN in water containing 0.1% aqueous NH3) to give the title compound (0.78 g, 61%) as a beige solid. MS (ESI): m / z [M+H] + 415.90.

[0498] Intermediate 18 i-18a Methyl 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate

[0499] [ka] According to GM1A, methyl 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate compound i-4d (185 mg, 0.51 mmol), 2,5-dichloropyrazine (CAS reg. no. 19745-07-4) (151 mg, 1.01 mmol), and Na2CO3 (161 mg, 1.52 mmol) were reacted in DMSO (5 mL) at 120 °C for 3 h to afford the title compound (93 mg, 42%) as a brown solid after aqueous workup and purification by preparative TLC (NH3 in MeOH:DCM = 1:20). MS (ESI): m / z [M+H] + 441.05.

[0500] Intermediate 19 (1S,3S)-N 1 -(5-(difluoromethoxy)pyrazin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Process Ai-19a 2-chloro-5-(difluoromethoxy)pyrazine

[0501] [ka] At 10 °C, diethyl (bromodifluoromethyl)phosphonate (CAS Registry Number 65094-22-6) (80 g, 299 mmol) was slowly added to a mixture of 5-chloropyrazin-2-ol (CAS Registry Number 89180-45-0) (13 g, 99.6 mmol) and aqueous potassium hydroxide (6 N) (180 mL, 1080 mmol) in acetonitrile (180 mL). The resulting solution was stirred at 20 °C for 30 min, after which the solvent was removed under reduced pressure. The residue was poured into saturated brine (400 mL) and extracted with EtOAc (3 × 200 mL). The organic layer was dried over Na SO , filtered, and evaporated to give a brown liquid. The crude product was purified by flash chromatography on silica (gradient: 0 to 2% EtOAc in PE) to give the title compound (9.00 g, 50%) as a pale yellow liquid.1 H-NMR (300MHz, CDCl3) δppm 7.36 (1H, t), 8.21 (2H, s).

[0502] Process Bi-19b tert-Butyl ((1S,3S)-3-((5-(difluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)carbamate

[0503] [ka] According to GM2, 2-chloro-5-(difluoromethoxy)pyrazine compound i-19a (1.0 g, 5.54 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (1.24 g, 6.20 mmol), CsCO (3.6 g, 11 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (0.19 g, 0.22 mmol) were reacted in 1,4-dioxane (30 mL) at 100 °C for 16 hours to afford the title compound (1.6 g, 84%) as a pale yellow solid after non-aqueous workup. MS (ESI): m / z [M+H] + 345.05. 1 H-NMR (300MHz, CDCl3) δ ppm 1.46(11H,s),1.95(2H,t),2.26(2H,dddd),4.09-4.25(2H,m),6.98(1H,d),7.47(1H,d),7.88(1H,d).

[0504] Process Ci-19c (1S,3S)-N 1 -(5-(difluoromethoxy)pyrazin-2-yl)cyclopentane-1,3-diamine x 2TFA

[0505] [ka] According to GM6B, tert-butyl ((1S,3S)-3-((5-(difluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)carbamate compound i-19b (1.55 g, 4.50 mmol) was deprotected with TFA (10 mL, 130 mmol) in DCM (20 mL) for 16 h to give the title compound (2.0 g, 94%) as a brown gum. MS (ESI): m / z [M-NH3+H] + 227.95. 1 H-NMR(300MHz,MeOH-d4)δ ppm 1.59-1.76(2H,m),1.98-2.12(2H,m),2.21-2.36(2H,m),3.75(1H,q),4.29-4.40(1H,m),7.15(1H,t),7.56(1H,d),7.80(1H,d).

[0506] Process Di-19d (1S,3S)-N 1 -(5-(difluoromethoxy)pyrazin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0507] [ka] According to GM1A, (1S,3S)-N 1 Compound i-19c (1.27 g, 2.69 mmol), 2-fluoro-5-iodopyridine (CAS reg. no. 171197-80-1) (500 mg, 2.24 mmol), and CsCO (1.46 g, 4.48 mmol) were reacted in DMSO (5 mL) at 100 °C for 16 hours to afford the title compound (1.03 mmol, 46%) as a yellow solid after aqueous workup. HRMS (ESI) m / z [M+H] + C 15 H 17 Calculated value for F2IN5O: 448.0440, Found value: 448.0412. 1H NMR(300MHz,MeOH-d4)δ 1.49-1.62(2H,m),1.95(2H,t),2.16-2.31(2H,m),4.18-4.33(2H,m),6 .39(1H,dd),7.25(1H,d),7.53-7.61(2H,m),7.77(1H,d),8.07(1H,dd).

[0508] Intermediate 20 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one Process Ai-20a tert-Butyl ((1S,3S)-3-((5-(2-oxo-1,8-naphthyridin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0509] [ka] According to GM2, 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one compound i-6a (100 mg, 0.39 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (117 mg, 0.58 mmol), CsCO (379 mg, 1.16 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (33 mg, 0.04 mmol) were reacted in 1,4-dioxane (5 mL) at 100 °C for 18 hours to afford the title compound (140 mg, 86%) as a pale yellow solid after aqueous workup and purification by preparative TLC (MeOH:DCM = 1:30). MS (ESI): m / z [M+H] + 422.10.

[0510] Process Bi-20b 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0511] [ka] According to GM6A, tert-butyl ((1S,3S)-3-((5-(2-oxo-1,8-naphthyridin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate compound i-20a (130 mg, 0.31 mmol) was reacted with HCl in methanol (5.0 mL of 4 M, 20 mmol) in MeOH (5 mL) at 80° C. for 2 hours to afford the unidentified HCl salt of the title compound (105 mg, 95%) as a light brown solid. MS (ESI): m / z [M+H] + 322.00.

[0512] Intermediate 21 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one Process Ai-21a 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one

[0513] [ka] According to GM5, quinolin-2(1H)-one (CAS Registry Number (59-31-4) (500 mg, 3.44 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry Number (444120-91-6) (1.63 g, 10.3 mmol), Cu(OTf)2 (2.49 g, 6.89 mmol), and N,N,N',N'-tetramethylethylenediamine (1.20 g, 1 0.3 mmol) in 1,4-dioxane (20 mL) at 100 °C for 16 h, and purified by C18-flash chromatography (gradient: 5-46% MeCN in water containing 0.1% aqueous NH3) to give 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one (211 mg, 24%) as a green solid. MS (ESI): m / z [M+H] + 256.95.

[0514] Process Bi-21b tert-Butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0515] [ka] According to GM2, 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one compound i-21a (90 mg, 0.35 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (211 mg, 1.05 mmol), CsCO (571 mg, 1.75 mmol), and Pd-PEPPSI-IpentCl 2-Methylpyridine (29.5 mg, 0.04 mmol) was reacted in 1,4-dioxane (10 mL) at 100° C. for 15 hours, and aqueous workup and purification by preparative TLC (MeOH:DCM=1:40) afforded tert-butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate (122 mg, 83%) as a white solid. MS (ESI): m / z [M+H] + 421.00.

[0516] Process Ci-21c 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[0517] [ka] According to GM6A, tert-butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate compound i-21b (110 mg, 0.26 mmol) was reacted with HCl in methanol (4 M, 5.0 mL, 20 mmol) in MeOH (10 mL) at 80° C. for 2 hours to give the unidentified HCl salt of 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one (90 mg, 96%) as a brown gum. MS (ESI): m / z [M+H] + 321.00.

[0518] Intermediate 22 (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Process Ai-22a tert-Butyl ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0519] [ka] m-CPBA (5.60 g, 25.95 mmol) was added portionwise to a solution of 3-(methylthio)-1,2,4-triazine (CAS Registry Number 28735-21-9) (3.0 g, 23.6 mmol) in DCM (80 mL) at 0 °C, and the resulting suspension was stirred at 20 °C for 2 h. The solvent was removed under reduced pressure without heating, the residue was dissolved in n-butanol (40 mL), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (5.20 g, 26.0 mmol) was added, and the resulting solution was stirred at 120 °C for 18 h. The reaction mixture was poured into 1 M NaOH (250 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the crude product as a brown solid, which was purified by flash chromatography on silica (gradient: 5-60% EtOAc in PE) to give (3.7 g, 56%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 280.

[0520] Process Bi-22b tert-Butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0521] [ka] A solution of Br in DCM (1 M, 15.9 mL, 15.9 mmol) was added dropwise to a solution of tert-butyl ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate Compound i-22a (3.7 g, 13.2 mmol) in a mixture of MeOH (60 mL) and water (30 mL), and the mixture was stirred at room temperature for 15 h. The solvent was removed under reduced pressure, and the residue was poured into saturated NaSO (aq) (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the crude product as a brown solid, which was purified by flash chromatography on silica (gradient: 5 to 30% EtOAc in PE) to give the title compound (3.5 g, 74%) as a yellow solid. MS (ESI): m / z [M+H] + 358.

[0522] Process Ci-22c tert-Butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0523] [ka] According to GM4B, tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (1.5 g, 4.2 mmol), potassium cyclopropyltrifluoroborate (2.48 g, 16.8 mmol), CsCO (5.46 g, 16.8 mmol), and CataCXium A Pd G3 (CAS Registry Number 1651823-59-4) (0.61 g, 0.84 mmol) were reacted in dioxane (70 mL) at 100 °C for 15 h. Combined with a second batch (prepared similarly, 1.12 mmol scale), the material was purified by preparative TLC (EtOAc:PE = 1:3) to afford the title compound (1.12 g, 66%) as a pale yellow solid. MS(ESI):m / z[M+H] + 320.

[0524] Process Di-22d (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 4TFA

[0525] [ka] According to GM6B, tert-butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22c (500 mg, 1.57 mmol) was reacted with TFA (5.0 mL, 65 mmol) in DCM (20 mL) at room temperature for 15 hours to give the title compound (940 mg, 89%) as a yellow gum (containing 4 mol equivalents of residual TFA). MS (ESI): m / z [M+H] + 220.

[0526] Process Ei-22e (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0527] [ka] According to GM1A, (1S,3S)-N 1 -(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4TFA Compound i-22d (880 mg, 1.30 mmol), 2-fluoro-5-iodopyridine (436 mg, 1.95 mmol), and K2CO3 (900 mg, 6.51 mmol) were reacted in DMSO (10 mL) at 120 °C for 15 hours to afford the title compound (369 mg, 67%) as a pale yellow solid after aqueous workup and purification by preparative TLC (EtOAc:PE = 3:1). MS (ESI): m / z [M+H] + 423.

[0528] Intermediate 23 i-23a 1-(6-chloropyridin-3-yl)-3-methylimidazolidine-2,4-dione

[0529] [ka] CuI (0.230 g, 1.57 mmol) was added to a mixture of 2-chloro-5-iodopyridine (CAS Registry Number 69045-79-0) (0.50 g, 2.09 mmol), 3-methylimidazolidine-2,4-dione (CAS Registry Number 6843-45-4) (0.48 g, 4.18 mmol), N,N-dimethylglycine hydrochloride (0.22 g, 1.57 mmol), and CsCO (1.36 g, 4.18 mmol) in dioxane (20 mL), and the resulting suspension was stirred at 100 °C under nitrogen for 15 h. The reaction mixture was poured into brine (125 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the crude product as a yellow gum, which was purified by preparative TLC (EtOAc:PE=1:1) to give (0.25 g, 53%) of the title compound as a pale yellow oil that solidified upon standing. MS (ESI): m / z [M+H] + 226.

[0530] Intermediate 24 i-24a 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0531] [ka] According to GM5, (6-chloropyridin-3-yl)boronic acid (CAS reg. no. 444120-91-6) (2.93 g, 18.6 mmol), 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (CAS reg. no. 50339-06-5) (1.11 g, 7.44 mmol), Cu(OTf) (4.04 g, 11.2 mmol), and TMEDA (2.59 g, 22.3 mmol) were reacted in dioxane (100 mL) at 100 °C for 16 h to give the title compound as a white solid after workup and purification by C18-flash chromatography (gradient: 5-40% MeCN in water containing 0.1% aqueous NH3) (0.235 g, 12%). MS (ESI): m / z [M+H] + 261.

[0532] Intermediate 25 i-25a 6'-chloro-3-methoxy-2H-[1,3'-bipyridin]-2-one

[0533] [ka] 3-Methoxypyridin-2(1H)-one (CAS Registry Number 20928-63-6) (1.35 g, 10.8 mol) and 2-chloro-5-iodopyridine (CAS Registry Number 69045-72-0) (1.03 g, 4.32 mmol) were added to dimethylglycine hydrochloride (301 mg, 2.16 mmol), CuI (411 mg, 2.16 mmol), and CsCO (4.22 g, 13.0 mmol) in dioxane (20 mL), and the resulting solution was stirred at 100 °C for 15 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative TLC (PE: EtOAc = 1:2) to give the title compound (250 mg, 55%) as a pale yellow solid. MS (ESI): m / z [M+H] + 237.

[0534] Intermediate 26 i-26a 6'-chloro-5-methoxy-2H-[1,3'-bipyridin]-2-one

[0535] [ka] CuI (159 mg, 0.84 mmol) and N,N-dimethylglycine hydrochloride (117 mg, 0.84 mmol) were added to a mixture of 2-chloro-5-iodopyridine (400 mg, 1.67 mmol), 5-methoxypyridin-2(1H)-one (CAS registrar no. 61941-79-5) (523 mg, 4.18 mmol), and CsCO (1.63 mg, 5.01 mmol) in dioxane (8 mL), and the resulting suspension was stirred at 100 °C under nitrogen for 15 h. The mixture was filtered through a Celite pad, the solvent was removed under reduced pressure, and the crude product was purified by preparative TLC (EtOAc:PE = 3:1) to give the title compound (179 mg, 45%) as a white solid. MS (ESI): m / z [M+H] + 237.

[0536] Intermediate 28 (1S,3S)-N 1 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 2TFA Process Ai-28a tert-Butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[0537] [ka] Compound i-22b (300 mg, 0.84 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.10 g, 8.37 mmol), KPO (356 mg, 1.67 mmol), and 1,1′-bis(di-tert-butylphosphite) were prepared according to GM4A. (phino)ferrocenepalladium dichloride (CAS reg. no. 95408-45-0) (55 mg, 0.08 mmol) was reacted in a mixture of dioxane (4 mL) and water (1 mL) at 100 °C for 15 hours. Aqueous workup and preparative TLC (MeOH:DCM = 1:20) followed by purification by C18-flash chromatography (gradient: 0 to 49% MeOH in water) afforded the title compound (103 mg, 42%) as a brown solid. MS (ESI): m / z [M+H] + 294.

[0538] Process Bi-28b (1S,3S)-N 1 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine x 2TFA

[0539] [ka] According to GM6B, tert-butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-28a (100 mg, 0.34 mmol) was reacted with TFA (5 mL) in DCM (5 mL) at room temperature for 15 hours to give the title compound (100 mg, 95%) as a white solid. MS (ESI): m / z [M+H] + 194.

[0540] Intermediate 31 (1S,3S)-N 1 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine Process Ai-31a tert-Butyl ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate

[0541] [ka] The reaction was carried out in three parallel batches.

[0542] According to GM2, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (420 mg, 2.10 mmol), 2-bromo-5-methylpyrazine (CAS Registry Number 98006-90-7) (363 mg, 2.10 mmol), CsCO (1.03 g, 3.15 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (62 mg, 0.07 mmol) were reacted in 1,4-dioxane (20 mL) at 100 °C for 15 h. The combined batches were subjected to non-aqueous workup and trituration (PE: EtOAc = 2:1, 20 mL). The solid was collected by filtration and dried under vacuum to give the title compound (1.2 g, 63%) as a gray solid. MS (ESI): m / z [M+H] + 293.3. 1 H NMR(300MHz,CDCl3)δ ppm 1.46(11H,s),1.93(2H,td),2.25(2H,ddt),2.39(3H,d),4.15(1H,d), 4.23(1H,p),4.47(1H,d),4.57(1H,s),7.80(1H,d),7.85-7.90(1H,m).

[0543] Process Bi-31b (1S,3S)-N 1 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine

[0544] [ka] According to GM6B, tert-butyl ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate compound i-31a (350 mg, 1.20 mmol) was reacted with TFA (2 mL, 26 mmol) in DCM (10 mL) at 20° C. for 15 h to afford the unidentified TFA salt of the title compound (704 mg, 91%) as a brown gum. MS (ESI): m / z [M+H] + 193.0. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.44-1.64(2H,m),1.91(2H,m),2.06-2.19(2H,m),2.26(3H,s),3.60-3.73(1H,m),4.21-4.32(1H,m),7.74-7.94(5H,m).

[0545] Intermediate 32 i-32a (1S,3S)-N 1 -(5-iodopyridin-2-yl)-N 3 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine

[0546] [ka] According to GM1A, (1S,3S)-N 1 -(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine Compound i-31b (1.65 g, 2.54 mmol), 2-fluoro-5-iodopyridine (CAS reg. no. 171197-80-1) (1.14 g, 5.09 mmol), and K2CO3 (2.11 g, 15.3 mmol) were reacted in DMSO (20 mL) at 120 °C for 15 h to afford the title compound (0.70 g, 70%) as a pale yellow oil that solidified upon standing after aqueous workup and purification by flash chromatography on silica (gradient: 2-25% EtOAc in PE). MS (ESI): m / z [M+H] + 396.15. 1H NMR(300MHz,CDCl3)δ ppm 1.26(2H,t),1.49-1.62(2H,m),1.95-2.04(2H,m),2.25-2.35(2H,m),2.36-2.42(3H,m),4.14-4.33( 2H,m),4.53(1H,d),4.75(1H,d),6.24(1H,dd),7.60(1H,dd),7.81(1H,d),7.86(1H,t),8.22(1H,dd).

[0547] Intermediate 33 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile Process Ai-33a tert-Butyl ((1S,3S)-3-((5-cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0548] [ka] According to GM2, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (425 mg, 2.12 mmol), 6′-chloro-2-oxo-2H-[1,3′-bipyridine]-5-carbonitrile (Intermediate 8). Compound i-8d (410 mg, 1.77 mmol), CsCO (1.73 g, 5.31 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (74 mg, 0.09 mmol) were reacted in 1,4-dioxane (10 mL) at 100° C. for 16 hours to afford the title compound (390 mg, 56%) as a yellow solid after non-aqueous workup and purification by preparative TLC (MeOH:DCM=1:15).

[0549] Process Bi-33b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile

[0550] [ka] According to GM6A, tert-butyl ((1S,3S)-3-((5-cyano-2-oxo-2H-[1,3′-bipyridin]-6′-yl)amino)cyclopentyl)carbamate compound i-33a (370 mg, 0.94 mmol) was reacted with HCl in dioxane (4 M, 8 mL, 16 mmol) at 60° C. for 15 hours to give the unidentified HCl salt of the title compound (310 mg, 100%) as a brown solid.

[0551] Intermediate 34 i-34a 6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyrazine

[0552] [ka] 6-Chloro-1H-pyrazolo[3,4-b]pyrazine (CAS reg. no. 1260664-81-0) (500 mg, 3.24 mmol) was added to KPO (2060 mg, 9.71 mmol) and iodomethane (1378 mg, 9.71 mmol) in acetonitrile (20 mL). The resulting mixture was stirred at 60 °C under nitrogen for 3 h. The reaction mixture was quenched with saturated brine (100 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:PE = 1:1) to give the title compound (209 mg, 38%) as a yellow solid. MS (ESI): m / z [M+H] + 169. 1 H NMR (300MHz, DMSO-d6) δ ppm 4.06 (3H, s), 8.51 (1H, s), 8.71 (1H, s).

[0553] Intermediate 35 Process Ai-35a tert-Butyl ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0554] [ka] In a slight variation of GM2, 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile compound i-10a (560 mg, 1.89 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (1.13 g, 5.66 mmol), CsCO (1.84 g, 5.66 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (79 mg, 0.09 mmol) were reacted in DMF (30 mL) at 100 °C for 15 h. The reaction mixture was filtered through a pad of Celite, the filter cake was washed with DCM (3 × 10 mL), and the combined filtrates were concentrated under reduced pressure. The resulting material was purified by C18-flash chromatography (gradient: 10-100% MeCN+0.1% NH3 (aq) in water, 910 mg of material isolated) followed by preparative TLC (EtOAc:PE=3:1) to give the title compound (174 mg, 23%) as a grey solid. MS (ESI): m / z [M+H] + 396.20.

[0555] Process Bi-35b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile x 4HCl

[0556] [ka] According to GM6A, tert-butyl ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-35a (865 mg, 2.19 mmol) was reacted with HCl in methanol (4 M, 8.0 mL, 32 mmol) in MeOH (20 mL) at 80°C for 2 hours to give the title compound (966 mg, 100%) as a brown gum. MS (ESI): m / z [M+H] + 296.00.

[0557] Intermediate 40 Process Ai-40a 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

[0558] [ka] 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-24a (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. for 15 hours under a nitrogen atmosphere. 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.

[0559] Process Bi-40b 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0560] [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 Compound i-41a (220 mg, 0.52 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 crude title compound (347 mg, 100%) as a brown gum. MS (ESI) m / z [M+H] + 325.0.

[0561] Intermediate 41 Process Ai-41a tert-Butyl ((1S,3S)-3-((5-(3-methyl-2,5-dioxoimidazolidin-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0562] [ka] CsCO (3.70 g, 11.4 mmol) was added to a solution of tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (1.3 g, 6.49 mmol), 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione compound i-7b (1.32 g, 5.84 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (0.142 g, 0.17 mmol) in 1,4-dioxane (30 mL) at room temperature, and the resulting suspension was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was poured into saturated brine (300 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to give a pale yellow gum. The crude gum was triturated with EtOAc (20 mL) to give a solid, which was collected by filtration and dried under vacuum (yellow solid). This solid was further purified by preparative TLC (EtOAc:PE = 100:1) to give the title compound (0.25 g, 10%) as a white solid. MS (ESI): m / z [M+H] + 390.

[0563] Process Bi-41b 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1-methylimidazolidine-2,4-dione × 2HCl

[0564] [ka] HCl (5 mL, 20 mmol) in MeOH (4 M) was added to tert-butyl ((1S,3S)-3-((5-(3-methyl-2,5-dioxoimidazolidin-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Compound i-41a (250 mg, 0.64 mmol) in MeOH (15 mL) at room temperature, and the resulting solution was stirred at 60° C. for 16 hours. The solvent was removed under reduced pressure to give (220 mg, 95%) 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]+ 290.

[0565] Intermediate 42 Process Ai-42a tert-Butyl ((1S,3S)-3-((5-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0566] [ka] rel-(1R,2R)-N 1 ,N 2

[0047] 1,4-Dimethylcyclohexane-1,2-diamine (53 mg, 0.37 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (300 mg, 0.74 mmol), 5-methoxypyridin-2-ol (233 mg, 1.86 mmol), CsCO (727 mg, 2.23 mmol), and Cu(I)I (70.8 mg, 0.37 mmol) in 1,4-dioxane (15 mL) at 25 °C. The resulting suspension was stirred at 100 °C for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and 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.

[0567] Process Bi-42b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one

[0568] [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 Compound i-42a (400 mg, 1.00 mmol) in DCM (15 mL) at 25°C. The resulting suspension was stirred at 25°C for 18 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.

[0569] Intermediate 43 Process Ai-43a tert-Butyl ((1S,3S)-3-((3-chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0570] [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 compound i-13a (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.

[0571] Process Bi-43b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-chloro-2H-[1,3'-bipyridin]-2-one

[0572] [ka] 4 M 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 Compound i-43a (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.

[0573] Intermediate 44 Process Ai-44a tert-Butyl ((1S,3S)-3-((5-chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0574] [ka] rel-(1R,2R)-N 1 ,N 2

[0047] 1,4-Dimethylcyclohexane-1,2-diamine (106 mg, 0.74 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (300 mg, 0.74 mmol), 5-chloropyridin-2(1H)-one (193 mg, 1.49 mmol), Cu(I)I (142 mg, 0.74 mmol), and CsCO (727 mg, 2.23 mmol) in 1,4-dioxane (25 mL) at 26 °C. The resulting solution was stirred at 100 °C for 18 h. The reaction mixture was diluted with EtOAc (75 mL) and 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.

[0575] Process Bi-44b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one

[0576] [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 Compound i-44a (220 mg, 0.54 mmol) in DCM (20 mL) at 25°C. The resulting solution was stirred at 100°C for 18 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.

[0577] Intermediate 45 Process Ai-45a tert-Butyl ((1S,3S)-3-((5-cyclopropylpyrazin-2-yl)amino)cyclopentyl)carbamate

[0578] [ka] 2-Bromo-5-cyclopropylpyrazine (CAS Registry Number 1086382-78-6) (150 mg, 0.75 mmol) was added to Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (32 mg, 0.04 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (151 mg, 0.75 mmol), and CsCO (737 mg, 2.26 mmol) in 1,4-dioxane (10 mL), and the resulting mixture was stirred at 100 °C under nitrogen 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 resulting crude product was purified by preparative TLC (EtOAc:PE=2:1) ​​to give (180 mg, 75%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 319.1

[0579] Process Bi-45b (1S,3S)-N 1 -(5-cyclopropylpyrazin-2-yl)cyclopentane-1,3-diamine x 3TFA

[0580] [ka] tert-Butyl ((1S,3S)-3-((5-cyclopropylpyrazin-2-yl)amino)cyclopentyl)carbamate Compound i-45a (160 mg, 0.50 mmol) was added to a mixture of TFA (2 mL) and DCM (6 mL). The resulting mixture was stirred at room temperature for 3 hours. The organic solvent was removed by evaporation to give the title compound (267 mg, 95%) as a brown oil, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 219.3.

[0581] Intermediate 46 Process Ai-46a tert-Butyl ((1S,3S)-3-((5-(trifluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)carbamate

[0582] [ka] A mixture of 2-chloro-5-(trifluoromethoxy)pyrazine (CAS Registry Number 1803596-66-8) (46 mg, 0.23 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (93 mg, 0.46 mmol), (oxybis(2,1-phenylene))bis(diphenylphosphane) (12 mg, 0.02 mmol), Pd2dba3 (21 mg, 0.02 mmol), and Cs2CO3 (0.226 g, 0.70 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 2 h. The mixture was diluted with DCM, water was added, and the phases were separated on a phase separator. The organic layer was concentrated and the residue was combined with another batch (scale 0.09 mmol) and purified by flash chromatography on silica (gradient: 0-100% EtOAc in n-heptane) to give (66 mg, 57%) of the title compound as a brown syrup. MS (ESI): m / z [M+H] + 363.2.

[0583] Process Bi-46b (1S,3S)-N 1 -(5-(trifluoromethoxy)pyrazin-2-yl)cyclopentane-1,3-diamine × TFA

[0584] [ka] A mixture of tert-butyl ((1S,3S)-3-((5-(trifluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)carbamate Compound i-46a (42 mg, 0.12 mmol) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and used directly in the next step without further purification (assumed quantitative yield). MS (ESI): m / z [M+H] + 263.2.

[0585] Intermediate 49 Process Ai-49a 6'-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[0586] [ka] Cu(I)I (103 mg, 1.04 mmol) was added to 6'-chloro-5-ethynyl-2H-[1,3'-bipyridin]-2-one compound i-63b (240 mg, 1.04 mmol) and 1-(azidomethyl)-4-methoxybenzene (255 mg, 1.56 mmol) in 1,4-dioxane (10 mL) at room temperature, and the resulting suspension was stirred at 100 °C under nitrogen for 16 hours. The mixture was filtered through a Celite pad, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound (410 mg, 100%) as a white solid. MS (ESI): m / z [M+H] + 394.0.

[0587] Process Di-49d 5-(1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)-6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0588] [ka] Cs2CO3 (207 mg, 0.63 mmol) was dissolved in 1,4-dioxane (3 mL) with 6'-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one, compound i-49a (50 mg, 0.13 mmol), (1S,3S)-N 1 A mixture of 2×HCl salt of -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine compound i-31b (67 mg, 0.25 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (CAS reg. no. 1612891-29-8) (11 mg, 0.01 mmol) was added at room temperature, and the resulting mixture was stirred at 100° C. under nitrogen for 16 hours. 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, evaporated, and the residue was purified by preparative TLC (NH in MeOH (7 M):DCM=1:20) to give the title compound (12 mg, 17%) as a brown solid. MS (ESI): m / z [M+H] + 550.0.

[0589] Intermediate 50 Process Ai-50a 5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol

[0590] [ka] A mixture of XPhos (0.431 g, 0.90 mmol), XPhos Pd G3 (CAS Registry Number 1445085-55-1) (0.383 g, 0.45 mmol), 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Registry Number 110539-88-0) (2.13 g, 6.79 mmol), 5-iodopyridin-2-ol (CAS Registry Number 13472-79-2) (1.0 g, 4.5 mmol), and CsCO3 (4.42 g, 13.6 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 80 °C under nitrogen for 15 h. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash C18-flash chromatography (elution gradient: 0-50% MeCN in water) to give (160 mg, 13%) of the title compound as a white solid. MS (ESI): m / z [M+H] + 282.0.

[0591] Process Bi-50b 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[0592] [ka] Cu(I)I (102 mg, 0.53 mmol) was dissolved in 1,4-dioxane (10 mL) at room temperature with 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol (compound i-50a) (150 mg, 0.53 mmol), 2-chloro-5-iodopyridine (CAS reg. no. 69045-79-0) (128 mg, 0.53 mmol), rel-(1R,2R)-N 1 ,N 2-dimethylcyclohexane-1,2-diamine (114 mg, 0.80 mmol) and Cs2CO3 (347 mg, 1.07 mmol) were added, and the resulting suspension was stirred at 60 °C under nitrogen for 5 h. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified first by preparative TLC (MeOH:DCM = 1:10) and then by flash C18-flash chromatography (elution gradient: 0-30% MeCN in water) to give the title compound (150 mg, 72%) as a white solid. MS (ESI): m / z [M+H] + 393.0.

[0593] Process Ei-50e 5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0594] [ka] Cs2CO3 (622 mg, 1.91 mmol) was dissolved in DMF (15 mL) to prepare a solution of 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one, compound i-50b (250 mg, 0.64 mmol), (1S,3S)-N 1To a mixture of -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine compound i-31b (245 mg, 1.27 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (54 mg, 0.06 mmol) was added at room temperature, and the resulting mixture was stirred at 100 °C under nitrogen for 16 hours. The reaction mixture was diluted with EtOAc (150 mL) and washed sequentially with saturated brine (7 × 200 mL). The organic layer was dried (NaSO), filtered, and evaporated, and the crude product was purified by preparative TLC (MeOH:DCM = 1:15) to give the title compound (150 mg, 43%) as a brown solid. MS (ESI): m / z [M+H] + 549.0.

[0595] Intermediate 55 i-55a 5-Bromo-2-(difluoromethoxy)-3-methylpyrazine

[0596] [ka] 5-Bromo-3-methylpyrazin-2-ol (CAS Registry Number 100047-56-1) (300 mg, 1.59 mmol) was added to KOH (5 mL, 30.0 mmol) and diethyl (bromodifluoromethyl)phosphonate (1271 mg, 4.76 mmol) in MeCN (5 mL), and the resulting mixture was stirred at 20 °C for 1 day. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over Na SO , filtered, evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 1:5) to give the title compound (130 mg, 34%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ ppm 2.46(d,3H),7.63(t,1H),8.39(d,1H).

[0597] Intermediate 56 i-56a 3-(trifluoromethoxy)pyridin-2(1H)-one

[0598] [ka] TFA (5.0 mL, 65 mmol) was added to 2-((4-methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine compound i-9a (0.92 g, 3.1 mmol) in DCM (2 mL). The purple solution was stirred at room temperature for 30 minutes and then concentrated. The residue was co-evaporated with toluene (×3), and a small amount of DCM was added to the residue. A solid was formed, which was filtered off and washed with a small amount of DCM and EtOAc. The solid was dried under vacuum to give the title compound (0.36 g, 65%) as a white solid. MS (ESI): m / z [M+H] + 179.9.

[0599] Intermediate 60 Process Ai-60a 3-((6-chloropyridin-3-yl)amino)-4-nitrobenzonitrile

[0600] [ka] K2CO3 (6.45 g, 46.7 mmol) was added to 3-fluoro-4-nitrobenzonitrile (CAS Registry Number 218632-01-0) (3.10 g, 18.7 mmol), 6-chloropyridin-3-amine (CAS Registry Number 5350-93-6) (2.0 g, 15.6 mmol), Pd(OAc)2 (0.262 g, 1.17 mmol), and XantPhos (1.35 g, 2.33 mmol) in MeCN (40 mL) at room temperature, and the resulting mixture was stirred at 80 °C under nitrogen for 15 h. The reaction mixture was filtered through Celite, and the filter cake was washed with DCM (3 × 50 mL). The combined filtrate was concentrated under reduced pressure and dissolved in EtOAc (250 mL). The organic layer was washed successively with saturated NaHCO3 (3 × 250 mL), dried (Na2SO4), filtered, and evaporated. The resulting residue was purified by preparative TLC (DCM) to give (0.63 g, 15%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 275.1.

[0601] Process Bi-60b 4-Amino-3-((6-chloropyridin-3-yl)amino)benzonitrile

[0602] [ka] Zinc (971 mg, 14.9 mmol) was added to 3-((6-chloropyridin-3-yl)amino)-4-nitrobenzonitrile Compound i-60a (510 mg, 1.86 mmol) and NH4Cl (795 mg, 14.8 mmol) in EtOH (15 mL) at room temperature, and the resulting mixture was stirred at 60 °C for 5 h. The reaction mixture was filtered through Celite, and the filter cake was washed with EtOH (3 × 50 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (363 mg, 80%) as a brown solid, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 245.1.

[0603] Process Ci-60c 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0604] [ka] CDI (795 mg, 4.90 mmol) was added to 4-amino-3-((6-chloropyridin-3-yl)amino)benzonitrile compound i-60b (300 mg, 1.23 mmol) in DMF (2 mL) at room temperature, and the resulting mixture was stirred at 80° C. for 24 hours. The solid was filtered off to give the crude product, which was triturated with MeCN and dried under vacuum to give (242 mg, 73%) of the title compound as a pink solid. MS (ESI): m / z [M+H] + 271.0.

[0605] Process Di-60d 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0606] [ka] CsCO (542 mg, 1.66 mmol) was added to a mixture of 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-60c (150 mg, 0.55 mmol) and CHI (118 mg, 0.83 mmol) in DMF (5 mL) at room temperature, which was stirred at 100 °C for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with brine (3 × 50 mL). The organic layer was dried (NaSO), filtered, and evaporated, and the resulting material was triturated with MeCN. The formed solid was collected by filtration and dried under vacuum to give the title compound (110 mg, 70%) as a pink solid. MS (ESI): m / z [M+H] + 285.1.

[0607] Intermediate 61 Process Ai-61a 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzonitrile

[0608] [ka] Pd(OAc) (0.262 g, 1.17 mmol) was added to a mixture of KCO (6.45 g, 46.7 mmol), 4-fluoro-3-nitrobenzonitrile (CAS Registry Number 1009-35-4) (2.84 g, 17.1 mmol), 6-chloropyridin-3-amine (CAS Registry Number 5350-93-6) (2.0 g, 15.6 mmol), and XantPhos (1.35 g, 2.33 mmol) in MeCN (40 mL) at room temperature, which was stirred at 80 °C under nitrogen for 15 h. The reaction mixture was filtered through Celite, and the filter cake was washed with DCM (3 × 200 mL). The combined filtrate was concentrated under reduced pressure and dissolved in EtOAc (300 mL). The organic layer was washed successively with saturated NaHCO (3 × 400 mL), dried (NaSO), filtered, and evaporated. The resulting material was purified by preparative TLC (DCM) to give (0.70 g, 16%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 275.0

[0609] Process Bi-61b 3-Amino-4-((6-chloropyridin-3-yl)amino)benzonitrile

[0610] [ka] Zinc (1.33 g, 20.4 mmol) was added to NH4Cl (1.09 g, 20.4 mmol), 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzonitrile Compound i-61a (0.70 g, 2.54 mmol) in EtOH (15 mL) at room temperature, and the resulting mixture was stirred at 60 °C for 5 h. The reaction mixture was filtered through Celite, and the filter cake was washed with EtOH (3 × 50 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (0.51 g, 81%) as a brown solid, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 245.1.

[0611] Process Ci-61c 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0612] [ka] CDI (1.19 g, 7.36 mmol) was added to 3-amino-4-((6-chloropyridin-3-yl)amino)benzonitrile Compound i-61b (450 mg, 1.84 mmol) in DMF (10 mL) at room temperature, and the resulting mixture was stirred at 80° C. for 24 hours. The solid was filtered off to give the crude product, which was triturated with MeCN and dried under vacuum to give (342 mg, 69%) of the title compound as a pink solid. MS (ESI): m / z [M+H] + 270.9.

[0613] Process Di-61d 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[0614] [ka] CHCl (157 mg, 1.11 mmol) was added to a mixture of 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-61c (200 mg, 0.74 mmol) and CsCO (722 mg, 2.22 mmol) in DMF (8 mL) at room temperature, which was stirred at 100° C. for 15 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with brine (3×100 mL). The organic layer was dried (NaSO), filtered, and evaporated to give the title compound (119 mg, 57%) as a yellow solid, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 285.0.

[0615] Intermediate 63 Process Ai-63a 5-((tert-butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one

[0616] [ka] Cs2CO3 (2.23 g, 6.86 mmol) was dissolved in 1,4-dioxane (20 mL) with 5-((tert-butyldimethylsilyl)ethynyl)pyridin-2(1H)-one (CAS Registry Number 2448766-74-1) (800 mg, 3.43 mmol), 2-chloro-5-iodopyridine (CAS Registry Number 69045-79-0) (821 mg, 3.43 mmol), Cu(I)I (653 mg, 3.43 mmol), and rel-(1R,2R)-N 1 ,N 2 The resulting suspension was stirred at 60°C under nitrogen for 5 hours. The mixture was combined with a second batch prepared in the same manner and filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL), and the combined filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (gradient: 0-50% EtOAc in n-heptane) to give the title compound (590 mg, 25%) as a white solid. MS (ESI): m / z [M+H] + 345.0.

[0617] Process Bi-63b 6'-chloro-5-ethynyl-2H-[1,3'-bipyridin]-2-one

[0618] [ka] A solution of TBAF in THF (1 M, 8.55 mL, 8.55 mmol) was added to 5-((tert-butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one compound i-63a (590 mg, 1.71 mmol) in THF (15 mL) at room temperature, and the resulting solution was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (EtOAc:PE = 2:1) followed by flash C18-flash chromatography (elution gradient: 0-30% MeCN in water) to give the title compound (290 mg, 74%) as a beige solid. MS (ESI): m / z [M+H] + 231.0.

[0619] Intermediate 65 Process Ai-65a 6'-chloro-5-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0620] [ka] Bis(4-nitrophenyl)phosphorazidate (CAS Registry Number 51250-91-0) (880 mg, 2.4 mmol) was added to a solution of 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide compound i-8c (300 mg, 1.20 mmol) in pyridine (5 mL) under air. The reaction 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.

[0621] Process Bi-65b 6'-chloro-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0622] [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 compound i-65a (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.

[0623] Intermediate 67 Process Ai-67a 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ol

[0624] [ka] A mixture of 5-iodo-2(1H)-pyridinone (CAS Registry Number 13472-79-2) (500 mg, 2.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Registry Number 761446-44-0) (565 mg, 2.71 mmol), and XPhos (CAS Registry Number 564483-18-7) (108 mg, 0.23 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was treated with XPhos Pd G3 (CAS Registry Number 1445085-55-1) (192 mg, 0.23 mmol) under nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filter cake was washed with EtOAc (100 mL) and the combined filtrates were concentrated under reduced pressure. The resulting material was purified by flash chromatography on silica (gradient: 10-20% MeOH in DCM) to afford the title compound (250 mg, 63%) as a green solid. MS (ESI): m / z [M+H] + 175.9.

[0625] Process Bi-67b 6'-chloro-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[0626] [ka] According to GM3, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ol compound i-67a (250 mg, 1.43 mmol), 2-chloro-5-iodopyridine (342 mg, 1.43 mmol), rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (203 mg, 1.43 mmol), CsCO (1.4 g, 4.3 mmol), and Cu(I)I (272 mg, 1.43 mmol) were reacted in 1,4-dioxane (8 mL) at 100 °C for 18 h to afford the title compound (250 mg, 61%) as a green solid after nonaqueous workup (EtOAc) and flash chromatography on silica (gradient: 0-10% MeOH in DCM). m / z [M+H] + 287.1 / 289 (Cl isotope pattern).

[0627] Intermediate 68b i-68b 6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-3-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[0628] [ka] 3-Chloro-6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 47 (150 mg, 0.38 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2.5 mL) with 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (CAS Registry Number 2710298-24-9) (211 mg, 0.76 mmol), CsCO (369 mg, 1.13 mmol), XPhos (CAS Registry Number 564483-18-7) (18 mg, 0.04 mmol), and XPhos Pd To the mixture of G3 (CAS reg. no. 1445085-55-1) (32 mg, 0.04 mmol) was added under nitrogen. The resulting reaction mixture was stirred at 100° C. for 15 hours and then poured into saturated brine (125 mL). It was extracted with EtOAc (4×100 mL), and the combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude material was purified by preparative TLC (7M NH3 in MeOH:DCM=1:15) to give the title compound (160 mg, 82%) as a yellow solid. MS (ESI): m / z [M+H] + 514.1.

[0629] Intermediate 69 Process Ai-69a tert-Butyl ((1S,3S)-3-((5-(3-methyl-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0630] [ka] rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (70.5 mg, 0.50 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate Compound i-1a (400 mg, 0.99 mmol), 6-methylpyridazin-3(2H)-one (CAS Registry Number 13327-27-0) (218 mg, 1.98 mmol), Cu(I)I (94 mg, 0.50 mmol), and CsCO (970 mg, 2.98 mmol) in 1,4-dioxane (20 mL) at 20 °C, and the resulting suspension was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was diluted with water (75 mL) and extracted with EtOAc (3 × 150 mL). The organic layers were combined, dried over Na2SO4, filtered, evaporated and the residue was purified by preparative TLC (EtOAc) to give the title compound (369 mg, 97%) as a yellow solid. MS (ESI): m / z [M+H] + 386.0.

[0631] Process Bi-69b 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-6-methylpyridazin-3(2H)-one 3 x HCl

[0632] [ka] A solution of HCl (4 M in MeOH, 5.0 mL, 20 mmol) was added to a stirred solution of tert-butyl ((1S,3S)-3-((5-(3-methyl-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Compound i-69a (355 mg, 0.92 mmol) in MeOH (10 mL) at 20 °C, and the resulting solution was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure to give the unidentified HCl salt of the title compound (360 mg, 99%) as a pale yellow solid, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 285.9.

[0633] Intermediate 70 Process Ai-70a tert-Butyl ((1S,3S)-3-((5-(5-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0634] [ka] tert-Butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (400 mg, 0.99 mmol) was dissolved in 4-chloropyridazin-3(2H)-one (CAS Registry Number 1677-79-8) (518 mg, 3.97 mmol), Cu(I)I (94 mg, 0.50 mmol), CsCO (970 mg, 2.98 mmol), and rel-(1R,2R)-N in dioxane (5 mL). 1 ,N 2 The resulting mixture was added to 1,2-dimethylcyclohexane-1,2-diamine (70.5 mg, 0.50 mmol) under a nitrogen atmosphere at 25° C., which was stirred at 100° C. for 18 h. The reaction mixture was concentrated, diluted with EtOAc (75 mL), and washed sequentially with NH (aq) (3×50 mL). The organic layer was retained, and the aqueous layers were combined and re-extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na SO , filtered, evaporated, and the residue purified by preparative TLC (7M NH in MeOH:DCM=1:30) to give the title compound (90 mg, 22%) as a yellow solid. This procedure was repeated once more, and the two batches were combined. MS (ESI): m / z [M+H] + 406.0.

[0635] Process Bi-70b 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-4-chloropyridazin-3(2H)-one

[0636] [ka] tert-Butyl ((1S,3S)-3-((5-(5-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Compound i-70a (165 mg, 0.41 mmol) was added to a mixture of HCl (4 M in MeOH, 1.2 mL) and MeOH (4.8 mL) at 25° C. The resulting solution was stirred at 25° C. for 1 h and then diluted with DCM (20 mL). The solvent was removed under reduced pressure to give the unidentified HCl salt of the title compound (123 mg, 99%) as a yellow solid, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 305.9.

[0637] Intermediate 71 Process Ai-71a tert-Butyl ((1S,3S)-3-((5-(3-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0638] [ka] rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (141 mg, 0.99 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (400 mg, 0.99 mmol), Cu(I)I (189 mg, 0.99 mmol), 6-chloropyridazin-3(2H)-one (CAS Registry Number 19064-67-6) (324 mg, 2.48 mmol), and KCO (411 mg, 2.98 mmol) in 1,4-dioxane (15 mL) at 25 °C, which was stirred at 100 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, diluted with EtOAc (150 mL), and washed successively with saturated brine (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, evaporated, and the residue was purified by preparative TLC (MeOH:DCM=1:20) to give the title compound (180 mg, 44%) as a yellow solid. MS (ESI): m / z [M+H] + 405.9.

[0639] Process Bi-71b 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-6-chloropyridazin-3(2H)-one HCl

[0640] [ka] A solution of HCl (4 M in 1,4-dioxane, 2 mL, 8 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((5-(3-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Compound i-71a (170 mg, 0.42 mmol) in MeOH (10 mL) at 25 °C, which was stirred at 60 °C for 3 h. The reaction mixture was concentrated, diluted with EtOAc (150 mL), and washed sequentially with saturated brine (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated, and the resulting residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound (140 mg, 98%) as a yellow solid. MS (ESI): m / z [M+H] +305.9.

[0641] Intermediate 78 Process Ai-78a 3-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one

[0642] [ka] 4-Methoxybenzyl chloride (720 mg, 4.60 mmol) was added to a mixture of 3-chloro-2(1H-pyrazinone (CAS reg. no. 105985-17-9) (500 mg, 3.83 mmol) and TEA (1.1 mL, 7.7 mmol) in MeCN (20 mL), and the resulting mixture was stirred at 60 °C for 4 h. The reaction mixture was poured into water (50 mL) and concentrated under reduced pressure. The residue was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated. The crude material was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound (200 mg, 21%) as a white solid. MS (ESI): m / z [M+H] + 250.9.

[0643] Process Bi-78b 6'-(((1S,3S)-3-((4-(4-methoxybenzyl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0644] [ka] According to GM2, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (388 mg, 1.44 mmol), 3-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one compound i-78a (300 mg, 1.20 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (101 mg, 0.12 mmol), and CsCO (780 mg, 2.39 mmol) were reacted in 1,4-dioxane (15 mL) at 100 °C for 8 hours, followed by filtration through Celite, aqueous workup, and purification by preparative TLC (DCM:MeOH = 15:1) to give the title compound (230 mg, 40%) as a brown gum. MS (ESI): m / z [M+H] + 485.2.

[0645] Intermediate 79 Process Ai-79a 3-chloro-1-(4-methoxybenzyl)-6-methylpyrazin-2(1H)-one

[0646] [ka] 4-Methoxybenzyl chloride (650 mg, 4.15 mmol) was added to a mixture of 3-chloro-6-methylpyrazin-2(1H)-one (CAS reg. no. 89283-34-1; F. Chillemi, G. Palamidassi, Farmaco, Edizione Scientifica 1963, 18(8), 557-65) (400 mg, 2.77 mmol) and KPO (1.1 mL, 7.7 mmol) in DMF (15 mL), and the resulting mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with saturated brine (125 mL) and extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried over NaSO, filtered, and evaporated. The crude material was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound (260 mg, 36%) as a white solid. MS(ESI):m / z[M+H] + 265.1 / 267 (Cl isotope pattern). 1H NMR (300MHz, DMSO-d6) δ ppm 2.27(3H,s),3.73(3H,s),5.23(2H,s),6.90-6.94(2H,m),7.14-7.16(2H,m),7.18(1H,s).

[0647] Process Bi-79b 6'-(((1S,3S)-3-((4-(4-methoxybenzyl)-5-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0648] [ka] According to GM2, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (102 mg, 0.38 mmol), 3-chloro-1-(4-methoxybenzyl)-6-methylpyrazin-2(1H)-one compound i-79a (100 mg, 0.38 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (318 mg, 0.38 mmol), and KPO (241 mg, 1.13 mmol) were reacted in 1,4-dioxane (1 mL) at 100 °C for 16 hours, filtered through Celite, purified by aqueous workup, and preparative TLC (DCM:MeOH = 10:1) to give the title compound (110 mg, 58%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.56(2H,m c ),1.86-2.00(2H,m),2.05-2.11(2H,m),2.14(3H,s),3.72(3H,s),4.05-4.37(2H,m),5.14(2H,s),6.27(1H,t),6.45(1H,d),6.5 4(1H,d),6.65(1H,d),6.81(1H,d),6.87-6.97(3H,m),7.08-7.18(2H,m),7.40(1H,dd),7.48(1H,dt),7.60(1H,dd),7.93(1H,d).

[0649] Intermediate 82 Process Ai-82a 6-((6-chloropyridin-3-yl)amino)-5-nitronicotinonitrile

[0650] [ka] Na2CO3 (1.73 g, 16.3 mmol) was added to a mixture of 6-chloro-5-nitronicotinonitrile (CAS Registry Number 160906-98-9) (1.00 g, 5.45 mmol), 6-chloropyridin-3-amine (CAS Registry Number 5350-93-6) (1.40 g, 10.9 mmol), XantPhos (CAS Registry Number 161265-03-8) (315 mg, 0.54 mmol), and Pd(OAc)2 (61 mg, 0.27 mmol) in 1,4-dioxane (15 mL) under nitrogen at room temperature, which was stirred at 80 °C for 3 hours. The reaction mixture was filtered through a filter membrane and concentrated under reduced pressure, and the crude material was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound (1.28 g, 85%) as a yellow solid. MS(ESI):m / z[M+H] + 275.8 / 278 (Cl isotope pattern).

[0651] Process Bi-82b 5-amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile

[0652] [ka] 6-((6-chloropyridin-3-yl)amino)-5-nitronicotinonitrile compound i-82a (1.28 g, 4.64 mmol) was added to a mixture of zinc (1.52 g, 23.2 mmol) and acetic acid (2.79 g, 46.4 mmol) in EtOH (15 mL) at room temperature, which was stirred at 60° C. for 2 hours. The reaction mixture was filtered through a filter membrane, the filtrate was concentrated under reduced pressure, and the crude material was purified by preparative TLC (EtOAc:PE=1:1) to give the title compound (1.26 g, 100%) as a yellow solid. MS (ESI): m / z [M+H] +246.0 / 248 (Cl isotope pattern).

[0653] Process Ci-82c 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[0654] [ka] 5-Amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile compound i-82b (1.26 g, 5.13 mmol) in DMF (15 mL) was treated with CDI (CAS Registry Number 530-62-1) (4.16 g, 25.6 mmol) at room temperature under nitrogen, which was stirred at 80 °C for 2 h. The reaction mixture was poured into water (100 mL), and the mixture was extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over NaSO, filtered, evaporated, and the crude material was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (590 mg, 38%) as a yellow oil. MS (ESI): m / z [M+H] + 271.9 / 274 (Cl isotope pattern).

[0655] Process Di-82d 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[0656] [ka] In a vial, a mixture of 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile compound i-82c (580 mg, 2.13 mmol) and K2CO3 (885 mg, 6.40 mmol) in DMF (2 mL) was treated with iodomethane (3.03 g, 21.4 mmol) under nitrogen at room temperature, and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was poured into water (100 mL), and the mixture was extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over Na2SO4, filtered, evaporated, and the crude material was purified by preparative TLC (DCM:PE = 10:1) to give the title compound (401 mg, 66%) as a brown oil. MS (ESI): m / z [M+H] + 285.9 / 288 (Cl isotope pattern).

[0657] Intermediate 88 Process Ai-88a Methyl 5-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)pyrazine-2-carboxylate

[0658] [ka] Na2CO3 (553 mg, 5.22 mmol) was added to tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry Number 645400-44-8) (418 mg, 2.09 mmol) and methyl 5-chloropyrazine-2-carboxylate (CAS Registry Number 33332-25-1) (300 mg, 1.74 mmol) in DMSO (20 mL) at room temperature, and the resulting mixture was stirred at 120 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (250 mL), and washed sequentially with brine (3 × 125 mL). The organic layer was dried (Na2SO4), filtered, and evaporated, and the residue was purified by preparative TLC (EtOAc) to give the title compound (533 mg, 91%) as a pale yellow solid. MS (ESI): m / z [M+H] + 337.

[0659] Process Bi-88b tert-Butyl ((1S,3S)-3-((5-(methylcarbamoyl)pyrazin-2-yl)amino)cyclopentyl)carbamate

[0660] [ka] Methyl 5-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)pyrazine-2-carboxylate Compound i-88a (533 mg, 1.58 mmol) was dissolved in methanamine (30% w / w) in EtOH (15 mL) and placed in a microwave tube. The tube was sealed and heated to 100° C. in a microwave reactor for 2 h. The solvent was removed under reduced pressure to give (525 mg, 99%) of the crude title compound as a yellow solid, which was used without further purification. MS (ESI): m / z [M+H] + 335.9.

[0661] Process Ci-88c 5-(((1S,3S)-3-aminocyclopentyl)amino)-N-methylpyrazine-2-carboxamide

[0662] [ka] HCl (4 M in dioxane, 2.5 mL, 10 mmol) was added to crude tert-butyl ((1S,3S)-3-((5-(methylcarbamoyl)pyrazin-2-yl)amino)cyclopentyl)carbamate Compound i-88b (525 mg, 1.57 mmol) in MeOH (10 mL) at room temperature, and the resulting mixture was stirred at 60 °C for 4 h. The solvent was removed under reduced pressure, and the residue was diluted with EtOAc (250 mL) and washed sequentially with saturated NaHCO (3 × 100 mL). The organic layer was dried (NaSO), filtered, and evaporated, and the resulting material was purified by preparative TLC (EtOAc:PE = 1:1) to afford the title compound (425 mg, 115%) as a pale yellow solid. MS (ESI): m / z [M+H] + 235.8.

[0663] Intermediate 89 i-89a Methyl 5-(((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)pyrazine-2-carboxylate

[0664] [ka] Methyl 5-chloropyrazine-2-carboxylate (CAS Registry Number 33332-25-1) (190 mg, 1.10 mmol) was added to a solution of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one compound i-3b (5×TFA salt) (480 mg, 0.55 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (4.6 mg, 5.5 μmol), and CsCO (539 mg, 1.65 mmol) in 1,4-dioxane (15 mL) at room temperature, and the resulting mixture was stirred at 100 °C under nitrogen for 15 hours. The reaction mixture was poured into water (125 mL) and extracted with EtOAc (4 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, evaporated and the residue was purified by preparative TLC (EtOAc) to give (164 mg, 68%) of the title compound as a yellow solid. MS (ESI): m / z [M+H] + 436.8.

[0665] Intermediate 93 i-93a 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0666] [ka] Cs2CO3 (371 mg, 1.14 mmol) was dissolved in 1,4-dioxane (5 mL) with 6'-chloro-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one, compound i-65b (90 mg, 0.23 mmol), (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)cyclopentane-1,3-diamine × 3TFA compound i-5b (187 mg, 0.34 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (CAS: 1612891-29-8) (9.6 mg, 0.01 mmol) were added at room temperature, and the resulting mixture was stirred at 100 °C under nitrogen for 15 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried (NaSO), filtered, and evaporated, and the residue was purified by preparative TLC (MeOH:DCM = 1:30) to give the title compound (111 mg, 86%) as a pale yellow solid. MS (ESI): m / z [M+H] + 564.9.

[0667] Intermediate 94 i-94a 5-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)-6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[0668] [ka] In a manner similar to that described for compound i-93a, (1S,3S)-N in 1,4-dioxane (5 mL) was prepared. 1

[0047] Prepared from -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine x 5TFA compound i-31b (261 mg, 0.34 mmol), 6'-chloro-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one compound i-65b (90 mg, 0.23 mmol), CsCO (371 mg, 1.14 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (9.6 mg, 0.01 mmol) and purified by preparative TLC (MeOH:DCM = 1:30) to afford the title compound (80 mg, 64%) as a beige solid. MS (ESI): m / z [M+H] + 550.9.

[0669] Intermediate 95 i-95a 6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0670] [ka] In a manner similar to that described for compound i-93a, (1S,3S)-N in 1,4-dioxane (5 mL) was prepared. 1 -(5-(difluoromethoxy)pyrazin-2-yl)cyclopentane-1,3-diamine×3TFA Compound i-19c (134 mg, 0.23 mmol), 6′-chloro-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3′-bipyridin]-2-one Compound i-65b (90 mg, 0.23 mmol), CsCO (371 mg, 1.14 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (9.6 mg, 0.01 mmol) were purified by preparative TLC (EtOAc) to afford the title compound (123 mg, 90%) as a pale yellow solid. MS (ESI): m / z [M+H] + 602.9.

[0671] Intermediate 96 Process Ai-96a tert-Butyl ((1S,3S)-3-((5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0672] [ka] Pd-PEPPSI-IPentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (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 compound i-65b (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 hours 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.

[0673] Process Bi-96b 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0674] [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 Compound i-96a (690 mg, 1.24 mmol) in DCM (10 mL) at room temperature, which was stirred under nitrogen atmosphere at room temperature for 2 hours. The solvent was removed under reduced pressure to give the unidentified 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.

[0675] Process Ci-96c 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[0676] [ka] A mixture of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one compound i-96b (150 mg, 0.33 mmol), 2,5-dichloropyrazine (CAS Registry Number 19745-07-4) (49 mg, 0.33 mmol), CsCO (320 mg, 0.98 mmol), and Pd-PEPPSI-IPentCl 2-methylpyridine (CAS: 1612891-29-8) (27 mg, 0.03 mmol) in 1,4-dioxane (8 mL) was stirred at 100 °C under a nitrogen atmosphere for 18 hours. The reaction mixture was quenched with water (75 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na2SO4), filtered, evaporated, and the residue was purified by preparative TLC (EtOAc:PE=1:0) to give (50 mg, 27%) of the title compound as a pale yellow solid. MS (ESI): m / z [M+H] + 571.3.

[0677] Intermediate 97 i-97a 6'-Fluoro-3-methoxy-2H-[1,3'-bipyridin]-2-one

[0678] [ka] A 500 mL flask was charged with 2-fluoro-5-iodopyridine (CAS Registry Number 171197-80-1) (11.84 g, 53.10 mmol), 3-methoxypyridin-2(1H)-one (CAS Registry Number 20928-63-6) (6.64 g, 53.1 mmol), Cu(I)I (2.022 g, 10.62 mmol), and KCO (14.68 g, 106.19 mmol). 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (1.68 mL, 10.6 mmol) was added, followed by dioxane (200 mL), the flask was filled with nitrogen (3x), and the resulting mixture was stirred at 100 °C for 24 h. The mixture was cooled to room temperature, diluted with water (200 mL), and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL), the phases were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 10% citric acid (50 mL) and brine (50 mL) and concentrated under reduced pressure to give the crude title compound (5.46 g, 46%) as a beige solid (91% pure). MS (ESI): m / z [M+H] + 221.2.

[0679] Intermediate 98 Process Ai-98a rel-tert-butyl((1R,3R)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate

[0680] [ka] 2-Chloro-5-methylpyrazine (CAS Registry Number 59303-10-5) (0.349 g, 2.71 mmol), rel-tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (CAS Registry Number 947732-58-3) (0.544 g, 2.72 mmol), Pd-PEPPSI™-IPent catalyst (CAS Registry Number 1158652-41-5) (91 mg, 0.11 mmol), CsCO (1.33 g, 4.08 mmol), and 1,4-dioxane (6 mL) were mixed at room temperature. The vial was capped, degassed, and backfilled with nitrogen (twice), and the mixture was stirred at 100 °C under a nitrogen atmosphere for 4 h. The mixture was cooled to room temperature and filtered through a small plug of silica. The plug was washed with EtOAc, and the filtrate was evaporated. The residue was suspended in 1:4 EtOAc:heptane (10 mL) and sonicated for 5 minutes. The solid was filtered off, washed with 1:4 EtOAc:heptane (50 mL), followed by heptane (10 mL), and dried overnight under vacuum to give the title compound (545 mg, 81%) as a gray / white solid. MS (ESI): m / z [M+H] + 293.2.

[0681] Process Bi98b rel-(1R,3R)-N 1 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine 3TFA

[0682] [ka] TFA (2.0 mL, 26 mmol) was added to a slurry of rel-tert-butyl ((1R,3R)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate Compound i-98a (0.545 g, 1.86 mmol) in DCM (2 mL), and the resulting solution was stirred at room temperature for 1 h. Toluene and MeOH were added, and the solvent was evaporated. The residue was co-evaporated twice with MeOH and toluene (combined) to give the crude title compound (0.878 g, 89%) as a brown oil containing 5 mol% toluene. MS (ESI): m / z [M+H] + 193.1.

[0683] Intermediate 99 i-99a Methyl 2-((5-bromopyrazin-2-yl)thio)acetate

[0684] [ka] 2,5-Dibromopyrazine (CAS Registry Number 23229-26-7) (500 mg, 2.10 mmol) was added to methyl 2-mercaptoacetate (44.6 mg, 0.42 mmol) and TEA (117 μL, 0.84 mmol) in DMF (5 mL) over 1 min at 20 °C under a nitrogen atmosphere, and the resulting suspension was stirred at 60 °C for 15 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (200 mL) and washed sequentially with saturated brine (3 × 150 mL). The organic layer was dried over Na SO , filtered, and evaporated, and the resulting residue was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound (106 mg, 96%) as a yellow solid. MS (ESI): m / z [M+H] + 262.8.

[0685] Intermediate 100 i-100a 6'-Fluoro-2H-[1,3'-bipyridin]-2-one

[0686] [ka] rel-(1R,2R)-N 1 ,N 21.50 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)δ ppm 6.36(1H,dt),6.52(1H,d),7.36(1H,dd),7.54(1H,ddd),7.73(1H,dd),8.14(1H,ddd),8.35(1H,dd).

[0687] Intermediate 101 Process Ai-101a 1-(6-(benzyloxy)pyridin-3-yl)-4-methylpiperazine

[0688] [ka] Sodium tert-butoxide (437 mg, 4.55 mmol) was added to a mixture of 2-(benzyloxy)-5-bromopyridine (CAS Registry Number 83664-33-9) (400 mg, 1.51 mmol), BINAP (94 mg, 0.15 mmol), Pd(dba) (139 mg, 0.15 mmol), and 1-methylpiperazine (455 mg, 4.54 mmol) in 1,4-dioxane (7 mL) at 25 °C. The resulting solution was stirred in a microwave reactor under nitrogen at 120 °C for 12 min. 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 and the resulting material was purified by C18-flash chromatography (gradient: 0-29% MeCN in water + 1% TFA) to afford the title compound (303 mg, 71%) as a brown oil that solidified upon standing. MS (ESI): m / z [M+H] + 284. 1 H(300MHz,DMSO-d6)δ ppm 2.88(5H,d),3.23-4.00(6H,m),5.27(2H,s),6.82(1H,d),7.21-7.49(6H,m),7.84(1H,d).

[0689] Process Bi-101b 5-(4-methylpiperazin-1-yl)pyridin-2-ol

[0690] [ka] Pd—C (22.5 mg, 0.21 mmol) was added to 1-(6-(benzyloxy)pyridin-3-yl)-4-methylpiperazine Compound i-101a (300 mg, 1.06 mmol) in MeOH (20 mL) at 25° C., and the resulting suspension was stirred at this temperature under a hydrogen atmosphere for 16 hours under hydrogen atmosphere. The mixture was filtered through a Celite pad, and the filter cake was washed with methanol (3×5 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (180 mg, 88%) as a black solid, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 194.

[0691] Intermediate 102 i-102a 6'-chloro-2'-methyl-2H-[1,3'-bipyridin]-2-one

[0692] [ka] The reaction was carried out in two parallel batches, one starting from 2 g and one from 1 g of boronic acid.

[0693] N,N,N',N'-Tetramethylethylenediamine (2.71 g, 23.3 mmol) was added to a mixture of pyridin-2-ol (3.33 g, 35.0 mmol), (6-chloro-2-methylpyridin-3-yl)boronic acid (2.0 g, 11.7 mmol), and copper(II) trifluoromethanesulfonate (8.44 g, 23.3 mmol) in DCM (10 mL) at 25 °C, which was stirred at 25 °C for 18 h. The two reaction mixtures were combined, evaporated to dryness, redissolved in EtOAc (100 mL), and washed sequentially with saturated brine (5 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound (36 mg, 0.9%) as a brown gum. MS (ESI): m / z [M+H] + 220.90. 1 H NMR (300MHz, DMSO-d6) δ ppm 2.20(3H,s),6.37(1H,dt),6.52(1H,dt),7.48-7.57(2H,m),7.60(1H,ddd),7.82(1H,d).

[0694] Intermediate 103 Process Ai-103a tert-Butyl ((1S,3S)-3-((5-(hydroxymethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0695] [ka] KPO (395 mg, 1.86 mmol) was dissolved in tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (250 mg, 0.62 mmol), 5-(hydroxymethyl)pyridin-2(1H)-one (CAS Registry Number 109205-68-1) (155 mg, 1.24 mmol), Cu(I)I (59 mg, 0.31 mmol), and N 1 ,N 2 The resulting mixture was added to a mixture of 1,2-dimethylethane-1,2-diamine (27 mg, 0.31 mmol) under a nitrogen atmosphere at 20° C., which was stirred at 100° C. for 16 hours. The reaction mixture was poured into water (100 mL), and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated brine (3×50 mL), dried over Na2SO4, filtered, evaporated, and the residue was purified by preparative TLC (7M NH3 in MeOH:DCM=1:20) to give the title compound (155 mg, 62%) as a purple solid. MS (ESI): m / z [M+H] + 401.1.

[0696] Process Bi-103b tert-Butyl ((1S,3S)-3-((5-(chloromethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[0697] [ka] Thionyl chloride (430 mg, 3.6 mmol) was added to a mixture of tert-butyl ((1S,3S)-3-((5-(hydroxymethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Compound i-103a (144 mg, 0.36 mmol) in DCM (10 mL) at 20°C, which was stirred at this temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude title compound (355 mg) was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 419 / 421 (Cl isotope pattern).

[0698] Process Ci-103c 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-((methylthio)methyl)-2H-[1,3'-bipyridin]-2-one

[0699] [ka] Sodium thiomethoxide (173 mg, 2.47 mmol) was added to a mixture of crude tert-butyl ((1S,3S)-3-((5-(chloromethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate Compound i-103b (345 mg) in EtOH (10 mL) at 20 °C, which was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting material was purified by preparative TLC (7M NH3 in MeOH:DCM = 1:20) to afford the title compound (88 mg, 32%) as a brown solid (along with 20 mg of the Boc-protected title compound). MS (ESI): m / z [M+H] + 331.1.

[0700] Process Di-103d 6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-5-((methylthio)methyl)-2H-[1,3'-bipyridin]-2-one

[0701] [ka] In a slight variation of GM2, CsCO (231 mg, 0.71 mmol) was added to a mixture of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-5-((methylthio)methyl)-2H-[1,3'-bipyridin]-2-one compound i-103c (78 mg, 0.24 mmol), 2-bromo-5-methylpyrazine (CAS Registry Number 98006-90-7) (82 mg, 0.47 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (99 mg, 0.12 mmol) in DMF (3 mL) at 20 °C, and the resulting mixture was stirred under nitrogen at 100 °C for 16 h. The reaction mixture was poured into saturated brine (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated brine (3 x 50 mL), dried over Na2SO4, filtered, evaporated, and the residue was purified by preparative TLC (7M NH3 in MeOH:DCM = 1:20) to give the title compound (76 mg, 76%) as a brown solid. MS (ESI): m / z [M+H] + 423.1.

[0702] Intermediate 106 Process Ai-106a tert-Butyl ((1S,3S)-3-((5-(5-cyano-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate

[0703] [ka] tert-Butyl ((1S,3S)-3-((5-(5-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Compound i-70a (420 mg, 1.03 mmol) was added to a mixture of Pd(dba) (95 mg, 0.10 mmol), dppf (574 mg, 1.03 mmol), zinc powder (135 mg, 2.07 mmol), and zinc cyanide (243 mg, 2.07 mmol) in DMF (15 mL) under a nitrogen atmosphere at 20 °C, and the mixture was stirred at 100 °C for 15 h. The reaction mixture was washed with saturated brine (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, evaporated, and the residue was purified by preparative TLC (MeOH:DCM=1:10) to give the title compound (232 mg, 57%) as an orange solid. MS (ESI): m / z [M+H] + 397.0.

[0704] Process Bi-106b 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile

[0705] [ka] A mixture of tert-butyl ((1S,3S)-3-((5-(5-cyano-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate Compound i-106a (200 mg, 0.50 mmol) in DCM (3 mL) was treated with TFA (1 mL) at 20° C., which was stirred at 20° C. for 3 h. The reaction mixture was concentrated under reduced pressure to afford the unidentified TFA salt of the title compound (370 mg, 97%) as a brown oil, which was used without further purification. 1H NMR(400MHz,DMSO-d6)δ ppm 1.53-1.64(2H,m),1.87-1.95(1H,m),1.98-2.04(1H,m),2.11-2.18(2H,m),3.63-3.72(1H,m),4.32-4 .39(1H,m),6.64(1H,d),7.56(1H,brs),7.65(1H,dd),7.91(2H,brs),8.19(1H,d),8.22-8.24(2H,m).

[0706] Intermediate 107 Process Ai-107a 4-Bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0707] [ka] 1-(Chloromethyl)-4-methoxybenzene (7.48 g, 47.8 mmol) was added to a mixture of 4-bromo-6-chloro-3(2H)-pyridazinone (CAS reg. no. 933041-13-5) (5.0 g, 24 mmol) and CsCO (15.6 g, 47.8 mmol) in MeCN (80 mL) at 15 °C, which was stirred at 60 °C for 3 h. The mixture was filtered through a pad of Celite, the filter cake was washed with DCM (3 × 20 mL), and the combined filtrate was concentrated under reduced pressure. The resulting material was triturated with 1:5 EtOAc:PE (25 mL), and the solid formed was collected by filtration and dried under vacuum to give the title compound (7.8 g, 98%) as a yellow solid. MS (ESI): m / z [M+H] + 329 / 331 (Br / Cl isotope pattern).

[0708] Process Bi-107b 6-chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0709] [ka] RockPhos Pd G3 (CAS Registry Number 2009020-38-4) (1.97 g, 2.35 mmol) was added to a mixture of 4-bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107a (7.75 g, 23.5 mmol), (E)-benzaldehyde oxime (3.70 g, 30.6 mmol), and CsCO3 (15.6 g, 47.8 mmol) in DMF (40 mL) and water (10 mL) at 15 °C, which was stirred at 80 °C for 15 h. The reaction mixture was poured into saturated brine (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated brine (3 x 100 mL), dried over Na2SO4, filtered, evaporated, and the residue purified by flash chromatography on silica (gradient: 0-100% EtOAc in PE) to give the title compound (4.0 g, 64%) as a tan solid. MS (ESI): m / z [M+H] + 267 / 269 (Cl isotope pattern).

[0710] Process Ci-107c 6-chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0711] [ka] CsCO (293 mg, 0.90 mmol) was added to a mixture of 6-chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107b (200 mg, 0.75 mmol), which was stirred at 20 °C for 1.5 hours. Sodium chlorodifluoroacetate (CAS Registry Number 1895-39-2) (343 mg, 2.25 mmol) was added, and the resulting mixture was stirred at 100 °C for 3.5 hours. The reaction mixture was poured into saturated brine (50 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL), dried over NaSO, filtered, evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound (175 mg, 74%) as a yellow gum. MS (ESI): m / z [M+H] + 317 / 319 (Cl isotope pattern).

[0712] Process Di-107d 4-(Difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0713] [ka] Pd-C (11 mg, 0.11 mmol) was added to a mixture of 6-chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107c (680 mg, 2.15 mmol) in MeOH (30 mL) at 20 °C, and the resulting suspension was stirred under a hydrogen atmosphere at this temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (576 mg, 95%) as a white solid, which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 283.0.

[0714] Process Ei-107e 4-(Difluoromethoxy)pyridazin-3(2H)-one

[0715] [ka] TFA (20 mL) was added to 4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one Compound i-107d (546 mg, 1.93 mmol) at 20° C., and the mixture was stirred at 80° C. for 15 hours. The reaction mixture was concentrated under reduced pressure to give the unidentified TFA salt of the title compound (483 mg, 90%) as a black gum, which was used without further purification. MS (ESI): m / z [M+H] + 162.9. [Example]

[0716] Example 1 3-Methyl-5-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)pyrazine-2-carbonitrile - Compound 1

[0717] [ka] According to GM1A, 5-chloro-3-methylpyrazine-2-carbonitrile (CAS reg. no. 1260665-75-5) (85 mg, 0.55 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (150 mg, 0.55 mmol), and TEA (232 μL, 1.66 mmol) were reacted in DMSO (5 mL) at 110 °C for 18 h. The mixture was evaporated, and the crude product was purified by preparative HPLC (Preparation Method B, gradient: 23-53%) to give the title compound (70 mg, 32%) as a yellow solid. HRMS (ESI) m / z [M+H] + C 21 H 22 Calculated value for N7O: 388.1880, Measured value: 388.1878. 1H NMR(400MHz,DMSO-d6)δ ppm 1.48-1.59(2H,m)1.87-1.99(2H,m)2.11-2.24(2H,m)2.43(3H,s)4.31-4.41(1H,m)6.28(1H ,td)6.45(1H,d)6.53(1H,d)6.98(1H,d)7.41(1H,dd)7.48(1H,ddd)7.61(1H,dd)7.81(1H,br s)7.93(1H,d)8.25(1H,br d).

[0718] Example 2 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one-Compound 2

[0719] [ka] In a variation of GM2, 5-chloro-2,3-dimethylpyrazine (CAS Registry Number 59489-32-6) (132 mg, 0.92 mmol) was added to 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (250 mg, 0.92 mmol), CsCO (904 mg, 2.77 mmol), and Pd(dba)-CHCl adduct (CAS Registry Number 52522-40-4) (191 mg, 0.18 mmol) in toluene (5 mL), and the reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:10) followed by preparative HPLC (Preparation Method B, gradient: 15-42%) to give the title compound (40 mg, 11%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 25 Calculated value for N6O: 377.2084, Measured value: 377.2078. 1H NMR(300MHz,DMSO-d6)δ ppm 1.40-1.56(2H,m)1.88(2H,t)2.07-2.22(2H,m)2.25(6H,d)4.15-4.42(2H,m)6.26(1H,td)6.44(1 H,d)6.52(1H,d)6.64(1H,d)6.91(1H,d)7.39(1H,dd)7.47(1H,ddd)7.56-7.64(2H,m)7.92(1H,d).

[0720] Example 3 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 3

[0721] [ka] According to GM2, 2,5-dichloropyrazine (CAS registrar no. 19745-07-4) (100 mg, 0.67 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (363 mg, 1.34 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (452 ​​mg, 0.54 mmol), and CsCO (656 mg, 2.01 mmol) were reacted in 1,4-dioxane (5 mL) at 100 °C for 18 hours. Purification by aqueous workup and preparative HPLC (Preparation Method B, 25-55% gradient) afforded the title compound (20 mg, 8%) as a white solid. HRMS (ESI) m / z [M+H] + C 19 H 20 Calculated for ClNO: 383.1382, Found: 383.1396. 1H NMR(300MHz,DMSO-d6)δ ppm 1.51(1H,br d),1.89(2H,t),2.08-2.20(2H,m),4.07-4.51(2H,m),6.28(1H,t),6.46(1H,s),6.53(1H ,d),6.95(1H,d),7.38-7.51(3H,m),7.61(1H,dd),7.73(1H,d),7.93(1H,d),8.04(1H,d).

[0722] Example 4 6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 4

[0723] [ka] In a variation of GM2, 2-bromo-5-methylpyrazine (CAS Registry Number 98006-90-7) (0.026 g, 0.15 mmol) was transferred to a vial and placed in the glove box. Sodium tert-butoxide (0.072 g, 0.75 mmol) was added, followed by 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (0.057 g, 0.15 mmol), tBuXPhos Pd G3 (CAS Registry Number 1447963-75-8) (0.012 g, 0.02 mmol), and tBuXPhos (CAS Registry Number 564483-19-8) (3.2 mg, 7.5 μmol) as a solution in DMA (1 mL) in a glovebox, and the mixture was stirred at 65 °C for 24 h. After cooling to room temperature, the reaction mixture was concentrated, redissolved in DMSO, and purified by preparative HPLC to give the title compound (6.6 mg, 12%). HRMS (ESI) m / z [M+H] + C 20 H 22 Calculated value for N6O: 363.1933, Measured value: 363.1935. 1H NMR(600MHz,DMSO-d6)δ ppm 1.43-1.55(2H,m),1.88(2H,t),2.11-2.19(2H,m),2.24(3H,),4.26(1H,q),4.33(1H,p),6.27(1H,td),6.45(1H,d t),6.53(1H,d),6.87(1H,d),6.94(1H,d),7.40(1H,dd),7.48(1H,ddd),7.61(1H,dd),7.82(2H,dd),7.93(1H,d).

[0724] Example 5 5-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)pyrazine-2-carbonitrile - Compound 5

[0725] [ka] According to GM1A, 5-chloropyrazine-2-carbonitrile (CAS reg. no. 36070-75-4) (62 mg, 0.44 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (100 mg, 0.37 mmol), and TEA (155 μL, 1.11 mmol) were reacted in DMSO (5 mL) at 110 °C for 18 hours. Non-aqueous workup and purification by preparative HPLC (Preparation Method A, gradient: 25-50%) afforded the title compound (47 mg, 34%) as a yellow solid. HRMS (ESI) m / z [M+H] + C 20 H 19 Calculated value for N7O: 374.1724, Measured value: 374.1726. 1H NMR(400MHz,DMSO-d6)δ ppm 1.59-1.49(2H,m),1.93(2H,t),2.23-2.13(2H,m),4.36(2H,q),6.28(1H,td),6.45(1H,dt),6.53(1H,d), 6.98(1H,d),7.41(1H,dd),7.48(1H,ddd),7.63-7.58(1H,m),7.98-7.92(2H,m),8.36(1H,d),8.48(1H,d).

[0726] Example 6 6'-(((1S,3S)-3-((5-acetylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 6

[0727] [ka] According to GM1A, 1-(5-chloropyrazin-2-yl)ethan-1-one (CAS Registry Number 160252-31-3) (70 mg, 0.44 mmol), 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (100 mg, 0.37 mmol), and Na2CO3 (118 mg, 1.11 mmol) were reacted in DMSO (5 mL) at 100 °C for 18 hours. Aqueous workup and purification by preparative HPLC (Preparation Method C, gradient: 1-39%) afforded the title compound (38 mg, 26%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value for N6O2: 391.1876, Measured value: 391.1868. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.56(2H,d),1.94(2H,t),2.19(2H,dd),2.46(3H,s),4.49-4.33(2H,m),6.49(2H,dd) ,6.96(1H,d),7.52-7.37(2H,m),7.60(1H,dd),7.94(2H,d),8.14(1H,d),8.55(1H,d).

[0728] Example 7 6'-(((1S,3S))-3-((5-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 7

[0729] [ka] According to GM2, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (130 mg, 0.48 mmol), 2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazine (CAS reg. no. 1217090-32-8) (153 mg, 0.72 mmol), Pd-PEPPSI-I pentoxide (I-1c) were used. 2-Methylpyridine (20 mg, 0.02 mmol) and CsCO (783 mg, 2.40 mmol) were reacted in 1,4-dioxane (10 mL) at 100 °C for 15 h, and the reaction mixture was purified by non-aqueous workup and preparative TLC (MeOH:DCM = 1:10) followed by preparative HPLC (Preparation Method E, gradient: 2-19%) to give the title compound (40 mg, 21%) as a white solid. HRMS (ESI) m / z [M+H] + C 22 H 24 Calculated value for N7O: 402.2036, Measured value: 402.2022. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.51(2H,td),1.91(2H,t),2.18(2H,td),3.73(3H,s),4.34(2H,d),6.18-6.33(2H,m),6.45(1H ,d),6.54(1H,d),6.62(1H,d),6.97(1H,d),7.36-7.55(3H,m),7.55-7.72(2H,m,),7.92(1H,d).

[0730] Example 8 6'-(((1S,3S)-3-((5-methyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 8

[0731] [ka] Prepared in the same manner as in Example 7 from 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (130 mg, 0.48 mmol) and 3-chloro-5-methyl-5H-pyrrolo[2,3-b]pyrazine (CAS Registry Number 1111638-11-9) (121 mg, 0.72 mmol), and purified by preparative TLC (MeOH:DCM = 1:10) followed by preparative HPLC (Preparation Method E, gradient: 2-19%) to give a pale yellow solid (24 mg, 12%). HRMS (ESI) m / z [M+H] + C 22 H 24 Calculated value for N7O: 402.2036, measured value: 402.2014. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.55(2H,dd),1.97(2H,dq),2.08-2.32(2H,m),3.66(3H,s),4.37(2H,q),6.27(1H,td),6.34(1H,d),6.46(1H, t),6.54(1H,d),6.96(2H,t),7.19(1H),7.41(1H,dd),7.48(1H,ddd),7.61(1H,dd),7.77(1H,s),7.93(1H,d).

[0732] Example 9 6'-(((1S,3S)-3-((1-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one - Compound 9

[0733] [ka] The compound i-34a was prepared in the same manner as in Example 7 from 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (100 mg, 0.37 mmol) and 6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyrazine compound i-34a (118 mg, 0.55 mmol). The compound was purified by preparative TLC (MeOH:DCM=1:10) followed by preparative HPLC (Preparation Method E, gradient: 3-25%) to give a white solid (11 mg, 7%). HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value for N8O: 403.1990, measured value: 403.1960. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.42-1.74(2H,m),1.99(2H,q),2.23(2H,dd),3.84(3H,s),4.40(2H,dt),6.28(1H,td),6.40-6.51 (1H,m),6.55(1H,d),7.00(1H,d),7.29-7.53(2H,m),7.61(1H,dd),7.84(1H,d),7.89-8.00(3H,m).

[0734] Example 11 1-(6-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one - Compound 11

[0735] [ka] According to GM2, 5-chloro-2,3-dimethylpyrazine (77 mg, 0.54 mmol), 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one compound i-2b (100 mg, 0.18 mmol), Pd-PEPPSI-I pentCl 2-Methylpyridine (12 mg, 0.01 mmol) and CsCO (292 mg, 0.90 mmol) were reacted in 1,4-dioxane (3 mL) at 100 °C for 18 h, followed by non-aqueous workup (filter cake washed with DCM) and preparative TLC (7 M NH in MeOH:DCM = 1:20), followed by preparative HPLC (Preparation Method C, gradient: 27-57%) to give the title compound (25 mg, 32%) as a white solid. HRMS (ESI) m / z [M+H] + C 24 H 28 Calculated value for N7O: 430.2350, Measured value: 430.2356. 1 H NMR(300MHz,DMSO-d6)δ ppm1.41-1.60(2H,m)1.90(2H,t)2.10-2.23(2H,m)2.27(6H,d)3.39(3H,s)4.20-4.44(2H,m)6.61(1H,d)6.67(1H, d)6.85-6.91(1H,m)6.97(1H,d)7.04(1H,td)7.12(1H,td)7.20-7.25(1H,m)7.46(1H,dd)7.63(1H,s)8.05(1H,d).

[0736] Example 12 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one - Compound 12

[0737] [ka] In the same manner as in Example 11, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one 2HCl was prepared from compound i-3b (150 mg, 0.40 mmol) and 5-chloro-2,3-dimethylpyrazine (CAS Registry Number 59489-32-6) (115 mg, 0.80 mmol) by preparative HPLC (Preparation Method C, gradient: 14-44%) to give a white solid (69 mg, 42%). HRMS (ESI) m / z [M+H] + C 22 H 27 Calculated value for N6O2: 407.2190, Measured value: 407.2186. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.48(2H,m)1.88(2H,t)2.09-2.21(2H,m)2.26(6H,d)3.73(3H,s)4.29(2H,m)6.20(1H,t)6.53(1H,br d)6.67(1H,br d)6.86(1H,br d)6.93(1H,br d)7.16(1H,br d)7.38(1H,dd)7.62(1H,s)7.91(1H,d).

[0738] Example 13 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one - Compound 13

[0739] [ka] In analogy to Example 11, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one 2HCl was prepared from compound i-3b (150 mg, 0.40 mmol) and 2,5-dichloropyrazine (239 mg, 1.61 mmol) and subjected to preparative HPLC (preparation method A, gradient 40-50%) to give a white solid (33 mg, 20%). HRMS (ESI) m / z [M+H]+C 20 H 22Calculated for ClN6O2: 413.1488, Found: 413.1482. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.24(2H,br s),1.89(2H,br t),2.16(2H,br s),3.73(3H,s),4.13-4.48(2H,m),6.20(1H,s),6.53(1H,d),6.87-6.89(1H,m),6.93-6 .95(1H,m),7.16-7.19(1H,m),7.36-7.44(2H,m),7.73(1H,s),7.92(1H,s),8.04(1H,s).

[0740] Example 14 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid - Compound 14

[0741] [ka] NaOH (30 mg, 0.75 mmol) was added to methyl 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate Compound i-4e (65 mg, 0.15 mmol) in a mixture of MeOH (6 mL) and water (2 mL) at 25 °C, and the resulting solution was stirred at this temperature for 1 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC (Preparation Method E, gradient: 8-17%) to give the title compound (14 mg, 19%) as a white solid. HRMS (ESI) m / z [M+H] + C 22 H 25 Calculated value for N6O3: 421.1982, Measured value: 421.1996. 1H NMR(400MHz,DMSO-d6)δ ppm 1.41-1.57(2H,m),1.88(2H,t),2.1-2.22(2H,m),2.26(6H,d),4.15-4.42(2H,m),6.52(2H,dd) ,6.68(1H,d),7.01(1H,d),7.44(1H,dd),7.62(1H,s),7.85(1H,dd),7.99(1H,d),8.16(1H,d).

[0742] Example 15 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one - Compound 15

[0743] [ka] According to GM3, (1S,3S)-N 1 -(5,6-dimethylpyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine Compound i-5c (100 mg, 0.24 mmol), 5-methoxypyridin-2(1H)-one (CAS Registry Number 61941-79-5) (153 mg, 1.22 mmol), Cu(I)I (47 mg, 0.24 mmol), CsCO (239 mg, 0.73 mmol), and rel-(1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (35 mg, 0.24 mmol) was reacted in 1,4-dioxane (5 mL) at 100 °C for 18 h, followed by aqueous workup and preparative TLC (DCM: 7M NH3 in MeOH = 20:1) followed by preparative HPLC (Preparation Method B, gradient: 21-51%) to give the title compound (45 mg, 45%) as a white solid. HRMS (ESI) m / z [M+H] + C 22 H 27 Calculated value for N6O2: 407.2190, Measured value: 407.2166. 1H NMR(300MHz,DMSO-d6)δ ppm 1.39-1.58(2H,m),1.81-1.97(2H,m),2.08-2.21(2H,m),2.26(6H,d),3.64(3H,s),4.16-4.40(2H,m),6.4 3(1H,d),6.53(1H,d),6.68(1H,d),6.92(1H,d),7.19(1H,d),7.32-7.45(2H,m),7.62(1H,s),7.97(1H,d).

[0744] [Table 19]

[0745] Example 20 1-(6-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one - Compound 20

[0746] [ka] According to GM2, 1-(6-chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one compound i-6a (100 mg, 0.39 mmol), (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)cyclopentane-1,3-diamine 5TFA compound i-5b (452 ​​mg, 0.58 mmol), CsCO (632 mg, 1.94 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (16 mg, 0.02 mmol) were reacted in 1,4-dioxane (10 mL) at 100 °C for 15 h. The resulting mixture was purified by aqueous workup and preparative TLC (7 M NH in MeOH:DCM = 1:40) followed by preparative HPLC (Preparation Method B, gradient: 24-42%) to give the title compound (100 mg, 60%) as a white solid. HRMS (ESI) m / z [M+H] + C 24 H 26 Calculated value for N7O: 428.2194, Measured value: 428.2178. 1H NMR(300MHz,DMSO-d6)δ ppm 1.39-1.63(2H,m),1.91(2H,t),2.11-2.22(2H,m),2.26(6H,d),4.19-4.45(2H,m),6.58(1H,d),6.69(1H,d),6 .76(1H,d),6.85(1H,d),7.15-7.39(2H,m),7.63(1H,s),7.79(1H,d),8.04(1H,d),8.21(1H,dd),8.44(1H,dd).

[0747] Example 21 3-(6-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one - Compound 21

[0748] [ka] In a manner similar to that of Example 20, 3-(6-chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-24a (90 mg, 0.35 mmol) and (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)cyclopentane-1,3-diamine 5TFA was prepared from compound i-5b (291 mg, 0.38 mmol) and purified by preparative TLC (7 M NH in MeOH:DCM = 1:25) followed by preparative HPLC (Preparation Method C, gradient: 24-42%) to give a white solid (65 mg, 43%). HRMS (ESI) m / z [M+H] + C 23 H 27 Calculated value for N8O: 431.2302, Measured value: 431.2272. 1H NMR(300MHz,DMSO-d6)δ ppm 1.40-1.61(2H,m),1.87-1.93(2H,m),2.11-2.21(2H,m),2.26(6H,d),3.41(3H,s),4.20-4.43(2H,m),6.59(1H,d) ,6.72(1H,d),6.93(1H,d),7.11-7.18(1H,m),7.50(1H,dd),7.58(1H,dd),7.63(1H,s),7.94(1H,dd),8.09(1H,d).

[0749] Example 22 3-(6-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-methylimidazolidine-2,4-dione - Compound 22

[0750] [ka] In a manner similar to that of Example 20, 3-(6-chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione compound i-7b (100 mg, 0.44 mmol) and (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)cyclopentane-1,3-diamine 5TFA was prepared from compound i-5b (438 mg, 0.58 mmol) and purified by preparative TLC (7 M NH3 in MeOH:DCM = 1:20) followed by preparative HPLC (Preparation Method C, gradient: 17-35%) to give a white solid (15 mg, 8%). HRMS (ESI) m / z [M+H] + C 20 H 26 Calculated value for N7O2: 396.2142, Measured value: 396.2134. 1H NMR(300MHz,DMSO-d6)δ ppm 1.41-1.54(2H,m),1.87(2H,t),2.10-2.20(2H,m),2.26(6H,d),2.91(3H,s),4.08(2H,s),4.20-4 .36(2H,m),6.52(1H,d),6.67(1H,d),6.84-7.04(1H,m),7.28(1H,dd),7.62(1H,s),7.85(1H,d).

[0751] Example 23 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile - Compound 23

[0752] [ka] In a manner similar to Example 20, 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile compound i-10a (120 mg, 0.52 mmol) and (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)cyclopentane-1,3-diamine 5TFA was prepared from compound i-5b (804 mg, 1.04 mmol) and subjected to preparative TLC (7M NH in MeOH:DCM = 1:22), followed by a second run of preparative TLC (EtOAc), and further purified using preparative HPLC (Preparation Method C, gradient: 20-40%) to give the title compound (5 mg, 2%) as a yellow solid. HRMS (ESI) m / z [M+H] + C 22 H 24 Calculated value for N7O: 402.2036, Measured value: 402.2054. 1H NMR(300MHz,DMSO-d6)δ ppm 1.41-1.58(2H,m),1.88(2H,m),2.07-2.22(2H,m),2.26(6H,s),4.30(2H,m),6.43-6.58(2H,m ),6.68(1H,d),7.06(1H,d),7.46(1H,m),7.62(1H,s),7.99(1H,d),8.06(1H,m),8.23(1H,m).

[0753] Example 24 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one - Compound 24

[0754] [ka] According to GM1A, 6'-(((1S,3S)-3-aminocyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one 3HCl compound i-15b (300 mg, 0.76 mmol), 2,5-dichloropyrazine (227 mg, 1.52 mmol), and Na2CO3 (242 mg, 2.29 mmol) were reacted in DMSO (3 mL) at 120 °C for 6 h. The resulting mixture was purified by aqueous workup and preparative TLC (MeOH:DCM = 1:20) followed by preparative HPLC (Preparation Method B, gradient: 31-61%) to give the title compound (75 mg, 25%) as a white solid. HRMS (ESI) m / z [M+H] + C 20 H 22 Calculated for ClNO: 397.1538, Found: 397.1510. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.51(2H,br s),1.89(2H,br t),2.02(3H,s),2.11-2.22(2H,m),4.25(1H,br d),4.34(1H,br d),6.20(1H,t),6.52(1H,d),6.93(1H,br d),7.35-7.47(4H,m),7.73(1H,s),7.90-7.94(1H,m),8.04(1H,s).

[0755] Example 25 2-(6-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one - Compound 25

[0756] [ka] In the same manner as in Example 24, 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one compound i-16b (141 mg, 0.52 mmol) and 2,5-dichloropyrazine (155 mg, 1.04 mmol) were prepared at 120° C. for 16 hours. The crude product was purified by preparative TLC (NH in MeOH (7 M):DCM=1:20) followed by preparative HPLC (Preparation Method B, gradient: 25-55%) to give the title compound (34 mg, 17%) as a yellow solid. HRMS (ESI) m / z [M+H] + C 18 H 19 Calculated for ClNO: 384.1334, Found: 384.1300. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.39-1.58(m,2H),1.88(t,2H),2.08-2.24(m,2H),4.28(dq,2H),6.43-6.58(m,1H) ,6.88-7.07(m,2H),7.32-7.56(m,3H),7.71(d,1H),7.93-8.04(m,2H),8.10(d,1H).

[0757] Example 26 1-(6-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-methylimidazolidine-2,4-dione - Compound 26

[0758] [ka] According to GM3, (1S,3S)-N 1-(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-17b (100 mg, 0.24 mmol), 3-methylimidazolidine-2,4-dione (CAS reg. no. 6843-45-4) (137 mg, 1.20 mmol), Cu(I)I (46 mg, 0.24 mmol), Cs2CO3 (235 mg, 0.72 mmol), and rel-(1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (34 mg, 0.24 mmol) was reacted in 1,4-dioxane (3 mL) at 100 °C for 15 h, followed by nonaqueous workup and preparative TLC (7 M NH3 in MeOH:DCM = 1:20, 161 mg of material isolated), followed by preparative HPLC (Preparation Method B, gradient: 27-57%) to give the title compound (50 mg, 52%) as a white solid. HRMS (ESI) m / z [M+H] + C 18 H 21 Calculated for ClN7O2: 402.1440, Found: 402.1410. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.49(2H,br s),1.87(2H,br t),2.07-2.18(2H,m),2.92(3H,s),4.25(2H,br d),4.38(2H,s),6.50(1H,br d),6.62(1H,br d),7.39(1H,br d),7.64(1H,br d),7.73(1H,s),8.04(1H,s),8.10(1H,br s).

[0759] [Table 20-1]

[0760] [Table 20-2]

[0761] Example 33 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid - Compound 33

[0762] [ka] NaOH (41.2 mg, 1.03 mmol) was added to methyl 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate Compound i-18a (91 mg, 0.21 mmol) in a mixture of MeOH (6 mL) and water (2 mL) at 20 °C, and the resulting solution was stirred at this temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (10 mL). The solvent was adjus...

Claims

1. Compounds of formula (I) A-B-C (I) or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof, wherein A is: 【Chemical 1】 where the wavy line indicates the point of attachment to B; X １ But, C-R Ａ１ and R Ａ１ but, (i) H, (ii) halo, (iii) CN, (iv) one or more of OH, CN, C １～６ Acyl, C １～６ C optionally substituted with alkoxy or one or more halo groups; １～６ hydrocarbons, (v) OH, one or more halo groups, C １～６ C optionally substituted with alkylamide １～６ Alkoxy, (vi) C １～６ Alkyl esters, (vii) C １～６ alkyl acyls, and (viii) selected from the group consisting of OH; R Ａ２ but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C １～６ Acyl, C １～６ C optionally substituted with alkoxy or one or more halo groups; １～６ hydrocarbons, (v) C optionally substituted with OH, alkylamido, or one or more halo groups. １～６ Alkoxy, (vi) C １～６ acylamides (wherein acyl is optionally substituted by H or methyl); (vii) C １～６ C optionally substituted with alkyl esters １～６ thioalkyl, (viii) C １～６ Alkyl esters, (ix) C １～６ alkyl acyls, (x) C ４～５ heterocyclyl, (xi) C ５ heteroaryl, (xii) C １～３ Alkylamide, CN, OH, C ２～３ Alkynyl, C ４～６ Heterocyclyl or C １～３ C optionally substituted with alkyl １～６ Alkylamides, wherein the C １～３ C, wherein the alkyl is optionally substituted with one or more halo or OH groups; １～６ Alkylamides, and (xiii) selected from the group consisting of OH; R Ａ３ but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C １～６ Thioalkyl, C １～６ Alkoxy, C １～６ Alkyl acyl, C １～６ Acyloxy, carboxy, C １～６ Alkyl esters, C １～６ Alkylamino, —C(═O)NH ２ , C １～６ Alkylamide, C １～６ Alkyl acylamido, C １～６ Alkylsulfinyl, C １～６ C optionally substituted with alkylsulfonyl or one or more halo groups; １～６ hydrocarbons, (v) OH, (vi) OH, NH ２ , C ４ C optionally substituted by heterocyclyl or one or more halo groups; １～６ Alkoxy, (vii) C １～６ acyloxy, (viii) C ４ heterocyclyl, (ix)-NH ２ 、 (x) CN, OH or C ４ C optionally substituted by heterocyclyl １～６ alkylamino, (xi) -NH ２ C optionally substituted by １～６ Dialkylamino, (xii) C １～６ acylamides (wherein the acyl substituent is H or Me); (xiii) carbimidoyl or methyl-carbimidoyl, (xiv) carboxyamino, (xv) OH or NH ２ C optionally substituted by １～６ thioalkyl, (xvi) C １～６ alkylsulfinyl, (xvi) C optionally substituted with one or more halo groups; １～６ alkylsulfonyl, (xvii) C １～６ sulfonimodil, (xviii) C １～６ alkylphosphinyl, (xix) carboxy, (xx)C(=O)NH ２ 、 (xxi) C １～６ Alkyl esters, (xxii) C optionally substituted with one or more halo groups; １～６ alkyl acyls, and (xxiii) C １～６ alkylamides; or R Ａ３ and R Ａ２ together with the carbon atoms to which they are attached, (i) optionally substituted C ５～７ heterocycles, (ii) optionally substituted C ５～７ heteroaromatic rings, (iii) optionally substituted C ６ carbon aromatic rings, (iv) optionally substituted C ５～７ forming a carbocyclic ring, The optional substituents are C １～６ Alkyl, halo, C １～６ Alkoxy, NH ２ , C １～６ selected from alkylamino, OH, and CN; B is of formula (B-1) or (B-2), i) 【Chemistry 2】 where the wavy lines indicate the points of attachment to A and C; R Ｂ１ is H, OH, =CHCH ２ —OH, —O—C １～４ Alkyl or C １～４ alkyl, １～４ alkyl is optionally substituted by OH or OMe; (ii) 【Chemistry 3】 where the wavy lines indicate the points of attachment to A and C; R Ｂ２ But C １～２ Alkyl-OH, CH ２ CONHMe or C １～３ is alkyl, C is C ６～１０ Carboaryl, C ５～６ Heteroaryl and C ５～１０ heterocyclyl, wherein these groups are selected from the group consisting of: (i) C ６～１０ Carboaryl, C ４～１０ Carbocyclyl, C ５～１０ Heteroaryl, C ４～１０ heterocyclyl, or C ５～１０ Bridged heterocycle, spiro C ６～１２ Heterocyclyl or spiro C ６～１２ Carbocyclyl (These are themselves the following groups: a) one or two =O groups, b) one or more halo groups; c)CN、NH ２ 、OH、 d) including branched and cyclic, OH, C １～６ one or more C groups optionally substituted with alkylsulfonyl or one or more halo groups; １～６ alkyl groups, e) C with optional substitution of one or more halo groups １～６ Alkoxy, f) C １～６ Alkyl esters, g) C with optional methyl, OH or ═O substituents ５～６ heterocyclyl, h) C optionally substituted with methyl ５～６ heteroaryl, i) C with optional methyl or ═O substituents ４～１０ carbocyclyl, j) C, having optional substitution of one or more halo groups ６～１０ Carboaryl, ,)@(=O)Me ２ 、 m) carboxy or CH ２ -carboxy, n) tetrazolyl, CH ２ -tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl), (ii) Carboxy, CN, halo, nitro, C １～６ Alkyl, C １～６ Thioalkyl, C １～６ Alkoxy, C １～６ Alkyl acyl, C １～６ Alkylamide, di-C １～６ Alkylamide, C １～６ Alkyl sulfonamides, and di-C １～６ A compound of formula (I) or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof, optionally substituted with one or more groups selected from alkylsulfonamides.

2. R Ａ１ but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C １～６ Acyl, C １～６ C optionally substituted with alkoxy or one or more halo groups; １～６ hydrocarbons, (v) OH, one or more halo groups, C １～６ C optionally substituted with alkylamide １～６ alkoxy, or (vi) OH, or a pharmaceutically acceptable salt thereof.

3. R Ａ１ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is H or OH.

4. R Ａ２ but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C １～６ Acyl, C １～６ C optionally substituted with alkoxy or one or more halo groups; １～６ hydrocarbons, (v) OH, (vi) OH, C １～６ alkylamide, or C optionally substituted with one or more halo groups; １～６ Alkoxy, (vii) C １～６ Alkyl esters, (viii) C １～６ alkyl acyls, (ix) C １～３ Alkylamide, C-N-C ２～３ Alkynyl, C ４～６ heterocyclyl, or C １～３ C optionally substituted with alkyl １～６ Alkylamides, wherein the alkyl is optionally substituted with one or more halo or OH groups; １～６ Alkylamides, and (x) C １～６ C optionally substituted with alkyl esters １～６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of thioalkyl.

5. R Ａ２ CN, methyl, Cl, -C(=O)CH ３ , OCHF ２ , cyclopropyl, OCF ３ , OCH ３ , H, -C(=O)NH(CH ３ ), S-CH ３ , -S-CH ２ CH ３ or -S-CH ２ -C(=O)-O-CH ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

6. R Ａ３ but, (i) H, (ii) halo, (iii) CN, (iv) OH, CN, C １～６ Thioalkyl, C １～６ Alkoxy, C １～６ Alkyl acyl, C １～６ Acyloxy, carboxy, C １～６ Alkyl esters, C １～６ Alkylamino, —C(═O)NH ２ , C １～６ Alkylamide, C １～６ Alkyl acylamido, C １～６ Alkylsulfinyl, C １～６ alkylsulfonyl, or C optionally substituted with one or more halo groups; １～６ hydrocarbons, (v) OH, and (vi) OH, NH ２ , C ４ C optionally substituted by heterocyclyl or one or more halo groups; １～６ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkoxy.

7. R Ａ３ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of H, CN and methyl.

8. R Ａ３ and R Ａ２ together with the carbon atom to which they are attached, optionally substituted C ６ Carbocyclic aromatic ring or C ５ Forms a heteroaromatic ring, and the optional substituents are methyl, NH ２ 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Cl, F and OMe.

9. B is represented by formula (B-1), 【Chemistry 4】 where the wavy lines indicate the points of attachment to A and C; R Ｂ１ is H, OH, OMe, —O-ethyl, —CH ２ OH, -CH ２ CH ２ OH and =CHCH ２ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of -OH.

10. B is represented by the following formula (B-1a): 【Chemistry 5】 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which is

11. 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 are selected from the following groups: a) one or two =O groups, b) one or more halo groups; c) CN, NH ２ Or OH, d) including branched and cyclic, OH, C １～６ one or more C with optional substituents selected from alkylsulfonyl or one or more halo groups; １～６ alkyl groups, e) C with optional substitution of one or more halo groups １～６ Alkoxy, f) C １～６ Alkyl esters, g) C with optional methyl, OH or ═O substituents ５～６ heterocyclyl, h) C with optional methyl substituents ５～６ heteroaryl, i) C with optional methyl or ═O substituents ４～１０ carbocyclyl, j) C, having optional substitution of one or more halo groups ６～１０ Carboaryl, ,)@(=O)Me ２ 、 m) carboxy or CH ２ -carboxy, and / or n) tetrazolyl, CH ２ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, optionally substituted by one or more of: -tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

12. C is of formula (C-1), 【Chemistry 6】 In the formula, D is C ６～１０ Carboaryl, C ５～１０ Heteroaryl or C ５～１０ heterocyclyl, each of which is itself i) one or two =O groups; ii) S(=O) ２ CH ３ one or two optionally branched C １～４ alkyl groups, iii) OMe; iv) piperazinyl optionally substituted with methyl; v) C(=O)OH (carboxy); vi) Cl, vii) F, viii) phenyl optionally substituted with one or more fluoro; ix) CN, x)CF ３ 、 x)) ３ 、 x))) ２ 、 xiii) pyrazolyl, triazolyl, tetrazolyl optionally substituted by methyl; xiv)NH ２ 、 xv) pyridinyl, xvi)CH ２ OH、 xvii) OH, or xviii) P(=O)Me ２ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, optionally substituted by:

13. D is represented by formula (D-1), 【Chemistry 7】 In the formula, R Ｄ１ , R Ｄ２ , R Ｄ３ and R Ｄ４ One or two of the i) C １～６ C optionally substituted with alkylsulfonyl or one or more halo groups; １～６ Alkyl, ii) optionally substituted with one or more halo groups; １～６ Alkoxy, iii) the C group has an optional methyl substituent; ５～６ Heterocyclyl or C ５～６ heteroaryl, iv) carboxy or CH ２ -carboxy, v)=O, halo, NH ２ Or CN, vi) phenyl optionally substituted with one or more halo atoms; The remainder is H, or R Ｄ３ and R Ｄ４ form an optionally substituted 6-membered carboaromatic, heterocyclic or heteroaromatic ring, the optional substituents being selected from OH, methyl, OMe, halo and C(═O)OH; or or R Ｄ１ , R Ｄ２ , R Ｄ３ and R Ｄ４ are all H, or a pharmaceutically acceptable salt thereof.

14. a) R Ｄ１ , R Ｄ２ , R Ｄ３ and R Ｄ４ is H, or b) R Ｄ３ is H; optionally substituted phenyl, wherein the optional substituents are halo, —S(═O) ２ CH ３ phenyl, methyl optionally substituted by OMe, C(═O)OH, Cl, CN; or piperazinyl optionally substituted by methyl, or pyrazolyl, triazolyl or tetrazolyl optionally substituted by methyl, wherein R Ｄ１ , R Ｄ２ , and R Ｄ４ are all H, or c) R Ｄ１ H, methyl, OMe, Cl, CF ３ , OCF ３ , pyrazolyl, triazolyl and CN optionally substituted by methyl; R Ｄ２ , R Ｄ３ , and R Ｄ４ are all H, or d) R Ｄ３ and R Ｄ４ The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein: forms an unsubstituted benzene ring or an unsubstituted pyridine ring.

15. D is represented by formula (D-2), 【Chemistry 8】 In the formula, X Ｄ But NR Ｄ５ａ or CR Ｄ５ａ R Ｄ５ｂ and R Ｄ５ａ is selected from H or methyl; R Ｄ５ｂ and R Ｄ６ｂ are both H or together form -CH ２ - 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 Together, CN, P(=O)Me ２ or a benzene ring or C optionally substituted by carboxy ６ form a heteroaromatic ring, R Ｄ６ｂ and R Ｄ７ｂ 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein:

16. 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein D is selected from the following group: 【Table 1-1】 【Table 1-2】

17. C is of formula (C-2), 【Chemistry 9】 In the formula, R Ｃ７ , R Ｃ８ , R Ｃ９ and R Ｃ１０ One of them is S(=O) ２ CH ３ Methyl optionally substituted with; OMe; piperazinyl optionally substituted with methyl; C(=O)OH (carboxy); Cl; F; pyrazolyl optionally substituted with methyl; triazolyl; tetrazole; optionally substituted phenyl (the optional substituents are methyl or halo); CN; CF ３ ; 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 benzene or 6-membered heteroaromatic ring, 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 11, or a pharmaceutically acceptable salt thereof, wherein all of are H.

18. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of: 【Table 2-1】 【Table 2-2】

19. ABC is of formula (IA), (IB), (I-Ba), (I-Bb), (IC), or (ID), 【Chemistry 10】 【Chemistry 11】 In the formula, X １ , R Ａ２ , R Ａ３ , C., D., R. Ｄ１ , R Ｄ２ , R Ｄ３ , R Ｄ４ , R Ｄ１ａ , R Ｄ２ａ , R Ｄ３ａ , R Ｄ４ａ , X Ｄ , R Ｄ６ａ , R Ｄ６ｂ , R Ｄ７ａ and R Ｄ７ｂ 19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. A compound of Table 1 or Table 2 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. 45. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 44, 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 dementia, 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 i) statins, ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors; iv) P2Y12 inhibitors; v) a citrate lyase inhibitor, and vi) the compound or a pharmaceutically acceptable salt thereof for use according to claim 23, administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of antihypertensive agents.

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