PCSK9 inhibitors and methods of use thereof

Abstract

A compound having the formula (I): A-B-C, wherein A has the following formula (II): wherein X1 is C-RA1; b has the formula (B-1) or (B-2) and C is selected from the group consisting of optionally substituted C6-10 carbon aryl groups, C5-6 heteroaryl groups and C5-10 heterocyclyl groups, and their use as PCSK9 inhibitors. # imgabs0 #

Description

[0001] The present disclosure relates to compounds that inhibit PCSK9 and their use in methods of treatment. This application claims the priority benefits of U.S. Application No. 63 / 376,791, filed on September 23, 2022, U.S. Application No. 63 / 483,797, filed on February 8, 2023, Pakistani Application No. 581 / 2023, filed on August 31, 2023, and U.S. Application No. 63 / 580,507, filed on September 5, 2023, the entire contents of which are incorporated herein by reference. Background Art

[0002] PCSK9, also known as "proprotein convertase subtilisin / kexin type 9", is a member of the subtilisin / kexin family of proprotein convertases and plays an important role in cholesterol metabolism. PCSK9 increases the level of circulating low-density lipoprotein cholesterol (LDL-C) by enhancing the degradation of LDLR without relying on its catalytic activity. Secreted PCSK9 binds to epidermal growth factor domain A (EGFA) of the low-density lipoprotein receptor (LDLR) at the cell surface, and the PCSK9 / LDLR complex is internalized into the endosomal / lysosomal compartment. The enhanced binding affinity of PCSK9 to LDLR at the acidic pH of late endosomes / lysosomes reduces LDLR recycling and instead targets LDLR for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduced incidence of adverse cardiovascular events.

[0003] For cardiovascular diseases, there are few options for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and primary human hepatocytes through increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since elevated PCSK9 levels reduce the abundance of LDLR on the cell surface, increasing statin doses fails to achieve a proportional reduction in LDL-C.

[0004] Two monoclonal antibodies (mAbs), alirocumab and evolocumab, which selectively bind to extracellular PCSK9 and prevent its interaction with LDLR, have recently been approved by the FDA for reducing LDL-C levels. In clinical trials, alirocumab showed a reduction in LDL levels of approximately 50% compared to placebo (Elbitar 2016). Patients taking evolocumab showed a reduction in LDL levels of approximately 60%-75%. The efficacy of these drugs demonstrates the potential of PCSK9 inhibitors as an effective treatment for those patients with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and may cause allergic reactions or other harmful immune responses in the body.

[0005] Unlike an infection that may occur accidentally, cardiovascular diseases generally require management throughout a person's life. Therefore, ease of administration becomes an important factor for patients to maintain compliance with drug treatment. There is a need for PCSK9 inhibitors with increased efficacy and easier administration that can be achieved with small molecule PCSK9 inhibitors.

[0006] WO 2020 / 150473 A2 relates to heteroaryl compounds and their pharmaceutical formulations. It also relates to methods of using the novel heterocyclic compounds for treating or preventing cardiovascular diseases, as well as methods of treating sepsis or septic shock.

[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 provides a compound having formula (I):

[0009] A - B - C (I)

[0010] or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof,

[0011] wherein A has the following formula:

[0012]

[0013] wherein the wavy line indicates the point of attachment to B;

[0014] X 1 is C - R A1 ;

[0015] R A1 is selected from the group consisting of:

[0016] (i) H;

[0017] (ii) a halogenated group;

[0018] (iii) CN;

[0019] (iv) C 1-6 hydrocarbon, which is optionally substituted by one or more OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogenated groups;

[0020] (v) C 1-6 alkoxy, which is optionally substituted by OH, one or more halogenated groups, C 1-6 alkylacylamino;

[0021] (vi) C 1-6 alkyl esters;

[0022] (vii) C 1-6 alkyl acyls; and

[0023] (viii) OH;

[0024] R A2 is selected from the group consisting of:

[0025] (i) H;

[0026] (ii) a halogenated group;

[0027] (iii) CN;

[0028] (iv) C 1-6 a hydrocarbon, optionally substituted by OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogenated groups;

[0029] (v) C 1-6 alkoxy, optionally substituted by OH, C 1-6 alkyl acylamino or one or more halogenated groups;

[0030] (vi) C 1-6 acyl acylamino (wherein the acyl is optionally substituted by H or methyl);

[0031] (vii) C 1-6 thioalkyl, optionally substituted by C 1-6 alkyl ester;

[0032] (viii) C 1-6 alkyl esters;

[0033] (ix) C 1-6 alkyl acyls;

[0034] (x) C 4-5 heterocyclic group;

[0035] (xi) C5 heteroaryl;

[0036] (xii) C 1-6 alkyl acylamino, optionally substituted by C 1-3 alkyl acylamino, CN, OH, C 2-3 alkynyl, C 4-6 heterocyclic group, C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogenated groups or OH groups; and

[0037] (xiii) OH;

[0038] R A3 is selected from the group consisting of:

[0039] (i) H;

[0040] (ii) a halogenated group;

[0041] (iii) CN;

[0042] (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 acyloxy, carboxyl, C 1-6 alkyl ester, C 1-6 alkylamino, -C(=O)NH2, C 1-6 alkylacylamino, C 1-6 alkylacylacylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or one or more halogenated group substituents;

[0043] (v) OH;

[0044] (vi) C 1-6 alkoxy, optionally substituted by OH, NH2, a C4 heterocyclic group or one or more halogenated group substituents;

[0045] (vii) C 1-6 acyloxy;

[0046] (viii) a C4 heterocyclic group;

[0047] (ix) NH2;

[0048] (x) C 1-6 alkylamino, optionally substituted by CN, OH, a C4 heterocyclic group;

[0049] (xi) C 1-6 dialkylamino, optionally substituted by -NH2;

[0050] (xii) C 1-6 acylacylamino (where the acyl substituent is H or Me);

[0051] (xiii) an amidino or methyl-amidino;

[0052] (xiv) carboxylamino;

[0053] (xv) C 1-6 thioalkyl, optionally substituted by OH or NH2;

[0054] (xvi) C 1-6 Alkylsulfinyl;

[0055] (xvii) C 1-6 Alkylsulfonyl, optionally substituted by one or more halo groups;

[0056] (xviii) C 1-6 Sulfinimido;

[0057] (xix) C 1-6 Alkylphosphinyl;

[0058] (xx) Carboxyl;

[0059] (xxi) C(=O)NH2

[0060] (xxii) C 1-6 Alkyl ester;

[0061] (xxiii) C 1-6 Alkylacyl, optionally substituted by one or more halo groups;

[0062] (xxiv) C 1-6 Alkylacylamino;

[0063] Or wherein R A3 and R A2 together with the carbon atom to which they are attached form:

[0064] (i) Optionally substituted C 5-7 Heterocycle;

[0065] (ii) Optionally substituted C 5-7 Heteroaromatic ring;

[0066] (iii) Optionally substituted C6 carbocyclic aromatic ring;

[0067] (iv) Optionally substituted C 5-7 Carbocycle

[0068] Wherein the optional substituent is selected from C 1-6 Alkyl, halo, C 1-6 Alkoxy, NH2, C 1-6 Alkylamino, OH and CN;

[0069] Wherein B has formula (B-1) or (B-2)

[0070] (i)

[0071]

[0072] Wherein the wavy line indicates the attachment points to A and C;

[0073] RB1 is H, OH, =CHCH2-OH, O-C 1-4 alkyl, C 1-4 alkyl, said C 1-4 alkyl is optionally substituted by OH or OMe;

[0074] (ii)

[0075]

[0076] wherein the wavy line indicates the attachment points to A and C;

[0077] R B2 is C 1-2 alkyl-OH, CH2CONHMe or C 1-3 alkyl;

[0078] wherein C is selected from the group consisting of C 6-10 carbaryl, C 5-6 heteroaryl and C 5-10 heterocyclic group, said groups being optionally substituted by:

[0079] (i) a group selected from C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[0080] which are themselves optionally substituted by one or more of the following groups;

[0081] a) one or two =O groups;

[0082] b) one or more halo groups;

[0083] c) CN, NH2, OH;

[0084] d) one or more C 1-6 alkyl groups, which include branched and cyclic and have optional substituents selected from OH, C 1-6 alkylsulfonyl or one or more halo groups;

[0085] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0086] f) C 1-6 alkyl ester;

[0087] g) C 5-6A heterocyclic group having an optional methyl, OH or ═O substituent;

[0088] h)C 5-6 A heteroaryl group optionally substituted with methyl;

[0089] i)C 4-10 A carbocyclic group having an optional methyl or ═O substituent;

[0090] j)C 6-10 A carbaryl group having an optional substituent of one or more halogenated groups;

[0091] l)P(═O)Me2;

[0092] m) A carboxyl group or CH2-carboxyl group; and / or

[0093] n) A tetrazolyl group, CH2-tetrazolyl group, 5-oxo-4H-1,2,4-oxadiazol-3-yl group;

[0094] and / or

[0095] (ii) One or more groups selected from a carboxyl group, CN, a halogenated group, a nitro group, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino and di-C 1-6 alkylsulfinylamino groups.

[0096] The second aspect provides a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable diluent, carrier or excipient.

[0097] The third aspect provides the compound of the first aspect for use in a method of treatment. The third aspect also provides the use of the compound of the first aspect in the manufacture of a medicament for the treatment of cardiovascular diseases. The third aspect also provides the compound of the first aspect for use in the treatment of cardiovascular diseases. The third aspect also provides a method of treating cardiovascular diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of the first aspect or the composition according to the second aspect.

[0098] The present disclosure includes combinations of the described aspects and features, unless such combinations are clearly impermissible or expressly avoided. Detailed Description

[0099] Aspects and embodiments will now be discussed. Additional aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0100] This document describes compounds of formula (I) and their use in the treatment of cardiovascular diseases. The compounds disclosed herein are PCSK9 inhibitors. The compounds can have higher PCSK9 inhibition, lower hERG activity, improved secondary pharmacological profiles (including GSK3β and / or other kinases), good stability, and / or improved activity in treating cardiovascular diseases. The compounds can have improved secondary pharmacological profiles or improved off-target profiles.

[0101] Definition

[0102] Substituent

[0103] As used herein, the phrase "optionally substituted" refers to a parent group that can be unsubstituted or can be substituted.

[0104] 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 meaning and refers to a chemical moiety that is covalently attached to the parent group or, if appropriate, fused to the parent group. The various substituents are well known, and the methods for their formation and introduction into various parent groups are also well known.

[0105] Examples of substituents are described in more detail below.

[0106] Unless otherwise specified, the halo group is selected from chlorine (Cl), fluorine (F), bromine (Br), and iodine (I), such as fluorine.

[0107] Cyano (nitrile, methyl cyanide): -CN.

[0108] Hydroxy: -OH.

[0109] Oxo group: =O (oxygen is double-bonded to the rest of the molecule).

[0110] C 1-6 Hydrocarbon: As used herein, the term "C 1-6 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 hydrocarbon compound can be aliphatic or cycloaliphatic, can be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated), and can also be branched. Thus, the term "hydrocarbon" includes the terms alkyl, alkenyl, alkynyl, cycloalkyl, etc., discussed below.

[0111] C 1-6 Alkyl: As used herein, the term "C1-6 "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, the hydrocarbon compound being saturated and may also be branched. As used herein, the term "C 1-4 "Alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having 1 to 4 carbon atoms, the hydrocarbon compound being saturated.

[0112] Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), and hexyl (C6).

[0113] 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 (pentyl) (C5), and n-hexyl (C6).

[0114] Examples of saturated branched-chain alkyl groups include isopropyl (C3), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), isopentyl (C5), and neopentyl (C5).

[0115] C 2-6 Alkenyl: As used herein, the term "C 2-6 "Alkenyl" refers to a hydrocarbon group having one or more carbon-carbon double bonds.

[0116] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2), isopropenyl (1-methylethenyl, -C(CH3)=CH2), butenyl (C4), pentenyl (C5), and hexenyl (C6).

[0117] C 2-6 Alkynyl: As used herein, the term "C 2-6 "Alkynyl" refers to a hydrocarbon group having one or more carbon-carbon triple bonds.

[0118] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and 2-propynyl (propargyl, -CH2C≡CH).

[0119] C 1-6 Alkoxy: As used herein, the term C 1-6 "Alkoxy" refers to an OR group, where R is a C 1-6 hydrocarbon group. C 16Examples 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).

[0120] C 1-6 Acetyloxy: As used herein, the term C 1-6 acetyloxy (reverse ester) refers to -OC(=O)R, where R is C 1-6 hydrocarbon group. Examples of acetyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, or -OC(=O)C(CH3)3.

[0121] Amino: -NR 1 R 2 where R 1 and R 2 are independently amino substituents, such as hydrogen, C 1-6 hydrocarbon group (also known as C 1-6 alkylamino or C 1-6 dialkylamino), or in the case of "cyclic" amino groups, R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle having 4 to 6 ring atoms. The amino group can be a primary amino group (-NH2), a secondary amino group (-NHR 1 ), or a tertiary amino group (-NHR 1 R 2 ), and in the cationic form, can be a quaternary ammonium group (- + 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, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and thiomorpholino.

[0122] C 1-6 Acylamide: Acylamide (acylamino): NR 1 C(=O)R 2 where R 1 is an amide substituent, such as hydrogen or C 1-6 hydrocarbon group, and R 2 is an acyl substituent, such as C 1-6Hydrocarbon group. Examples of acylamide groups include, but are not limited to, NHC(=O)CH3 and NHC(=O)CH2CH3. In some embodiments, R 1 and R 2 can together form a cyclic or bicyclic structure and form a cyclic acylamidino group. Examples of such groups include succinimido, maleimido, phthalimido, 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:

[0123]

[0124] Amidino: -C(=NH)(NH2).

[0125] Methyl-amidino: -C(=N-CH3)NH2.

[0126] Carboxylamino: -N(H)(C(=O)OH).

[0127] C 1-6 Thioalkyl: As used herein, the term C 1-6 thioalkyl refers to -SR, where R is a C 1-6 hydrocarbon group. Examples of C 1-6 alkylthio groups include, but are not limited to, -SCH3 and -SCH2CH3.

[0128] C 1-6 Alkylsulfinyl: The term C 1-6 alkylsulfinyl refers to a sulfinyl (sulfinyl group, sulfoxide) having the structure -S(=O)R, where R is a C 1-6 hydrocarbon group. Examples of C 1-6 alkylsulfinyl groups include, but are not limited to, -S(=O)CH3 and -S(=O)CH2CH3.

[0129] C 1-6 Alkylsulfonyl: As used herein, the term C 1-6 alkylsulfonyl refers to a -S(=O)2R group, where R is a C 1-6 hydrocarbon group, including, for example, fluorinated or perfluorinated C 1-6 alkyl groups. Examples of C 1-6Examples of alkylsulfonyl groups include, but are not limited to, -S(=O)2CH3 (methanesulfonyl / mesyl), -S(=O)2CF3 (trifluoromethanesulfonyl), -S(=O)2CH2CH3 (ethanesulfonyl), -S(=O)2C4F9 (perfluorobutanesulfonyl), and -S(=O)2CH2CF3 (trifluoroethanesulfonyl). C 1-6 Sulfinimido: The term C 1-6 Sulfinimido is also known as sulfinamido (aminosulfinyl; sulfonic acid amide; sulfonamide) and has the structure -S(=O)2NR 1 R 2 where R 1 and R 2 are independently amino substituents as defined for amino groups. Examples of sulfinamido groups include, but are not limited to, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3)2, -S(=O)2NH(CH2CH3), and -S(=O)2N(CH2CH3)2.

[0130] C 1-6 Alkylphosphinyl: The term C 1-6 Alkylphosphinyl (phosphine oxide) has the structure -P(=O)R2, where each R is independently a C 1-6 hydrocarbon group. C 1-6 Examples of alkylphosphinyl groups include, but are not limited to, P(=O)(CH3)2, P(=O)(CH2CH3)2, and P(=O)(tBu)2. Each R group can be the same or different groups.

[0131] Carboxyl (carboxylic acid): -C(=O)OH.

[0132] C 1-6 Alkyl ester: The term C 1-6 Alkyl ester (carboxylate / carboxylic acid ester, oxycarbonyl) has the structure -C(=O)OR, where R is a C 1-6 hydrocarbon group. Examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, and -C(=O)OC(CH3)3.

[0133] C 1-6 Alkylacyl: The term C 1-6 Alkylacyl, also known as acyl (keto group), has the structure -C(=O)R, where R is a C 1-6 hydrocarbon group. C 1-6Examples of alkyl acyl groups include, but are not limited to, -C(=O)CH3 (acetyl), -C(=O)CH2CH3 (propionyl), or -C(=O)C(CH3)3 (tert - butyryl).

[0134] C 1-6 Alkyl acylamino: The term C 1-6 alkyl acylamino (also referred to as carbamoyl, carbamyl, aminocarbonyl, formamide) has the structure -C(=O)NR 1 R 2 , where R 1 and R 2 are independently amino substituents as defined for amino groups, such as hydrogen, C 1-6 hydrocarbon groups (also referred to as C 1-6 alkyl acylamino or C 1-6 dialkyl acylamino), or in the case of "cyclic" acylamino groups, R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle having 4 to 6 ring atoms. Examples of acylamino groups include, but are not limited to, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, and -C(=O)N(CH2CH3)2, and acylamino groups in which R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic structure, such as the acylamino groups in piperidinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinylcarbonyl.

[0135] C 3-12 Cycloalkyl: As used herein, the term "C 3-12 cycloalkyl" refers to an alkyl group that is also a cyclic group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has 3 to 7 carbon atoms, including 3 to 7 ring atoms. The carbocycle can be saturated or unsaturated and can be bridged or unbridged. The ring can be a fused ring or a monocyclic ring.

[0136] Examples of cycloalkyl groups include, but are not limited to, those derived from:

[0137] Saturated monocyclic hydrocarbon compounds:

[0138] 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);

[0139] Unsaturated monocyclic hydrocarbon compounds:

[0140] Cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (C6), methylcyclopentene (C6), dimethylcyclopentene (C7), and methylcyclohexene (C7); and

[0141] Saturated polycyclic hydrocarbon compounds:

[0142] Norcarane (C7), norpinane (C7), norbornane (C7).

[0143] C 3-10 Heterocyclic group: As used herein, the term "C 3-10 heterocyclic group" 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, where 1 to 5 are ring heteroatoms. In certain embodiments, each ring has 3 to 7 ring atoms, where 1 to 4 are ring heteroatoms. The ring can be saturated or unsaturated and can be bridged or unbridged. The ring can be a fused ring or a monocyclic ring. For the avoidance of doubt, substituents on a heterocycloalkyl ring can be attached through a carbon atom or a heteroatom.

[0144] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0145] In this context, a prefix (such as C 3-10 、C 3-7 、C 5-6 etc.) indicates the number of ring atoms or a range of the number of ring atoms, regardless of whether they are carbon atoms or heteroatoms. For example, as used herein, the term "C 5-6 heterocyclic group" refers to a heterocyclic group having 5 or 6 ring atoms.

[0146] Examples of monocyclic heterocyclic groups include, but are not limited to, those derived from the following:

[0147] N1: Aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoxazole) (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7);

[0148] O1: Oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepin (C7);

[0149] S1: Thietane (C3), Thietene (C4), Tetrahydrothiophene (C5), Tetrahydropyran (C6), Thiepane (C7);

[0150] O2: Dioxolane (C5), Dioxane (C6) and Dioxepane (C7);

[0151] O3: Trioxane (C6);

[0152] N2: Imidazolidine (C5), Pyrazolidine (Diazene) (C5), Imidazoline (C5), Pyrazoline (Dihydropyrazole) (C5), Piperazine (C6);

[0153] N1O1: Oxazolidine (C5), Dihydrooxazole (C5), Isoxazolidine (C5), Dihydroisoxazole (C5), Morpholine (C6), Oxazine (C6), Dihydrooxazine (C6), Oxazine (C6);

[0154] N1S1: Thiazoline (C5), Thiazolidine (C5), Thiamorpholine (C6);

[0155] N2O1: Oxadiazine (C6);

[0156] O1S1: Oxathiacyclopentadiene (C5) and Oxathiane (Thioxane) (C6); and,

[0157] N1O1S1: Oxathiazine (C6).

[0158] Examples of bicyclic heterocyclic groups include, but are not limited to, those derived from the following:

[0159]

[0160] C 6-10 Carboaryl: As used herein, the term "C 6-10 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 and all of the ring atoms are carbon atoms, as in a "carboaryl group". The ring may be a fused ring or a monocyclic ring. Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C 10 ) and azulene (C 10 ).

[0161] In this context, the prefixes (e.g., C 5-7 , C 5-6 , C 5-10 , etc.) indicate the number of ring atoms or the range of the number of ring atoms. For example, as used herein, the term "C 5-6"Aryl" refers to an aryl group having 5 or 6 ring atoms.

[0162] Examples of carbocyclic aryl groups containing fused rings, where at least one is an aromatic ring, include but are not limited to those derived from indane (e.g., 2,3-dihydro-1H-indene) (C9), indene (C9), isoindene (C9), and tetrahydronaphthalene (1,2,3,4-tetrahydronaphthalene) (C 10 ).

[0163] C 5-10 Heteroaryl: As used herein, the term "C 5-10 heteroaryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which has 5 to 10 ring atoms, where 1 to 5 are ring heteroatoms. In certain embodiments, each ring has 5 to 7 ring atoms, where 1 to 4 are ring heteroatoms. For the avoidance of doubt, substituents on the heteroaryl ring may be attached through a carbon atom or a heteroatom. The ring may be a fused ring or a monocyclic ring.

[0164] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0165] Examples of monocyclic heteroaryl groups include but are not limited to those derived from the following:

[0166] N1: Pyrrole (azole) (C5), pyridine (azine) (C6);

[0167] O1: Furan (oxole) (C5);

[0168] S1: Thiophene (thiole) (C5);

[0169] N1O1: Oxazole (C5), isoxazole (C5), isoxazine (C6);

[0170] N2O1: Oxadiazole (furazan) (C5);

[0171] N3O1: Oxatriazole (C5);

[0172] N1S1: Thiazole (C5), isothiazole (C5);

[0173] 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);

[0174] N3: Triazole (C5), triazine (C6); and,

[0175] N4: Tetrazole (C5).

[0176] Examples of heteroaryls containing fused rings include, but are not limited to, those derived from the following C9 (with 2 fused rings):

[0177]

[0178]

[0179] Examples of heteroaryls containing fused rings include, but are not limited to, those derived from the following C 10 (with 2 fused rings):

[0180]

[0181] Spiro C 6-12 Carbocyclic group: As used herein, the term spiro C 6-12 carbocyclic group refers to a moiety having at least two molecular rings (sharing only one common atom). The simplest spiro compounds are bicyclic (having only two rings), or have a bicyclic moiety as part of a larger ring system, in either case, the two rings being connected by a defined single common atom. Spiro C 6-12 carbocyclic group refers to a cyclic 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, where the rings share a common atom.

[0182] Spiro C 6-12 Heterocyclic group: As used herein, the term spiro C 6-12 heterocyclic group refers to a moiety having at least two molecular rings (sharing only one common atom). The simplest spiro compounds are bicyclic (having only two rings), or have a bicyclic moiety as part of a larger ring system, in either case, the two rings being connected by a defined single common atom. Spiro C 6-12 heterocyclic 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, where 1 to 3 are ring heteroatoms, and where the rings share a common atom. In certain embodiments, each ring has 9 to 11 ring atoms, where 1 to 2 are ring heteroatoms. For the avoidance of doubt, substituents on a heteroaryl ring may be attached through a carbon atom or a heteroatom.

[0183] For the avoidance of doubt, when multiple substituents are independently selected from a given group, the selected substituents may include the same or different substituents from within the given group.

[0184] Pharmaceutically acceptable salt

[0185] The term "pharmaceutically acceptable" is used to indicate that an entity (e.g., a salt, a dosage form, or an excipient) is suitable for use in a patient. A list of examples of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl and C.G. Wermuth, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Suitable pharmaceutically acceptable salts of the compounds of formula (I) are, for example, acid addition salts. The acid addition salts of the compounds of formula (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art. The 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. The acid addition salts can also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0186] Accordingly, in one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, citrate, maleate, oxalate, acetate, formate, benzoate, fumarate, succinate, tartrate, lactate, pyruvate, methanesulfonate, benzenesulfonate, or p-toluenesulfonate. 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. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a monomethanesulfonate, i.e., the stoichiometry of the compound of formula (I) with methanesulfonic acid is 1:1.

[0187] Other forms

[0188] The compounds and salts described in this specification can exist in solvated and unsolvated forms. For example, the solvated form can be a hydrated form such as a hemihydrate, monohydrate, dihydrate, trihydrate, or alternative amounts thereof. The compounds of formula (I) encompass all such solvated and unsolvated forms of the compounds of formula (I), particularly insofar as such forms have PCSK9 kinase inhibitory activity, as measured, for example, using the tests described herein.

[0189] The compounds and salts described in this specification include one or more chiral (i.e., asymmetric) centers. To the extent that the structures or chemical names in this specification do not indicate chirality, such structures or names are intended to encompass any single stereoisomer (i.e., any single chiral isomer) corresponding to such structure or name, as well as any mixture of stereoisomers (e.g., racemates). In some embodiments, a single stereoisomer is obtained by separating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatography separation. In other embodiments, a single stereoisomer is obtained by direct synthesis from, for example, chiral starting materials.

[0190] A particular enantiomer of the compounds described herein may be more active than other enantiomers of the same compound.

[0191] According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a single enantiomer with an enantiomeric excess (%ee) of ≥95%, ≥98% or ≥99%. Conveniently, the single enantiomer is present with an enantiomeric excess (%ee) of ≥99%.

[0192] According to another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients, wherein the compound is a single enantiomer with an enantiomeric excess (%ee) of ≥95%, ≥98% or ≥99%. Conveniently, the single enantiomer is present with an enantiomeric excess (%ee) of ≥99%.

[0193] Isotope

[0194] The atoms of the compounds and salts described in this specification may exist as their isotopes. Compounds of formula (I) encompass all compounds of formula (I) in which one or more of the atoms are replaced by one or more of their isotopes (e.g., compounds of formula (I) in which one or more carbon atoms are 11 C or 13 C carbon isotopes, or compounds of formula (I) in which one or more hydrogen atoms are 2 H or 3 H isotopes).

[0195] Tautomer

[0196] The compounds and salts described in this specification may exist as a mixture of tautomers. "Tautomers" are structural isomers that exist in equilibrium due to the migration of a hydrogen atom. Compounds of formula (I) include all tautomers of compounds of formula (I), particularly insofar as such tautomers have PCSK9 inhibitory activity.

[0197] For example, some exemplary compounds in which R A1The tautomeric forms of OH) can be as shown below.

[0198]

[0199] Crystalline form

[0200] The compounds and salts described in this specification can be crystalline and can exhibit one or more crystalline forms. The compounds of formula (I) encompass any crystalline or amorphous form of the compounds of formula (I) having PCSK9 inhibitory activity, or mixtures of such forms.

[0201] It is generally known that crystalline materials can be characterized using conventional techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of crystalline materials can be determined by Karl Fischer analysis.

[0202] Therapy, prophylaxis and related terms

[0203] The term "therapy" is intended to have its normal meaning of treating a disease so as to relieve one, some, or all of its symptoms completely or partially, or so as to correct or compensate for the underlying pathology. The term "therapy" also includes "prevention" unless there is a specific indication to the contrary. The terms "treatment" and "therapeutically" should be interpreted in a corresponding manner.

[0204] The term "prevention" is intended to have its normal meaning and includes primary prevention of the development of a disease and secondary prevention in which the disease has developed and the patient is temporarily or permanently protected against the exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0205] The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" can be considered "application of therapy", where "therapy" is as defined herein.

[0206] The "subjects" to whom administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys. Preferred subjects are humans.

[0207] As used herein, "effective amount" means an amount sufficient to achieve the desired biological effect. As used herein, "therapeutically effective amount" means an amount sufficient to achieve the desired therapeutic effect. For example, a therapeutically effective amount can mean an amount sufficient to ameliorate at least one sign or symptom of a disease to be treated.

[0208] Pharmaceutical composition

[0209] The compounds of formula (I) and their pharmaceutically acceptable salts can be administered as pharmaceutical compositions which contain one or more pharmaceutically acceptable excipients.

[0210] Accordingly, in one embodiment, there is provided a pharmaceutical composition which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0211] The excipients chosen to be included in a particular composition will depend on factors such as the mode of administration and the form of the composition being provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, 6th Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients can serve, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickening agents, and coating agents. As will be understood by those skilled in the art, certain pharmaceutically acceptable excipients can serve more than one function and can serve alternative functions, depending on how much excipient is present in the composition and which other excipients are present in the composition.

[0212] The pharmaceutical composition can be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft gelatin capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders) or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular injection) or in the form of suppositories suitable for rectal administration. The compositions can be obtained by conventional procedures well known in the art. Compositions intended for oral use can contain additional components, such as one or more coloring agents, sweetening agents, flavoring agents, and / or preservatives.

[0213] In the therapeutic treatment of humans, a suitable daily dose of the compounds disclosed herein or a pharmaceutically acceptable salt thereof is from about 0.0001 mg / kg body weight to 100 mg / kg body weight.

[0214] The pharmaceutical preparations as described herein can be formulated by methods known to those skilled in the art to provide a dose of the active compound in the range of 0.1 mg to 1000 mg. The daily dose must vary depending on the host being treated, the particular route of administration, any therapies co-administered, and the severity of the disease being treated. Thus, the physician treating any particular patient can determine the optimal dose.

[0215] The pharmaceutical compositions described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof and are thus expected to be useful in therapy.

[0216] Thus, in one embodiment, there is provided a pharmaceutical composition for use in therapy, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0217] 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, 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.

[0218] Method of use

[0219] The compounds described herein can be used in a method of treatment. There is also provided a method of treatment which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I. The term "therapeutically effective amount" is an amount sufficient to show benefit to the patient. Such benefit can be at least the improvement of at least one symptom. The actual amount administered, as well as the rate and duration of administration, will depend on the nature and severity of the disease being treated. Therapeutic regimens (e.g., decisions regarding dosage) are within the responsibility of general practitioners and other physicians.

[0220] The compounds can be administered alone or in combination with other treatments simultaneously or sequentially depending on the condition to be treated.

[0221] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for use in therapy. In one embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) for the manufacture of a medicament. In another embodiment, there is provided a method of treatment which comprises 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).

[0222] The compounds described herein are PCSK9 inhibitors. The PCSK9 gene was identified using genetic mapping techniques with 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. Although not wishing to be bound by any particular theory, studies of mutations in the gene suggest its putative role is to reduce LDLR at the cell surface, independent of its catalytic activity. (Abifadel 2010). The binding of PCSK9 to LDLR results in their lysosomal degradation. This enhanced LDLR degradation leads to an increase in the amount of circulating low density lipoprotein (LDL). PCSK9 is upregulated by statins, SREBP-1a and SREBP-2, LXR agonists, and insulin, but is downregulated by dietary cholesterol, glucagon, ethinyl estradiol, chenodeoxycholic acid, and the farnesoid X receptor (FXR) activated by cholic acid (Maxwell 2003; Persson 2009; Langhi 2008). Since elevated PCSK9 levels reduce the abundance of LDLR on the cell surface, increasing statin doses do not achieve a proportional reduction in LDL-C. Accordingly, methods are disclosed herein for treating a variety of cardiovascular diseases and conditions that would benefit from inhibition of PCSK9 to reduce LDL-C.

[0223] In certain embodiments, the method of inhibiting PCSK9 is carried out in a subject in need thereof, thereby treating a PCSK9-mediated disease or disorder. Methods of treating or preventing a PCSK9-mediated disease or disorder are also disclosed herein, which methods comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, methods of treating a PCSK9-mediated disease or disorder are disclosed herein, which methods comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, methods of preventing a PCSK9-mediated disease or disorder are disclosed herein, which methods comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the prevention of cardiovascular events by inhibition of PCSK9 has been described in Robinson 2015.

[0224] In some embodiments, a method of treating a cardiovascular disease is provided, the method 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) is provided for use in treating a cardiovascular disease. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) is provided for manufacturing a medicament for treating a cardiovascular disease.

[0225] 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, abnormal lipoproteinemia, 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.

[0226] In certain embodiments, the disclosed method of treatment can reduce elevated levels of circulating serum cholesterol, such as LDL-C and VLDL-cholesterol. Additionally, the disclosed method can be used to reduce circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL-C, and atherogenic lipoproteins. In certain embodiments, the diseases or conditions treated with the disclosed compounds and compositions include atherosclerosis and atherosclerotic plaque formation. Subjects having a gain-of-function mutation in the PCSK9 gene also benefit from treatment with the disclosed compounds and compositions by inhibiting PCSK9 to counteract the mutation.

[0227] Combination therapy

[0228] The disclosed compounds and compositions can be administered in combination with other therapeutic agents, such as other agents suitable for treating elevated levels of LDL-C and triglycerides. In certain embodiments, administering one or more additional therapeutic agents in combination with the compounds described herein provides a synergistic effect. In certain embodiments, administering one or more additional therapeutic agents in combination provides an additive effect.

[0229] In some embodiments in which combination therapy is used, the amounts of the compounds or salts described in this specification and the amounts of other pharmaceutically active agents are therapeutically effective when combined for treating a target disorder in an animal patient. In this context, the combination amounts are "therapeutically effective amounts" if, when combined, they are sufficient to meet one or more of the following conditions: reducing or completely alleviating the symptoms or other adverse effects of the disorder; curing the disorder; reversing, completely arresting, or slowing the progression of the disorder; or reducing the risk of the disorder worsening. Generally, such amounts can be determined by one of ordinary skill in the art, for example, by starting with the dosage ranges of the compounds or salts described in this specification and the approved or otherwise disclosed dosage ranges of other pharmaceutically active compounds.

[0230] The pharmaceutical compositions of this specification may contain one or more additional active ingredients, and examples of combinations of the compounds (or their pharmaceutically acceptable salts) of this specification and one or more additional active ingredients are described herein, where appropriate.

[0231] This specification further relates to a combination therapy in which the compounds or their pharmaceutically acceptable salts of this specification and a second active ingredient are administered simultaneously, sequentially, or in admixture for treating one or more of the conditions listed above. Such combinations can be used in combination with one or more other active ingredients.

[0232] In one aspect, a combination is provided (e.g., for use as a medicament for treating one of the diseases or conditions listed herein such as cardiovascular disease), the combination comprising a compound or its pharmaceutically acceptable salt of this specification and at least one active ingredient selected from the following:

[0233] i) Statins;

[0234] ii) Cholesterol absorption inhibitors;

[0235] iii) SGLT2 inhibitors;

[0236] iv) P2Y12 inhibitors;

[0237] v) Citrate lyase inhibitors; and

[0238] vi) Antihypertensive drugs.

[0239] In another aspect of this specification, a pharmaceutical composition is provided (e.g., for use as a medicament for treating one of the diseases or conditions listed herein such as cardiovascular disease), the pharmaceutical composition comprising a compound or its pharmaceutically acceptable salt of this specification and at least one active ingredient selected from the following:

[0240] i) Statins;

[0241] ii) Cholesterol absorption inhibitors;

[0242] iii) SGLT2 inhibitor;

[0243] iv) P2Y12 inhibitor;

[0244] v) Citrate lyase inhibitor;

[0245] vi) Antihypertensive drug.

[0246] 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 statins, wherein the statins are selected from atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin. In another aspect, the statin is rosuvastatin (Crestor).

[0247] 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 cholesterol absorption inhibitors, wherein the cholesterol absorption inhibitor is ezetimibe (Ezetrol).

[0248] 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 SGLT2 inhibitors, wherein the SGLT2 inhibitors are 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).

[0249] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with at least one additional active ingredient selected from P2Y12 inhibitors, wherein the P2Y12 inhibitor is selected from Ticagrelor and Clopidogrel (Plavix).

[0250] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with at least one additional active ingredient selected from citrate lyase inhibitors, wherein the citrate lyase inhibitor is Bempedoic acid (Nexletol).

[0251] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with 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.

[0252] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with at least one additional active ingredient selected from antihypertensive drugs. In some aspects, the antihypertensive drugs are selected from valsartan (Diovan), metoprolol (Lopressor), HCTZ (hydrochlorothiazide), olmesartan (Benicar), lisinopril (Prinivil, Zestril), amlodipine besylate (Norvasc), candesartan, or calcium channel blockers, or combinations thereof. In another aspect, a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with the following is provided:

[0253] i) valsartan;

[0254] ii) metoprolol;

[0255] iii) valsartan and HCTZ;

[0256] iv) olmesartan;

[0257] v) olmesartan and HCTZ;

[0258] vi) lisinopril;

[0259] vii) Amlodipine;

[0260] viii) Candesartan;

[0261] ix) A calcium channel blocker; or

[0262] x) HCTZ.

[0263] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional active ingredient for use in the simultaneous, separate or sequential treatment of cardiovascular diseases. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cardiovascular diseases, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with at least one additional active substance selected from ezetimibe, rosuvastatin, dapagliflozin and ticagrelor.

[0264] In another embodiment, there is provided a method of treating a cardiovascular disease in a subject, the method 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 at least one additional active substance is selected from ezetimibe, rosuvastatin, dapagliflozin and ticagrelor.

[0265] Further embodiments

[0266] The following embodiments can be applied to all aspects as described above or can relate to a single aspect. These embodiments can be combined together in any combination.

[0267] X 1

[0268] X 1 is C-R A1 .

[0269] R A1

[0270] In some embodiments, R A1 is selected from the group consisting of:

[0271] (i) H

[0272] (ii) A halogen group;

[0273] (iii) CN;

[0274] (iv) C 1-6 hydrocarbon, which is optionally substituted with one or more OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogen groups;

[0275] (v)C 1-6 an alkoxy group, optionally substituted by OH, one or more halo groups, C 1-6 alkylcarbonylamino;

[0276] (vi)C 1-6 alkyl esters;

[0277] (vii)C 1-6 alkylcarbonyl; and

[0278] (viii)OH.

[0279] In some embodiments, R A1 is selected from the group consisting of:

[0280] (i)H

[0281] (ii) halo group;

[0282] (iii) CN;

[0283] (iv)C 1-6 a hydrocarbon, optionally substituted by one or more OH, CN, C 1-6 carbonyl, C 1-6 alkoxy or one or more halo groups; and

[0284] (v)C 1-6 an alkoxy group, optionally substituted by OH, halo or C 1-6 alkylcarbonylamino.

[0285] In some embodiments, R A1 is selected from the group consisting of:

[0286] (i)H

[0287] (ii) halo group;

[0288] (iii) CN;

[0289] (iv)C 1-6 a hydrocarbon, optionally substituted by one or more OH, CN, C 1-6 carbonyl, C 1-6 alkoxy or one or more halo groups;

[0290] (v)C 1-6 an alkoxy group, optionally substituted by OH, one or more halo groups or C 1-6 alkylcarbonylamino; and

[0291] (vi)OH.

[0292] When R A1is an optionally substituted C 1-6 hydrocarbon, it is an optionally substituted C 1-6 alkyl group. In some embodiments, it is an optionally substituted methyl or an optionally substituted ethyl. In a further embodiment, it is an optionally substituted methyl. In a further embodiment, it is an unsubstituted methyl.

[0293] When R A1 is an optionally substituted C 1-6 alkyl group, in some embodiments, the optional substituent is selected from OH, CN or one or more halo groups. In a further embodiment, the optional substituent is selected from OH, F and Br.

[0294] When R A1 is an optionally substituted C 1-6 alkoxy group, in some embodiments, it is an optionally substituted OMe or ethoxy. In some embodiments, R A1 is an unsubstituted OMe.

[0295] When R A1 is an optionally substituted C 1-6 alkoxy group, in some embodiments, the optional substituent is selected from alkylamido or one or more halo groups. In another embodiment, the optional substituent is selected from one, two or three F atoms.

[0296] When R A1 is a halo group, in some embodiments, it is F, Br or Cl. In other embodiments, it is Br or Cl.

[0297] In some embodiments, R A1 is OH.

[0298] In some embodiments, R A1 is CN.

[0299] In some embodiments, R A1 is methyl.

[0300] In some embodiments, R A1 is -OCF2H.

[0301] In some embodiments, R A1 is selected from H, Br, Cl, CN, OMe, ethoxy, methyl or ethyl. In a further embodiment, R 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.

[0302] In some embodiments, R A1 is selected from the group consisting of: H, OH, Br, Cl, CN, OCF2H, OMe, ethoxy, methyl, and ethyl. In some embodiments, R A1 is selected from the group consisting of: H, Br, Cl, CN, OCF2H, OMe, ethoxy, methyl, and ethyl. In some embodiments, R A1 is selected from the group consisting of: H, OH, -OCF2H, Br, and Cl. In some embodiments, R A1 is selected from the group consisting of: H, -OCF2H, Br, and Cl.

[0303] In some embodiments, R A1 is H.

[0304] In some embodiments, R A1 is OH or H.

[0305] R A2

[0306] In some embodiments, R A2 is selected from the group consisting of:

[0307] (i) H;

[0308] (ii) a halogenated group;

[0309] (iii) CN;

[0310] (iv) C 1-6 hydrocarbon, which is optionally substituted by OH, CN, C 1-6 acyl, C 1-6 alkoxy, or one or more halogenated group;

[0311] (v) C 1-6 alkoxy, which is optionally substituted by OH, alkyl acylamino, or one or more halogenated group;

[0312] (vi) C 1-6 acyl acylamino (wherein the acyl is optionally substituted by H or methyl);

[0313] (vii) C 1-6 thioalkyl, which is optionally substituted by C 1-6 alkyl ester;

[0314] (viii) C 1-6 alkyl ester;

[0315] (ix) C 1-6 alkyl acyl,

[0316] (x) C4-5 heterocyclic group;

[0317] (xi) C5 heteroaryl;

[0318] (xii) C 1-6 alkylcarbonylamino, optionally substituted by C 1-3 alkylcarbonylamino, CN, OH, C 2-3 alkynyl, C 4-6 heterocyclic group, C 1-3 alkyl substituted, said alkyl optionally substituted by one or more halogen atoms or OH groups; and

[0319] (xiii) OH.

[0320] In some embodiments, R A2 is selected from the group consisting of:

[0321] (i) H;

[0322] (ii) halogen atom;

[0323] (iii) CN;

[0324] (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogen atoms;

[0325] (v) C 1-6 alkoxy, optionally substituted by OH, alkylcarbonylamino or one or more halogen atoms;

[0326] (vi) C 1-6 acylcarbonylamino (wherein said acyl is optionally substituted by H or methyl);

[0327] (vii) C 1-6 thioalkyl,

[0328] (viii) C 1-6 alkyl ester;

[0329] (ix) C 1-6 alkylcarbonyl,

[0330] (x) C 4-5 heterocyclic group;

[0331] (xi) C5 heteroaryl;

[0332] (xii) C 1-6 alkylcarbonylamino, optionally substituted by C 1-3 alkylcarbonylamino, CN, C 2-3 alkynyl, C 4-6 heterocyclic group, C1-3 alkyl-substituted, wherein the alkyl is optionally substituted with one or more halogen groups or OH groups; and

[0333] (xiii) OH.

[0334] In a further embodiment, R A2 is selected from the group consisting of:

[0335] (i) H;

[0336] (ii) a halogen group;

[0337] (iii) CN;

[0338] (iv) C 1-6 hydrocarbon, which is optionally substituted with OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogen groups;

[0339] (v) C 1-6 alkoxy, which is optionally substituted with OH, C 1-6 alkylamido or one or more halogen groups;

[0340] (vi) C 1-6 thioalkyl;

[0341] (viii) C 1-6 alkyl ester; and

[0342] (ix) C 1-6 alkylamido, which is optionally substituted with C 1-3 alkylamido, CN, C 2-3 alkynyl, C 4-6 heterocyclic group or C 1-3 alkyl-substituted, wherein the alkyl is optionally substituted with one or more halogen groups or OH groups.

[0343] In a further embodiment, R A2 is selected from the group consisting of:

[0344] (i) H;

[0345] (ii) a halogen group;

[0346] (iii) CN;

[0347] (iv) C 1-6 hydrocarbon, which is optionally substituted with OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogen groups;

[0348] (v) OH;

[0349] (vi) C 1-6 alkoxy groups, optionally substituted by OH, C 1-6 alkylamido groups or one or more halogen groups;

[0350] (vii) C 1-6 alkyl esters;

[0351] (viii) C 1-6 alkyl acyl groups; and

[0352] (ix) C 1-6 alkylamido groups, optionally substituted by C 1-3 alkylamido groups, CN, C 2-3 alkynyl groups, C 4-6 heterocyclic groups or C 1-3 alkyl groups, the alkyl groups being optionally substituted by one or more halogen groups or OH groups.

[0353] In some embodiments, R A2 is selected from:

[0354] (i) H;

[0355] (ii) halogen groups;

[0356] (iii) CN;

[0357] (iv) C 1-6 hydrocarbons, optionally substituted by OH, CN, C 1-6 acyl groups, C 1-6 alkoxy groups or one or more halogen groups;

[0358] (v) OH;

[0359] (vi) C 1-6 alkoxy groups, optionally substituted by OH, C 1-6 alkylamido groups or one or more halogen groups;

[0360] (vii) C 1-6 alkyl esters;

[0361] (viii) C 1-6 alkyl acyl groups;

[0362] (ix) C 1-6 alkylamido groups, optionally substituted by C 1-3 alkylamido groups, CN, C 2-3 alkynyl groups, C 4-6 heterocyclic groups or C 1-3 alkyl groups, the alkyl groups being optionally substituted by one or more halogen groups or OH groups; and

[0363] (x) C1-6 Thioalkyl, optionally substituted with C 1-6 alkyl ester.

[0364] In some embodiments, R A2 is selected from:

[0365] (i) H;

[0366] (ii) Halo group;

[0367] (iii) CN;

[0368] (iv) C 1-6 hydrocarbon, optionally substituted with OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halo groups;

[0369] (v) C 1-6 alkoxy, optionally substituted with OH, alkylamido or one or more halo groups;

[0370] (vi) C 1-6 thioalkyl, optionally substituted with C 1-6 alkyl ester;

[0371] (vii) C 1-6 alkyl ester; or (viii) C 1-6 alkylamido, optionally substituted with C 1-3 alkylamido, CN, C 2-3 alkynyl, C 4-6 heterocyclic group or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halo groups or OH groups.

[0372] In some embodiments, R A2 is selected from:

[0373] (i) H;

[0374] (ii) Halo group;

[0375] (iii) CN;

[0376] (iv) C 1-6 alkyl;

[0377] (v) Cyclopropyl;

[0378] (vi) C 1-6 alkoxy, optionally substituted with one or more halo groups;

[0379] (vii) C 1-6 alkyl ester;

[0380] (viii) C 1-6 Alkylamido;

[0381] (ix) C 1-6 Thioalkyl, optionally substituted by C 1-6 alkyl ester; or

[0382] (x) OH.

[0383] In a further embodiment, R A2 is selected from:

[0384] (i) H;

[0385] (ii) Cl;

[0386] (iii) CN;

[0387] (iv) Methyl;

[0388] (v) Cyclopropyl;

[0389] (vii) C 1-2 Alkoxy, optionally substituted by two or three fluorine groups;

[0390] (viii) C 1-3 Thioalkyl, optionally substituted by C 1-3 alkyl ester;

[0391] (viii) C(=O)CH3; or

[0392] (ix) C(=O)NH(CH3).

[0393] When R A2 is a halogen group, in some embodiments, it is Br or Cl. In a further embodiment, it is Cl.

[0394] In some embodiments, R A2 is selected from CN, Cl, OMe, methyl, cyclopropyl, -OCF2H, -OCF3 and optionally substituted C 1-6 alkylamido.

[0395] In some embodiments, R A2 is CN.

[0396] In some embodiments, R A2 is H.

[0397] In some embodiments, R A2 is OH.

[0398] In some embodiments, R A2 is -C(=O)CH3.

[0399] In some embodiments, R A2 is -OCF2H.

[0400] In some embodiments, R A2 is cyclopropyl.

[0401] In some embodiments, R A2 is Cl.

[0402] In some embodiments, R A2 is methyl.

[0403] In some embodiments, R A2 is -S-CH3.

[0404] In some embodiments, R A2 is -S-CH2CH3.

[0405] In some embodiments, R A2 is -S-CH2-C(=O)-O-CH3.

[0406] In some embodiments, R A2 is C(=O)NH(CH)3.

[0407] When R A2 is C 1-6 hydrocarbon, it is an optionally substituted C 1-6 alkyl. In some embodiments, it is an optionally substituted methyl, an optionally substituted ethyl, or an optionally substituted cyclopropyl. In further embodiments, it is an optionally substituted methyl. In further embodiments, it is an unsubstituted methyl. In other embodiments, it is an unsubstituted cyclopropyl.

[0408] When R A2 is an optionally substituted C 1-6 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.

[0409] When R A2 is an optionally substituted C 1-6 alkoxy, in some embodiments, it is an optionally substituted OMe or ethoxy.

[0410] When R A2 is an optionally substituted C 1-6 alkoxy, in some embodiments, the optional substituents are selected from alkylamido or one or more halo groups. In another embodiment, the optional substituents are selected from one or more F. In another embodiment, in RA2 When it is an optionally substituted C 1-6 alkoxy group, it is difluoromethoxy (OCHF2).

[0411] When R A2 is a C 1-6 alkyl ester, in some embodiments, it is -C(=O)OCH2CH3.

[0412] When R A2 is a C 1-6 alkylamido group, in some embodiments, the optional substituent is selected from one or more methyl groups, an oxetane ring, a C2 alkylamido group, an ethyl group, and the ethyl group is optionally substituted by OH or one or more halogen groups. In other embodiments, when R A2 is a C 1-6 alkylamido group, it is C(=O)NHCH2C(=O)NH2, C(=O)NHCH2CHCH, -C(=O)NH-oxetane, C(=O)NHCH2CHF2, C(=O)NHCH2CH2OH, C(=O)NHCH2CH3, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2. When R A2 is a C 1-6 alkylamido group, in some embodiments, the optional substituent is OH.

[0413] When R A2 is a C 1-6 thioalkyl group, in some embodiments, the optional substituent is a C 1-6 alkyl ester. When R A2 is a C 1-6 thioalkyl group, in some embodiments, the optional substituent is selected from C(=O)-O-CH3 or C(=O)-O-CH2CH3. In some embodiments, the thioalkyl group is unsubstituted and is -S-CH3 or -S-CH2CH3. In some embodiments, when R A2 is an optionally substituted C 1-6 thioalkyl group, it is S-CH3, -S-CH2CH3 or -S-CH2-C(=O)-O-CH3.

[0414] In other embodiments, R A2 is selected from -OCHF2, Cl, -OMe, methyl, C(=O)CH3, CN, -CH2OH, H and cyclopropyl. In further embodiments, R A2 is selected from methyl, -OCHF2, Cl, -CH2OH, H, CN, -C(=O)CH3, -OMe.

[0415] In further embodiments, RA2 Selected from methyl, -OCHF2, Cl, and cyclopropyl.

[0416] In a further embodiment, R A2 is selected from H, -COOH, -CH2OH, methyl, CN, cyclopropyl, -C(=O)CH3, -OCF2H, Cl, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3.

[0417] 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.

[0418] 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.

[0419] In some embodiments, R A2 is selected from CN, methyl, Cl, -C(=O)CH3, -C(C=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCF2H, H, -OMe, -OCF3. These groups are shown in the following table:

[0420]

[0421] In some embodiments, R A2 is selected from the following groups:

[0422]

[0423] In some embodiments, R A2 is selected from the following groups:

[0424]

[0425] R A3

[0426] In some embodiments, R A3 is selected from the group consisting of:

[0427] (i) H;

[0428] (ii) a halo group;

[0429] (iii) CN;

[0430] (iv) C 1-6 hydrocarbon, which is optionally substituted by OH, CN, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 acyloxy, carboxyl, C 1-6 alkyl ester, C 1-6 alkylamino; -C(=O)NH2, C 1-6 alkylacylamino, C 1-6 alkylacylacylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or one or more halo group substituents;

[0431] (v) OH;

[0432] (vi) C 1-6 alkoxy, which is optionally substituted by OH, NH2, a C4 heterocyclic group or one or more halo group substituents.

[0433] In the case where R A3 is a halo group, in some embodiments, it is Br or Cl. In some embodiments, it is Cl. In a further embodiment, R A3 is Br.

[0434] In the case where R A3 is C 1-6 hydrocarbon, it is optionally substituted C 1-6Alkyl. In some embodiments, it is optionally substituted methyl or optionally substituted ethyl. In further embodiments, it is optionally substituted methyl. In further embodiments, it is unsubstituted methyl.

[0435] When R A3 is an optionally substituted C 1-6 alkyl, in some embodiments, the optional substituent is selected from OH, CN, or one or more halo groups. In further embodiments, the optional substituent is selected from OH, F, and Br.

[0436] In some embodiments, R A3 is OH.

[0437] When R A3 is an optionally substituted C 1-6 alkoxy, in some embodiments, it is optionally substituted OMe or ethoxy. In further embodiments, it is OMe.

[0438] When R A3 is an optionally substituted C 1-6 alkoxy, in some embodiments, the optional substituent is selected from alkylamido or one or more halo groups. In another embodiment, the optional substituent is selected from one or more F.

[0439] In some embodiments, R A3 is selected from H, CF3, CN, C 1-2 alkyl, NH2, and halo. In other embodiments, R A3 is selected from H, methyl, CN, and Cl.

[0440] In some embodiments, R A3 is selected from H, OMe, CF3, CN, C 1-2 alkyl, NH2, and halo.

[0441] In some embodiments, R A3 is CN.

[0442] In some embodiments, R A3 is H.

[0443] In some embodiments, R A3 is methyl.

[0444] In some embodiments, R A3 is OMe.

[0445] In some embodiments, R A3 is selected from methyl, H, and CN.

[0446] R A2and R A3

[0447] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C6 carbocyclic aromatic ring or a C 5-7 heteroaromatic ring, they form an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0448] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C6 carbocyclic aromatic ring or a C 5-7 heteroaromatic ring, the optional substituents are selected from NH2, C 1-6 alkyl, C 1-6 alkoxy and halo groups. In other embodiments, the optional substituents are selected from methyl, ethyl, OMe, NH2, F, Cl, and Br. In other embodiments, the optional substituents are selected from methyl, NH2, Cl, F, and OMe. In other embodiments, the optional substituent is methyl.

[0449] In one embodiment, when R A2 and R A3 together with the carbon atom to which they are attached form an optionally substituted C 5-7 heteroaromatic ring, they form an optionally substituted pyridine. In some embodiments, the optional substituent is NH2. In another embodiment, R A2 and R A3 together with the carbon atom to which they are attached form an unsubstituted pyridine. In another embodiment, R A2 and R A3 together form an optionally substituted pyrazole, an optionally substituted pyrrole, or an optionally substituted thiazole. In some embodiments, the optional substituent is methyl.

[0450] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C 5-7 heteroaromatic ring, the optional substituents are selected from C 1-6 alkyl, C 1-6 alkoxy, NH2, and halo groups. In other embodiments, the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH2, and halo groups. In other embodiments, the optional substituents are selected from NH2 and methyl.

[0451] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C 5-7When they form a heterocycle, they form a 5-membered ring containing one or two atoms selected from N, O, and S. In some embodiments, the 5-membered ring contains one N and one S. In other embodiments, the 5-membered ring contains one N. In other embodiments, the 5-membered ring contains one N and one O. In other embodiments, the 5-membered ring contains two Ns. In some embodiments, R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted pyrrole or pyrazole.

[0452] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C 5-7 heterocycle, the optional substituents are selected from NH2, C 1-6 alkyl, C 1-6 alkoxy, and halo groups. In other embodiments, the optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH2, F, Cl, and Br. In other embodiments, the optional substituent is methyl.

[0453] In other embodiments, R A2 and R A3 together with the carbon atom to which they are attached form:

[0454] (i) an optionally substituted C6 heteroaromatic ring; wherein the optional substituent is NH2;

[0455] (ii) an optionally substituted C6 carbocyclic aromatic ring; wherein the optional substituents are F, OMe, Cl;

[0456] (iii) an optionally substituted C5 heteroaromatic or C5 heterocycle, wherein the optional substituent is methyl.

[0457] In some embodiments, R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C6 carbocyclic aromatic ring or C 5-7 heteroaromatic ring, wherein the optional substituents are selected from C 1-6 alkyl and halo groups.

[0458] In some embodiments, R A2 and R A3 together form an unsubstituted 2-pyrazole, a 2-pyrrole substituted with methyl, a pyridine optionally substituted with NH2, or a phenyl optionally substituted with Cl, F, or OMe.

[0459] In some embodiments, R A2 and R A3 together form a ring selected from:

[0460]

[0461] B

[0462] In some embodiments, B has formula (B-1):

[0463]

[0464] where the wavy line indicates the attachment points to A and C; where R B1 is H, OH, -OMe, -O-ethyl, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0465] In other embodiments, R B1 is H, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0466] In other embodiments, R B1 is -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0467] In other embodiments, R B1 is H.

[0468] In another embodiment, B has formula (B-1a):

[0469]

[0470] In a further embodiment, B has formula (B-1b):

[0471]

[0472] Thus, in some embodiments, the compound of formula (I) is the S,S-enantiomer.

[0473] In some embodiments, B has formula (B-2):

[0474]

[0475] where the wavy line indicates the attachment points to A and C;

[0476] R B2 is C 1-2 alkyl-OH, CH2CONHMe or C 1-3 alkyl.

[0477] In some of these embodiments, R B2 is C 1-2 alkyl-OH or C 1-3 alkyl.

[0478] In some embodiments, when B has the formula (B-2), it has the formula (B-2a) below, where the wavy line indicates the attachment points to A and C; and R B2 is C 1-2 alkyl-OH, CH2CONHMe or C 1-2 alkyl;

[0479]

[0480] C

[0481] C is selected from the group consisting of C 6-10 carbaryl, C 5-6 heteroaryl and C 5-10 heterocyclic group, and the groups are optionally substituted with the following:

[0482] (i) C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[0483] which are optionally substituted with one or more of the following groups;

[0484] a) one or two ═O groups;

[0485] b) one or more halo groups;

[0486] c) CN, NH2, OH;

[0487] d) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH, C 1-6 alkylsulfonyl or one or more halo groups;

[0488] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0489] f) C 1-6 alkyl ester;

[0490] g) C 5-6 heterocyclic group, which has optional methyl, OH or ═O substituents;

[0491] h) C 5-6 heteroaryl, which has optional methyl substituents;

[0492] i) C 4-10A carbocyclic group having an optional methyl or ═O substituent;

[0493] j)C 6-10 A carboaryl group having an optional substituent of one or more halo groups;

[0494] l)P(═O)Me2;

[0495] m) A carboxyl group or CH2-carboxyl;

[0496] n) A tetrazolyl group, CH2-tetrazolyl group, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[0497] (ii) One or more groups selected from carboxyl, CN, halo, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino and di-C 1-6 alkylsulfinylamino groups.

[0498] In some embodiments, C is selected from the group consisting of C 6-10 carboaryl, C 5-6 heteroaryl and C 5-10 heterocyclic group, said groups being optionally substituted with:

[0499] (i) C 6-10 carboaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[0500] which are themselves optionally substituted with one or more of the following groups;

[0501] a) One or two ═O groups;

[0502] b) One or more halo groups;

[0503] c) CN, NH2, OH;

[0504] d) One or more C 1-6 alkyl groups, which include branched and cyclic and have an optional substituent selected from OH or one or more halo groups;

[0505] e) C 1-6An alkoxy group having an optional substituent of one or more halogenated groups;

[0506] f)C 1-6 An alkyl ester;

[0507] g)C 5-6 A heterocyclic group having optional methyl, OH or ═O substituents;

[0508] h)C 5-6 A heteroaryl group;

[0509] i)C 4-10 A carbocyclic group having optional methyl or ═O substituents;

[0510] j)C 6-10 A carbaryl group having an optional substituent of one or more halogenated groups;

[0511] l)P(═O)Me2;

[0512] m)A carboxyl group or CH2-carboxyl; and / or

[0513] n)A tetrazolyl group, CH2-tetrazolyl group, 5-oxo-4H-1,2,4-oxadiazol-3-yl group;

[0514] (ii)One or more groups selected from carboxyl, CN, halogenated, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino and di-C 1-6 alkylsulfinylamino groups.

[0515] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl group, wherein the optional substituents are selected from C 6-10 carbaryl, C 4-10 carbocyclic, C 5-10 heteroaryl, C 5-10 heterocyclic, C 5-10 bridged heterocyclic, spiro C 6-12 heterocyclic or spiro C 6-12 carbocyclic groups, which are themselves optionally substituted with one or more of the following groups:

[0516] a)One or two ═O groups;

[0517] b)One or more halogenated groups;

[0518] c)CN, NH2 or OH;

[0519] d) one or more C 1-6 alkyl groups, which include branched-chain and cyclic ones and have optional substituents selected from OH, C 1-6 alkylsulfonyl or one or more halo groups;

[0520] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0521] f) C 1-6 alkyl esters;

[0522] g) C 5-6 heterocyclic groups, which have optional methyl, OH or ═O substituents;

[0523] h) C 5-6 heteroaryl groups, which have optional methyl substituents;

[0524] i) C 4-10 carbocyclic groups, which have optional methyl or ═O substituents;

[0525] j) C 6-10 carboaryl groups, which have optional substituents of one or more halo groups;

[0526] l) P(═O)Me2;

[0527] m) carboxyl or CH2-carboxyl; and / or

[0528] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0529] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl, wherein the optional substituents are selected from C 6-10 carboaryl, C 4-10 carbocyclic, C 5-10 heteroaryl, C 5-10 heterocyclic, C 5-10 bridged heterocyclic, spiro C 6-12 heterocyclic or spiro C 6-12 carbocyclic, which are themselves optionally substituted by one or more of the following groups:

[0530] a) one or two ═O groups;

[0531] b) one or more halo groups;

[0532] c) CN, NH2 or OH;

[0533] d) one or more C 1-6An alkyl group, which includes branched-chain and cyclic ones and has optional substituents selected from OH or one or more halogenated groups;

[0534] e)C 1-6 An alkoxy group, which has optional substituents of one or more halogenated groups;

[0535] f)C 1-6 An alkyl ester;

[0536] g)C 5-6 A heterocyclic group, which has optional methyl, OH or ═O substituents;

[0537] h)C 5-6 A heteroaryl;

[0538] i)C 4-10 A carbocyclic group, which has optional methyl or ═O substituents;

[0539] j)C 6-10 A carboaryl, which has optional substituents of one or more halogenated groups;

[0540] l)P(═O)Me2;

[0541] m)A carboxyl group or CH2-carboxyl; and / or

[0542] n)A tetrazolyl group, CH2-tetrazolyl group, 5-oxo-4H-1,2,4-oxadiazol-3-yl group.

[0543] When C is an optionally substituted C 5-6 heteroaryl, in some embodiments, it is an optionally substituted C6 heteroaryl. In other embodiments, it is an optionally substituted pyridyl group, pyrazinyl group or pyrimidinyl group. In other embodiments, it is an optionally substituted pyridyl group.

[0544] When C is an optionally substituted C 5-6 heteroaryl, it may optionally be substituted with:

[0545] (i)C 6-10 carboaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 5-10 heterocyclic group or C 5-10 bridged heterocyclic group, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[0546] which are themselves optionally substituted with one or more groups selected from the following groups:

[0547] a)One or two ═O groups;

[0548] b) one or more halo groups;

[0549] c) CN, NH2, OH;

[0550] d) C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH, C 1-6 alkylsulfonyl or one or more halo groups;

[0551] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0552] f) C 1-6 alkyl esters;

[0553] g) C 5-6 heterocyclic groups, which have optional methyl, OH or =O substituents;

[0554] h) C 5-6 heteroaryl groups, which have optional methyl substituents;

[0555] i) C 4-10 carbocyclic groups, which have optional methyl or =O substituents;

[0556] j) C 6-10 carboaryl groups, which have optional substituents of one or more halo groups;

[0557] l) P(=O)Me2;

[0558] m) carboxyl or CH2-carboxyl; and / or

[0559] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[0560] (ii) one or more groups selected from carboxyl, CN, halo, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino and di-C 1-6 alkylsulfinylamino groups.

[0561] In the case where C is substituted by C 6-10 carboaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, it may carry a number of substituent groups. The substituents are selected from:

[0562] a) One or two ═O groups;

[0563] b) One or more halo groups, CN, NH2;

[0564] c) One or more C 1-6 alkyl (including (CH3)2), C 1-6 alkoxy or C 1-6 alkyl ester, each of which is optionally substituted by one or more halo groups;

[0565] d) C 5-6 heterocyclic group or C 5-6 heteroaryl, which has an optional methyl substituent;

[0566] e) C 6-10 carbaryl, which is optionally substituted by one or more halo atoms;

[0567] f) P(═O)Me2; or

[0568] g) Carboxyl or CH2-carboxyl.

[0569] When C is substituted by C 6-10 carbaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, it may carry a number of substituent groups. The substituents are selected from:

[0570] a) One or two ═O groups;

[0571] b) One or more halo groups, CN or NH2;

[0572] c) One or more C 1-6 alkyl groups, C 1-6 alkoxy or C 1-6 alkyl ester, each of which is optionally substituted by one or more halo groups;

[0573] d) C 5-6 heterocyclic group or C 5-6 heteroaryl, which has an optional methyl substituent;

[0574] e) C 6-10 carbaryl, which is optionally substituted by one or more halo atoms;

[0575] f) Carboxyl or CH2-carboxyl; or

[0576] g) Tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0577] When C is substituted by C 6-10 carbaryl, C5-10 When it is a heteroaryl or a C 5-10 heterocyclic group substituted, it may bear a number of substituent groups. The substituents are selected from:

[0578] a) one or two ═O groups;

[0579] b) one or more halo groups,

[0580] c) CN;

[0581] d) one or more C 1-6 alkyl groups, which are optionally substituted by one or more halo groups or C 1-6 alkylsulfonyl groups;

[0582] e) C 1-6 alkoxy groups, which are optionally substituted by one or more halo groups;

[0583] f) C 5-6 heterocyclic groups or C 5-6 heteroaryl groups, which have optional methyl substituents;

[0584] g) C6 carbaryl groups, which are optionally substituted by one or more halo atoms; or

[0585] h) carboxyl groups.

[0586] In some embodiments, when C is an optionally substituted C 5-6 heteroaryl, the optional substituents are selected from C 1-6 alkyl and halo. In further embodiments, the optional substituent is methyl. In further embodiments, C is substituted by methyl at the meta position. In some embodiments, C is C 6-10 carbaryl, C 5-6 heteroaryl and C 5-10 heterocyclic groups, each of which is substituted by methyl.

[0587] In some embodiments, one substituent of C is at the para position.

[0588] In other embodiments, when C is substituted by an optionally substituted C 6-10 carbaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, it may be substituted by an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyridazine, an optionally substituted imidazolidine, an optionally substituted pyrrolidine, an optionally substituted dihydroquinolinyl, an optionally substituted naphthyridine, an optionally substituted 2,3-dihydro-1H-imidazo[4,5-b]pyridine, an optionally substituted 3H-imidazo[4,5-b]pyridine, an optionally substituted benzimidazolyl or an optionally substituted imidazopyridyl. In other embodiments, when C is substituted by an optionally substituted C6-10 carbon aryl, C 5-10 heteroaryl or C 5-10 heterocyclic group substituted, it may be substituted by an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted imidazolidinyl group, an optionally substituted dihydroquinolinyl group, an optionally substituted benzimidazolyl group or an optionally substituted imidazopyridinyl group. These groups themselves may optionally be substituted by one or two ═O groups, a halogenated group, CN, one or more C 1-6 alkyl groups, C 1-6 alkoxy groups, C 1-6 alkyl esters, C 5-6 heterocyclic groups (having an optional methyl substituent), phenyl groups substituted by F at the para position, carboxyl groups, CH2-carboxyl groups, tetrazolyl groups, pyrazolyl groups, triazolyl groups or P(═O)Me2. In other embodiments, the optionally substituted phenyl group, the optionally substituted pyridyl group, the optionally substituted imidazolidinyl group, the optionally substituted dihydroquinolinyl group, the optionally substituted benzimidazolyl group or the optionally substituted imidazopyridinyl group may be substituted by one or two ═O groups, a halogenated group, CN, one or more optionally substituted by one or more halogenated groups or C 1-6 alkylsulfonyl-substituted C 1-6 alkyl groups, C 1-6 alkoxy groups, C 5-6 heterocyclic groups (having an optional methyl substituent), C 5-6 heteroaryl groups (having an optional methyl substituent), phenyl groups substituted by F or carboxyl groups.

[0589] In other embodiments, when C is an optionally substituted pyridyl group, pyrazinyl group or pyrimidinyl group, it may carry a number of substituent groups. The substituents are selected from optionally substituted C 5-10 heteroaryl groups and C 5-10 heterocyclic groups, which are themselves optionally substituted by one or two ═O groups, one or more halogenated groups, CN, one or more C 1-6 alkyl groups, C 1-6 alkoxy groups, C 1-6 alkyl esters, C 5-6 heterocyclic groups (having an optional methyl substituent), phenyl groups optionally substituted by one or two halogenated groups, carboxyl groups, CH2-carboxyl groups, tetrazolyl groups, pyrazolyl groups, triazolyl groups, pyridine rings, NH2 or OH. In other embodiments, the optionally substituted C 5-10 heteroaryl groups and C 5-10 heterocyclic groups may optionally be substituted by one or two ═O groups, a halogenated group, CN, one or more optionally substituted by one or more halogenated groups or C 1-6 alkylsulfonyl-substituted C 1-6 alkyl groups, C 1-6 alkoxy groups, C5-6 Heterocyclic group (with optional methyl substituents), C 5-6 Heteroaryl group (with optional methyl substituents), phenyl group substituted by F or carboxyl group. In some embodiments, the substituent is optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted imidazolidine, optionally substituted dihydroquinoline, optionally substituted benzimidazolyl group or optionally substituted imidazopyridyl group. In some embodiments, the substituent is optionally substituted pyridyl group, optionally substituted pyridazine, optionally substituted imidazolidyl group, optionally substituted pyrrolidinyl group, optionally substituted dihydroquinolinyl group, optionally substituted naphthyridine, optionally substituted benzimidazolyl group, 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.

[0590] In some embodiments, C is an optionally substituted pyridyl group, pyrazinyl group or pyrimidinyl group, wherein the optional substituent is selected from:

[0591] i) C 6-10 Carboaryl, C 5-10 Heteroaryl, C 5-10 Heterocyclic group, which is itself optionally substituted by one or more of the following groups;

[0592] a) One or two ═O groups;

[0593] b) One or more halo groups;

[0594] c) CN, NH2, OH;

[0595] d) One or more C 1-6 Alkyl groups, which include branched-chain and cyclic ones and have optional substituents selected from OH, C 1-6 Alkylsulfonyl or one or more halo groups;

[0596] e) C 1-6 Alkoxy, which has an optional substituent of one or more halo groups;

[0597] f) C 1-6 Alkyl ester;

[0598] g) C 5-6 Heterocyclic group, which has optional methyl, OH or ═O substituents;

[0599] h) C 5-6 Heteroaryl;

[0600] i) C 4-10A carbocyclic group having an optional methyl or ═O substituent;

[0601] j)C 6-10 A carboaryl group having an optional substituent of one or more halogen groups;

[0602] l) P(═O)Me2;

[0603] m) Carboxyl, CH2-carboxyl; and / or

[0604] n) Tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[0605] ii) One or more groups selected from carboxyl, CN, halogen, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino and di-C 1-6 alkylsulfinylamino groups.

[0606] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl, wherein the optional substituent is selected from C 6-10 carboaryl, C 5-10 heteroaryl, C 5-10 heterocyclic group, which is itself optionally substituted by one or more groups selected from:

[0607] a) One or two ═O groups;

[0608] b) One or more halogen groups;

[0609] c) CN, NH2, OH;

[0610] d) One or more C 1-6 alkyl groups, which include branched-chain and cyclic ones and have an optional substituent selected from OH or one or more halogen groups;

[0611] e) C 1-6 alkoxy having an optional substituent of one or more halogen groups;

[0612] f) C 1-6 alkyl ester;

[0613] g) C 5-6 heterocyclic group having an optional methyl, OH or ═O substituent;

[0614] h) C 5-6Heteroaryl;

[0615] i)C 4-10 Carbocyclic group having an optional methyl or ═O substituent;

[0616] j)C 6-10 Carbaryl having an optional substituent of one or more halo groups;

[0617] l) P(═O)Me2;

[0618] m) Carboxyl, CH2-carboxyl; and / or

[0619] n) Tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0620] In some embodiments, C is an optionally substituted pyridyl group, wherein the optional substituent is selected from C 6-10 Carbaryl, C 5-10 Heteroaryl, C 5-10 Heterocyclic group, which is itself optionally substituted by one or more groups selected from:

[0621] a) One or two ═O groups;

[0622] b) One or more halo groups,

[0623] c) CN;

[0624] d) One or more C 1-6 Alkyl group, which is optionally substituted by sulfonyl or one or more halo groups;

[0625] e) C 1-6 Alkoxy group, which is optionally substituted by one or more halo groups;

[0626] f) C 5-6 Heterocyclic group or C 5-6 Heteroaryl group having an optional methyl substituent;

[0627] g) C6 carbaryl, which is optionally substituted by one or more halo atoms; or

[0628] h) Carboxyl.

[0629] In another embodiment, C has the formula (C-1):

[0630] where D is C 6-10 Carbaryl, C 5-10 Heteroaryl or C 5-10 Heterocyclic group, which is itself optionally substituted by: ═O, halo, CN, NH2, OH, one or more C1-6 An alkyl group (the alkyl group is optionally substituted by a halogenated group or a C 1-6 alkylsulfonyl group), a C 1-6 alkoxy group optionally substituted by a halogenated group, a C 1-6 alkyl ester, a C 5-6 heterocyclic group (having an optional methyl substituent), a carboxyl group, CH2-carboxyl, P(=O)Me2, a tetrazolyl group, a pyrazolyl group or a triazolyl group optionally substituted by a methyl group. In some embodiments, the optional substituent is selected from =O, CN, F, Cl, Br, methyl, ethyl, OMe, ethoxy, O-CF3, OMe, CF3, P(=O)Me2 and C 1-2 alkyl ester. In some embodiments, the optional substituent is selected from =O, OMe, carboxyl, Cl, methyl optionally substituted by -S(=O)2CH3, CN, phenyl substituted by F, piperazinyl substituted by methyl, CF3, OCF3, pyrazolyl optionally substituted by methyl, tetrazolyl or triazolyl.

[0631] In some embodiments, C has the formula (C-1):

[0632]

[0633] wherein D is a C 6-10 carbaryl group, a C 5-10 heteroaryl group or a C 5-10 heterocyclic group, each of which is optionally substituted by the following:

[0634] i) one or two =O groups;

[0635] ii) one or two C 1-4 alkyl groups, which can be branched;

[0636] i) OMe;

[0637] ii) piperazinyl group, which is optionally substituted by a methyl group;

[0638] iii) C(=O)OH (carboxyl group);

[0639] iv) Cl;

[0640] v) F;

[0641] vi) phenyl group, which is optionally substituted by one or more fluorines;

[0642] vii) CN;

[0643] viii) CF3;

[0644] ix) O-CF3;

[0645] x) OMe;

[0646] xi) tetrazolyl, pyrazolyl, triazolyl;

[0647] xii) NH2;

[0648] xiii) (CH3)2;

[0649] xiv) pyridyl;

[0650] xv) CH2OH;

[0651] xvi) OH; or

[0652] xvii) P(=O)Me2.

[0653] In some embodiments, C has formula (C-1):

[0654]

[0655] where D is C 6-10 carbaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, each of which is optionally substituted with the following:

[0656] i) one or two =O groups;

[0657] ii) one or two C 1-4 alkyl groups, which can be branched and are optionally substituted with S(=O)2CH3;

[0658] i) OMe;

[0659] ii) piperazinyl, which is optionally substituted with methyl;

[0660] iii) C(=O)OH (carboxyl);

[0661] iv) Cl;

[0662] v) F;

[0663] vi) phenyl, which is optionally substituted with one or more fluorines;

[0664] vii) CN;

[0665] viii) CF3;

[0666] ix) O-CF3;

[0667] x) OMe;

[0668] xi) tetrazolyl, pyrazolyl optionally substituted with methyl, triazolyl;

[0669] xii) NH2;

[0670] xiii) pyridyl;

[0671] xiv) CH2OH;

[0672] xv) OH; or

[0673] xvi) P(=O)Me2.

[0674] 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, OCF3, -C(=O)OH (carboxyl), CN, pyrazolyl, triazolyl, tetrazolyl, phenyl optionally substituted with an F substituent in the para position, or piperazinyl having a methyl substituent. In some embodiments, the pyridin-2-one is unsubstituted. In some embodiments, the optional substituents are selected from OMe, carboxyl, Cl, methyl optionally substituted with -S(=O)2CH3, CN, phenyl substituted with F, piperazinyl substituted with methyl, CF3, OCF3, pyrazolyl optionally substituted with methyl, tetrazolyl or triazolyl. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0675] When C is (C-1), in some embodiments, D is an optionally substituted 6-membered heteroaryl containing one or two N atoms, wherein one N atom is bonded to (C-1) substituted with ═O in the ortho position, and the other optional substituents are selected from methyl, OMe, piperazine substituted with methyl, -C(=O)OH (carboxyl), Cl, phenyl substituted with fluorine, CN, CF3, F, pyrazolyl, triazolyl, tetrazolyl or O-CF3. In some embodiments, the optional substituents are selected from OMe, -C(=O)OH (carboxyl), Cl, methyl optionally substituted with -S(=O)2CH3, CN, phenyl substituted with F, piperazinyl substituted with methyl, CF3, OCF3, pyrazolyl optionally substituted with methyl, tetrazolyl or triazolyl.

[0676] In some embodiments, when C is (C-1), D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, wherein one N atom is bonded to (C-1) substituted with ═O in the ortho position, wherein the optional substituents are selected from:

[0677] i) methyl;

[0678] ii) OMe;

[0679] iii) piperazinyl substituted with methyl;

[0680] iv) C(=O)OH (carboxyl);

[0681] v) Cl;

[0682] vi) F;

[0683] vii) phenyl substituted by fluorine;

[0684] viii) CN;

[0685] ix) CF3;

[0686] x) O - CF3;

[0687] xi) pyrazole, triazole, tetrazole.

[0688] In some embodiments, when C is (C - 1), D is an optionally substituted 6 - membered heteroaryl containing 1 or 2 N atoms, wherein one N atom is bonded to (C - 1) substituted by ═O at the ortho - position, and the optional substituents are selected from:

[0689] i) methyl optionally substituted by - S(═O)2CH3;

[0690] ii) OMe;

[0691] iii) piperazinyl substituted by methyl;

[0692] iv) C(═O)OH (carboxyl);

[0693] v) Cl;

[0694] vi) phenyl substituted by fluorine;

[0695] vii) CN;

[0696] viii) CF3;

[0697] ix) O - CF3;

[0698] x) pyrazole, triazole or tetrazole optionally substituted by methyl.

[0699] In a further embodiment, C has the formula (C - 1) and D is an optionally substituted pyridinyl, phenyl or pyridazinyl optionally substituted by methyl (the methyl is optionally substituted by - S(═O)2CH3), OMe, piperazinyl substituted by methyl, C(═O)OH (carboxyl), Cl, phenyl substituted by fluorine, CN, CF3, O - CF3, pyrazole, triazole or tetrazole optionally substituted by methyl. In some embodiments, D is an optionally substituted pyridinyl or pyridazinyl.

[0700] In some embodiments, C has the formula (C - 1) and D is an optionally substituted phenyl or piperidinyl, wherein there is one or two optional substituents selected from F, OMe and CN.

[0701] In some embodiments, C has formula (C-1) and D is an optionally substituted C 10 heterocyclic group, wherein the optional substituent is an =O group. In some embodiments, D is an optionally substituted 1,2,3,4-tetrahydro-1,8-naphthyridine or 1,2,3,4-tetrahydroquinoline, wherein 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, wherein 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).

[0702] In another embodiment, D has formula (D-1):

[0703]

[0704] wherein R D1 、R D2 、R D3 and R D4 one or both of which are selected from C 1-6 alkyl optionally substituted with alkylsulfonyl or one or more halo groups; C 1-6 alkoxy optionally substituted with one or more halo groups, C 1-6 heterocyclic group having an optional methyl substituent or C 5-6 heteroaryl, C(=O)OH, =O, halo, NH2, CN or phenyl optionally substituted with one or more halo atoms; or 5-6

[0705] wherein R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2 and C(=O)OH;

[0706] or wherein R D1 、R D2 、R D3 and R D4 are all H.

[0707] In another embodiment, D has formula (D-1):

[0708]

[0709] wherein one or both of R D1 、R D2 、R D3 and R D4 are selected from C 1-6 alkyl optionally substituted with one or more halo groups; C 1-6 alkoxy optionally substituted with one or more halo groups, C 5-6 heterocyclyl or C 5-6 heteroaryl having an optional methyl substituent, C(=O)OH, =O, halo, NH2, CN or phenyl optionally substituted with one or more halo atoms; or

[0710] wherein R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2 and C(=O)OH;

[0711] or wherein R D1 、R D2 、R D3 and R D4 are all H.

[0712] In some embodiments, D has the formula (D-1):

[0713]

[0714] wherein one or both of R D1 、R D2 、R D3 and R D4 are selected from

[0715] i) C 1-6 alkyl, which is optionally substituted with one or more halo groups;

[0716] ii) C 1-6 alkoxy, which is optionally substituted with one or more halo groups;

[0717] iii) C 5-6 heterocyclyl or C 5-6 heteroaryl, said groups having an optional methyl substituent;

[0718] iv) C(=O)OH or CH2-C(=O)OH;

[0719] v) =O, halo, NH2 or CN;

[0720] vi) phenyl, which is optionally substituted with one or more halo atoms;

[0721] and the remainder is H; or

[0722] wherein R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo and C(=O)OH;

[0723] or wherein R D1 、R D2 、R D3 and R D4 are all H.

[0724] In another embodiment, one or both of R D1 、R D2 、R D3 and R D4 are selected from C 1-6 alkyl optionally substituted with -S(=O)2CH3 or one or more halo groups, C 1-6 alkoxy optionally substituted with one or more halo groups, C 5-6 heterocyclic group having an optional methyl substituent or C 5-6 heteroaryl, C(=O)OH, halo, CN or phenyl optionally substituted with one or more halo atoms, and the remainder is H.

[0725] In some embodiments, D has the formula (D-1) and one or both of R D1 、R D2 、R D3 and R D4 are selected from:

[0726] i) methyl;

[0727] ii) OMe;

[0728] iii) piperazine substituted with methyl;

[0729] iv) C(=O)OH (carboxyl);

[0730] v) Cl;

[0731] vi) phenyl substituted with fluorine;

[0732] vii) CN;

[0733] viii) CF3;

[0734] ix) F;

[0735] x) pyrazolyl, triazolyl, tetrazolyl;

[0736] xi) O-CF3

[0737] and R D1 、R D2 、R D3 and R D4 and the remainder of R

[0738] In some embodiments, D has formula (D-1) and one or both of R D1 、R D2 、R D3 and R D4 are selected from:

[0739] i) methyl;

[0740] ii) OMe;

[0741] iii) piperazinyl substituted with methyl;

[0742] iv) C(=O)OH (carboxyl);

[0743] v) Cl;

[0744] vi) phenyl substituted with fluorine;

[0745] vii) CN;

[0746] viii) CF3;

[0747] ix) O-CF3

[0748] x) F;

[0749] xi) pyrazolyl, triazolyl or tetrazolyl;

[0750] and R D1 、R D2 、R D3 and R D4 and the remainder of R

[0751] In some embodiments, D has formula (D-1) and one or both of R D1 、R D2 、R D3 and R D4 are selected from:

[0752] i) methyl optionally substituted with -S(=O)2CH3;

[0753] ii) OMe;

[0754] iii) piperazine substituted with methyl;

[0755] iv) C(=O)OH (carboxyl);

[0756] v) Cl;

[0757] vi) phenyl substituted by fluorine;

[0758] vii) CN;

[0759] viii) CF3;

[0760] ix) pyrazolyl, triazolyl, tetrazolyl optionally substituted by methyl;

[0761] x) O - CF3

[0762] and R D1 、R D2 、R D3 and R D4 the rest of them are H.

[0763] In another embodiment, one or both of R D1 、R D2 、R D3 and R D4 are selected from methyl, - OMe, halogen, - C(=O)OH, CN, CF3, - OCF3, - OCHF2, and the rest of R D1 、R D2 、R D3 and R D4 are H. In another embodiment, one or both of R D1 、R D2 、R D3 and R D4 are selected from methyl optionally substituted by - S(=O)2CH3, - OMe, halogen, - C(=O)OH, CN, CF3, - OCF3, pyrazolyl, triazolyl, tetrazolyl optionally substituted by methyl, phenyl substituted by fluorine, piperazinyl substituted by methyl, and the rest of R D1 、R D2 、R D3 and R D4 are H.

[0764] In one embodiment, all of R D1 、R D2 、R D3 and R D4 are H.

[0765] In some embodiments, R D3 is selected from the group consisting of: H; phenyl optionally substituted, wherein the optional substituent is halogen, methyl, OMe, C(=O)OH, Cl, CN; or piperazinyl optionally substituted by methyl; or pyrazolyl, triazolyl or tetrazolyl, and wherein R D1 、R D2and R D4 are both H. In another embodiment, R D3 is selected from the group consisting of: H; optionally substituted phenyl, wherein the optional substituent is a halogen group, methyl optionally substituted with -S(=O)2CH3, OMe, C(=O)OH, Cl, CN; or piperazinyl optionally substituted with methyl; or pyrazolyl, triazolyl or tetrazolyl optionally substituted with methyl, and wherein R D1 and R D2 and R D4 are both H. In another embodiment, R D3 is selected from H, optionally substituted phenyl (wherein the optional substituent is a halogen group), methyl, OMe, -C(=O)OH, -OCHF2, Cl, CN and piperazinyl optionally substituted with methyl, wherein R D1 and R D2 and R D4 are both H. In another embodiment, R D3 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.

[0766] In other embodiments, R D1 is selected from H, methyl, OMe, Cl, CF3, OCF3OCHF2 and CN, and R D2 R D3 and R D4 are both H. In another embodiment, R D1 is selected from H, methyl, OMe, Cl, F, CF3OCF3 and CN, and wherein R D2 and R D3 and R D4 are both H. In other embodiments, R D1 is selected from H, methyl, OMe, Cl, CF3, OCF3, pyrazolyl, triazolyl and CN optionally substituted with methyl, and R D2 and R D3 and R D4 are both H.

[0767] In another embodiment, R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituent is selected from OH, CN, P(=O)Me2, methyl, OMe, halogen group and C(=O)OH.

[0768] In some embodiments, R D3 and R D4Form an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0769] In some embodiments, R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0770] In another embodiment, D has the formula (D-2):

[0771]

[0772] wherein X D is NR D5a or CR D5a R D5b ;

[0773] R D5a is selected from H or methyl;

[0774] R D5b and R D6b are both H or together they are -CH2-;

[0775] R D6a is selected from H, =O, methyl, -CH2OH or -C(=O)OH, where when R D6a is =O, R D6b is absent;

[0776] R D7a is selected from H, =O, methyl, -CH2OH or -C(=O)OH;

[0777] R D7b is H, where when R D7a is =O, R D7b is absent;

[0778] Or where R D6a and R D7a together form a benzene ring or a C6 heteroaromatic ring, which is optionally substituted with CN, P(=O)Me2 or carboxyl, and R D6b and R D7b are absent.

[0779] In some embodiments, C has the formula (C-1) and D has the formula (D-2), and X D is N and R D5a is methyl.

[0780] In some embodiments, C has the formula (C-1) and D has the formula (D-2), and R D6a and R D6b are both H, and R D7aSelected from ═O, -CH2OH or -C(═O)OH and R D7b is H, or when R D7a is ═O, R D7b does not exist.

[0781] In some embodiments, C has formula (C-1) and D has formula (D-2), and X D is N and R D5a is methyl, where R D7a is selected from H and ═O and R D6a is H and ═O, where when R D7a is ═O, R D6a and R D6b are H, and where R D6a is ═O, R D7a is H and R D6b does not exist, and R D7b is H, or when R D7a is ═O, R D7b does not exist.

[0782] In some embodiments, C has formula (C-1) and D has formula (D-2), R D7a is ═O, X D is C, and R D5b and R D6b together are -CH2-, and R D6a and R D5a are methyl.

[0783] In another embodiment, R D6a and R D7a together form a benzene ring or a C6 heteroaromatic ring optionally substituted with CN, P(═O)Me2 or -C(═O)OH, and R D6b and R D7b do not exist. In some embodiments, R D6a and R D7a together form a benzene ring or a pyridyl ring optionally substituted with CN.

[0784] In some embodiments, R D6a and R D7a form an unsubstituted benzene ring and R D6b and R D7b do not exist. In some embodiments, R D6a and R D7a form an unsubstituted pyridine ring and R D6b and R D7b do not exist.

[0785] In some embodiments, X D is N and RD5a is H or methyl.

[0786] In some embodiments, X D is C and R D5a is H or methyl, and R D5b is H. In further embodiments, R D5a and R D5b are both H.

[0787] In some embodiments, R D7a is carboxyl, -CH2OH or =O. In some embodiments, R D7a is =O. R D7b is H, or when R D7a is =O, R D7b does not exist.

[0788] In some embodiments, R D6a is H or =O. In some embodiments, R D6a is =O and R D6b does not exist.

[0789] In some embodiments, when R D7a is =O, R D6a and R D6b are H and R D7b does not exist, and when R D6a is =O, R D7a and R D7b are H and R D6a does not exist.

[0790] In some embodiments, X D is N and R D5a is H or methyl, R D6b is H and R D6a and R D7a together form a pyridine ring or a benzene ring optionally substituted with -C(=O)OH or CN or P(=O)Me2, and R D6b and R D7b do not exist.

[0791] In some embodiments, X D is CR D5a R D5b , R D5a and R D6a are methyl, R D7a is =O and R D7b does not exist, and R D6b and R D5b together form a 3-membered ring.

[0792] 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]hex-3-yl].

[0793] In some embodiments, D is selected from the following table:

[0794]

[0795]

[0796]

[0797]

[0798] In some embodiments, D is selected from the following table

[0799]

[0800]

[0801] In some embodiments, D is selected from the following table

[0802]

[0803]

[0804]

[0805] In another embodiment, C has the formula (C-2):

[0806]

[0807] wherein one or both of R C7 and R C8 and R C9 and R C10 are selected from methyl optionally substituted with -S(=O)2CH3, OMe, halo, -C(=O)OH, piperazine optionally substituted with methyl, phenyl optionally substituted (wherein the optional substituent is methyl or halo), CN, CF3, -O-CF3, tetrazolyl, pyrazolyl optionally substituted with methyl, or triazolyl, and the remainder of R C7 and R C8 and R C9 and R C10 are H; or R C9 and R C10Form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2 or -C(=O)OH; or

[0808] wherein R C7 , R C8 , R C9 and R C10 are all H.

[0809] In some embodiments, one of R C7 , R C8 , R C9 and R C10 is selected from the group consisting of: methyl; OMe; piperazinyl optionally substituted with methyl; -C(=O)OH (carboxyl); Cl; F; pyrazolyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN; CF3; O-CF3; and the remaining ones of R C7 , R C8 , R C9 and R C10 are H; or

[0810] R C9 and R C10 form a benzene or 6-membered heteroaromatic ring, and both R C7 and R C8 are H; or wherein R C7 , R C8 , R C9 and R C10 are all H. In other embodiments, one of R C7 , R C8 , R C9 and R C10 is selected from the group consisting of: methyl optionally substituted with -S(=O)2CH3; OMe; piperazinyl optionally substituted with methyl; -C(=O)OH (carboxyl); Cl; F; pyrazolyl optionally substituted with methyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN; CF3; O-CF3; and the remaining ones of R C7 , R C8 , R C9 and R C10 are H; or R C9 and R C10 form a benzene or 6-membered heteroaromatic ring, and both R C7 and R C8 are H; or wherein R C7 , R C8 , R C9 and R C10All are H.

[0811] In some embodiments, one or both of R C7 , R C8 , R C9 and R C10 are selected from methyl optionally substituted with -S(=O)2CH3, OMe, halo, -C(=O)OH, piperazine optionally substituted with methyl, phenyl optionally substituted (where the optional substituents are methyl or halo), CN, CF3, -O-CF3, tetrazolyl, pyrazolyl optionally substituted with methyl, or triazolyl, and the remainder of R C7 , R C8 , R C9 and R C10 are H; or R C9 and R C10 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring, or heteroaromatic ring, where the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2, or -C(=O)OH; or

[0812] wherein R C7 , R C8 , R C9 and R C10 are all H.

[0813] In one embodiment, C has formula (C-1) and R C7 , R C8 , R C9 and R C10 are all H.

[0814] In another embodiment, one or both of R C7 , R C8 , R C9 and R C10 are selected from

[0815] methyl, Cl, OMe, phenyl substituted with F in the para position, -C(=O)OH, CN, OCF3, CF3, F, pyrazolyl, triazolyl, tetrazolyl, piperazinyl substituted with methyl, and the remainder of R C7 , R C8 , R C9 and R C10 are H. In another embodiment, one or both of R C7 , R C8 , R C9 and R C10 are selected from

[0816] methyl optionally substituted with -S(=O)2CH3, Cl, OMe, phenyl substituted with F at the para position, -C(=O)OH, CN, OCF3, CF3, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, piperazinyl substituted with methyl, and R C7 、R C8 、R C9 and R C10 the remainder of are H.

[0817] In another embodiment, one of R C7 and R C9 is independently selected from methyl, -OMe, Cl, -C(=O)OH, piperazinyl optionally substituted with methyl, phenyl optionally substituted (where the optional substituent is F), CF3, -O-CF3, F, pyrazolyl, triazolyl or tetrazolyl and the other is H, and R C10 and R C8 are H. In another embodiment, one of R C7 and R C9 is independently selected from methyl optionally substituted with -S(=O)2CH3, Cl, OMe, phenyl substituted with F at the para position, -C(=O)OH, CN, OCF3, CF3, pyrazolyl optionally substituted with methyl, triazolyl, tetrazolyl, piperazinyl substituted with methyl, and R C8 and R C10 are H.

[0818] In another embodiment, R C9 is selected from H, phenyl optionally substituted (where the optional substituent is a halogen group), methyl, OMe, C(=O)OH, Cl, CN, pyrazolyl, triazolyl, tetrazolyl and piperazinyl optionally substituted with methyl, and 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 optionally substituted with methyl, triazolyl or tetrazolyl.

[0819] In other embodiments, R C7 is selected from H, methyl, OMe, Cl, F, CF3, -OCF3 and CN, and 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, and RC8 , R C9 and R C10 are all H.

[0820] In some embodiments:

[0821] a) R C7 , R C8 , R C9 and R C10 are all H; or

[0822] b) R C9 is selected from H, optionally substituted phenyl (where the optional substituent is F), methyl optionally substituted by -S(=O)2CH3, OMe, C(=O)OH, Cl, pyrazolyl optionally substituted by methyl, triazolyl, tetrazolyl, CN, and piperazinyl optionally substituted by methyl, and R C7 , R C8 and R C10 are all H; or

[0823] c) R C7 is selected from H, methyl, OMe, O-CF3, CF3, Cl, pyrazolyl optionally substituted by methyl, triazolyl, and CN, and R C8 , R C9 and R C10 are all H.

[0824] In other embodiments:

[0825] a) R C7 , R C8 , R C9 and R C10 are all H; or

[0826] b) R C9 is selected from H, optionally substituted phenyl (where the optional substituent is F), methyl, OMe, -C(=O)OH, Cl, F, pyrazolyl, triazolyl, tetrazolyl, CN, and piperazinyl optionally substituted by methyl, and R C7 , R C8 and R C10 are all H; or

[0827] c) R C7 is selected from H, methyl, OMe, O-CF3, CF3, Cl, F, pyrazolyl, and CN, and R C8 , R C9 and R C10 are all H.

[0828] In another embodiment, C is selected from the group consisting of groups 1 to 48 listed in the following table:

[0829]

[0830]

[0831]

[0832] In another embodiment, C is selected from the group consisting of the groups listed in the following table:

[0833]

[0834] In another embodiment, C is selected from the group consisting of the groups listed in the following table:

[0835]

[0836]

[0837]

[0838] A-B-C

[0839] In other embodiments, the compound of formula A-B-C has formula (I-A):

[0840]

[0841] wherein X 1 is C-R A1 .

[0842] In some embodiments, R A1 is H, OH, CN, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl or ethyl, wherein the optional substituent on the -OMe, -O-ethyl, methyl or ethyl group is selected from OH, CN or one or more halo groups. In some embodiments, R A1 is H, CN, OH, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl or ethyl, wherein the optional substituent on the -OMe, -O-ethyl, methyl or ethyl group is selected from OH, CN or one or more halo groups. In a further embodiment, R A1 is optionally substituted O-methyl, wherein the optional substituent is one or more F groups. In a further embodiment, R A1 is H. In a further embodiment, R A1 is OH.

[0843] In some embodiments, R A2 is selected from the group consisting of: Br, Cl, CN, H, -C(=O)CH3, C 1-6 alkylamido (the alkylamido is optionally substituted by C1-3 alkylacylamino-substituted), optionally C 1-3 alkyl ester-substituted thioalkyl, CN, C 2-3 alkynyl, C 4-6 heterocyclyl, C 1-3 alkyl (the alkyl optionally substituted by one or more halogen atoms or OH groups), optionally substituted methoxy, methyl, ethyl or cyclopropyl (wherein the optional substituent is selected from OH, CN or one or more halogen atom groups), optionally substituted methoxy or ethoxy (wherein the optional substituent is selected from alkylacylamino or one or more halogen atom groups). In some embodiments, R A2 is selected from the group consisting of: Br, Cl, CN, H, -C(=O)CH3, C 1-6 alkylacylamino (the alkylacylamino optionally substituted by C 1-3 alkylacylamino substitution), CN, C 2-3 alkynyl, C 4-6 heterocyclyl, C 1-3 alkyl (the alkyl optionally substituted by one or more halogen atoms or OH groups), optionally substituted methoxy, methyl, ethyl or cyclopropyl (wherein the optional substituent is selected from OH, CN or one or more halogen atom groups), optionally substituted methoxy or ethoxy (wherein the optional substituent is selected from alkylacylamino or one or more halogen atom groups). In further embodiments, R A2 is selected from CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCF2H, H, -OMe, -OCF3. 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.

[0844] In some embodiments, R A3 is selected from the group consisting of: CN, Br, Cl, OH, H, CF3, C 1-2 alkyl, C 1-2 alkoxy, NH2. In further embodiments, R A3 is selected from H, methyl and CN.

[0845] In other embodiments, R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C6 carbocyclic aromatic ring or a C 5-7 heteroaromatic ring, and the optional substituents are selected from NH2, C 1-6 alkyl, C 1-6 alkoxy, and halo groups. In other embodiments, the optional substituents are selected from NH2, methyl, ethyl, OMe, F, Cl, and Br.

[0846] In some embodiments, R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted pyridine, an optionally substituted benzene, pyrrole, or pyrazole. In some embodiments, R A2 and R A3 together form an unsubstituted 2 - pyrazole, a 2 - pyrrole substituted with methyl, a pyridine optionally substituted with NH2, or a benzene optionally substituted with Cl, F, or OMe.

[0847] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl group. In some embodiments, the optional substituents are selected from:

[0848] (i) C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 5-10 heterocyclic group, or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic group, or spiro C 6-12 carbocyclic group, which are themselves optionally substituted with one or more groups selected from the following groups:

[0849] a) one or two ═O groups;

[0850] b) one or more halo groups;

[0851] c) CN, NH2, OH;

[0852] d) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH, C 1-6 alkylsulfonyl, or one or more halo groups;

[0853] e) C 1-6 alkoxy, which has an optional substituent of one or more halo groups;

[0854] f) C 1-6 alkyl ester;

[0855] g) C5-6 A heterocyclic group having an optional methyl, OH or ═O substituent;

[0856] h)C 5-6 A heteroaryl group having an optional methyl substituent;

[0857] i)C 4-10 A carbocyclic group having an optional methyl or ═O substituent;

[0858] j)C 6-10 A carboaryl group having an optional substituent of one or more halo groups;

[0859] k)Carboxyl, CH2-carboxyl;

[0860] l)P(═O)Me2;

[0861] (ii)One or more groups selected from carboxyl, CN, halo, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino, di-C 1-6 alkylsulfinylamino groups.

[0862] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl. In some embodiments, the optional substituent is selected from:

[0863] (i)C 6-10 carboaryl, C 4-10 carbocyclic, C 5-10 heteroaryl, C 5-10 heterocyclic or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic or spiro C 6-12 carbocyclic, which are themselves optionally substituted with one or more groups selected from the following groups:

[0864] a)One or two ═O groups;

[0865] b)One or more halo groups;

[0866] c)CN, NH2, OH;

[0867] d)One or more C 1-6 alkyl groups, including branched and cyclic and having an optional substituent selected from OH or one or more halo groups;

[0868] e)C1-6 an alkoxy group having an optional substituent of one or more halo groups;

[0869] f)C 1-6 an alkyl ester;

[0870] g)C 5-6 a heterocyclic group having optional methyl, OH or ═O substituents;

[0871] h)C 5-6 a heteroaryl;

[0872] i)C 4-10 a carbocyclic group having optional methyl or ═O substituents;

[0873] j)C 6-10 a carboaryl having an optional substituent of one or more halo groups;

[0874] k) a carboxyl, CH2-carboxyl;

[0875] l) P(═O)Me2;

[0876] (ii) one or more groups selected from carboxyl, CN, halo, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino, di-C 1-6 alkylsulfinylamino groups.

[0877] In other embodiments, the compound of formula A-B-C has formula (I-B):

[0878]

[0879] wherein X 1 , R A2 and R A3 are as defined in (I-A).

[0880] In some embodiments, formula (I-B) can be formula (I-Ba) or (I-Bb) as shown below:

[0881]

[0882] In some embodiments, D is C 6-10 carboaryl, C 4-10 carbocyclic, C 5-10 heteroaryl or C 5-10Heterocyclic groups, which are optionally substituted by one or more groups selected from the following:

[0883] a) One or two ═O groups;

[0884] b) One or more halo groups;

[0885] c) CN, NH2, OH;

[0886] d) One or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH, C 1-6 alkylsulfonyl or one or more halo groups;

[0887] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0888] f) C 1-6 alkyl esters;

[0889] g) C 5-6 heterocyclic groups, which have optional methyl, OH or ═O substituents;

[0890] h) C 5-6 heteroaryl groups, which are optionally substituted by methyl;

[0891] i) C 4-10 carbocyclic groups, which have optional methyl or ═O substituents;

[0892] j) C 6-10 carboaryl groups, which have optional substituents of one or more halo groups;

[0893] l) Carboxyl, CH2 - carboxyl

[0894] m) P(═O)Me2.

[0895] In some embodiments, D is C 6-10 carboaryl, C 4-10 carbocyclic, C 5-10 heteroaryl or C 5-10 heterocyclic groups, which are optionally substituted by one or more groups selected from the following:

[0896] a) One or two ═O groups;

[0897] b) One or more halo groups;

[0898] c) CN, NH2, OH;

[0899] d) One or more C 1-6An alkyl group, which includes branched-chain and cyclic ones and has optional substituents selected from OH or one or more halo groups;

[0900] e)C 1-6 An alkoxy group, which has optional substituents of one or more halo groups;

[0901] f)C 1-6 Alkyl esters;

[0902] g)C 5-6 A heterocyclic group, which has optional methyl, OH or ═O substituents;

[0903] h)C 5-6 Heteroaryl;

[0904] i)C 4-10 A carbocyclic group, which has optional methyl or ═O substituents;

[0905] j)C 6-10 A carbaryl group, which has optional substituents of one or more halo groups;

[0906] l) Carboxyl, CH2-carboxyl

[0907] m) P(═O)Me2.

[0908] 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 (CF3), OCF3, carboxyl (C(═O)OH), CN, phenyl optionally having an F substituent at the para position or piperazine having a methyl substituent. In some embodiments, the pyridin-2-one is unsubstituted. In some embodiments, the optional substituents are selected from OMe, carboxyl, Cl, methyl optionally substituted with -S(═O)2CH3, CN, phenyl substituted with F, piperazinyl substituted with methyl, CF3, OCF3, pyrazolyl optionally substituted with methyl, tetrazolyl or triazolyl. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0909] In some embodiments, D is an optionally substituted 6-membered heteroaryl containing one or two N atoms, wherein one N atom is bonded to a C substituted with =O at the ortho position, and the other optional substituents are selected from methyl, OMe, piperazinyl substituted with methyl, C(=O)OH (carboxyl), Cl, F, pyrazolyl, triazolyl, tetrazolyl, phenyl substituted with fluorine, 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 (carboxyl), Cl, phenyl substituted with fluorine, CN, CF3, O-CF3, pyrazole, triazole or tetrazole optionally substituted with methyl.

[0910] In other embodiments, the compound of formula A-B-C has formula (I-C):

[0911]

[0912] wherein X 1 , R A2 and R A3 are as defined in (I-A).

[0913] In some embodiments, one or both of R D1 , R D2 , R D3 and R D4 are selected from C 1-6 alkyl optionally substituted with one or more halo groups; C 1-6 alkoxy optionally substituted with one or more halo groups, C 5-6 heterocyclic group having an optional methyl substituent or C 5-6 heteroaryl, carboxyl, =O, halo, NH2, CN, or phenyl optionally substituted with one or more halo atoms, or C 1-6 alkyl optionally substituted with C 1-6 alkylsulfonyl; or

[0914] wherein R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, CN, P(=O)Me2 and C(=O)OH;

[0915] or wherein R D1 , R D2 , R D3 and R D4 are all H.

[0916] In some embodiments, R D1 , R D2 , RD3 and R D4 one or both of which are selected from C 1-6 alkyl optionally substituted with one or more halo groups or -S(=O)2CH3; C 1-6 alkoxy optionally substituted with one or more halo groups, C with an optional methyl substituent 5-6 heterocyclic group or C 5-6 heteroaryl, carboxyl, =O, halo, NH2, CN or phenyl optionally substituted with one or more halo atoms; or

[0917] wherein R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, C(=O)OH.

[0918] In another embodiment, one or both of R D1 , R D2 , R D3 and R D4 are selected from methyl, OMe, halo, C(=O)OH, CN, CF3, OCF3, OCHF2, pyrazolyl, triazolyl, tetrazolyl, and the rest are H. In another embodiment, one or both of R D1 , R D2 , R D3 and R D4 are selected from methyl, OMe, halo, C(=O)OH, CN, CF3, OCF3, pyrazolyl, triazolyl, tetrazolyl optionally substituted with -S(=O)2CH3, phenyl substituted with fluorine, piperazine substituted with methyl, and the rest of R D1 , R D2 , R D3 and R D4 are H.

[0919] In one embodiment, all R D1 , R D2 , R D3 and R D4 are H.

[0920] In some embodiments, R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0921] In other embodiments, the compound of formula A-B-C has the formula (I-D):

[0922] 1 In some embodiments, X A1 , R A1 and R 1-6 are as defined in (I-A). 1-6 1-6 In some embodiments, X 1-6 is NR 1-6 or CR 1-6 R 1-6 ; A2 1-6 R 1-6 is selected from H or methyl; 1-6 1-6 R 1-6 and R 1-6 are both H or together they are -CH2-; 1-6 1-6 R 1-6 is selected from H, =O, methyl, CH2OH or C(=O)OH; 1-6 4-5 R 1-6 is selected from H, =O, methyl, CH2OH or C(=O)OH; 1-3 2-3 R 4-6 is H, where when R 1-3 is =O, R 1-3 is absent; A3 1-6 Or where R 1-6 and R 1-6 together form a benzene ring or a C6 heteroaromatic ring, which is optionally substituted with CN, P(=O)Me2 or carboxyl, and R 1-6 and R 1-6 are absent. 1-6 1-6 In some embodiments, the compound has the formula (I) 1-6 1-6 A - B - C (I) 1-6 1-6 or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof, 1-6 1-6 wherein A has the following formula: 1-6 1-6 1-6 1-6 1-6 where the wavy line indicates the point of attachment to B; 1-6 1-6 X 1-6 is C - R 1-6 ; 1-6 1-6 R A3 is selected from the group consisting of A2

[0939] (i) H;

[0940] (ii) a halogen group;

[0941] (iii) CN;

[0942] (iv) C 1-6 hydrocarbon, which is optionally substituted by one or more OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogen groups;

[0943] (v) C 1-6 alkoxy, which is optionally substituted by OH, one or more halogen groups, C 1-6 alkylamido;

[0944] (vi) C 1-6 alkyl ester;

[0945] (vii) C 1-6 alkyl acyl; and

[0946] (viii) OH;

[0947] R A2 is selected from the group consisting of:

[0948] (i) H;

[0949] (ii) a halogen group;

[0950] (iii) CN;

[0951] (iv) C 1-6 hydrocarbon, which is optionally substituted by OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogen groups;

[0952] (v) C 1-6 alkoxy, which is optionally substituted by OH, alkylamido or one or more halogen groups;

[0953] (vi) C 1-6 acylamido (wherein the acyl is optionally substituted by H or methyl);

[0954] (vii) C 1-6 thioalkyl;

[0955] (viii) C 1-6 alkyl ester;

[0956] (ix) C 1-6 alkyl acyl;

[0957] (x) C4-5 Heterocyclic group;

[0958] (xi) C5 heteroaryl;

[0959] (xii) C 1-6 alkylcarbonylamino, optionally substituted by C 1-3 alkylcarbonylamino, CN, C 2-3 alkynyl, C 4-6 heterocyclic group or C 1-3 alkyl substituted, wherein said C 1-3 alkyl is optionally substituted by one or more halogenated groups or OH groups; and

[0960] (xiii) OH;

[0961] R A3 is selected from the group consisting of:

[0962] (i) H;

[0963] (ii) halogenated group;

[0964] (iii) CN;

[0965] (iv) C 1-6 hydrocarbon, optionally substituted by OH, CN, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 acyloxy, carboxyl, C 1-6 alkyl ester, C 1-6 alkylamino, -C(=O)NH2, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylcarbonylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or one or more halogenated groups;

[0966] (v) OH;

[0967] (vi) C 1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclic group or one or more halogenated groups;

[0968] (vii) C 1-6 acyloxy;

[0969] (viii) C4 heterocyclic group;

[0970] (ix) -NH2;

[0971] (x) C 1-6 alkylamino, optionally substituted by CN, OH or C4 heterocyclic group;

[0972] (xi) C 1-6 Dialkylamino, optionally substituted with -NH2;

[0973] (xii) C 1-6 Acylamido (wherein the acyl substituent is H or Me);

[0974] (xiii) Amidino or methyl - amidino;

[0975] (xiv) Carboxylamino;

[0976] (xv) C 1-6 Thioalkyl, optionally substituted with OH or NH2;

[0977] (xvi) C 1-6 Alkylsulfinyl;

[0978] (xvi) C 1-6 Alkylsulfonyl, optionally substituted with one or more halogen groups;

[0979] (xvii) C 1-6 Sulfonimido;

[0980] (xviii) C 1-6 Alkylphosphono;

[0981] (xix) Carboxyl;

[0982] (xx) C(=O)NH2

[0983] (xxi) C 1-6 Alkyl ester;

[0984] (xxii) C 1-6 Alkylacyl, optionally substituted with one or more halogen groups; and

[0985] (xxiii) C 1-6 Alkylamido;

[0986] Or wherein R A3 and R A2 together with the carbon atom to which they are attached form:

[0987] (i) Optionally substituted C 5-7 Heterocycle;

[0988] (ii) Optionally substituted C 5-7 Heteroaromatic ring;

[0989] (iii) Optionally substituted C6 carbon aromatic ring;

[0990] (iv) Optionally substituted C 5-7 Carbocycle

[0991] Wherein the optional substituents are selected from C 1-6 alkyl, halo, C 1-6 alkoxy, NH2, C 1-6 alkylamino, OH and CN;

[0992] Wherein B has the formula (B-1) or (B-2)

[0993] i)

[0994]

[0995] Wherein the wavy line indicates the attachment points to A and C;

[0996] R B1 is H, OH, =CHCH2-OH, -O-C 1-4 alkyl or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted by OH or OMe;

[0997] (ii)

[0998]

[0999] Wherein the wavy line indicates the attachment points to A and C;

[1000] R B2 is C 1-2 alkyl-OH, CH2CONHMe or C 1-3 alkyl;

[1001] Wherein C is selected from the group consisting of C 6-10 carbaryl, C 5-6 heteroaryl and C 5-10 heterocyclic group, said groups being optionally substituted by:

[1002] (i)C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[1003] which are themselves optionally substituted by one or more of the following groups;

[1004] a) one or two =O groups;

[1005] b) one or more halo groups;

[1006] c) CN, NH2, OH;

[1007] d) one or more C 1-6 alkyl groups, which include branched and cyclic and have optional substituents selected from OH or one or more halo groups;

[1008] e) C 1-6 alkoxy groups, which have optional substituents of one or more halo groups;

[1009] f) C 1-6 alkyl esters;

[1010] g) C 5-6 heterocyclic groups, which have optional methyl, OH or =O substituents;

[1011] h) C 5-6 heteroaryl;

[1012] i) C 4-10 carbocyclic groups, which have optional methyl or =O substituents;

[1013] j) C 6-10 carboaryl, which have optional substituents of one or more halo groups;

[1014] l) P(=O)Me2;

[1015] m) carboxyl or CH2-carboxyl; and / or

[1016] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[1017] (ii) one or more groups selected from carboxyl, CN, halo, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino and di-C 1-6 alkylsulfinylamino groups.

[1018] In some embodiments, the compound has the formula (I)

[1019] A-B-C (I)

[1020] or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof,

[1021] wherein A has the following formula:

[1022]

[1023] Wherein the wavy line indicates the attachment point to B;

[1024] R A2 is C substituted by C 1-6 alkyl ester, 1-6 alkylthio or alkylacylamino substituted by OH;

[1025] C is selected from the group consisting of C 6-10 carbaryl, C 5-6 heteroaryl and C 5-10 heterocyclic group, and the said groups are optionally substituted by the following:

[1026] (i) selected from C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[1027] which are optionally substituted by one or more of the following groups;

[1028] one or more C 1-6 alkyl groups (including branched and cyclic ones, having C 1-6 alkylsulfonyl substituent) or C 5-6 heteroaryl substituted by methyl;

[1029] wherein X 1 、R A3 and B are as defined above.

[1030] In some embodiments, the compounds of formula (I) are selected from Table 1 below.

[1031] Table 1.

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039] Additional compounds are shown in Table 2:

[1040] Table 2.

[1041]

[1042]

[1043]

[1044]

[1045]

[1046] In some embodiments, the compound is selected from 36, 47, and 103. In some embodiments, the compound is 36.

[1047] Additional compounds are shown in Table 2a:

[1048] Table 2a

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055] General synthesis

[1056] Compounds according to general formula (I-B) can be prepared according to Scheme 1, 2, or 3 below. The schemes and procedures described below illustrate the synthetic routes of the compounds of general formula (I-B) and are not intended to be limiting. Obviously, the order of the transformations illustrated in Scheme 1, 2, or 3 can be modified in various ways. Therefore, the order of the transformations illustrated in these schemes is not intended to be limiting.

[1057] The routes for preparing the compounds of general formula (I-B) and the corresponding intermediates are described in Scheme 1, 2, or 3.

[1058] Scheme 1 .

[1059]

[1060] Scheme 1: Route for the preparation of compounds of general formula (I-B), where X is a leaving group, PG is a protecting group, and D, X 1 , R A2 and R A3 have the meanings given above for general formula (I-B).

[1061] The monoarylated diamine of general formula (A3) can be obtained by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination between a mono-protected diamine (A1) or its corresponding salt and a heteroaryl (A2a) where X is a leaving group such as halogen or -S(O)Me, as depicted in Scheme 1. For the S N Ar method (where X is a group such as, for example, fluorine or -S(O)Me), the 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 in the absence of any additional base, in a polar solvent such as DMSO, NMP or nBuOH, at a temperature between 100 °C and 130 °C. The reaction time can vary between 1 hour and 24 hours. In some cases, the application of microwave heating may be beneficial.

[1062] For palladium-catalyzed Buchwald-Hartwig amination, all methods known in the art can be applied. For example, the diamine (A1) can be reacted with (A2a) in the presence of a palladium catalyst such as Pd PEPPSI-IpentCl [CAS 1612891-29-8], Pd2(dba)3 or tBuXPhos Pd G3 [1447963-75-8] and a base such as Cs2CO3 or NaOtBu, in an aprotic solvent such as 1,4-dioxane, DMF, toluene or DMA, at a temperature between room temperature and 130 °C, preferably at 65 °C - 100 °C for 15 hours - 24 hours.

[1063] The diamine of general formula (A1) and the heteroaryl of general formula (A2a) are commercially available or can be prepared according to procedures available from the public domain. For the synthesis of the diamine (A1), see, for example, WO2004004726 and the references therein.

[1064] The aryl diamine of general formula (A6) can be obtained from (A3) by copper-catalyzed Ullmann coupling with the heterocycle (A4) or by palladium-catalyzed Suzuki coupling with the boronic acid derivative (A5). For the Ullmann coupling, all methods known in the art can be applied. For example, (A3) can react with (A4) in the presence of a copper catalyst (such as Cu(I)I, Cu(OTf)2 or Cu(OAc)2) and a base (such as Cs2CO3 or K2CO3) in a polar aprotic solvent (such as 1,4-dioxane, DMF or pyridine) at a temperature between room temperature and 120 °C, preferably at 100 °C, for 15 to 20 hours. In some cases, a ligand (such as N 1 ,N 2 -dimethylcyclohexane-1,2-diamine, TMEDA, N 1 ,N 2 -dimethylethane-1,2-diamine or N,N-dimethylglycine) can be added to the reaction mixture.

[1065] For the Suzuki coupling for (A6), all methods known in the art can be applied. For example, (A3) can react with the boronic acid derivative (A5) in the presence of a palladium catalyst (such as 1,1'-bis(di-tert-butylphosphino)ferrocene dichloride [CAS 95408-45-0] or 1,1'-bis(diphenylphosphino)ferrocene dichloride [CAS 72287-26-4]) and a base (such as Cs2CO3, K2CO3 or K3PO4) in a polar solvent (such as 1,4-dioxane, THF and water or a mixture thereof) at a temperature between room temperature and 120 °C for 2 to 15 hours.

[1066] The heterocycle of general formula (A4) and the boronic acid derivative of general formula (A5) are commercially available or can be prepared according to procedures available from the public domain.

[1067] The primary amine of general formula (A7) can be obtained from the mono-protected diamine of general formula (A6) by a deprotection method. Depending on the protecting group applied, these methods can be, for example, acidic, basic, oxidative or hydrogenative methods. Suitable protecting moieties for the amino group and their introduction and cleavage are well known in the art. For an overview of protecting group chemistry, see, for example, Wuts 2014.

[1068] The final compound of general formula (I-B) can be obtained from the primary amine of general formula (A7) by nucleophilic aromatic substitution (S NSynthesized by aryl (Ar)- or palladium-catalyzed Buchwald-Hartwig amination. Primary amines of general formula (A7) can react with heteroaryl groups of general formula (A8) (wherein X is a leaving group such as a halogen (such as chlorine) or -S(O)Me) using procedures similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a). Heteroaryl groups of general formula (A8) are commercially available or can be prepared according to procedures available in the public domain.

[1069] An alternative route for compounds of general formula (I-B) starts with the deprotection of diamines of general formula (A3) to obtain primary amines of general formula (A9), as depicted in Scheme 1. For deprotection, the same procedures as those described for the synthesis of (A7) from (A6) are applied.

[1070] The primary amines of general formula (A9) can in turn react with heteroaryl groups of general formula (A8) by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination reaction to obtain aryl iodides of general formula (A10), using procedures similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a).

[1071] The final compounds of general formula (I-B) can be synthesized from aryl iodides of general formula (10) by copper-catalyzed Ullmann coupling with heterocycle H-D (A4) or by palladium-catalyzed Suzuki coupling with boronic acid derivatives (A5), using procedures similar to those described in Scheme 1 for the synthesis of compound (A6) from (A3).

[1072] Another method for compounds of general formula (I-B) starts with a mono-protected diamine (1) or its corresponding salt and a pre-assembled heteroaryl group (A11a) (wherein X is a leaving group such as a halogen or -S(O)Me), through nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination to obtain aryl-substituted diamines of general formula (A6). The procedures that can be applied are similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a). Heteroaryl groups of general formula (A11a) are commercially available or can be prepared according to procedures available in the public domain (e.g., by Chan-Lam coupling). Specific examples of (A11a) are described in the subsequent paragraphs.

[1073] Alternative routes for the preparation of compounds of general formula (I-B) and intermediates of general formula (A10) are depicted in Scheme 2.

[1074] Scheme 2

[1075]

[1076] Scheme 2: Route for the preparation of compounds of general formula (I-B) and intermediate (A10), where X is a leaving group, PG is a protecting group, and D, X 1 , R A2 and R A3 have the meanings given above for general formula (I-B).

[1077] The monoarylated diamine of general formula (A12) can be obtained by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination between a mono-protected diamine (A1) or its corresponding salt and a heteroaryl (A8) where X is a leaving group such as halogen or -S(O)Me. The procedures that can be applied are similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a).

[1078] Deprotection of the diamine of general formula (A12) can give the primary amine of general formula (A13). For deprotection, the same procedures as described in Scheme 1 for the synthesis of (A7) from (A6) are applied.

[1079] The final compound of general formula (I-B) can in turn be synthesized from the primary amine (A13) or its corresponding salt and a pre-assembled heteroaryl (A11a) where X is a leaving group such as halogen or -S(O)Me, by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination. The procedures that can be applied are similar to those described in Scheme 1 for the synthesis of (A6) from (A1) and (A11a).

[1080] For the synthesis of the intermediate of general formula (A10), the primary amine (A13) or its corresponding salt can react with a heteroaryl (A2a) where X is a leaving group such as halogen or -S(O)Me in a nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination. The procedures that can be applied are similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a).

[1081] The carboxylic acid derivative of general formula (A21) can be synthesized according to the route depicted in Scheme 3. The nitro compound of general formula (A15) can be obtained by reacting a mono-protected diamine (A1) or its corresponding salt with a nitroaryl (A14) where X is a leaving group such as chlorine in a nucleophilic aromatic substitution (S NIt can be obtained by reacting in (Ar). This reaction can be carried out 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 hours to 12 hours. The nitroaryl of general formula (A14) is commercially available or can be prepared according to procedures available from the public domain.

[1082] The aniline of general formula (A16) can be obtained by reducing the nitro compound of general formula (A15). For the reduction, all methods known in the art can be applied. For example, the nitro compound of general formula (A15) can be reacted in the presence of a metal catalyst (such as palladium / carbon), in a hydrogen atmosphere (1 bar to 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 hours to 24 hours.

[1083] Scheme 3

[1084]

[1085] Scheme 3: Route for preparing the compound of general formula (A21), where X is a leaving group, PG is a protecting group, Alk is methyl or ethyl, and X 1 、R A2 and R A3 have the meanings given above for general formula (I-B).

[1086] The pyridone of general formula (A18) can be obtained by condensing aniline (A16) with oxo-pyran of general formula (A17) (where 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 hours to 12 hours. The oxo-pyran of general formula (A17) is commercially available or can be prepared according to procedures available from the public domain.

[1087] The primary amine of general formula (A19) can be synthesized from (A18) by removing the protecting group. For deprotection, the same procedure as described for synthesizing (A7) from (A6) in Scheme 1 is applied.

[1088] The carboxylic acid ester of general formula (A20) can be obtained from the primary amine (A19) and the heteroaryl (A8) by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination, applying procedures similar to those described for synthesizing (A3) from (A1) and (A2a) in Scheme 1.

[1089] The carboxylic acid derivatives of general formula (A21) can be synthesized from the carboxylic acid esters of general formula (A20) by ester hydrolysis. For saponification, all methods known in the art can be applied. For example, the ester (A20) can be reacted with a base (such as sodium hydroxide) in a polar protic solvent (such as methanol, water, or a mixture thereof) at a temperature between 0 °C and the boiling point of the solvent for 0.5 to 2 hours.

[1090] For the synthesis of the final compounds of general formula (B-2), routes and methods analogous to those described in Schemes 1 to 3 can be applied. The routes for the compounds of general formula (A43) are given in Schemes 6 to 7 for further illustration but are not intended to be limiting. The diamines of general formula (A39) are commercially available or can be prepared according to procedures available from the public domain.

[1091] Scheme 6

[1092]

[1093] Scheme 6: Route for the preparation of compounds of general formula (A43), where X is a leaving group, PG is a protecting group, and D, X 1 , R A2 , R A3 and R B2 have the meanings given above for general formulas (I-B) and (B-2).

[1094] Scheme 7

[1095]

[1096] Scheme 7: Route for the preparation of compounds of general formula (A43) and intermediate (A45), where X is a leaving group, PG is a protecting group, and D, X 1 , R A2 , R A3 and R B2 have the meanings given above for general formulas (I-B) and (B-2).

[1097] Additional compounds with different formulas as described above can be prepared by similar methods.

[1098] Experimental section

[1099] NMR peaks are stated as they appear in the spectrum without considering possible higher-order effects.

[1100] The following table lists the abbreviations used in this section and in the Examples section, provided they are not explained in the text. Other abbreviations have their customary meanings to those skilled in the art.

[1101] Abbreviations

[1102] Aq Aqueous

[1103] BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene

[1104] Boc tert-Butyloxycarbonyl

[1105] Brine Saturated sodium chloride aqueous solution

[1106] nBuOH Butan-1-ol

[1107] CataCXium A Bis(adamantan-1-yl)(butyl)phosphine (CAS Registry Number 321921-71-5)

[1108] CataCXium A Pd G3 (Diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) 3rd generation precatalyst

[1109] CDI 1,1'-Carbonyldiimidazole

[1110] CHAPS 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate

[1111] m-CPBA 3-Chloroperoxybenzoic acid

[1112] DavePhos 2'-(Dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (CAS Registry Number 213697-53-1)

[1113] dba (All-E)-Dibenzylideneacetone

[1114] DCC Dicyclohexylcarbodiimide

[1115] DCM Dichloromethane

[1116] DEA Diethylamine

[1117] DIPEA N-Ethyl-N-isopropylpropan-2-amine

[1118] DMA N,N-Dimethylacetamide

[1119] DME Dimethoxyethane

[1120] DMF N,N-Dimethylformamide

[1121] DMSO Dimethyl sulfoxide

[1122] DPPA Diphenylphosphoryl azide

[1123] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[1124] EDC 2-(((Ethylimino)methylene)amino)-N,N-dimethylethan-1-amine hydrochloride

[1125] ESI Electrospray ionization

[1126] EtOAc Ethyl acetate

[1127] EtOH Ethanol

[1128] FA Formic acid

[1129] G3 Generation 3

[1130] GMean Geometric mean

[1131] HATU (1-(Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[1132] HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)

[1133] HOAt 3H-[1,2,3]Triazolo[4,5-b]pyridin-3-ol

[1134] HOBt 1H-Benzotriazol-1-ol

[1135] HPLC High performance liquid chromatography

[1136] HRMS High resolution mass spectrometry

[1137] IC 50 Half maximal inhibitory concentration

[1138] K D Dissociation constant

[1139] MeCN Acetonitrile

[1140] MeOH Methanol

[1141] MS Mass spectrometry

[1142] MTBD 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[1143] MTBE Methyl tert-butyl ether

[1144] MW Microwave

[1145] NBS N-Bromosuccinimide

[1146] NMP 1-Methylpyrrolidin-2-one

[1147] NMR Nuclear Magnetic Resonance

[1148] O.n Overnight

[1149] OTf Trifluoromethanesulfonate

[1150] Pd-118 / PdCl2(dtbpf) Palladium(II) Dichloride [1,1'-Bis(di-tert-butylphosphino)ferrocene]

[1151] Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)

[1152] Pd2(dba)3·CHCl3 Tris(dibenzylideneacetone)dipalladium(0) Chloroform Adduct

[1153] PdCl2(dppf) Palladium(II) Dichloride [1,1'-Bis(diphenylphosphino)ferrocene]

[1154] Pd-PEPPSI-IpentCl

[1155] 2-Methylpyridine (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-yl]dichloride(2-methylpyridine)palladium (CAS Registry Number 1612891-29-8)

[1156] PE Petroleum Ether

[1157] PG Protecting Group

[1158] prep. Preparative

[1159] PyBOP ((1H-Benzotriazol-1-yl)oxy)tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate

[1160] qToF Quadrupole Time-of-Flight

[1161] RockPhos Di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine

[1162] rt Room Temperature

[1163] sat. Saturated

[1164] SFC Supercritical Fluid Chromatography

[1165] S N Ar Aromatic Nucleophilic Substitution

[1166] T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide

[1167] TEA Triethylamine

[1168] TFA Trifluoroacetic acid

[1169] TFAA 2,2,2-Trifluoroacetic anhydride

[1170] THF Tetrahydrofuran

[1171] TLC Thin layer chromatography

[1172] TMEDA N 1 ,N 1 ,N 2 ,N 2 -Tetramethylethane-1,2-diamine

[1173] t R Retention time

[1174] UPLC Ultra performance liquid chromatography

[1175] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

[1176] XPhos Dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine

[1177] Units

[1178] atm Atmosphere

[1179] C Celsius

[1180] g Gram

[1181] h Hour

[1182] Hz Hertz

[1183] L Liter

[1184] M Mole per liter

[1185] mg Milligram

[1186] MHz Megahertz

[1187] min Minute

[1188] mL Milliliter

[1189] mm Millimeter

[1190] mM millimole per liter

[1191] mol mole

[1192] mmol millimole

[1193] nA nanoampere

[1194] nL nanoliter

[1195] μm micrometer

[1196] μL microliter

[1197] N normal per liter

[1198] nm nanometer

[1199] ppm parts per million

[1200] angstrom

[1201] 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.

[1202] The exemplary test experiments described herein are used to illustrate this embodiment and are not limited to the examples given.

[1203] Experimental section - General part

[1204] General conditions

[1205] (i) Operations are carried out at room temperature (rt) (i.e., in the range of 17 °C to 28 °C) and, if necessary, under an atmosphere of an inert gas such as N2.

[1206] (ii) In cases where the reaction involves degassing or purging, this can be carried out, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (e.g., 5 minutes to 10 minutes) or by repeatedly evacuating the vessel and backfilling with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g)).

[1207] (iii) In cases where the reaction involves the use of a microwave reactor, one of the following microwave reactors is used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry SmithCreator, or CEM Explorer.

[1208] (iv) Generally, the reaction progress was monitored by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) usually coupled with a mass spectrometer (LCMS);

[1209] (v) To remove excess water, the organic solution was dried over anhydrous MgSO4 or Na2SO4, or by using a phase separator, and the post-treatment procedures were carried out using traditional phase separation techniques;

[1210] (vi) Evaporation was carried out by rotary evaporation in vacuo or in a Genevac TM HT-4 / EZ-2 or V10;

[1211] (vii) Unless otherwise stated, flash column chromatography was carried out on normal phase silica using Merck silica gel (Art. 9385) or pre-packed cartridges such as SNAP cartridges (40μm - 63μm silica, 4g - 330g), silica HC D cartridges (20μm, 10g - 100g), Interchim puriFlash TM cartridges (25μm, 4g - 120g), Interchim puriFlash TM cartridges (50μm, 25g - 330g), Grace TM GraceResolv TM silica flash cartridges (4g - 120g) or Agela flash column silica - CS cartridges (80g - 330g), or on reverse phase silica using Agela Technologies C-18 spherical cartridges (20μm - 35μm, 100A, 80g–330g) using Grace X2 rapid system or similar systems manually or automatically;

[1212] (viii) Using an isocratic or gradient mobile phase as described in the experimental section, preparative reverse phase HPLC and preparative reverse phase SFC were carried out using standard HPLC and SFC instruments equipped with MS and / or UV-triggered fraction collection instruments respectively; the relevant fractions were collected, combined and freeze-dried or evaporated to obtain the purified compound, or the relevant fractions were collected, combined and concentrated under reduced pressure, extracted with DCM or EtOAc, and the organic phase was dried over Na2SO4 or by using a phase separator, and then concentrated under reduced pressure to obtain the purified compound;

[1213] (ix) Perform chiral preparative chromatography using HPLC or SFC, respectively, on a standard HPLC or SFC instrument and using isocratic or gradient runs with mobile phases as described in the experimental section;

[1214] (x) Perform preparative thin layer chromatography (TLC) using TLC glass plates and applying a suitable solvent or solvent mixture;

[1215] (xi) The yield (where present) is not necessarily the maximum obtainable, and if a larger amount of the reaction product is required, some reactions are repeated;

[1216] (xii) In cases where certain compounds are obtained as acid addition salts (e.g., mono-hydrochloride or di-hydrochloride), the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and the exact stoichiometry of the salt usually cannot be determined, for example, from elemental analysis data. The salt is treated according to methods known from the literature before use to produce the corresponding free base;

[1217] (xiii) Generally, the structure of the end product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; proton NMR chemical shift values are measured on a δ scale using Bruker Avance III 300, 400, 500, and 600 spectrometers (operating at 1 300 MHz, 400 MHz, 500 MHz, and 600 MHz H frequencies, respectively). Experiments are usually 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 only reported if detected in the NMR and may thus be missing. In some cases, protons may be obscured or partially obscured by solvent peaks and are thus 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 doublets, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; qn, quintet; p, pentet. Electrospray mass spectrometry data are obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or a similar device, acquiring cationic and anionic data, and usually only reporting ions related to the parent structure; high-resolution electrospray mass spectrometry data are obtained using a Waters XEVO qToF mass spectrometer or a similar device coupled to a Waters Acquity UPLC, acquiring cationic and anionic data, and usually only reporting ions related to the parent structure;

[1218] (xiv) The intermediates were not fully purified in some cases, but their structures and purities were evaluated by TLC, analytical HPLC / UPLC and / or NMR analysis and / or mass spectrometry;

[1219] (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. The salts were treated according to methods known from the literature before use to produce the corresponding free bases;

[1220] (xvi) Compounds containing asymmetric carbon and / or sulfur atoms were not resolved unless otherwise stated;

[1221] (xvii) In general, the examples and intermediate compounds were named using ChemDraw Professional version 21.0.0.28 from PerkinElmer. ChemDraw Professional version 21.0.0.28 uses the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate the names of chemical structures and adheres as strictly as possible to the IUPAC rules when generating chemical names. Stereoisomers are distinguished from each other by stereodescriptors cited in the name and are assigned according to the CIP rules.

[1222] Where applicable, ChemDraw uses markers such as “&” and “or” in the illustration of stereocenters to describe the configuration of the stereochemical centers present in the structure. The numbers following the “&” and “or” symbols are assigned to each stereocenter present.

[1223] In some cases, the purification methods described above can provide compounds of formula (I) having sufficiently basic or acidic functional groups in salt form, such as, in the case of compounds of formula (I) that are sufficiently basic, for example trifluoroacetate or formate, or in the case of compounds of formula (I) that are sufficiently acidic, for example ammonium salts. This type of salt can be converted separately into its free base or free acid form by various methods known in the art or used as a salt in subsequent biological assays. It should be understood that the specific forms of the compounds of formula (I) isolated and as described herein (e.g., salts, free bases, etc.) are not necessarily the only forms in which the compounds can be applied in biological assays to quantify a specific biological activity.

[1224] Purification method

[1225] Preparative HPLC method :

[1226] Preparation method A: The compound was purified by preparative HPLC on XBridge TMPurification was carried out on a C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeOH in a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1227] Preparation method B: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150×30 mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1228] Preparation method C: The compound was purified by preparative HPLC on an XBridge TM Shield RP18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1229] Preparation method D: The compound was purified by preparative HPLC on an XBridge TM C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1230] Preparation method E: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in a buffer system of H2O / FA (0.1%) as the mobile phase;

[1231] Preparation method F: The compound was purified by preparative HPLC on an XBridge TM C18 column (10 μm, 250×50 mm ID) using a gradient of MeCN in a buffer system of H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase;

[1232] Preparation method G: The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×20 mm ID) using a gradient of MeCN in a buffer system of H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase;

[1233] Preparation method H: The compound was purified by preparative HPLC on an XBridge TMPurification was carried out using a gradient of MeCN in the buffer system of H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase on a C18 column (10 μm, 250×19 mm ID);

[1234] Preparation method I: The compound was purified by preparative HPLC on an XBridge TM C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM, pH 9) as the mobile phase.

[1235] Preparation method J: The compound was purified by preparative HPLC on a Waters TM Sunfire TM C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / FA (0.1%) as the mobile phase;

[1236] Preparation method K: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) as the mobile phase;

[1237] Preparation method L: The compound was purified by preparative HPLC on a Waters TM Sunfire TM C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1238] Preparation method M: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1239] Preparation method N: The compound was purified by preparative HPLC on an XBridge TM OBD phenyl column (5 μm, 150×19 mm ID) using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1240] Preparation method O: The compound was purified by preparative HPLC on an XBridge TMPurification was carried out using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) as the mobile phase on a C18 OBD column (5 μm, 150×30 mm ID);

[1241] Preparation method P: The compound was purified by preparative HPLC using a gradient of MeCN in H2O as the mobile phase on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID);

[1242] Preparation method Q: The compound was purified by preparative HPLC using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) as the mobile phase on an XBridge TM Shield RP18 OBD column (5 μm, 250×19 mm ID);

[1243] Preparation method R: The compound was purified by preparative HPLC on a Waters TM Sunfire TM C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / FA (10 mM) as the mobile phase;

[1244] Preparation method S: The compound was purified by preparative HPLC using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) as the mobile phase on an XBridge TM C18 OBD column (5 μm, 150×30 mm ID);

[1245] Preparation method T: The compound was purified by preparative HPLC using a gradient of 20 mM NaOH + 10% MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) as the mobile phase on an XBridge TM C18 OBD column (5 μm, 150×30 mm ID);

[1246] Preparation method U: The compound was purified by preparative HPLC using a gradient of MeCN in the buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) as the mobile phase on an XBridge TM OBD phenyl column (5 μm, 250×19 mm ID);

[1247] Preparation method V: The compound was purified by preparative HPLC on an XBridge TMPurification was carried out using a gradient of MeCN in an H2O / TFA (0.05%) buffer system as the mobile phase on an OBD phenyl column (5 μm, 250×19 mm ID);

[1248] Preparation method X: The compound was purified by preparative HPLC using a gradient of MeCN in an H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase on a YMC-Actus Triart C18 ExRS column (5 μm, 150×30 mm ID);

[1249] Preparation method Y: The compound was purified by preparative HPLC on an XBridge TM Shield RP18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1250] Preparation method Z: The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in an H2O / FA (0.1%) buffer system as the mobile phase;

[1251] Preparation method Z1: The compound was purified by preparative HPLC on a Waters Xselect Peptide CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) buffer system as the mobile phase;

[1252] Preparation method Z2: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1253] Preparation method Z3: The compound was purified by preparative HPLC on an XBridge TM C18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1254] Preparation method Z4: The compound was purified by preparative HPLC on an XBridgeTM Purification was carried out using a gradient of MeCN in a H2O / TFA (0.005%) buffer system as the mobile phase on a C18 OBD column (5 μm, 250×19 mm ID);

[1255] Preparation method Z5: The compound was purified by preparative HPLC using a gradient of MeOH in a H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase on a Waters Xselect CSH C18 OBD column (5 μm, 250×19 mm ID);

[1256] Preparation method Z6: The compound was purified by preparative HPLC on an XBridge TM Shield RP18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) buffer system as the mobile phase;

[1257] Preparation method Z7: The compound was purified by preparative HPLC on an XBridge TM C18 OBD column (5 μm, 100×50 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) buffer system as the mobile phase;

[1258] Preparation method Z8: The compound was purified by preparative HPLC on an XBridge TM RP18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in a H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) buffer system as the mobile phase;

[1259] Preparation method Z9: The compound was purified by preparative HPLC on an XBridge TM 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;

[1260] Preparation method Z10: The compound was purified by preparative HPLC on an XBridge TM C8 column (5 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;

[1261] Preparative SFC method :

[1262] Preparation method SFC-A: The compound was purified by preparative SFC on Waters TM BEH (5 μm, 250×30 mm ID) using MeOH / H2O (NH3, 50 mM) (97 / 3) in CO2 as the mobile phase;

[1263] Preparation method SFC-B: The compound was purified by preparative SFC on Phenomenex Luna Hilic (3.5 μm, 100×3 mm ID) using MeOH / NH3 20 mM in CO2 as the mobile phase;

[1264] Preparation method SFC-C: The compound was purified by preparative SFC on Waters TM Acquity UPC2 BEH (3.5 μm, 100×3 mm ID) using MeOH / H2O (NH3, 50 mM) (97 / 3) in CO2 as the mobile phase.

[1265] Preparation method SFC-D: The compound was purified by preparative SFC on Waters TM BEH (5 μm, 250×30 mm ID) using MeOH / NH3 (20 mM) in CO2 as the mobile phase;

[1266] Preparation method SFC-E: The compound was purified by preparative SFC on Phenomenex Luna Hilic (5 μm, 250×30 mm ID) using MeOH / NH3 20 mM in CO2 as the mobile phase.

[1267] Preparative HPLC method for parallel experimental setup :

[1268] Parallel preparation method A: The compound was purified by preparative HPLC on Waters TM XBridge TM C18 column (5 μm, 100×10 mm ID) using a gradient of MeCN in H2O / NH3 (pH 10) buffer system (2% - 94%) as the mobile phase;

[1269] Parallel preparation method B: The compound was purified by preparative HPLC on Waters TM Xselect TM CSH fluorophenyl column (5 μm, 100×10 mm ID) using a gradient of MeCN in H2O / FA (pH 3) buffer system (2% - 94%) as the mobile phase.

[1270] Parallel Preparation Method C: The compound is purified by preparative HPLC on a Waters TM XBridge TM C18 OBD column (5 μm, 150×19 mm ID) using a gradient (5%-95%) of MeCN in a H2O / MeCN / NH3 (95 / 5 / 0.2) (pH 10) buffer system as the mobile phase;

[1271] Parallel Preparation Method D: The compound is purified by preparative HPLC on an XBridge TM C18 OBD column (5 μm, 150×19 mm ID) using a gradient (5%-95%) of MeCN in a H2O / NH4HCO3 (10 mM) (pH 9) buffer system as the mobile phase.

[1272] Synthesis method

[1273] General method 1 (GM1): Nucleophilic aromatic substitution (S N Ar)

[1274] Condition A (GM1A): Conventional heating

[1275] At room temperature, a base (1 equivalent - 7 equivalents) and the corresponding heteroaryl electrophile (0.9 equivalent - 2 equivalents) are added to a solution of the corresponding amine nucleophile or its salt (1 equivalent) in DMSO (alternatively NMP or n-BuOH or 1,4-dioxane), and the resulting mixture is stirred at heating (100 °C - 130 °C) until TLC and / or LCMS indicate complete consumption of the starting material (usually overnight). The reaction mixture is concentrated under reduced pressure and the obtained crude material is subjected to chromatography or preparative TLC and / or preparative HPLC to give the desired aniline product.

[1276] In an alternative aqueous workup, the reaction mixture is poured into saturated brine or water and extracted with EtOAc. The combined organic layers are washed with water or brine, dried over Na2SO4, filtered and evaporated, and the obtained crude material is subjected to silica gel chromatography to give the desired aniline product.

[1277] Condition B (GM1B): Microwave heating

[1278] To a mixture of the corresponding amine nucleophile or its salt (1 equivalent) and the corresponding heteroaryl electrophile (1 equivalent - 1.5 equivalents) in a microwave vial, NMP and a base (1 equivalent - 3 equivalents) are added, the vial is capped and heated under microwave irradiation until TLC and / or LCMS indicate consumption of the starting material (usually 0.5 hour - 2 hours). The reaction mixture is concentrated under reduced pressure and the obtained crude material is subjected to preparative HPLC to give the desired aniline product.

[1279] General method 2 (GM2): Buchwald - Hartwig amination

[1280] A solution of the corresponding amine nucleophile or its salt (1 equiv) in 1,4-dioxane is treated under nitrogen at room temperature with the corresponding heteroaryl electrophile (0.5 equiv - 4 equiv), Cs2CO3 (1.2 equiv - 5 equiv), and Pd PEPPSI-IpentCl [CAS 1612891-29-8] (3 mol% - 7 mol%), and the reaction mixture is stirred under heating (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (usually overnight). The reaction mixture is filtered through a Celite pad or silica gel, the filter cake is washed with EtOAc, and the combined filtrate is concentrated under reduced pressure. The obtained crude material is triturated with PE / EtOAc or subjected to preparative TLC and / or preparative HPLC to give the desired aniline product.

[1281] In an alternative aqueous workup, the reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and water. The phases are separated, and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with water and / or brine, dried over Na2SO4, filtered, and evaporated, and the obtained crude material is subjected to preparative TLC and / or preparative HPLC to give the desired aniline product.

[1282] General method 3 (GM3): Ullmann coupling

[1283] A solution of the corresponding aryl halide (1 equiv) in 1,4-dioxane is treated under nitrogen at room temperature with the corresponding heteroatom nucleophile H-D(A4) (1 equiv - 10 equiv), Cs2CO3 (3 equiv - 6 equiv), Cu(I)I (0.2 equiv - 2 equiv), and rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine [CAS 67579-81-1] (0.2 equiv - 2 equiv), and the reaction mixture is stirred under heating (80 °C - 100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (usually 15 h - 18 h). The reaction mixture is diluted with EtOAc and washed successively 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 obtained crude material is triturated with PE / EtOAc or subjected to preparative TLC and / or preparative HPLC to give the desired coupling product.

[1284] In an alternative non-aqueous workup, the reaction mixture is filtered through a Celite pad, the filter cake is washed with DCM, and the combined filtrate is concentrated under reduced pressure. The obtained crude material is subjected to preparative TLC and / or preparative HPLC to give the desired coupling product.

[1285] Condition A (GM3A): Parallel experimental setup

[1286] Under argon, to a mixture of a pre - mixture of the corresponding heteroatom nucleophile H - D(A4) (50 μmol, 2 equivalents), Cu(I)I (1.9 mg, 10 μmol, 0.40 equivalent) and K2CO3 (10.4 mg, 75.0 μmol, 3.0 equivalents) was added (1S,3S)-N 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 equivalent) and rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane - 1,2 - diamine [CAS 67579 - 81 - 1] (2.8 mg, 20 μmol, 0.80 equivalent) in a stock solution in DMSO (100 μL). The reaction mixture was stirred at 120 °C for 17 h - 22 h and then diluted with DMSO (500 μL). A solution of SiliaMetS TM imidazole metal scavenger (42 mg, 50 μmol, loading: 1.20 mmol / mg) in DMSO (200 μL) was added to each vial and the mixture was shaken overnight at 25 °C at 800 rpm on a microplate shaker. The reaction mixture was transferred to a 24 - well filter plate and filtered into a 4 mL high - recovery vial using a Pressure+manifold. The vial was rinsed with DMSO (1 mL) 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 coupling product. TM

[1287] General method 4 (GM4): Suzuki coupling

[1288] Condition A (GM4A): Coupling with boronic acid derivative

[1289] A solution of the corresponding aryl halide (1 equiv) in a mixture of 1,4-dioxane and water is treated under nitrogen at room temperature with the corresponding boronic acid derivative (A5) (1.5 equiv - 2 equiv) or (A26) (10 equiv), Cs2CO3 (3 equiv) or K2CO3 (3 equiv) or K3PO4 (2 equiv - 3 equiv) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium [CAS 95408-45-0] (5 mol% - 10 mol%) or 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium [CAS 72287-26-4] (10 mol%), and the reaction mixture is stirred under heating (80 °C - 100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (2 h - 18 h). The reaction mixture is filtered through a Celite pad, the cake is washed with DCM and the combined filtrates are concentrated under reduced pressure. The crude material obtained is subjected to preparative TLC and / or preparative HPLC to afford the desired coupling product.

[1290] In an alternative aqueous workup, the reaction mixture is diluted with water, the phases are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are dried over Na2SO4, filtered and evaporated, and the crude material obtained is subjected to preparative TLC and / or C18 flash chromatography or preparative HPLC to afford the desired coupling product.

[1291] Condition B (GM4B): Coupling with trifluoroborate

[1292] A solution of the corresponding aryl halide (1 equiv) in 1,4-dioxane is treated under nitrogen at room temperature with the corresponding potassium trifluoroborate (A25) (4 equiv), Cs2CO3 (4 equiv) and CataCXium A Pd G3 [CAS 1651823-59-4] (20 mol%), and the reaction mixture is stirred under heating (100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (usually 15 h). The reaction mixture is filtered through a Celite pad, the cake is washed with DCM and the combined filtrates are concentrated under reduced pressure. The crude material obtained is subjected to preparative TLC and / or preparative HPLC to afford the desired coupling product.

[1293] General method 5 (GM5): Chan - Lam coupling

[1294] A mixture of the corresponding heteroatom nucleophile H-D(A4) (1 equiv) in 1,4-dioxane was treated at room temperature with the corresponding boronic acid (2 equiv - 3 equiv), TMEDA (3 equiv), and Cu(OTf)2 (1.2 equiv - 2 equiv), and the reaction mixture was stirred under heating (100 °C) until TLC and / or LCMS indicated complete consumption of the starting material (usually 16 h). The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, the combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated. The crude material obtained was subjected to C18 - flash chromatography to give the desired coupling product.

[1295] General method 6 (GM6): Boc deprotection

[1296] Condition A (GM6A): Deprotection with HCl

[1297] A solution of the corresponding Boc-protected amine (1 equiv) in MeOH was treated at room temperature with a solution of 4 M HCl in MeOH (13 equiv - 77 equiv), and the reaction mixture was stirred under heating (60 °C - 80 °C) until TLC and / or LCMS indicated complete consumption of the starting material (usually 2 h - 3 h). The reaction mixture was concentrated under reduced pressure to give the desired amine as the (unspecified) HCl salt.

[1298] Condition B (GM6B): Deprotection with TFA

[1299] A solution of the corresponding Boc-protected amine (1 equiv) in DCM was treated at room temperature with TFA (11 equiv - 190 equiv), and the reaction mixture was stirred at room temperature until TLC and / or LCMS indicated complete consumption of the starting material (3 h - 16 h). The reaction mixture was concentrated under reduced pressure to give the desired amine as the (unspecified) TFA salt.

[1300] General method 7 (GM7): Amide formation

[1301] In a microwave vial, a solution of the corresponding ester (A35) in MeOH was treated at room temperature with the corresponding amine or its salt (A36) (4 equiv - 100 equiv, pure or as a solution in THF) and additionally with DIPEA (4 equiv - 8 equiv) where applicable. The vial was capped, and the reaction mixture was stirred at room temperature or under heating (60 °C - 70 °C) until TLC and / or LCMS indicated complete consumption of the starting material (3 h - 5 days). The reaction mixture was concentrated under reduced pressure, and the crude material obtained was subjected to preparative HPLC to give the desired amide.

[1302] General method 8 (GM8): Methyl - thioether oxidation

[1303] Cool a solution of methyl-sulfide (1 equiv) in DCM to 0 °C and treat it slowly with 3-chloroperoxybenzoic acid (m-CPBA) [CAS 937-14-4] (0.9 equiv - 1.2 equiv), and stir the resulting mixture at room temperature until TLC and / or LCMS indicate complete consumption of the starting material (0.5 h - 2 h). Use the reaction mixture directly for the next step.

[1304] Alternatively, concentrate the reaction mixture under reduced pressure and subject the obtained crude material to flash chromatography on silica gel to give the desired oxidation product.

[1305] Intermediate

[1306] Intermediate 1

[1307] 6'-(((1S,3S)-3 - aminocyclopentyl)amino)-2H - [1,3'-bipyridin]-2 - one

[1308] Step A.i - 1a

[1309] tert - Butyl ((1S,3S)-3 - ((5 - iodopyridin - 2 - yl)amino)cyclopentyl)carbamate

[1310]

[1311] According to GM1A, add 2-fluoro-5-iodopyridine (CAS Registry Number 171197-80-1) (2.23 g, 9.99 mmol) to a solution of 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). Stir the resulting solution at 125 °C under a nitrogen atmosphere for 18 h. Dilute the reaction mixture with EtOAc (50 mL) and wash with water (3 × 75 mL). Dry the organic layer over Na2SO4, filter, and evaporate. Purify the crude material by flash chromatography on silica gel (gradient: 0 - 50% EtOAc / PE) to give the title compound as a pale yellow solid (2.70 g, 67%). MS (ESI): m / z [M+H] + 403.9.

[1312] Step B.i - 1b

[1313] tert - Butyl ((1S,3S)-3 - ((2 - oxo - 2H - [1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate

[1314]

[1315] In a slightly modified GM3, rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (CAS Registry Number 67579-81-1) (0.212 g, 1.49 mmol) and Cu(I)I (0.283 g, 1.49 mmol) were added to a solution of ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (3.0 g, 7.44 mmol), K2CO3 (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 for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (25 mL) and washed successively with water (3 × 25 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude material was triturated with EtOAc:PE (5:1) to give a solid, which was collected by filtration and dried in vacuo to afford the title compound as a yellow solid (2.70 g, 98%). MS (ESI): m / z [M+H] + 371.2。

[1316] Step C.i - 1c

[1317] 6'-(((1S,3S)-3 - aminocyclopentyl)amino)-2H - [1,3'-bipyridin]-2 - one

[1318]

[1319] In modified GM6A, at 25 °C, HCl (2 M ethereal solution, 27 mL, 54 mmol) was slowly added to a solution of ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1b (1.0 g, 2.70 mmol) in DCM (10 mL). The resulting mixture was stirred at 25 °C for 3 h. The synthetic procedure was repeated for a second batch of ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester 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, which was collected by filtration and dried in vacuo to afford the unspecified HCl salt of the title compound as a yellow solid (2.5 g, 100%). MS (ESI): m / z [M+H] + 270.9。

[1320] Intermediate 2

[1321] 1-(6 - (((1S,3S)-3 - aminocyclopentyl)amino)pyridin - 3 - yl)-3 - methyl - 1,3 - dihydro - 2H - benzo [d]imidazol - 2 - one × 3TFA

[1322] Step A.i - 2a

[1323] ((1S,3S)-3 - ((5-(3 - methyl - 2 - oxo - 2,3 - dihydro - 1H - benzo[d]imidazol - 1 - yl)pyridin - 2 - yl) amino)cyclopentyl)carbamate

[1324]

[1325] According to GM3, make rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (88 mg, 0.62 mmol), ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (250 mg, 0.62 mmol), 1-methyl-1,3-dihydro-2H-benzimidazol-2-one (CAS Registry Number 1849-01-0) (184 mg, 1.24 mmol), Cs2CO3 (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 hours. After aqueous workup and preparative TLC (7M NH3 / MeOH:DCM = 1:20), the title compound was obtained as a brown gum (172 mg, 65%). MS (ESI): m / z [M+H] + 424.

[1326] Step B.i - 2b

[1327] 1-(6 - (((1S,3S)-3 - aminocyclopentyl)amino)pyridin - 3 - yl)-3 - methyl - 1,3 - dihydro - 2H - benzo [d]imidazol - 2 - one × 3TFA

[1328]

[1329] In a slightly modified GM6B, ((1S,3S)-3-((5-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester 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 diatomaceous earth. The filter cake was washed with DCM (2 × 5 mL) and the filtrate was concentrated under reduced pressure to give the title compound as a brown gum (216 mg, 83%). MS (ESI): m / z [M+H] + 324.

[1330] Intermediate 3

[1331] 6'-(((1S,3S)-3 - aminocyclopentyl)amino)-3 - methoxy - 2H - [1,3'-bipyridin]-2 - one × 2 HCl

[1332] Step A.i - 3a

[1333] ((1S,3S)-3 - ((3 - methoxy - 2 - oxo - 2H - [1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino formate

[1334]

[1335] 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 No. 20928-63-6) (776 mg, 6.20 mmol), rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (176 mg, 1.24 mmol), Cs2CO3 (2020 mg, 6.20 mmol) and Cu(I)I (236 mg, 1.24 mmol) were reacted in 1,4-dioxane (5 mL) at 100 °C for 15 h. After aqueous workup and preparative TLC (MeOH:DCM = 1:20), the title compound as a brown solid was obtained (387 mg, 78%). MS (ESI): m / z [M+H] + 401.3.

[1336] Step B.i - 3b

[1337] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methoxy-2H-[1,3'-bipyridin]-2-one × 2HCl

[1338]

[1339] 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 a MeOH solution of 4 M HCl (10 mL, 40 mmol) in MeOH (15 mL) at 60 °C for 2 h to give the crude title compound as a brown solid (340 mg, 99%). MS (ESI): m / z [M+H] + 301.1.

[1340] Intermediate 4

[1341] 6'-(((1S,3S)-3-((5,6-Dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1, 3'-bipyridin]-5-carboxylic acid methyl ester

[1342] Step A.i-4a

[1343] ((1S,3S)-3-((5-Nitropyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1344]

[1345] According to GM1A, K2CO3 (4.14 g, 29.96 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 645400-44-8) (3.0 g, 14.98 mmol), and 2-chloro-5-nitropyridine (CAS Registry No. 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 after aqueous workup was triturated with PE:EtOAc (2:1, 20 mL) to give a solid, which was collected by filtration and dried under vacuum to give the title compound as a brown solid (4.0 g, 83%). MS (ESI): m / z [M+H] + 323.1。

[1346] Step B.i-4b

[1347] ((1S,3S)-3-((5-Aminopyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1348]

[1349] A solution of 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) was stirred at 20 °C under H2 (g, 2 atm) for 15 h. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure to give the crude title compound as a dark oil (1.4 g, 96%), which solidified on standing. MS (ESI): m / z [M+H] + 293.0。

[1350] Step C.i-4c

[1351] 6'-(((1S,3S)-3-((tert-Butoxycarbonyl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyr idin]-5-carboxylic acid methyl ester

[1352]

[1353] At 20 °C, methyl 2-oxo-2H-pyran-5-carboxylate (CAS Registry Number 6018-41-3) (506 mg, 3.28 mmol) was added to a solution of tert-butyl ((1S,3S)-3-((5-aminopyridin-2-yl)amino)cyclopentyl)carbamate compound i-4b (800 mg, 2.74 mmol) in EtOH (20 mL). 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 column chromatography on silica gel (gradient: 2%-30% EtOAc / PE) to give the title compound as a yellow oil (800 mg, 68%), which solidified on standing. MS (ESI): m / z [M+H] + 429.1。

[1354] Step D.i-4d

[1355] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-5-carboxylic acid methyl ester

[1356]

[1357] 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 solution, 6.0 mL, 24 mmol) in MeOH (6 mL) at 60 °C for 2 h to give the unspecified HCl salt of the title compound as a brown solid (661 mg, 97%). MS (ESI): m / z [M+H] + 329.0。

[1358] Step E.i-4e

[1359] 6'-(((1S,3S)-3-((5,6-Dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1, 3'-bipyridin]-5-carboxylic acid methyl ester

[1360]

[1361] According to GM2, at 25 °C, Cs2CO3 (893 mg, 2.74 mmol) was added to a solution of 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). The resulting suspension was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated, and the obtained material was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:30) to give the title compound as a brown solid (68 mg, 17%). MS (ESI): m / z [M+H] + 435.1。

[1362] Intermediate 5

[1363] (1S,3S)-N 1 -(5,6-dimethylpyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[1364] Step A.i-5a

[1365] ((1S,3S)-3-((5,6-Dimethylpyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1366]

[1367] The reaction was carried out in 3 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), Cs2CO3 (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 h. After combining the batches, non-aqueous work-up and trituration (PE:EtOAc = 5:1, 25 mL), the solid was collected by filtration and dried under vacuum to give the title compound as a pale yellow solid (1.5 g, 75%). MS (ESI): m / z [M+H] + 307.1。

[1368] Step B.i-5b

[1369] (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)cyclopentane-1,3-diamine × 5TFA

[1370]

[1371] According to GM6B, the compound tert-butyl ((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)carbamate 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 h to give the crude title compound as a yellow gum (3.80 g, 100%). MS (ESI): m / z [M+H] + 207.2。

[1372] Step C.i-5c

[1373] (1S,3S)-N 1 -(5,6-Dimethylpyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[1374]

[1375] 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 Registry 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 and purification by flash column chromatography on silica gel (gradient: 2%-25% EtOAc / PE), the title compound was obtained as a pale yellow oil (1.6 g, 80%), which solidified on standing. MS (ESI): m / z [M+H] + 410.0。

[1376] Intermediate 6

[1377] i-6a

[1378] 1-(6-Chloropyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[1379]

[1380] According to GM5, (6-chloropyridin-3-yl)boronic acid (CAS Registry No. 444120-91-6) (1.29 g, 8.21 mmol), 1,8-naphthyridin-2(1H)-one (CAS Registry No. 15936-09-1) (600 mg, 4.11 mmol), N 1 ,N 1 ,N 2 ,N 2 ,N-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. After purification by C18 - flash chromatography (gradient: 5% - 43% MeCN / water + 0.1% NH3 (aqueous solution)), the title compound as a pale yellow solid was obtained (252 mg, 23%). MS (ESI): m / z [M+H] + 257.9.

[1381] Intermediate 7

[1382] 3-(6-Chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione

[1383] Step A.i-7a

[1384] (6-Chloropyridin-3-yl)p-nitrophenyl carbamate

[1385]

[1386] At 20 °C, phenyl 4-nitrophenyl carbonate (CAS Registry No. 7693-46-1) (1.73 g, 8.56 mmol) was added to a solution of 6-chloropyridin-3-amine (CAS Registry No. 5350-93-6) (1.0 g, 7.8 mmol) in MeCN (20 mL), and the resulting solution was stirred at this temperature for 30 min. The reaction mixture was diluted with MeCN (200 mL), filtered through an organic phase filter and evaporated to give the crude title compound as a purple solid (2.18 g, 96%). MS (ESI): m / z [M+H] + 293.9.

[1387] Step B.i-7b

[1388] 3-(6-Chloropyridin-3-yl)-1-methylimidazolidine-2,4-dione

[1389]

[1390] At 20 °C, DIPEA (3.90 mL, 22.3 mmol) was added to a solution of methyl glycine methyl ester HCl (CAS Registry Number 13515-93-0) (1.04 g, 7.44 mmol) in MeCN (20 mL). The resulting suspension was stirred at 20 °C for 15 minutes, then (6-chloropyridin-3-yl) 4-nitrophenylcarbamate compound i-7a (2.18 g, 7.44 mmol) was added and stirring was continued at 20 °C for 10 minutes. The mixture was concentrated under reduced pressure and the obtained crude material was purified by flash chromatography on silica gel (gradient: 65%-70% EtOAc / PE) to give the title compound as a white solid (1.55 g, 92%). MS (ESI): m / z [M+H] + 225.8。

[1391] Intermediate 8

[1392] 6'-Chloro-2-oxo-2H-[1,3'-bipyridin]-5-carbonitrile

[1393] Step A.i-8a

[1394] 6'-Chloro-2-oxo-2H-[1,3'-bipyridin]-5-carboxylic acid methyl ester

[1395]

[1396] At 15 °C, 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), and it 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 as a purple solid (1.53 g, 74%). MS (ESI): m / z [M+H] + 265.2。

[1397] Step B.i-8b

[1398] 6'-Chloro-2-oxo-2H-[1,3'-bipyridin]-5-carboxylic acid

[1399]

[1400] At 20 °C, methyl 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate compound i-8a (300 mg, 1.13 mmol) was added to a mixture solution of NaOH (91 mg, 2.3 mmol) in THF (8 mL) and water (2 mL), 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 Na2SO4, filtered, and evaporated to give the crude title compound as a white solid (230 mg, 81%). MS (ESI): m / z [M+H] + 251.

[1401] Step C.i-8c

[1402] 6'-Chloro-2-oxo-2H-[1,3'-bipyridin]-5-carboxamide

[1403]

[1404] Under a nitrogen atmosphere, 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid compound i-8b (160 mg, 0.64 mmol) was added to a solution of HATU (485 mg, 1.28 mmol), TEA (0.712 mL, 5.11 mmol), and NH4Cl (137 mg, 2.55 mmol) in DMF (10 mL). 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 residue obtained was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound as a white solid (130 mg, 82%). MS (ESI): m / z [M+H] + 250.

[1405] Step D.i-8d

[1406] 6'-Chloro-2-oxo-2H-[1,3'-bipyridin]-5-carbonitrile

[1407]

[1408] 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). At 0 °C, TFAA (1.19 mL, 8.41 mmol) was slowly added to the mixture, and it was stirred at 20 °C for 1 h. The synthetic 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 as a white solid (540 mg, 72%). MS (ESI): m / z [M+H] + 232.1。

[1409] Intermediate 9

[1410] 3-(Trifluoromethoxy)pyridin-2-ol

[1411] Step A.i-9a

[1412] 2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine

[1413]

[1414] At 20 °C, KOtBu (682 mg, 6.07 mmol) was added to a solution of (4-methoxyphenyl)methanol (CAS Registry No. 105-13-5) (629 mg, 4.56 mmol) in 1,4-dioxane (2 mL), and it was stirred at 20 °C for 2 h. 2-Chloro-3-(trifluoromethoxy)pyridine (CAS Registry No. 1206980-39-3) (600 mg, 3.04 mmol) was added to the reaction mixture, and the resulting suspension was stirred at 100 °C for 15 h. The reaction mixture was poured into saturated brine (125 mL) and extracted with EtOAc (3 × 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated, and the residue obtained was purified by preparative TLC (EtOAc:PE = 1:5) to give the title compound as a pale yellow liquid (600 mg, 66%). MS (ESI): m / z [M+H] + 300.0。

[1415] Step B.i-9b

[1416] 3-(Trifluoromethoxy)pyridin-2-ol

[1417]

[1418] At 25 °C, 2-((4-methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine compound i-9a (500 mg, 1.67 mmol) was added to TFA (10 mL), the mixture was 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 obtained residue was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound as a pale yellow solid (150 mg, 50%). MS (ESI): m / z [M+H] + 180.0。

[1419] Intermediate 10

[1420] i-10a

[1421] 6'-Chloro-2-oxo-2H-[1,3'-bipyridin]-3-carbonitrile

[1422]

[1423] In modified GM5, at 25 °C, pyridine (0.81 mL, 10 mmol) was added to 2-oxo-1,2-dihydropyridine-3-carbonitrile (CAS Registry No. 20577-27-9) (600 mg, 5.00 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry No. 444120-91-6) (1.57 g, 10 mmol), Cu(OAc)2 (1.82 g, 10 mmol) and molecular sieve (500 mg, dried at 200 °C for 24 hours) in a mixture of DCM (100 mL) and DMF (15 mL). Air was diffused through a CaCl2 tube into the reaction mixture. The resulting mixture was stirred at 25 °C for 15 hours, then filtered through diatomaceous earth. The filter cake was washed with DCM (3 × 10 mL), the combined filtrates were concentrated under reduced pressure and the residue was partitioned between EtOAc (400 mL) and water (150 mL). The aqueous layer was extracted with EtOAc (5 × 200 mL), the combined organic layers were washed with saturated brine (5 × 100 mL), dried over Na2SO4, filtered and evaporated. The dry solid was triturated with DMF (3 × 5 mL), the solid was filtered off and the filter cake was washed with MTBE (3 × 5 mL). The solid was dried in vacuo to give the title compound as a grey solid (105 mg, 9%). MS (ESI): m / z [M+H] + 232.1。

[1424] Intermediate 13

[1425] i-13a

[1426] 3-Chloro-6'-fluoro-2H-[1,3'-bipyridin]-2-one

[1427]

[1428] In slightly modified GM3, 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (560 mg, 2.51 mmol), 3-chloropyridin-2(1H)-one (CAS Registry No. 13466-35-8) (651 mg, 5.02 mmol), tripotassium phosphate (1.60 g, 7.53 mmol), Cu(I)I (478 mg, 2.51 mmol), and rel-(1R,2R)-N 1 ,N 2 ,N-dimethylcyclohexane-1,2-diamine (357 mg, 2.51 mmol) were reacted in 1,4-dioxane (60 mL) at 100 °C for 18 h. The reaction mixture was poured into saturated brine (350 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3 × 250 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated. The crude material was purified by flash chromatography on silica gel (gradient: 0-30% EtOAc / PE) to give the title compound as a pale yellow solid (258 mg, 45%). MS (ESI): m / z [M+H] + 224.9.

[1429] Intermediate 15

[1430] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one × 3 HCl

[1431] Step A.i-15a

[1432] ((1S,3S)-3-((3-Methyl-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1433]

[1434] According to GM3, ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (400 mg, 0.99 mmol), 3-methylpyridin-2(1H)-one (CAS Registry No. 1003-56-1) (1.08 g, 9.92 mmol), Cs2CO3 (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. After aqueous workup and preparative TLC (MeOH:DCM = 1:15), the title compound as a yellow solid was obtained (375 mg, 98%); MS (ESI): m / z [M+H] + 385.30。

[1435] Step B.i-15b

[1436] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-methyl-2H-[1,3'-bipyridin]-2-one × 3HCl

[1437]

[1438] According to GM6A, ((1S,3S)-3-((3-Methyl-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-15a (360 mg, 0.94 mmol) was reacted with a MeOH solution of HCl (4 M, 10 mL, 40 mmol) in MeOH (15 mL) at 60 °C for 2 h to give the title compound as a yellow solid (356 mg, 97%). MS (ESI): m / z [M+H] + 285.20。

[1439] Intermediate 16

[1440] 2-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[1441] Step A.i-16a

[1442] ((1S,3S)-3-((5-(6-Oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1443]

[1444] In a slightly modified GM3, ((1S,3S)-3-((5-Iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (250 mg, 0.62 mmol), pyridazin-3(2H)-one (CAS Registry Number 504-30-3) (119 mg, 1.24 mmol), Cs2CO3 (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. After aqueous workup and preparative TLC (NH3 / MeOH(7M):DCM = 1:30), the title compound as a brown solid was obtained (173 mg, 75%). MS(ESI): m / z(ESI), [M+H] + 372.0。

[1445] Step B.i-16b

[1446] 2-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)pyridazin-3(2H)-one

[1447]

[1448] According to GM6A, ((1S,3S)-3-((5-(6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-16a (168 mg, 0.45 mmol) was reacted with a MeOH solution of HCl (4 M, 5.0 mL, 20 mmol) in MeOH (5 mL) at 60 °C for 3 h to give the unspecified HCl salt of the title compound as a brown solid (156 mg, 100%). MS(ESI): m / z [M+H] + 272.00。

[1449] Intermediate 17

[1450] (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[1451] Step A.i-17a

[1452] (1S,3S)-N 1 -(5-Iodopyridin-2-yl)cyclopentane-1,3-diamine × 3 HCl

[1453]

[1454] According to GM6A, ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (Intermediate 1, Step A) (1.29 g, 3.19 mmol) was reacted with a MeOH solution of HCl (4 M, 10 mL, 40 mmol) in MeOH (20 mL) at 80 °C for 2 h to give the title compound as a beige solid (1.27 g, 96%). MS(ESI): m / z [M+H] + 303.90。

[1455] Step B.i-17b

[1456] (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[1457]

[1458] According to GM1A, make (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 registration number 19745-07-4) (0.910 g, 6.11 mmol) and Na2CO3 (1.62 g, 15.3 mmol) were reacted in DMSO (25 mL) at 120 °C for 15 hours. The mixture was filtered through a Celite pad and the filtrate was purified by flash C18- flash chromatography (gradient: 10%-61% MeCN / water, containing 0.1% aqueous NH3 solution) to give the title compound as a beige solid (0.78 g, 61%). MS (ESI): m / z [M+H] + 415.90.

[1459] Intermediate 18

[1460] i-18a

[1461] 6'-(((1S,3S)-3-((5-Chloropyrazin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyr idine]-5-carboxylic acid methyl ester

[1462]

[1463] According to GM1A, make 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 registration number 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 hours. After aqueous workup and purification by preparative TLC (NH3 / MeOH:DCM = 1:20), the title compound was obtained as a brown solid (93 mg, 42%). MS (ESI): m / z [M+H] + 441.05.

[1464] Intermediate 19

[1465] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrazin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-di Amine

[1466] Step A.i-19a

[1467] 2-Chloro-5-(difluoromethoxy)pyrazine

[1468]

[1469] 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). After the resulting solution was stirred at 20 °C for 30 minutes, the solvent was removed under reduced pressure. The residue was poured into saturated brine (400 mL), extracted with EtOAc (3 × 200 mL), the organic layer was dried over Na2SO4, filtered and evaporated to give a brown liquid. The crude product was purified by flash chromatography on silica gel (gradient: 0 - 2% EtOAc / PE) to give the title compound as a pale yellow liquid (9.00 g, 50%). 1 1H-NMR (300 MHz, CDCl3) δ ppm 7.36 (1H, t), 8.21 (2H, s).

[1470] Step B.i-19b

[1471] ((1S,3S)-3-((5-(Difluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1472]

[1473] 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), Cs2CO3 (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. After non-aqueous workup, the title compound as a pale yellow solid was obtained (1.6 g, 84%). MS (ESI): m / z [M+H] + 345.05。 1 1H-NMR (300 MHz, 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).

[1474] Step C.i-19c

[1475] (1S,3S)-N 1 -(5-(Difluoromethoxy)pyrazin-2-yl)cyclopentane-1,3-diamine × 2TFA

[1476]

[1477] 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 hours to give the title compound as a brown gum (2.0 g, 94%). MS (ESI): m / z [M-NH3+H] + 227.95。 1 1H-NMR (300 MHz, 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).

[1478] Step D.i-19d

[1479] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrazin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-di Amine

[1480]

[1481] According to GM1A, (1S,3S)-N 1 -(5-(difluoromethoxy)pyrazin-2-yl)cyclopentane-1,3-diamine compound i-19c (1.27 g, 2.69 mmol), 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (500 mg, 2.24 mmol) and Cs2CO3 (1.46 g, 4.48 mmol) were reacted in DMSO (5 mL) at 100 °C for 16 hours. After aqueous workup, the title compound was obtained as a yellow solid (1.03 mmol, 46%). HRMS (ESI) m / z [M+H] + C 15 H 17 Calculated for C12H10F2IN5O: 448.0440, Found: 448.0412. 11H NMR (300 MHz, 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).

[1482] Intermediate 20

[1483] 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[1484] Step A.i-20a

[1485] ((1S,3S)-3-((5-(2-Oxo-1,8-naphthyridin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1486]

[1487] 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 No. 645400-44-8) (117 mg, 0.58 mmol), Cs2CO3 (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 h. After aqueous workup and purification by preparative TLC (MeOH:DCM = 1:30), the title compound was obtained as a pale yellow solid (140 mg, 86%). MS (ESI): m / z [M+H] + 422.10.

[1488] Step B.i-20b

[1489] 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[1490]

[1491] According to GM6A, ((1S,3S)-3-((5-(2-oxo-1,8-naphthyridin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-20a) (130 mg, 0.31 mmol) was reacted with a methanol solution of HCl (4 M, 5.0 mL, 20 mmol) in MeOH (5 mL) at 80 °C for 2 hours to obtain the unspecified HCl salt of the title compound as a light brown solid (105 mg, 95%). MS (ESI): m / z [M+H] + 322.00。

[1492] Intermediate 21

[1493] 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[1494] Step A.i-21a

[1495] 1-(6-Chloropyridin-3-yl)quinolin-2(1H)-one

[1496]

[1497] According to GM5, quinolin-2(1H)-one (CAS Registry No. 59-31-4) (500 mg, 3.44 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry No. 444120-91-6) (1.63 g, 10.3 mmol), Cu(OTf)2 (2.49 g, 6.89 mmol) and N,N,N',N'-tetramethylethylenediamine (1.20 g, 10.3 mmol) were reacted in 1,4-dioxane (20 mL) at 100 °C for 16 hours. After purification by C18-rapid column chromatography (gradient: 5%-46% MeCN / water, containing 0.1% aqueous NH3 solution), 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one was obtained as a green solid (211 mg, 24%). MS (ESI): m / z [M+H] + 256.95。

[1498] Step B.i-21b

[1499] ((1S,3S)-3-((5-(2-Oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1500]

[1501] 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), Cs2CO3 (571 mg, 1.75 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (29.5 mg, 0.04 mmol) were reacted in 1,4-dioxane (10 mL) at 100 °C for 15 h. After aqueous workup and purification by preparative TLC (MeOH:DCM = 1:40), tert-butyl ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamate was obtained as a white solid (122 mg, 83%). MS (ESI): m / z [M+H] + 421.00。

[1502] Step C.i-21c

[1503] 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[1504]

[1505] 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 a methanol solution of HCl (4 M, 5.0 mL, 20 mmol) in MeOH (10 mL) at 80 °C for 2 h to give the unspecified HCl salt of 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one as a brown gum (90 mg, 96%). MS (ESI): m / z [M+H] + 321.00。

[1506] Intermediate 22

[1507] (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-di Amine

[1508] Step A.i-22a

[1509] ((1S,3S)-3-((1,2,4-Triazin-3-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1510]

[1511] At 0 °C, m-CPBA (5.60 g, 25.95 mmol) was added in small portions 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), 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) and ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (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 column chromatography on silica gel (gradient: 5%-60% EtOAc / PE) to give the title compound as a yellow solid (3.7 g, 56%). MS (ESI): m / z [M+H] + 280。

[1512] Step B.i-22b

[1513] tert-Butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[1514]

[1515] A solution of Br2 in DCM (1 M, 15.9 mL, 15.9 mmol) was added dropwise to a solution of ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester 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 Na2SO3 (aqueous solution) (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the crude product as a brown solid, which was purified by flash column chromatography on silica gel (gradient: 5%-30% EtOAc / PE) to give the title compound as a yellow solid (3.5 g, 74%). MS (ESI): m / z [M+H] + 358。

[1516] Step C.i-22c

[1517] tert-Butyl ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[1518]

[1519] According to GM4B, tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (1.5 g, 4.2 mmol), potassium cyclopropyltrifluoroborate (2.48 g, 16.8 mmol), Cs2CO3 (5.46 g, 16.8 mmol) and CataCXium A Pd G3 (CAS Registry No. 1651823-59-4) (0.61 g, 0.84 mmol) were reacted in dioxane (70 mL) at 100 °C for 15 h. After combining with a second batch (prepared in the same manner, 1.12 mmol scale), the material was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound as a pale yellow solid (1.12 g, 66%). MS (ESI): m / z [M+H] + 320。

[1520] Step D.i-22d

[1521] (1S,3S)-N 1 -(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 4TFA

[1522]

[1523] 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 h to give the title compound as a yellow gum (940 mg, 89%) (containing 4 mol equivalents of residual TFA). MS (ESI): m / z [M+H] + 220。

[1524] Step E.i-22e

[1525] (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-di Amine

[1526]

[1527] According to GM1A, (1S,3S)-N 1-(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4TFA compound i-22d (880 mg, 1.30 mmol), 2-fluoro-5-iodopyridine (436 mg, 1.95 mmol) and K2CO3 (900 mg, 6.51 mmol) were reacted in DMSO (10 mL) at 120 °C for 15 h. After aqueous workup and purification by preparative TLC (EtOAc:PE = 3:1), the title compound was obtained as a pale yellow solid (369 mg, 67%). MS (ESI): m / z [M+H] + 423。

[1528] Intermediate 23

[1529] i-23a

[1530] 1-(6-Chloropyridin-3-yl)-3-methylimidazolidine-2,4-dione

[1531]

[1532] CuI (0.230 g, 1.57 mmol) was added to a mixture of 2-chloro-5-iodopyridine (CAS Registry No. 69045-79-0) (0.50 g, 2.09 mmol), 3-methylimidazolidine-2,4-dione (CAS Registry No. 6843-45-4) (0.48 g, 4.18 mmol), N,N-dimethylglycine hydrochloride (0.22 g, 1.57 mmol) and Cs2CO3 (1.36 g, 4.18 mmol) in dioxane (20 mL), and the resulting suspension was stirred under nitrogen at 100 °C for 15 h. The reaction mixture was poured into brine (125 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the crude product as a yellow gum, which was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound as a pale yellow oil (0.25 g, 53%), which solidified on standing. MS (ESI): m / z [M+H] + 226。

[1533] Intermediate 24

[1534] i-24a

[1535] 3-(6-Chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1536]

[1537] According to GM5, (6-chloropyridin-3-yl)boronic acid (CAS Registry No. 444120-91-6) (2.93 g, 18.6 mmol), 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (CAS Registry No. 50339-06-5) (1.11 g, 7.44 mmol), Cu(OTf)2 (4.04 g, 11.2 mmol) and TMEDA (2.59 g, 22.3 mmol) were reacted in dioxane (100 mL) at 100 °C for 16 h. After work-up and purification by C18-rapid chromatography (gradient: 5%-40% MeCN / water, containing 0.1% aqueous NH3 solution), the title compound as a white solid was obtained (0.235 g, 12%). MS(ESI): m / z [M+H] + 261.

[1538] Intermediate 25

[1539] i-25a

[1540] 6'-Chloro-3-methoxy-2H-[1,3'-bipyridin]-2-one

[1541]

[1542] 3-Methoxypyridin-2(1H)-one (CAS Registry No. 20928-63-6) (1.35 g, 10.8 mmol) and 2-chloro-5-iodopyridine (CAS Registry No. 69045-72-0) (1.03 g, 4.32 mmol) were added to a solution of dimethylglycine hydrochloride (301 mg, 2.16 mmol), CuI (411 mg, 2.16 mmol) and Cs2CO3 (4.22 g, 13.0 mmol) in dioxane (20 mL), and the resulting solution was stirred at 100 °C for 15 h. The solvent was removed under reduced pressure, and the crude product was purified by preparative TLC (PE:EtOAc = 1:2) to give the title compound as a pale yellow solid (250 mg, 55%). MS(ESI): m / z [M+H] + 237.

[1543] Intermediate 26

[1544] i-26a

[1545] 6'-Chloro-5-methoxy-2H-[1,3'-bipyridin]-2-one

[1546]

[1547] CuI (159 mg, 0.84 mmol) and N, N-dimethylglycine hydrochloride (117 mg, 0.84 mmol) were added to a mixture of 2-chloro-5-iodopyridine (400 mg, 1.67 mmol), 5-methoxypyridin-2 (1H) -one (CAS Reg. No. 61941-79-5) (523 mg, 4.18 mmol) and Cs2CO3 (1.63 mg, 5.01 mmol) in dioxane (8 mL), and the resulting suspension was stirred at 100 ° C. for 15 hours under nitrogen. 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.

[1548] Intermediate 28

[1549] (1S,3S)-N 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 2 TFA

[1550] Step A.i-28a

[1551] tert-Butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[1552]

[1553] According to GM4A, tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (300 mg, 0.84 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane in THF (2.10 g, 8.37 mmol), K3PO4 (356 mg, 1.67 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (CAS Reg. No. 95408-45-0) (55 mg, 0.08 mmol) were reacted in a mixture of dioxane (4 mL) and water (1 mL) at 100°C for 15 hours, worked up in an aqueous solution and purified by preparative TLC (MeOH:DCM=1:20), followed by C18-flash chromatography (gradient: 0-49% After purification with MeOH / water), the title compound (103 mg, 42%) was obtained as a brown solid. MS (ESI): m / z [M+H] + 294.

[1554] Step B.i-28b

[1555] (1S,3S)-N 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 2 TFA

[1556]

[1557] According to GM6B, methyl 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 as a white solid (100 mg, 95%). MS (ESI): m / z [M+H] + 194.

[1558] Intermediate 31

[1559] (1S,3S)-N 1 -(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine

[1560] Step A.i-31a

[1561] tert-Butyl ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamate

[1562]

[1563] The reaction was carried out in 3 parallel batches.

[1564] According to GM2, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 645400-44-8) (420 mg, 2.10 mmol), 2-bromo-5-methylpyrazine (CAS Registry No. 98006-90-7) (363 mg, 2.10 mmol), Cs2CO3 (1.03 g, 3.15 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (62 mg, 0.07 mmol) were reacted in 1,4-dioxane (20 mL) at 100 °C for 15 hours. After combining the batches, 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 as a grey solid (1.2 g, 63%). MS (ESI): m / z [M+H] + 293.3. 1 1H NMR (300 MHz, CDCl3) δ ppm 1.46 (11H, s), 1.93 (2H, td), 2.25 (2H, ddt), 2.39 (3H, d), 4.15 (1H, d), 4.23 (1H, p), 4.47 (1H, d), 4.57 (1H, s), 7.80 (1H, d), 7.85–7.90 (1H, m).

[1565] Step B.i-31b

[1566] (1S,3S)-N 1 -(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine

[1567]

[1568] According to GM6B, the compound i-31a ((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester (350 mg, 1.20 mmol) was reacted with TFA (2 mL, 26 mmol) in DCM (10 mL) at 20 °C for 15 h to give the unspecified TFA salt of the title compound as a brown gum (704 mg, 91%). MS (ESI): m / z [M+H] + 193.0。 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.44–1.64 (2H, m), 1.91 (2H, m), 2.06–2.19 (2H, m), 2.26 (3H, s), 3.60–3.73 (1H, m), 4.21–4.32 (1H, m), 7.74–7.94 (5H, m).

[1569] Intermediate 32

[1570] i-32a

[1571] (1S,3S)-N 1 -(5-Iodopyridin-2-yl)-N 3 -(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine

[1572]

[1573] 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 Registry 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. After aqueous workup and purification by flash column chromatography on silica gel (gradient: 2%-25% EtOAc / PE), the title compound was obtained as a pale yellow oil (0.70 g, 70%), which solidified on standing. MS (ESI): m / z [M+H] + 396.15。 11H NMR (300 MHz, 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).

[1574] Intermediate 33

[1575] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-5-carbonitrile

[1576] Step A.i-33a

[1577] ((1S,3S)-3-((5-Cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1578]

[1579] According to GM2, ((1S,3S)-3-aminocyclopentyl) tert-butyl carbamate (425 mg, 2.12 mmol), 6'-chloro-2-oxo-2H-[1,3'-bipyridin]-5-carbonitrile (intermediate 8) compound i-8d (410 mg, 1.77 mmol), Cs2CO3 (1.73 g, 5.31 mmol) and Pd-PEPPSI-IpentCl2-methylpyridine (74 mg, 0.09 mmol) were reacted in 1,4-dioxane (10 mL) at 100 °C for 16 h. After non-aqueous workup and purification by preparative TLC (MeOH:DCM = 1:15), the title compound as a yellow solid (390 mg, 56%) was obtained.

[1580] Step B.i-33b

[1581] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-5-carbonitrile

[1582]

[1583] According to GM6A, ((1S,3S)-3-((5-cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl) tert-butyl carbamate compound i-33a (370 mg, 0.94 mmol) was reacted with a dioxane solution of HCl (4 M, 8 mL, 16 mmol) at 60 °C for 15 h to give the unspecified HCl salt of the title compound as a brown solid (310 mg, 100%).

[1584] Intermediate 34

[1585] i-34a

[1586] 6-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyrazine

[1587]

[1588] 6-Chloro-1H-pyrazolo[3,4-b]pyrazine (CAS Registry No. 1260664-81-0) (500 mg, 3.24 mmol) was added to a solution of K3PO4 (2060 mg, 9.71 mmol) and methyl iodide (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), extracted with EtOAc (3 × 100 mL), the organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound as a yellow solid (209 mg, 38%). MS (ESI): m / z [M+H] + 169。 1 1H NMR (300 MHz, DMSO-d6) δ ppm 4.06 (3H, s), 8.51 (1H, s), 8.71 (1H, s).

[1589] Intermediate 35

[1590] Step A.i-35a

[1591] ((1S,3S)-3-((3-Cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1592]

[1593] In slightly modified GM2, 6'-chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile compound i-10a (560 mg, 1.89 mmol), ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (CAS Registry Number 645400-44-8) (1.13 g, 5.66 mmol), Cs2CO3 (1.84 g, 5.66 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (79 mg, 0.09 mmol) were reacted in DMF (30 mL) at 100 °C for 15 h. The reaction mixture was filtered through a Celite pad, the filter cake was washed with DCM (3 × 10 mL) and the combined filtrates were concentrated under reduced pressure. The obtained material was purified by C18-rapid chromatography (gradient: 10%-100% MeCN / water + 0.1% NH3 (aqueous solution), 910 mg of separated material), followed by purification by preparative TLC (EtOAc:PE = 3:1) to give the title compound as a grey solid (174 mg, 23%). MS (ESI): m / z [M+H] + 396.20。

[1594] Step B.i-35b

[1595] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-3-carbonitrile × 4HCl

[1596]

[1597] According to GM6A, ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-35a (865 mg, 2.19 mmol) was reacted with a methanol solution of HCl (4 M 8.0 mL, 32 mmol) in MeOH (20 mL) at 80 °C for 2 h to give the title compound as a brown gum (966 mg, 100%). MS (ESI): m / z [M+H] + 296.00。

[1598] Intermediate 40

[1599] Step A.i-40a

[1600] ((1S,3S)-3-((5-(1-Methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)py ridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1601]

[1602] At 30 °C, 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 a solution of tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (307 mg, 1.53 mmol), Cs2CO3 (750 mg, 2.30 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (32 mg, 0.04 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100 °C for 15 h 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 Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc) to give the title compound as a yellow solid (233 mg, 71%); MS (ESI) m / z [M+H] + 425.1

[1603] Step B.i-40b

[1604] 3-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo [4,5-b]pyridin-2-one

[1605]

[1606] At 30 °C, TFA (2 mL, 25.96 mmol) was added to a solution of 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). The resulting mixture was stirred at 30 °C for 2 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound as a brown gum (347 mg, 100%); MS (ESI) m / z [M+H] + 325.0

[1607] Intermediate 41

[1608] Step A.i-41a

[1609] ((1S,3S)-3-((5-(3-Methyl-2,5-dioxoimidazolidin-1-yl)pyridin-2-yl)amino)cyclopentyl)amm onium carbamate tert-butyl ester

[1610]

[1611] At room temperature, Cs2CO3 (3.70 g, 11.4 mmol) was added to a solution of ((1S,3S)-3-aminocyclopentyl) tert-butyl 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), and the resulting suspension was stirred at 100 °C under nitrogen for 16 h. The reaction mixture was poured into saturated brine (300 mL), extracted with EtOAc (3 × 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 in vacuo (yellow solid). The solid was further purified by preparative TLC (EtOAc:PE = 100:1) to give the title compound as a white solid (0.25 g, 10%). MS (ESI): m / z [M+H] + 390。

[1612] Step B.i-41b

[1613] 3-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)-1-methylimidazolidine-2,4-dione × 2HCl

[1614]

[1615] At room temperature, a solution of HCl in MeOH (4 M) (5 mL, 20 mmol) was added to a solution of ((1S,3S)-3-((5-(3-methyl-2,5-dioxoimidazolidin-1-yl)pyridin-2-yl)amino)cyclopentyl) tert-butyl carbamate compound i-41a (250 mg, 0.64 mmol) in MeOH (15 mL), and the resulting solution was stirred at 60 °C for 16 h. The solvent was removed under reduced pressure to give the title compound as a pale yellow oil (220 mg, 95%), which solidified on standing. The product was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 290。

[1616] Intermediate 42

[1617] Step A.i-42a

[1618] ((1S,3S)-3-((5-Methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino tert-Butyl carbamate

[1619]

[1620] At 25 °C, rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (53 mg, 0.37 mmol) was added to a solution of ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (300 mg, 0.74 mmol), 5-methoxypyridin-2-ol (233 mg, 1.86 mmol), Cs2CO3 (727 mg, 2.23 mmol) and Cu(I)I (70.8 mg, 0.37 mmol) in 1,4-dioxane (15 mL). 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 Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc) to give the title compound as a brown solid (263 mg, 88%). MS (ESI) m / z [M+H] + 401.0。

[1621] Step B.i-42b

[1622] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one

[1623]

[1624] At 25 °C, TFA (5 ml, 64.90 mmol) was added to a solution of ((1S,3S)-3-((5-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-42a (400 mg, 1.00 mmol) in DCM (15 mL). The resulting suspension was stirred at 25 °C for 18 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound as a black gum (1.1 g, 100%). MS (ESI) m / z [M+H] + 301.0。

[1625] Intermediate 43

[1626] Step A.i-43a

[1627] ((1S,3S)-3-((3-Chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic tert-Butyl ester

[1628]

[1629] At 25 °C, ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (467 mg, 2.33 mmol) was added to a solution of 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). 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 as a white solid (456 mg, 97%). MS (ESI) m / z [M+H] + 404.9。

[1630] Step B.i-43b

[1631] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-chloro-2H-[1,3'-bipyridin]-2-one

[1632]

[1633] At 30 °C, a solution of 4M HCl in dioxane (2 mL, 8.00 mmol) was added to a solution of ((1S,3S)-3-((3-chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-43a (425 mg, 1.05 mmol) in MeOH (20 mL). The resulting solution was stirred at 30 °C for 2 h. The solvent was removed under reduced pressure to give the HCl salt of the crude title compound as a yellow oil (329 mg, 83%). MS (ESI) m / z [M+H] + 305.0。

[1634] Intermediate 44

[1635] Step A.i-44a

[1636] ((1S,3S)-3-((5-Chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic tert-Butyl ester

[1637]

[1638] At 26 °C, rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (106 mg, 0.74 mmol) was added to a solution of tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (300 mg, 0.74 mmol), 5-chloropyridin-2(1H)-one (193 mg, 1.49 mmol), Cu(I)I (142 mg, 0.74 mmol), and Cs2CO3 (727 mg, 2.23 mmol) in 1,4-dioxane (25 mL). 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 Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound as a green solid (298 mg, 99%). MS (ESI) m / z [M+H] + 405.0。

[1639] Step B.i-44b

[1640] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one

[1641]

[1642] At 25 °C, TFA (5 mL, 64.90 mmol) was added to a solution of 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). The resulting solution was stirred at 100 °C for 18 h. The solvent was removed under reduced pressure to give the TFA salt of the crude title compound as a brown gum (432 mg, 91%). MS (ESI) m / z [M+H] + 304.9。

[1643] Intermediate 45

[1644] Step A.i-45a

[1645] ((1S,3S)-3-((5-Cyclopropylpyrazin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1646]

[1647] 2-Bromo-5-cyclopropylpyrazine (CAS Registry No. 1086382-78-6) (150 mg, 0.75 mmol) was added to a solution of Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry No. 1612891-29-8) (32 mg, 0.04 mmol), ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (CAS Registry No. 645400-44-8) (151 mg, 0.75 mmol) and Cs2CO3 (737 mg, 2.26 mmol) in 1,4-dioxane (10 mL), and the resulting mixture was stirred under nitrogen at 100 °C for 15 h. The reaction mixture was filtered through Celite. The filter cake was washed with EtOAc (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound as a yellow solid (180 mg, 75%). MS (ESI): m / z [M+H] + 319.1

[1648] Step B.i-45b

[1649] (1S,3S)-N 1 -(5-Cyclopropylpyrazin-2-yl)cyclopentane-1,3-diamine × 3TFA

[1650]

[1651] ((1S,3S)-3-((5-Cyclopropylpyrazin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester 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 h. The organic solvent was removed by evaporation to give the title compound as a brown oil (267 mg, 95%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 219.3。

[1652] Intermediate 46

[1653] Step A.i-46a

[1654] ((1S,3S)-3-((5-(Trifluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1655]

[1656] A mixture of 2-chloro-5-(trifluoromethoxy)pyrazine (CAS Registry No. 1803596-66-8) (46 mg, 0.23 mmol), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 645400-44-8) (93 mg, 0.46 mmol), (oxybis(2,1-phenylene))bis(diphenylphosphine) (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 column chromatography on silica gel (gradient: 0 - 100% EtOAc / heptane) to give the title compound as a brown paste (66 mg, 57%). MS (ESI): m / z [M+H] + 363.2。

[1657] Step B.i-46b

[1658] (1S,3S)-N 1 -(5-(Trifluoromethoxy)pyrazin-2-yl)cyclopentane-1,3-diamine × TFA

[1659]

[1660] 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 h. The mixture was concentrated under reduced pressure and used directly in the next step without further purification (assuming quantitative yield). MS (ESI): m / z [M+H] + 263.2。

[1661] Intermediate 49

[1662] Step A.i-49a

[1663] 6'-Chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1664]

[1665] At room temperature, Cu(I)I (103 mg, 1.04 mmol) was added to a solution of 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), and the resulting suspension was stirred under nitrogen at 100 °C for 16 h. The mixture was filtered through a Celite pad and the 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 as a white solid (410 mg, 100%). MS (ESI): m / z [M+H] + 394.0。

[1666] Step D.i-49d

[1667] 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

[1668]

[1669] At room temperature, Cs2CO3 (207 mg, 0.63 mmol) was added to a mixture of 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 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine compound i-31b 2xHCl salt (67 mg, 0.25 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (11 mg, 0.01 mmol) in 1,4-dioxane (3 mL), and the resulting mixture was stirred under nitrogen at 100 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the residue was purified by preparative TLC (NH3 / MeOH(7M):DCM = 1:20) to give the title compound as a brown solid (12 mg, 17%). MS (ESI): m / z [M+H] + 550.0。

[1670] Intermediate 50

[1671] Step A.i-50a

[1672] 5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol

[1673]

[1674] A solution 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 Cs2CO3 (4.42 g, 13.6 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 80 °C under a nitrogen atmosphere for 15 h. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash C18 - flash chromatography (elution gradient: 0 - 50% MeCN / water) to give the title compound as a white solid (160 mg, 13%). MS (ESI): m / z [M+H] + 282.0。

[1675] Step B.i-50b

[1676] 6'-Chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1677]

[1678] At room temperature, Cu(I)I (102 mg, 0.53 mmol) was added to 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol compound i-50a (150 mg, 0.53 mmol), 2-chloro-5-iodopyridine (CAS Registry Number 69045-79-0) (128 mg, 0.53 mmol), rel-(1R,2R)-N 1 ,N 2In a solution of (114 mg, 0.80 mmol) of 1,2 - dimethylcyclohexane - 1,2 - diamine and Cs2CO3 (347 mg, 1.07 mmol) in 1,4 - dioxane (10 mL), and the resulting suspension was stirred under nitrogen at 60 °C 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 obtained residue was first purified by preparative TLC (MeOH:DCM = 1:10), and then by flash C18 - flash chromatography (elution gradient: 0 - 30% MeCN / water) to give the title compound as a white solid (150 mg, 72%). MS (ESI): m / z [M+H] + 393.0。

[1679] Step E.i-50e

[1680] 5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino yl)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[1681]

[1682] At room temperature, Cs2CO3 (622 mg, 1.91 mmol) was added to a mixture 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 1 -(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) in DMF (15 mL), and the resulting mixture was stirred under nitrogen at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (150 mL) and washed successively with saturated brine (7×200 mL). The organic layer was dried (Na2SO4), filtered and evaporated, and the crude product was purified by preparative TLC (MeOH:DCM = 1:15) to give the title compound as a brown solid (150 mg, 43%). MS (ESI): m / z [M+H]+549.0。

[1683] Intermediate 55

[1684] i-55a

[1685] 5-Bromo-2-(difluoromethoxy)-3-methylpyrazine

[1686]

[1687] 5-Bromo-3-methylpyrazin-2-ol (CAS Registry No. 100047-56-1) (300 mg, 1.59 mmol) was added to a solution of 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 Na2SO4, filtered, and evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 1:5) to give the title compound as a white solid (130 mg, 34%). 1 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (d, 3H), 7.63 (t, 1H), 8.39 (d, 1H).

[1688] Intermediate 56

[1689] i-56a

[1690] 3-(Trifluoromethoxy)pyridin-2(1H)-one

[1691]

[1692] TFA (5.0 mL, 65 mmol) was added to a solution of 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 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 as a white solid (0.36 g, 65%). MS (ESI): m / z [M+H] + 179.9.

[1693] Intermediate 60

[1694] Step A.i-60a

[1695] 3-((6-chloropyridin-3-yl)amino)-4-nitrobenzonitrile

[1696]

[1697] At room temperature, K2CO3 (6.45 g, 46.7 mmol) was added to a solution of 3-fluoro-4-nitrobenzonitrile (CAS Registry No. 218632-01-0) (3.10 g, 18.7 mmol), 6-chloropyridin-3-amine (CAS Registry No. 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), and the resulting mixture was stirred under nitrogen at 80 °C for 15 h. The reaction mixture was filtered through Celite, and the filter cake was washed with DCM (3 × 50 mL). The combined filtrates were 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 residue obtained was purified by preparative TLC (DCM) to give the title compound as a yellow solid (0.63 g, 15%). MS (ESI): m / z [M+H] + 275.1。

[1698] Step B.i-60b

[1699] 4-amino-3-((6-chloropyridin-3-yl)amino)benzonitrile

[1700]

[1701] At room temperature, zinc (971 mg, 14.9 mmol) was added to a solution of 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), 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 filtrates were concentrated under reduced pressure to give the title compound as a brown solid (363 mg, 80%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 245.1。

[1702] Step C.i-60c

[1703] 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1704]

[1705] At room temperature, CDI (795 mg, 4.90 mmol) was added to a solution of 4-amino-3-((6-chloropyridin-3-yl)amino)benzonitrile compound i-60b (300 mg, 1.23 mmol) in DMF (2 mL), and the resulting mixture was stirred at 80 °C for 24 h. The solid was filtered off to give the crude product, which was triturated with MeCN and dried in vacuo to give the title compound as a pink solid (242 mg, 73%). MS (ESI): m / z [M+H] + 271.0。

[1706] Step D.i-60d

[1707] 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1708]

[1709] At room temperature, Cs2CO3 (542 mg, 1.66 mmol) was added to a mixture of 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-60c (150 mg, 0.55 mmol) and CH3I (118 mg, 0.83 mmol) in DMF (5 mL), and it was stirred at 100 °C for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with brine (3 × 50 mL). The organic layer was dried (Na2SO4), filtered and evaporated, and the material obtained was triturated with MeCN. The solid formed was collected by filtration and dried in vacuo to give the title compound as a pink solid (110 mg, 70%). MS (ESI): m / z [M+H] + 285.1。

[1710] Intermediate 61

[1711] Step A.i-61a

[1712] 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzonitrile

[1713]

[1714] At room temperature, Pd(OAc)2 (0.262 g, 1.17 mmol) was added to a mixture of K2CO3 (6.45 g, 46.7 mmol), 4-fluoro-3-nitrobenzonitrile (CAS Registry No. 1009-35-4) (2.84 g, 17.1 mmol), 6-chloropyridin-3-amine (CAS Registry No. 5350-93-6) (2.0 g, 15.6 mmol) and XantPhos (1.35 g, 2.33 mmol) in MeCN (40 mL), and the 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 × 200 mL). The combined filtrates were concentrated under reduced pressure and dissolved in EtOAc (300 mL). The organic layer was washed successively with saturated NaHCO3 (3 × 400 mL), dried over (Na2SO4), filtered and evaporated. The obtained material was purified by preparative TLC (DCM) to give the title compound as a yellow solid (0.70 g, 16%). MS (ESI): m / z [M+H] + 275.0

[1715] Step B.i-61b

[1716] 3-amino-4-((6-chloropyridin-3-yl)amino)benzonitrile

[1717]

[1718] At room temperature, zinc (1.33 g, 20.4 mmol) was added to a solution of NH4Cl (1.09 g, 20.4 mmol), 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzonitrile compound i-61a (0.70 g,

[1719] 2.54 mmol) in EtOH (15 mL), 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 filtrates were concentrated under reduced pressure to give the title compound as a brown solid (0.51 g, 81%), which was used in the next step without further purification. MS (ESI): m / z [M+H] + 245.1。

[1720] Step C.i-61c

[1721] 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1722]

[1723] At room temperature, CDI (1.19 g, 7.36 mmol) was added to a solution of 3-amino-4-((6-chloropyridin-3-yl)amino)benzonitrile compound i-61b (450 mg, 1.84 mmol) in DMF (10 mL), and the resulting mixture was stirred at 80 °C for 24 h. The solid was filtered off to give the crude product, which was triturated with MeCN and dried in vacuo to give the title compound as a pink solid (342 mg, 69%). MS (ESI): m / z [M+H] + 270.9

[1724] Step D.i-61d

[1725] 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1726]

[1727] At room temperature, CH3I (157 mg, 1.11 mmol) was added to a mixture of 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile compound i-61c (200 mg, 0.74 mmol) and Cs2CO3 (722 mg, 2.22 mmol) in DMF (8 mL), and it was stirred at 100 °C for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with brine (3 × 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the title compound as a yellow solid (119 mg, 57%), which was used in the next step without further purification. MS (ESI): m / z [M+H] + 285.0

[1728] Intermediate 63

[1729] Step A.i-63a

[1730] 5-((tert-butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one

[1731]

[1732] At room temperature, Cs2CO3 (2.23 g, 6.86 mmol) was added to 5-((tert-butyldimethylsilyl)ethynyl)pyridin-2(1H)-one (CAS Registry No. 2448766-74-1) (800 mg, 3.43 mmol), 2-chloro-5-iodopyridine (CAS Registry No. 69045-79-0) (821 mg, 3.43 mmol), Cu(I)I (653 mg, 3.43 mmol) and rel-(1R,2R)-N 1,N 2 In a 1,4-dioxane (20 mL) solution of 1,2-dimethylcyclohexane-1,2-diamine (731 mg, 5.14 mmol), and the resulting suspension was stirred under nitrogen at 60 °C for 5 h. 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 filtrates were concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (gradient: 0 - 50% EtOAc / heptane) to give the title compound as a white solid (590 mg, 25%). MS (ESI): m / z [M+H] + 345.0。

[1733] Step B.i-63b

[1734] 6'-chloro-5-ethynyl-2H-[1,3'-bipyridin]-2-one

[1735]

[1736] At room temperature, a solution of TBAF in THF (1 M, 8.55 mL, 8.55 mmol) was added to a solution of 5-((tert-butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one compound i-63a (590 mg, 1.71 mmol) in THF (15 mL), 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 / water) to give the title compound as a beige solid (290 mg, 74%). MS (ESI): m / z [M+H] + 231.0。

[1737] Intermediate 65

[1738] Step A.i-65a

[1739] 6'-chloro-5-(1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[1740]

[1741] Under air, 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). The resulting mixture was stirred at 90 °C for 16 h, then cooled to room temperature and concentrated under reduced pressure. The residue obtained was purified by C18- flash chromatography (gradient: 0 - 20% MeCN / water) to afford the title compound as a white solid (210 mg, 64%). MS (ESI): m / z [M+H] + 275.0。

[1742] Step B.i-65b

[1743] 6'-chloro-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[1744]

[1745] 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'-bipyridine]-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 / water) to afford the title compound as a white solid (1000 mg, 86%). MS (ESI): m / z [M+H] + 395.1。

[1746] Intermediate 67

[1747] Step A.i-67a

[1748] 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ol

[1749]

[1750] 5-Iodo-2(1H)-pyridone (CAS Registry No. 13472-79-2) (500 mg, 2.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Registry No. 761446-44-0) (565 mg, 2.71 mmol), and XPhos (CAS Registry No. 564483-18-7) (108 mg, 0.23 mmol) in a mixture of 1,4-dioxane (10 mL) and water (1 mL) were treated with XPhos Pd G3 (CAS Registry No. 1445085-55-1) (192 mg, 0.23 mmol) under nitrogen and stirred at 100 °C for 18 h. The reaction mixture was cooled to 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 material obtained was purified by flash chromatography on silica gel (gradient: 10%-20% MeOH / DCM) to afford the title compound as a green solid (250 mg, 63%). MS (ESI): m / z [M+H] + 175.9。

[1751] Step B.i-67b

[1752] 6'-chloro-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1753]

[1754] 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), Cs2CO3 (1.4 g, 4.3 mmol), and Cu(I)I (272 mg, 1.43 mmol) were reacted in 1,4-dioxane (8 mL) at 100 °C for 18 h. After non-aqueous workup (EtOAc) and flash chromatography on silica gel (gradient: 0-10% MeOH / DCM), the title compound was obtained as a green solid (250 mg, 61%). m / z [M+H] + 287.1 / 289 (Cl isotopic pattern).

[1755] Intermediate 68b

[1756] i-68b

[1757] 6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-3-(2-(tetrahydro-2H-pyr an-2-yl)-2H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1758]

[1759] Under nitrogen, 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 added to 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), Cs2CO3 (369 mg, 1.13 mmol), XPhos (CAS Registry Number 564483-18-7) (18 mg, 0.04 mmol) and XPhos Pd G3 (CAS Registry Number 1445085-55-1) (32 mg, 0.04 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2.5 mL). The resulting reaction mixture was stirred at 100 °C for 15 h, 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 / MeOH:DCM = 1:15) to give the title compound as a yellow solid (160 mg, 82%). MS (ESI): m / z [M+H] + 514.1。

[1760] Intermediate 69

[1761] Step A.i-69a

[1762] ((1S,3S)-3-((5-(3-methyl-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)amino tert-butyl formate

[1763]

[1764] At 20 °C, rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (70.5 mg, 0.50 mmol) was added to a mixture of ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (400 mg, 0.99 mmol), 6-methylpyridazin-3(2H)-one (CAS Registry No. 13327-27-0) (218 mg, 1.98 mmol), Cu(I)I (94 mg, 0.50 mmol), and Cs2CO3 (970 mg, 2.98 mmol) in 1,4-dioxane (20 mL), 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, and evaporated, and the residue was purified by preparative TLC (EtOAc) to give the title compound as a yellow solid (369 mg, 97%). MS (ESI): m / z [M+H] + 386.0。

[1765] Step B.i-69b

[1766] 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-6-methylpyridazin-3(2H)-one 3xHCl

[1767]

[1768] At 20 °C, HCl solution (4 M in MeOH solution, 5.0 mL, 20 mmol) was added to a stirred solution of ((1S,3S)-3-((5-(3-methyl-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-69a (355 mg, 0.92 mmol) in MeOH (10 mL), and the resulting solution was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure to give the unspecified HCl salt of the title compound as a pale yellow solid (360 mg, 99%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 285.9。

[1769] Intermediate 70

[1770] Step A.i-70a

[1771] ((1S,3S)-3-((5-(5-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)amino meth tert-butyl formate

[1772]

[1773] Under a nitrogen atmosphere, at 25 °C, ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (400 mg, 0.99 mmol) was added to 4-chloropyridazin-3(2H)-one (CAS Registry Number 1677-79-8) (518 mg, 3.97 mmol), Cu(I)I (94 mg, 0.50 mmol), Cs2CO3 (970 mg, 2.98 mmol), and rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (70.5 mg, 0.50 mmol) in a mixture of dioxane (5 mL), and the mixture was stirred at 100 °C for 18 h. The reaction mixture was concentrated, diluted with EtOAc (75 mL) and washed successively with NH3 (aqueous solution) (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 Na2SO4, filtered and evaporated, and the residue was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:30) to give the title compound as a yellow solid (90 mg, 22%). The procedure was repeated once and the two batches were combined. MS (ESI): m / z [M+H] + 406.0。

[1774] Step B.i-70b

[1775] 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-4-chloropyridazin-3(2H)-one

[1776]

[1777] At 25 °C, ((1S,3S)-3-((5-(5-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-70a (165 mg, 0.41 mmol) was added to a mixture of HCl (4M solution in MeOH, 1.2 mL) and MeOH (4.8 mL). The resulting solution was stirred at 25 °C for 1 h, then diluted with DCM (20 mL). The solvent was removed under reduced pressure to give the unspecified HCl salt of the title compound as a yellow solid (123 mg, 99%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 305.9。

[1778] Intermediate 71

[1779] Step A.i-71a

[1780] ((1S,3S)-3-((5-(3-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1781]

[1782] At 25 °C, rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (141 mg, 0.99 mmol) was added to a mixture of ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (400 mg, 0.99 mmol), Cu(I)I (189 mg, 0.99 mmol), 6-chloropyridazin-3(2H)-one (CAS Registry No. 19064-67-6) (324 mg, 2.48 mmol) and K2CO3 (411 mg, 2.98 mmol) in 1,4-dioxane (15 mL), and the mixture was stirred at 100 °C for 18 h 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 and evaporated, and the residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound as a yellow solid (180 mg, 44%). MS (ESI): m / z [M+H] + 405.9。

[1783] Step B.i-71b

[1784] 2-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-6-chloropyridazin-3(2H)-one HCl

[1785]

[1786] At 25 °C, HCl solution (4 M in 1,4-dioxane, 2 mL, 8 mmol) was added to a mixture of ((1S,3S)-3-((5-(3-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-71a (170 mg, 0.42 mmol) in MeOH (10 mL), and the mixture was stirred at 60 °C for 3 h. 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 and evaporated, and the obtained residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound as a yellow solid (140 mg, 98%). MS (ESI): m / z [M+H] + 305.9。

[1787] Intermediate 78

[1788] Step A.i-78a

[1789] 3-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one

[1790]

[1791] 4-Methoxybenzyl chloride (720 mg, 4.60 mmol) was added to a mixture of 3-chloro-2(1H)-pyrazinone (CAS Registry 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 Na2SO4, filtered and evaporated. The crude material was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound as a white solid (200 mg, 21%). MS (ESI): m / z [M+H] + 250.9。

[1792] Step B.i-78b

[1793] 6'-(((1S,3S)-3-((4-(4-methoxybenzyl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)cyclopent yl)amino)-2H-[1,3'-bipyridin]-2-one

[1794]

[1795] 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 Cs2CO3 (780 mg, 2.39 mmol) were reacted in 1,4-dioxane (15 mL) at 100 °C for 8 h. After filtration through diatomaceous earth, aqueous workup and purification by preparative TLC (DCM:MeOH = 15:1), the title compound was obtained as a brown solid (230 mg, 40%). MS (ESI): m / z [M+H] + 485.2。

[1796] Intermediate 79

[1797] Step A.i-79a

[1798] 3-chloro-1-(4-methoxybenzyl)-6-methylpyrazin-2(1H)-one

[1799]

[1800] 4-Methoxybenzyl chloride (650 mg, 4.15 mmol) was added to a mixture of 3-chloro-6-methylpyrazin-2(1H)-one (CAS Registry No. 89283-34-1; F. Chillemi, G. Palamidassi, Farmaco, Edizione Scientifica 1963, 18(8), 557-65) (400 mg, 2.77 mmol) and K3PO4 (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), extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound as a white solid (260 mg, 36%). MS (ESI): m / z [M+H] + 265.1 / 267 (Cl isotopic pattern). 1 H NMR (300 MHz, 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).

[1801] Step B.i-79b

[1802] 6'-(((1S,3S)-3-((4-(4-methoxybenzyl)-5-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino yl)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[1803]

[1804] According to GM2, the 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 K3PO4 (241 mg, 1.13 mmol) were reacted in 1,4-dioxane (1 mL) at 100 °C for 16 hours. After filtration through diatomaceous earth, aqueous work-up and purification by preparative TLC (DCM:MeOH = 10:1), the title compound as a white solid was obtained (110 mg, 58%). 1 H NMR (300 MHz, 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), 6.54 (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).

[1805] Intermediate 82

[1806] Step A.i-82a

[1807] 6-((6-chloropyridin-3-yl)amino)-5-nitronicotinonitrile

[1808]

[1809] Under nitrogen, at room temperature, Na2CO3 (1.73 g, 16.3 mmol) was added to a mixture of 6-chloro-5-nicotinonitrile (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), and the mixture was stirred at 80 °C for 3 hours. The reaction mixture was filtered through a membrane filter, concentrated under reduced pressure, and the crude material was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound as a yellow solid (1.28 g, 85%). MS (ESI): m / z [M+H] + 275.8 / 278 (Cl isotope pattern).

[1810] Step B.i-82b

[1811] 5-amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile

[1812]

[1813] At room temperature, 6-((6-chloropyridin-3-yl)amino)-5-nicotinonitrile 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), and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was filtered through a membrane filter, 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 as a yellow solid (1.26 g, 100%). MS (ESI): m / z [M+H] + 246.0 / 248 (Cl isotope pattern).

[1814] Step C.i-82c

[1815] 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[1816]

[1817] A solution of 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) under nitrogen at room temperature and the mixture 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 Na2SO4, filtered and evaporated, and the crude material was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound as a yellow oil (590 mg, 38%). MS (ESI): m / z [M+H] + 271.9 / 274 (Cl isotope pattern).

[1818] Step D.i-82d

[1819] 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[1820]

[1821] 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 methyl iodide (3.03 g, 21.4 mmol) under nitrogen at room temperature and the mixture was stirred at 60 °C for 1 h. The reaction mixture was poured into water (100 mL) and the mixture was extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the crude material was purified by preparative TLC (DCM:PE = 10:1) to give the title compound as a brown oil (401 mg, 66%). MS (ESI): m / z [M+H] + 285.9 / 288 (Cl isotope pattern).

[1822] Intermediate 88

[1823] Step A.i-88a

[1824] methyl 5-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)pyrazine-2-carboxylate

[1825]

[1826] At room temperature, Na2CO3 (553 mg, 5.22 mmol) was added to a solution of ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (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), 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 successively 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 as a pale yellow solid (533 mg, 91%). MS (ESI): m / z [M+H] + 337.

[1827] Step B.i-88b

[1828] ((1S,3S)-3-((5-(methylcarbamoyl)pyrazin-2-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1829]

[1830] Methyl 5-(((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)amino)pyrazine-2-carboxylate compound i-88a (533 mg, 1.58 mmol) was dissolved in a solution of methylamine (30% w / w) in EtOH (15 mL) and placed in a microwave tube. The tube was sealed and heated in a microwave reactor at 100 °C for 2 h. The solvent was removed under reduced pressure to give the crude title compound as a yellow solid (525 mg, 99%), which was used without further purification. MS (ESI): m / z [M+H] + 335.9.

[1831] Step C.i-88c

[1832] 5-(((1S,3S)-3-aminocyclopentyl)amino)-N-methylpyrazine-2-carboxamide

[1833]

[1834] At room temperature, HCl (4 M dioxane solution, 2.5 mL, 10 mmol) was added to a solution of 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), 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 successively with saturated NaHCO3 (3 × 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated, and the obtained material was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound as a pale yellow solid (425 mg, 115%). MS (ESI): m / z [M+H] + 235.8。

[1835] Intermediate 89

[1836] i-89a

[1837] methyl 5-(((1S,3S)-3-((3-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino yl)pyrazine-2-carboxylate

[1838]

[1839] At room temperature, 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 5xTFA salt compound i-3b (480 mg, 0.55 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (4.6 mg, 5.5 μmol) and Cs2CO3 (539 mg, 1.65 mmol) in 1,4-dioxane (15 mL), and the resulting mixture was stirred under nitrogen at 100 °C for 15 h. The reaction mixture was poured into water (125 mL) and extracted with EtOAc (4 × 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated, and the residue was purified by preparative TLC (EtOAc) to give the title compound as a yellow solid (164 mg, 68%). MS (ESI): m / z [M+H] + 436.8。

[1840] Intermediate 93

[1841] i-93a

[1842] 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-5-(1-(4-methoxy benzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[1843]

[1844] At room temperature, Cs2CO3 (371 mg, 1.14 mmol) was added to a solution of 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) in 1,4-dioxane (5 mL), and the resulting mixture was stirred under nitrogen at 100 °C for 15 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried (Na2SO4), filtered and evaporated, and the residue was purified by preparative TLC (MeOH:DCM = 1:30) to give the title compound as a pale yellow solid (111 mg, 86%). MS (ESI): m / z [M+H] + 564.9。

[1845] Intermediate 94

[1846] i-94a

[1847] 5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino yl)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[1848]

[1849] In a similar manner to that described for compound i-93a from (1S,3S)-N 1-(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine × 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), Cs2CO3 (371 mg, 1.14 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (9.6 mg, 0.01 mmol) in 1,4-dioxane (5 mL) were prepared and purified by preparative TLC (MeOH:DCM = 1:30) to give the title compound as a beige solid (80 mg, 64%). MS (ESI): m / z [M+H] + 550.9。

[1850] Intermediate 95

[1851] i-95a

[1852] 6'-(((1S,3S)-3-((5-(Difluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)amino)-5-(1-(4-meth oxybenzyl)-1H-tetrazol-5-yl)-2H-[1,3'-bipyridin]-2-one

[1853]

[1854] In a similar manner to that described for compound i-93a, from (1S,3S)-N 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), Cs2CO3 (371 mg, 1.14 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (9.6 mg, 0.01 mmol) in 1,4-dioxane (5 mL) were prepared and purified by preparative TLC (EtOAc) to give the title compound as a light yellow solid (123 mg, 90%). MS (ESI): m / z [M+H] + 602.9。

[1855] Intermediate 96

[1856] Step A.i-96a

[1857] ((1S,3S)-3-((5-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)-2-oxo-2H-[1,3'-bipyr idin]-6'-yl)amino)cyclopentyl) tert-butyl carbamate

[1858]

[1859] Pd-PEPPSI-IPentCl 2-methylpyridine (CAS Registry No. 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), Cs2CO3 (1.37 g, 4.26 mmol) and ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (CAS Registry No. 645400-44-8) (0.43 g, 2.13 mmol) in DMF (13 mL), and the mixture was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was filtered through Celite and the cake was washed with EtOAc (20 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (gradient: 0-10% MeOH / DCM) to afford the title compound as a yellow solid (0.70 g, 59%). MS (ESI): m / z [M+H] + 559.3。

[1860] Step B.i-96b

[1861] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2H- [1,3'-bipyridin]-2-one

[1862]

[1863] At room temperature, TFA (3 mL, 39 mmol) was added to a solution of ((1S,3S)-3-((5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-96a (690 mg, 1.24 mmol) in DCM (10 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The solvent was removed under reduced pressure to afford the undesignated TFA salt of the title compound as an orange gum (600 mg, 85%), which was used without further purification. MS (ESI): m / z [M+H] + 459.0。

[1864] Step C.i-96c

[1865] 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

[1866]

[1867] The 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 No. 19745-07-4) (49 mg, 0.33 mmol), Cs2CO3 (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 for 18 h under a nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 1:0) to give the title compound as a pale yellow solid (50 mg, 27%). MS (ESI): m / z [M+H] + 571.3。

[1868] Intermediate 97

[1869] i-97a

[1870] 6'-Fluoro-3-methoxy-2H-[1,3'-bipyridin]-2-one

[1871]

[1872] A 500 mL flask was charged with 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (11.84 g, 53.10 mmol), 3-methoxypyridin-2(1H)-one (CAS Registry No. 20928-63-6) (6.64 g, 53.1 mmol), Cu(I)I (2.022 g, 10.62 mmol) and K2CO3 (14.68 g, 106.19 mmol). rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (1.68 mL, 10.6 mmol) was added followed by dioxane (200 mL). The flask was backfilled with nitrogen (3×) 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 × 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 as a beige solid (5.46 g, 46%) (91% pure). MS (ESI): m / z [M+H] + 221.2。

[1873] Intermediate 98

[1874] Step A.i-98a

[1875] rel-((1R,3R)-3-((5-Methylpyrazin-2-yl)amino)cyclopentyl) tert-butyl carbamate

[1876]

[1877] 2-Chloro-5-methylpyrazine (CAS Registry Number 59303-10-5) (0.349 g, 2.71 mmol), rel-((1R,3R)-3-aminocyclopentyl)carbamic acid tert-butyl ester (CAS Registry Number 947732-58-3) (0.544 g, 2.72 mmol), Pd-PEPPSI TM -IPent catalyst (CAS Registry Number 1158652-41-5) (91 mg, 0.11 mmol), Cs2CO3 (1.33 g, 4.08 mmol) and 1,4-dioxane (6 mL) were mixed at room temperature. The vial was capped, degassed and filled with nitrogen (2×), and the mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered through a small silica plug. The plug was washed with EtOAc and the filtrate was evaporated. The residue was suspended in EtOAc:heptane = 1:4 (10 mL) and sonicated for 5 min. The solid was filtered off, washed with EtOAc:heptane = 1:4 (50 mL), then with heptane (10 mL) and dried overnight in vacuo to give the title compound as a grey / white solid (545 mg, 81%). MS (ESI): m / z [M+H] + 293.2。

[1878] Step B.i.98b

[1879] rel-(1R,3R)-N 1 -(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine 3TFA

[1880]

[1881] TFA (2.0 mL, 26 mmol) was added to a slurry of tert-butyl rel-((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 as a brown oil (0.878 g, 89%) containing 5 mol% toluene. MS (ESI): m / z [M+H] + 193.1

[1882] Intermediate 99

[1883] i-99a

[1884] Methyl 2-((5-bromopyrazin-2-yl)thio)acetate

[1885]

[1886] Under a nitrogen atmosphere, at 20 °C, over a 1 min period, 2,5-dibromopyrazine (CAS Registry No. 23229-26-7) (500 mg, 2.10 mmol) was added to a solution of methyl 2-mercaptoacetate (44.6 mg, 0.42 mmol) and TEA (117 μL, 0.84 mmol) in DMF (5 mL), and the resulting suspension was stirred at 60 °C for 15 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc (200 mL) and washed successively with saturated brine (3 × 150 mL). The organic layer was dried over Na2SO4, filtered and evaporated, and the residue obtained was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound as a yellow solid (106 mg, 96%). MS (ESI): m / z [M+H] + 262.8

[1887] Intermediate 100

[1888] i-100a

[1889] 6'-Fluoro-2H-[1,3'-bipyridin]-2-one

[1890]

[1891] rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (1.50 g, 10.5 mmol) was added to a mixture of pyridin-2(1H)-one (CAS Registry No. 142-08-5) (5.0 g, 52.6 mmol), 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (17.6 g, 78.9 mmol), Cu(I)I (4.01 g, 21.0 mmol) and K2CO3 (14.53 g, 105.2 mmol) in 1,4-dioxane (50 mL), and the mixture was stirred at 90 °C for 18 h under a nitrogen atmosphere. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (gradient: 0 - 50% EtOAc / PE) to give the title compound as a brown solid (11.6 g, 116%). MS (ESI): m / z [M+H] + 191.1。 1 1H NMR (300 MHz, DMSO-d6) δ ppm 6.36 (1H, dt), 6.52 (1H, d), 7.36 (1H, dd), 7.54 (1H, ddd), 7.73 (1H, dd), 8.14 (1H, ddd), 8.35 (1H, dd).

[1892] Intermediate 101

[1893] Step A.i-101a

[1894] 1-(6-(Benzyloxy)pyridin-3-yl)-4-methylpiperazine

[1895]

[1896] At 25 °C, sodium tert-butoxide (437 mg, 4.55 mmol) was added to a mixture of 2-(benzyloxy)-5-bromopyridine (CAS Registry No. 83664-33-9) (400 mg, 1.51 mmol), BINAP (94 mg, 0.15 mmol), Pd2(dba)3 (139 mg, 0.15 mmol) and 1-methylpiperazine (455 mg, 4.54 mmol) in 1,4-dioxane (7 mL). The resulting solution was stirred in a microwave reactor at 120 °C for 12 min under nitrogen. The reaction mixture was filtered through Celite, and the cake was washed with DCM (2 × 5 mL). The combined filtrates were concentrated under reduced pressure, and the material obtained was purified by C18-flash chromatography (gradient: 0 - 29% MeCN / water + 1% TFA) to give the title compound as a brown oil (303 mg, 71%), which solidified on standing. MS (ESI): m / z [M+H] + 284。 1H (300 MHz, 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).

[1897] Step B.i-101b

[1898] 5-(4-Methylpiperazin-1-yl)pyridin-2-ol

[1899]

[1900] At 25 °C, Pd-C (22.5 mg, 0.21 mmol) was added to a solution of 1-(6-(benzyloxy)pyridin-3-yl)-4-methylpiperazine compound i-101a (300 mg, 1.06 mmol) in MeOH (20 mL), and the resulting suspension was stirred at this temperature under a hydrogen atmosphere for 16 h. The mixture was filtered through a pad of Celite and the cake was washed with methanol (3 × 5 mL). The combined filtrates were concentrated under reduced pressure to give the title compound as a black solid (180 mg, 88%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 194.

[1901] Intermediate 102

[1902] i-102a

[1903] 6'-Chloro-2'-methyl-2H-[1,3'-bipyridin]-2-one

[1904]

[1905] The reaction was carried out in 2 parallel batches (1 batch starting from 2 g of boric acid and 1 batch starting from 1 g of boric acid).

[1906] At 25 °C, 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), and the mixture was stirred at 25 °C for 18 h. The two reaction mixtures were combined, evaporated to dryness, redissolved in EtOAc (100 mL) and washed successively 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 as a brown gum (36 mg, 0.9%). MS (ESI): m / z [M+H] + 220.90。 1 H NMR (300 MHz, 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).

[1907] Intermediate 103

[1908] Step A.i-103a

[1909] ((1S,3S)-3-((5-(Hydroxymethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl) am ino tert-butyl carbamate

[1910]

[1911] Under a nitrogen atmosphere, at 20 °C, K3PO4 (395 mg, 1.86 mmol) was added to ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-1a (250 mg, 0.62 mmol), 5-(hydroxymethyl)pyridin-2(1H)-one (CAS Registry No. 109205-68-1) (155 mg, 1.24 mmol), Cu(I)I (59 mg, 0.31 mmol) and N 1 ,N 2-Dimethylethane-1,2-diamine (27 mg, 0.31 mmol) in a mixture of DMF (5 mL) and the mixture was stirred at 100 °C for 16 h. 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 and evaporated, and the residue was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a purple solid (155 mg, 62%). MS (ESI): m / z [M+H] + 401.1。

[1912] Step B.i-103b

[1913] ((1S,3S)-3-((5-(Chloromethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl) am ino tert-butyl carbamate

[1914]

[1915] At 20 °C, thionyl chloride (430 mg, 3.6 mmol) was added to ((1S,3S)-3-((5-(hydroxymethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl compound i-103a (144 mg, 0.36 mmol) in a mixture of DCM (10 mL) and the mixture was stirred at this temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the crude title compound obtained (355 mg) was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 419 / 421 (Cl isotope pattern).

[1916] Step C.i-103c

[1917] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-((methylthio)methyl)-2H-[1,3'-bipyridin]-2- one

[1918]

[1919] At 20 °C, sodium methanethiolate (173 mg, 2.47 mmol) was added to a mixture of crude ((1S,3S)-3-((5-(chloromethyl)-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-103b (345 mg) in EtOH (10 mL), and the mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the obtained material was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a brown solid (88 mg, 32%) (along with 20 mg of the Boc-protected title compound). MS (ESI): m / z [M+H] + 331.1。

[1920] Step D.i-103d

[1921] 6'-(((1S,3S)-3-((5-Methylpyrazin-2-yl)amino)cyclopentyl)amino)-5-((methylthio)methyl)- 2H-[1,3'-bipyridin]-2-one

[1922]

[1923] In a slightly modified GM2, at 20 °C, Cs2CO3 (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 No. 98006-90-7) (82 mg, 0.47 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (99 mg, 0.12 mmol) in DMF (3 mL), and the resulting mixture was stirred at 100 °C for 16 h under nitrogen. 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 × 50 mL), dried over Na2SO4, filtered and evaporated, and the residue was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a brown solid (76 mg, 76%). MS (ESI): m / z [M+H] + 423.1。

[1924] Intermediate 106

[1925] Step A.i-106a

[1926] ((1S,3S)-3-((5-(5-Cyano-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl) amino tert-butyl carbamate

[1927]

[1928] Under a nitrogen atmosphere, at 20 °C, ((1S,3S)-3-((5-(5-chloro-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-70a (420 mg, 1.03 mmol) was added to a mixture of Pd2(dba)3 (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), and the mixture was stirred at 100 °C for 15 h. The reaction mixture was quenched with saturated brine (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated, and the residue was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound as an orange solid (232 mg, 57%). MS (ESI): m / z [M+H] + 397.0。

[1929] Step B.i-106b

[1930] 2-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile Nitrile

[1931]

[1932] A mixture of ((1S,3S)-3-((5-(5-cyano-6-oxopyridazin-1(6H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-106a (200 mg, 0.50 mmol) in DCM (3 mL) was treated with TFA (1 mL) at 20 °C and stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give the undesignated TFA salt of the title compound as a brown oil (370 mg, 97%), which was used without further purification. 1 H NMR (400 MHz, 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).

[1933] Intermediate 107

[1934] Step A.i-107a

[1935] 4-Bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1936]

[1937] At 15 °C, 1-(chloromethyl)-4-methoxybenzene (7.48 g, 47.8 mmol) was added to a mixture of 4-bromo-6-chloro-3(2H)-pyridazinone (CAS Registry No. 933041-13-5) (5.0 g, 24 mmol) and Cs2CO3 (15.6 g, 47.8 mmol) in MeCN (80 mL), and the mixture was stirred at 60 °C for 3 h. The mixture was filtered through a Celite pad, the cake was washed with DCM (3 × 20 mL), and the combined filtrates were concentrated under reduced pressure. The material obtained was triturated with EtOAc:PE = 1:5 (25 mL), the solid formed was collected by filtration and dried in vacuo to give the title compound as a yellow solid (7.8 g, 98%). MS (ESI): m / z [M+H] + 329 / 331 (Br / Cl isotope pattern).

[1938] Step B.i-107b

[1939] 6-Chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1940]

[1941] At 15 °C, RockPhos Pd G3 (CAS Registry No. 2009020-38-4) (1.97 g, 2.35 mmol) was added to a mixture of 4-bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107a (7.75 g, 23.5 mmol), (E)-benzaldoxime (3.70 g, 30.6 mmol) and Cs2CO3 (15.6 g, 47.8 mmol) in DMF (40 mL) and water (10 mL), and the mixture 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 × 100 mL), dried over Na2SO4, filtered and evaporated, and the residue was purified by flash column chromatography on silica gel (gradient: 0 - 100% EtOAc / PE) to give the title compound as a tan solid (4.0 g, 64%). MS (ESI): m / z [M+H] + 267 / 269 (Cl isotope pattern).

[1942] Step C.i-107c

[1943] 6-Chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1944]

[1945] Cs2CO3 (293 mg, 0.90 mmol) was added to a mixture of 6-chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107b (200 mg, 0.75 mmol), and the mixture was stirred at 20 °C for 1.5 h. Sodium chlorodifluoroacetate (CAS Registry Number 1895-39-2) (343 mg, 2.25 mmol) was added, and the resulting mixture was stirred at 100 °C for 3.5 h. The reaction mixture was poured into saturated brine (50 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 50 mL), dried over Na2SO4, filtered and evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound as a yellow gum (175 mg, 74%). MS (ESI): m / z [M+H] + 317 / 319 (Cl isotope pattern).

[1946] Step D.i-107d

[1947] 4-(Difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1948]

[1949] At 20 °C, 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), and the resulting suspension was stirred at this temperature under a hydrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (576 mg, 95%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 283.0.

[1950] Step E.i-107e

[1951] 4-(Difluoromethoxy)pyridazin-3(2H)-one

[1952]

[1953] At 20 °C, TFA (20 mL) was added to 4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107d (546 mg, 1.93 mmol), and the mixture was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give the unspecified TFA salt of the title compound as a black gum (483 mg, 90%), which was used without further purification. MS (ESI): m / z [M+H] + 162.9.

[1954] Example

[1955] Example 1

[1956] 3-Methyl-5-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)pyrazine-2-carbonitrile – Compound 1 Example 2

[1957]

[1958] According to GM1A, 5-chloro-3-methylpyrazine-2-carbonitrile (CAS Registry 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 as a yellow solid (70 mg, 32%). HRMS (ESI) m / z [M+H] + C 21 H 22 Calculated for C H N7O: 388.1880, found: 388.1878. 1 H NMR (400 MHz, 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).

[1959] 6'-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one – Compound 2

[1960] Example 3 6'-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one – Compound 3

[1961]

[1962] In the modified GM2, 5-chloro-2,3-dimethylpyrazine (CAS Registry Number 59489-32-6) (132 mg, 0.92 mmol) was added to a toluene (5 mL) solution of 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (250 mg, 0.92 mmol), Cs2CO3 (904 mg, 2.77 mmol), and Pd2(dba)3-CHCl3 adduct (CAS Registry Number 52522-40-4) (191 mg, 0.18 mmol), and the reaction mixture was stirred at 90 °C for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (3 × 50 mL). The organic layer was dried over Na2SO4, 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 as a white solid (40 mg, 11%). HRMS (ESI) m / z [M+H] + C 21 H 25 Calculated for C H N6O: 377.2084, found: 377.2078. 1 H NMR (300 MHz, 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 (1H, 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).

[1963] Example 4

[1964] 6'-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one – Compound 4 Example 5

[1965]

[1966] According to GM2, 2,5-dichloropyrazine (CAS Registry 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 Cs2CO3 (656 mg, 2.01 mmol) were reacted in 1,4-dioxane (5 mL) at 100 °C for 18 hours. After aqueous workup and purification by preparative HPLC (preparation method B, gradient 25%-55%), the title compound as a white solid (20 mg, 8%) was obtained. HRMS (ESI) m / z [M+H] + C 19 H 20 Calculated for C H ClN6O: 383.1382, found: 383.1396. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 1.51 ...

Claims

1. A compound of formula (I) A - B - C (I) or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof, wherein A has the formula: where the wavy line indicates the point of attachment to B; X 1 is C-R A1 ; R A1 selected from the group consisting of: (i) H; (ii) a halogenated group; (iii) CN; (iv) C 1-6 a hydrocarbon, optionally substituted by one or more OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halo groups; (v)C 1-6 an alkoxy group, which is optionally substituted by OH, one or more halogenated groups, C 1-6 alkylcarbonylamino; (vi)C 1-6 alkyl ester; (vii)C 1-6 alkyl acyl; and (viii) OH; R A2 selected from the group consisting of: (i) H; (ii) a halogenated group; (iii) CN; (iv) C 1-6 hydrocarbons, optionally substituted by OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halo groups; (v)C 1-6 an alkoxy group, which is optionally substituted with OH, alkylamido or one or more halo groups; (vi) C 1-6 an acylamino group (wherein said acyl group is optionally substituted by H or methyl); (vii) C 1-6 Thioalkyl, optionally substituted with C 1-6 alkyl ester; (viii) C 1-6 alkyl ester; (ix)C 1-6 alkyl acyl; (x)C 4-5 heterocyclic group; (xi) a C5 heteroaryl; (xii) C 1-6 Alkylamido, which is optionally substituted by C 1-3 Alkylamido, CN, OH, C 2-3 Alkynyl, C 4-6 Heterocyclic group or C 1-3 Alkyl is substituted, wherein the C 1-3 Alkyl is optionally substituted by one or more halogenated groups or OH groups; and (xiii) OH; R A3 selected from the group consisting of: (i) H; (ii) a halogenated group; (iii) CN; (iv) C 1-6 a hydrocarbon, optionally substituted by OH, CN, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 acyloxy, carboxyl, C 1-6 alkyl ester, C 1-6 alkylamino, -C(=O)NH2, C 1-6 alkylacylamino, C 1-6 alkylacylacylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or one or more halo groups; (v) OH; (vi) C 1-6 an alkoxy group, optionally substituted by OH, NH2, a C4 heterocyclic group or one or more halo groups; (vii) C 1-6 acyloxy; (viii) a C4 heterocyclic group; (ix) - NH2; (x)C 1-6 an alkylamino group, which is optionally substituted with CN, OH or a C4 heterocyclic group; (xi) C 1-6 Dialkylamino, optionally substituted by -NH2; (xii) C 1-6 Acylamido (wherein the acyl substituent is H or Me); (xiii) amidino or methyl - amidino; (xiv) carboxylamino; (xv)C 1-6 Thioalkyl, optionally substituted by OH or NH2; (xvi)C 1-6 Alkylsulfinyl; (xvi)C 1-6 alkylsulfonyl, optionally substituted by one or more halo groups; (xvii)C 1-6 sulfonylimino group; (xviii)C 1-6 alkylphosphinyloxy; (xix) carboxyl; (xx) C(=O)NH2 (xxi)C 1-6 alkyl ester; (xxii)C 1-6 an alkyl acyl group, optionally substituted with one or more halogen groups; and (xxiii)C 1-6 alkyl acylamino; or wherein R A3 and R A2 together with the carbon atoms to which they are attached form: (i) Optionally substituted C 5-7 heterocycle; (ii) Optionally substituted C 5-7 heteroaromatic ring; (iii) an optionally substituted C6 carbocyclic aromatic ring; (iv) Optionally substituted C 5-7 carbocyclic ring Wherein the optional substituents are selected from C 1-6 alkyl, halogen, C 1-6 alkoxy, NH2, C 1-6 alkylamino, OH and CN; wherein B has the formula (B - 1) or (B - 2) i) where the wavy line indicates the points of attachment to A and C; R B1 is H, OH, =CHCH2-OH, -O-C 1-4 alkyl or C 1-4 alkyl, where the C 1-4 alkyl is optionally substituted by OH or OMe; (ii) where the wavy line indicates the points of attachment to A and C; R B2 is C 1-2 alkyl-OH, CH2CONHMe or C 1-3 alkyl; wherein C is selected from the group consisting of C 6-10 carbaryl, C 5-6 heteroaryl, and C 5-10 heterocyclic group, and said group is optionally substituted with the following: (i) C 6-10 carboaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocycle, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group, which are themselves optionally substituted by one or more of the following groups; a) one or two =O groups; b) one or more halogenated groups; c) CN, NH2, OH; d) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH, C 1-6 alkylsulfonyl or one or more halogenated groups; e)C 1-6 an alkoxy group having an optional substituent of one or more halogenated groups; f)C 1-6 alkyl ester; g)C 5-6 A heterocyclic group having an optional methyl, OH or ═O substituent; h)C 5-6 a heteroaryl group, optionally substituted by methyl; i)C 4-10 A carbocyclic group having an optional methyl or ═O substituent; j)C 6-10 A carbon aryl having an optional substituent of one or more halo groups; l) P(=O)Me2; m) carboxyl or CH2 - carboxyl; n) tetrazolyl, CH2 - tetrazolyl, 5 - oxo - 4H - 1,2,4 - oxadiazol - 3 - yl; (ii) one or more groups selected from carboxyl, CN, halogen, nitro, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 alkylacylamino, di-C 1-6 alkylacylamino, C 1-6 alkylsulfinylamino and di-C 1-6 alkylsulfinylamino groups.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R A1 is selected from the group consisting of: (i) H; (ii) a halogenated group; (iii) CN; (iv) C 1-6 a hydrocarbon, optionally substituted by OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halo groups; (v) C 1-6 An alkoxy group, which is optionally substituted by OH, one or more halogenated groups, C 1-6 alkylcarbonylamino; or (vi) OH.

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

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R A2 is selected from the group consisting of: (i) H; (ii) a halogenated group; (iii) CN; (iv) C 1-6 a hydrocarbon, optionally substituted by OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halo groups; (v) OH; (vi) C 1-6 An alkoxy group, which is optionally substituted by OH, C 1-6 alkylcarbonylamino or one or more halogen groups; (vii)C 1-6 alkyl ester; (viii)C 1-6 alkyl acyl; (ix) C 1-6 Alkylamido, which is optionally substituted by C 1-3 Alkylamido, CN, C 2-3 Alkynyl, C 4-6 Heterocyclic group or C 1-3 Alkyl substituted, and the alkyl is optionally substituted by one or more halogen groups or OH groups; and (x)C 1-6 Thioalkyl, which is optionally substituted by C 1-6 alkyl ester.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein 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.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R A3 is selected from the group consisting of: (i) H; (ii) a halogenated group; (iii) CN; (iv) C 1-6 a hydrocarbon, optionally substituted by OH, CN, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkylacyl, C 1-6 acyloxy, carboxyl, C 1-6 alkyl ester, C 1-6 alkylamino; -C(=O)NH2, C 1-6 alkylacylamino, C 1-6 alkylacylacylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or one or more halo groups; (v) OH; and (vi) C 1-6 An alkoxy group, which is optionally substituted by OH, NH2, a C4 heterocyclic group or one or more halogenated groups.

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

8. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R A3 and R A2 together with the carbon atoms to which they are attached form an optionally substituted C6 carbocyclic aromatic ring or a C5 heteroaromatic ring, wherein the optional substituents are selected from methyl, NH2, Cl, F and OMe.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein B has the formula (B - 1) where the wavy line indicates the points of attachment to A and C; wherein R B1 is selected from the group consisting of: H, OH, OMe, -O-ethyl, -CH2OH, -CH2CH2OH and =CHCH2 - OH.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein B has the following formula (B - 1a):

11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl group, wherein the optional substituents are selected from C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 5-10 heterocyclic group, C 5-10 bridged heterocyclic group, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group, which are themselves optionally substituted by one or more of the following groups: a) one or two =O groups; b) one or more halogenated groups; c) CN, NH2 or OH; d) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH, C 1-6 alkylsulfonyl or one or more halo groups; e)C 1-6 an alkoxy group having an optional substituent of one or more halogenated groups; f)C 1-6 alkyl ester; g)C 5-6 a heterocyclic group having an optional methyl, OH or ═O substituent; h)C 5-6 a heteroaryl group having an optional methyl substituent; i)C 4-10 A carbocyclic group having an optional methyl or ═O substituent; j)C 6-10 A carbon aryl group having an optional substituent of one or more halo groups; l) P(=O)Me2; m) carboxyl or CH2 - carboxyl; and / or n) tetrazolyl, CH2 - tetrazolyl, 5 - oxo - 4H - 1,2,4 - oxadiazol - 3 - yl.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein C has the formula (C - 1): where D is C 6-10 carbaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, each of which is optionally substituted by the following: i) one or two =O groups; ii) one or two C 1-4 alkyl groups, which can be branched and are optionally substituted by substituted with S(=O)2CH3; iii) OMe; iv) piperazinyl, which is optionally substituted with methyl; v) C(=O)OH (carboxyl); vi) Cl; vii) F; viii) phenyl, which is optionally substituted with one or more fluorines; ix) CN; x) CF3; xi) O - CF3; xii) O - CF2; xiii) pyrazolyl, triazolyl optionally substituted with methyl; tetrazolyl; xiv) NH2; xv) pyridinyl; xvi) CH2OH; xvii) OH; or xviii) P(=O)Me2.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein D has the formula (D-1): wherein R D1 , R D2 , R D3 and R D4 one or both of which are selected from i)C 1-6 alkyl, optionally substituted by C 1-6 alkylsulfonyl or one or more halo groups; ii)C 1-6 an alkoxy group, optionally substituted with one or more halogen groups; iii)C 5-6 heterocyclic group or C 5-6 heteroaryl group, said group having an optional methyl substituent; iv) carboxyl or CH2-carboxyl; v) =O, halo, NH2 or CN; vi) phenyl, which is optionally substituted with one or more halo atoms; and the remainder are H; or wherein R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocyclic ring or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halogen and C(=O)OH; or wherein R D1 , R D2 , R D3 and R D4 are all H.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: a) R D1 , R D2 , R D3 and R D4 are H; or b) R D3 is selected from the group consisting of: H; optionally substituted phenyl, wherein the optional substituent is a halogen, methyl optionally substituted with -S(=O)2CH3, OMe, C(=O)OH, Cl, CN; or piperazinyl optionally substituted with methyl; or pyrazolyl, triazolyl or tetrazolyl optionally substituted with methyl, and wherein R D1 , R D2 and R D4 are both H; or c) R D1 selected from H, methyl, OMe, Cl, CF3, OCF3, pyrazolyl optionally substituted by methyl, triazolyl and CN, and wherein R D2 , R D3 and R D4 are all H; or d) R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.

15. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein D has the formula (D-2): where X D is NR D5a or CR D5a R D5b ; R D5a selected from H or methyl; R D5b and R D6b both are H or together they are -CH2-; R D6a selected from H, =O, methyl, -CH2OH or -C(=O)OH, where when R D6a is =O, R D6b Does not exist; R D7a selected from H, =O, methyl, -CH2OH or -C(=O)OH; R D7b is H, where when R D7a is =O, R D7b does not exist; or wherein R D6a and R D7a together form a benzene ring or a C6 heteroaromatic ring, which is optionally substituted with CN, P(=O)Me2 or carboxyl, and R D6b and R D7b are absent.

16. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein D is selected from the following groups:

17. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein C has the formula (C-2): wherein R C7 , R C8 , R C9 and R C10 is selected from the group consisting of: methyl optionally substituted with S(=O)2CH3; OMe; piperazinyl optionally substituted with methyl; C(=O)OH (carboxyl); Cl; F; pyrazolyl optionally substituted with methyl; triazolyl; tetrazole; optionally substituted phenyl (wherein the optional substituent is methyl or halo); CN; CF3; O-CF3; and R C7 , R C8 , R C9 and R C10 are the remainder H; or R C9 and R C10 form a benzene or 6-membered heteroaromatic ring, and both R C7 and R C8 are H; or wherein R C7 , R C8 , R C9 and R C10 are all H.

18. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of:

19. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein A-B-C has the formula (I-A), (I-B), (I-Ba), (I-Bb), (I-C) or (I-D): wherein X 1 、R A2 、R A3 、C, D, R D1 、R D2 、R D3 、R D4 、R D1a 、R D2a 、R D3a 、R D4a 、X D 、R D6a 、R D6b 、R D7a and R D7b are defined as in any one of the preceding claims.

20. A compound of Table 1 or Table 2 or a pharmaceutically acceptable salt thereof.

21. The 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 the 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. The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 44 for use in the treatment of cardiovascular diseases, optionally wherein the cardiovascular diseases are 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 or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the compound is administered simultaneously, separately or sequentially in combination with an additional active ingredient selected from the group consisting of: i) statins; ii) cholesterol absorption inhibitors; iii) SGLT2 inhibitors; iv) P2Y12 inhibitors; v) citrate lyase inhibitors; and vi) antihypertensive drugs.

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