PCSK9 inhibitors and methods of use thereof

Abstract

A compound having the formula (I): A-B-C wherein A has the formula (Ia) wherein X1 is N; b has the formula (B-1) or (B-2) and C is selected from the group consisting of optionally substituted C6-10 carbon aryl, C5-6 heteroaryl and C5-10 heterocyclyl, as well as the use of the compounds 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, and U.S. Application No. 63 / 580,500, 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 endosome / lysosome compartment. The enhanced binding affinity of PCSK9 for 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, that 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 ~50% reduction in LDL levels compared to placebo (Elbitar 2016). Patients taking evolocumab showed a ~60%-75% reduction in LDL levels. The potency 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 infections that may occur incidentally, cardiovascular diseases generally require management over a person's lifetime. Therefore, ease of administration becomes an important factor for patients to adhere to maintenance drug therapy. There is a need for PCSK9 inhibitors with increased efficacy achievable with small molecule PCSK9 inhibitors and easier administration.

[0006] WO 2020 / 150473 A2 relates to heteroaryl compounds and their pharmaceutical formulations. It also relates to methods of treating or preventing cardiovascular diseases using the novel heterocyclic compounds described, 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] In a first aspect, there is provided 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 N;

[0015] R A2 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 with OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogenated group substituents;

[0020] (v) C 1-6 alkoxy, which is optionally substituted with OH, C 1-6 alkylamino or one or more halogenated group substituents;

[0021] (vi) C 1-6 acylamino (wherein the acyl is optionally substituted with H or methyl);

[0022] (vii) C 1-6 Thioalkyl;

[0023] (viii) C 1-6 Alkyl ester;

[0024] (ix) C 1-6 Alkyl acyl;

[0025] (x) C 4-5 Heterocyclic group;

[0026] (xi) C-5 heteroaryl;

[0027] (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 substituted, wherein the C 1-3 Alkyl is optionally substituted by one or more halogen groups or OH groups;

[0028] (xiii) OH; and

[0029] (xiv) C 1-6 Alkylamino;

[0030] R A3 Selected from the group consisting of:

[0031] (i) H;

[0032] (ii) Halogen group;

[0033] (iii) CN;

[0034] (iv) C 1-6 Hydrocarbon, optionally substituted by OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyl oxy, carboxyl, C 1-6 Alkyl ester, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl acylamino, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl or one or more halogen groups substituted;

[0035] (v) OH;

[0036] (vi) C 1-6An alkoxy group, which is optionally substituted by OH, NH2, a C4 heterocyclic group or one or more halo groups;

[0037] (vii) C 1-6 Acetyloxy;

[0038] (viii) A C4 heterocyclic group;

[0039] (ix) NH2;

[0040] (x) C 1-6 An alkylamino group, which is optionally substituted by CN, OH or a C4 heterocyclic group;

[0041] (xi) C 1-6 A dialkylamino group, which is optionally substituted by -NH2;

[0042] (xii) C 1-6 An acylamino group (wherein the acyl substituent is H or Me);

[0043] (xiii) An amidino or methyl-amidino group;

[0044] (xiv) A carboxylamino group;

[0045] (xv) C 1-6 A thioalkyl group, which is optionally substituted by OH or NH2;

[0046] (xvi) C 1-6 An alkylsulfinyl group;

[0047] (xvii) C 1-6 An alkylsulfonyl group, which is optionally substituted by one or more halo groups;

[0048] (xviii) C 1-6 A sulfonimide group;

[0049] (xix) C 1-6 An alkyloxyphosphinyl group;

[0050] (xx) A carboxyl group;

[0051] (xxi) C(=O)NH2;

[0052] (xxii) C 1-6 An alkyl ester;

[0053] (xxiii) C 1-6 An alkylacyl group, which is optionally substituted by one or more halo groups;

[0054] (xxiv) C 1-6 An alkylacylamino group.

[0055] Or where RA3 and R A2 together with the carbon atom to which they are attached form:

[0056] (i) an optionally substituted C 5-7 heterocycle;

[0057] (ii) an optionally substituted C 5-7 heteroaromatic ring;

[0058] (iii) an optionally substituted C6 carbocyclic aromatic ring;

[0059] (iv) an optionally substituted C 5-7 carbocycle

[0060] wherein the optional substituent is selected from C 1-6 alkyl, halo, C 1-6 alkoxy, NH2, C 1-6 alkylamino, OH, and CN;

[0061] wherein B has formula (B-1) or (B-2)

[0062] (i)

[0063]

[0064] where the wavy line indicates the attachment points to A and C;

[0065] R B1 is H, OH, =CHCH2-OH, O-C 1-4 alkyl, C 1-4 alkyl, said C 1-4 alkyl being optionally substituted by OH or OMe;

[0066] (ii)

[0067]

[0068] where the wavy line indicates the attachment points to A and C;

[0069] R B2 is C 1-2 alkyl-OH, CH2CONHMe, or C 1-3 alkyl;

[0070] where C is selected from the group consisting of C 6-10 carbaryl, C 5-6 heteroaryl, and C 5-10 heterocyclyl, said groups being optionally substituted by:

[0071] (i) selected from C 6-10 carbaryl, C 4-10 carbocyclic, C 5-10Heteroaryl, C 4-10 Heterocyclyl or C 5-10 Bridged heterocyclyl, spiro C 6-12 Heterocyclyl or spiro C 6-12 A group of a carbocyclic group,

[0072] which is optionally substituted by one or more groups selected from the following groups;

[0073] a) One or two ═O groups;

[0074] b) One or more halo groups;

[0075] c) CN, NH2, OH;

[0076] d) One or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from

[0077] OH or one or more halo groups;

[0078] e) C 1-6 Alkoxy, which has optional substituents of one or more halo groups;

[0079] f) C 1-6 Alkyl esters;

[0080] g) C 5-6 Heterocyclyl, which has optional methyl, OH or ═O substituents;

[0081] h) C 5-6 Heteroaryl;

[0082] i) C 4-10 Carbocyclic group, which has optional methyl or ═O substituents;

[0083] j) C 6-10 Carboaryl, which has optional substituents of one or more halo groups;

[0084] l) P(═O)Me2;

[0085] m) Carboxyl or CH2-carboxyl;

[0086] n) Tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[0087] And / or

[0088] (ii) One or more selected from carboxyl, CN, halo, nitro, C 1-6 alkyl, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6Alkyl acyl, C 1-6 Alkyl acylamino, di-C 1-6 Alkyl acylamino, C 1-6 Alkylsulfinylamino and di-C 1-6 groups of alkylsulfinylamino.

[0089] The second aspect provides a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable diluent, carrier or excipient.

[0090] 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.

[0091] The present disclosure includes combinations of the described aspects and features, unless such combinations are clearly impermissible or explicitly avoided. Detailed Description

[0092] 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.

[0093] Compounds of formula (I) and their use in the treatment of cardiovascular diseases are described herein. 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.

[0094] Definition

[0095] Substituent

[0096] As used herein, the phrase "optionally substituted" refers to a parent group that may be unsubstituted or may be substituted.

[0097] Unless otherwise indicated, as used herein, the term "substituted" refers to a parent group bearing one or more substituents. The term "substituent" is used herein in its conventional sense and refers to a chemical moiety that is covalently attached to the parent group or, if appropriate, fused to the parent group. A variety of substituents are well known, and the methods for their formation and introduction into various parent groups are also well known.

[0098] Examples of substituents are described in more detail below.

[0099] Unless otherwise indicated, a halo group is selected from chlorine (Cl), fluorine (F), bromine (Br), and iodine (I), such as fluorine.

[0100] Cyano (nitrile, methyl cyanide): -CN.

[0101] Hydroxy: -OH.

[0102] Oxo group: =O (oxygen is double-bonded to the rest of the molecule).

[0103] 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 from 1 to 6 carbon atoms, which hydrocarbon compound may be aliphatic or alicyclic, may be saturated or unsaturated (e.g., partially unsaturated, fully unsaturated), and may also be branched. Thus, the term "hydrocarbon" includes the terms alkyl, alkenyl, alkynyl, cycloalkyl, etc., discussed below.

[0104] C 1-6 Alkyl: As used herein, the term "C 1-6 alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 6 carbon atoms, which hydrocarbon compound is 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 from 1 to 4 carbon atoms, which hydrocarbon compound is saturated.

[0105] Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), and hexyl (C6).

[0106] 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).

[0107] Examples of saturated branched alkyl groups include isopropyl (C3), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), isopentyl (C5), and neopentyl (C5).

[0108] 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.

[0109] 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).

[0110] 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.

[0111] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and 2-propynyl (propargyl, -CH2C≡CH).

[0112] 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 16 Examples of alkoxy groups include, but are not limited to, OMe, OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), O(nBu) (n-butoxy), O(sBu) (sec-butoxy), O(iBu) (isobutoxy), and O(tBu) (tert-butoxy).

[0113] C 1-6 Acetoxy: As used herein, the term C 1-6 acetoxy (reverse ester) refers to -OC(=O)R, where R is a C 1-6 hydrocarbon group. Examples of acetoxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, or -OC(=O)C(CH3)3.

[0114] Amino: -NR 1 R 2 where R 1 and R 2 are independently amino substituents, such as hydrogen, C 1-6 hydrocarbon group (also referred to as C 1-6alkylamino or C 1-6 dialkylamino), or in the case of a "cyclic" amino group, R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle having 4 to 6 ring atoms. The amino group can be a primary amino group (-NH2), secondary amino group (-NHR 1 ), or 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.

[0115] C 1-6 Acylamido: Acylamido (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 1-6 hydrocarbon 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 acylamido 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:

[0116]

[0117]

[0118] Amidino: -C(=NH)(NH2).

[0119] Methyl-amidino: -C(=N-CH3)NH2.

[0120] Carboxylamino: -N(H)(C(=O)OH).

[0121] 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.

[0122] 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.

[0123] C 1-6 Alkylsulfonyl: As used herein, the term C- 1-6 alkylsulfonyl refers to the -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- 1-6 alkylsulfonyl groups include, but are not limited to, -S(=O)2CH3 (methanesulfonyl / mesyl), -S(=O)2CF3 (trifluoromethanesulfonyl), -S(=O)2CH2CH3 (ethylsulfonyl), -S(=O)2C4F9 (perfluorobutanesulfonyl), and -S(=O)2CH2CF3 (trifluoroethylsulfonyl).

[0124] C 1-6 Sulfonimidoyl: The term C 1-6 sulfonimidoyl is also referred to 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.

[0125] C 1-6 Alkyloxyphosphinyl: The term C 1-6 alkyloxyphosphinyl (phosphine oxide) has the structure -P(=O)R2, where each R is independently a C1-6 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.

[0126] Carboxyl (carboxylic acid): -C(=O)OH.

[0127] 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 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.

[0128] C 1-6 Alkyl acyl: The term C also known as acyl (keto group) 1-6 Alkyl acyl has the structure -C(=O)R, where R is C 1-6 Hydrocarbon group. C 1-6 Examples of alkyl acyl groups include, but are not limited to, -C(=O)CH3 (acetyl), -C(=O)CH2CH3 (propionyl), or -C(=O)C(CH3)3 (tert-butyl acyl).

[0129] C 1-6 Alkyl amido: The term C 1-6 Alkyl amido (also known 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 the amino group, for example hydrogen, C 1-6 hydrocarbon group (also known as C 1-6 alkyl amido or C 1-6 dialkyl amido), or in the case of a "cyclic" amido group, R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle having 4 to 6 ring atoms. Examples of amido groups include, but are not limited to, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2, C(=O)NHCH2CH3, and C(=O)N(CH2CH3)2, and where R 1 and R 2An amido group that forms a heterocyclic structure together with the nitrogen atom to which it is attached, such as the amido groups in piperidinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinylcarbonyl.

[0130] 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.

[0131] Examples of cycloalkyl groups include, but are not limited to, those derived from the following:

[0132] Saturated monocyclic hydrocarbon compounds:

[0133] 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);

[0134] Unsaturated monocyclic hydrocarbon compounds:

[0135] Cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (C6), methylcyclopentene (C6), dimethylcyclopentene (C7), and methylcyclohexene (C7); and

[0136] Saturated polycyclic hydrocarbon compounds:

[0137] Norcarane (C7), norpinane (C7), nortricyclane (C7).

[0138] 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 the heterocycloalkyl ring can be attached through a carbon atom or a heteroatom.

[0139] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0140] In this context, a prefix (e.g., 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, whether 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.

[0141] Examples of monocyclic heterocyclic groups include, but are not limited to, those derived from the following:

[0142] 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);

[0143] O1: Oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C6), pyran (C6), oxepine (C7);

[0144] S1: Thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiane (tetrahydrothiopyran) (C6), thiepine (C7);

[0145] O2: Dioxolane (C5), dioxane (C6), and dioxepane (C7);

[0146] O3: Trioxane (C6);

[0147] N2: Imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6);

[0148] N1O1: Tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C6), oxazine (C6);

[0149] N1S1: Thiazoline (C5), thiazolidine (C5), thiomorpholine (C6);

[0150] N2O1: Oxadiazine (C6);

[0151] O1S1: oxathiacyclopentadiene (C5) and oxathiane (thiomorpholine) (C6); and,

[0152] N1O1S1: oxathiazine (C6).

[0153] Examples of bicyclic heterocyclic groups include, but are not limited to, those derived from the following:

[0154]

[0155] 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 "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 ).

[0156] In this context, the prefix (e.g., C 5-7 , C 5-6 , C 5-10 , etc.) indicates 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.

[0157] Examples of carboaryl groups containing a fused ring (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 ).

[0158] 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 moiety 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.

[0159] In this context, the term "heteroatom" means O, S, N, Si, or B (boron).

[0160] Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from the following:

[0161] N1: Pyrrole(azole)(C5), Pyridine(azine)(C6);

[0162] O1: Furan(oxole)(C5);

[0163] S1: Thiophene(thiole)(C5);

[0164] N1O1: Oxazole(C5), Isoxazole(C5), Isoxazine(C6);

[0165] N2O1: Oxadiazole(furazan)(C5);

[0166] N3O1: Oxatriazole(C5);

[0167] N1S1: Thiazole(C5), Isothiazole(C5);

[0168] 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);

[0169] N3: Triazole(C5), Triazine(C6); and,

[0170] N4: Tetrazole(C5).

[0171] Examples of heteroaryl containing fused rings include, but are not limited to, C9(containing 2 fused rings) derived from the following:

[0172]

[0173]

[0174] Examples of heteroaryl containing fused rings include, but are not limited to, C 10 (containing 2 fused rings):

[0175]

[0176]

[0177] Spiro C 6-12 Spirocyclic group: As used herein, the term spiro C 6-12 spirocyclic group refers to a moiety having at least two molecular rings(connected by only one common atom). The simplest spiro compounds are bicyclic(containing only two rings), or contain 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 6-12A carbocyclic group refers to 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 6 to 12 carbon atoms, including 3 to 7 ring atoms, wherein the rings share a common atom.

[0178] Spiro C 6-12 Heterocyclic group: As used herein, the term Spiro C 6-12 A 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 A 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, wherein 1 to 3 are ring heteroatoms, and wherein the rings share a common atom. In certain embodiments, each ring has 9 to 11 ring atoms, wherein 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.

[0179] 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.

[0180] Pharmaceutically acceptable salt

[0181] The term "pharmaceutically acceptable" is used to indicate that an entity (such as a salt, dosage form or excipient) is suitable for 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 the person skilled in the art. Acid addition salts can be formed, for example, using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Acid addition salts 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.

[0182] Accordingly, in one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, citrate, maleate, oxalate, acetate, formate, benzoate, fumarate, succinate, tartrate, lactate, pyruvate, mesylate, benzenesulfonate or tosylate. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is mesylate. In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is monomesylate, i.e., the stoichiometry of the compound of formula (I) to methanesulfonic acid is 1:1.

[0183] Other forms

[0184] The compounds and salts described in this specification may exist in solvated and unsolvated forms. For example, the solvated form may be a hydrated form such as hemihydrate, monohydrate, dihydrate, trihydrate or alternative amounts thereof. The compounds of formula (I) encompass all such solvated and unsolvated forms of the compounds of formula (I), particularly insofar as such forms have PCSK9 kinase inhibitory activity, for example as measured using the tests described herein.

[0185] The compounds and salts described in this specification include one or more chiral (i.e., asymmetric) centers. Where the structures or chemical names in this specification do not indicate chirality, the structure or name is intended to cover any single stereoisomer (i.e., any single chiral isomer) corresponding to the 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. In other embodiments, a single stereoisomer is obtained by direct synthesis from, for example, chiral starting materials.

[0186] Particular enantiomers of the compounds described herein may be more active than other enantiomers of the same compound.

[0187] According to one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof which is a single enantiomer having an enantiomeric excess (%ee) of ≥95%, ≥98% or ≥99%. Conveniently, the single enantiomer is present with an enantiomeric excess (%ee) of ≥99%.

[0188] 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 having an enantiomeric excess (%ee) of ≥95%, ≥98% or ≥99%. Conveniently, the single enantiomer is present with an enantiomeric excess (%ee) of ≥99%.

[0189] Isotope

[0190] 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 (for example, 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).

[0191] Tautomer

[0192] The compounds and salts described in this specification may exist as mixtures 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), especially insofar as such tautomers have PCSK9 inhibitory activity.

[0193] For example, the tautomeric forms of some exemplary compounds (where R A3 is OH) may be shown as follows.

[0194]

[0195] Crystalline form

[0196] The compounds and salts described in this specification may be crystalline and may exhibit one or more crystalline forms. Compounds of formula (I) encompass any crystalline or amorphous form of compounds of formula (I) having PCSK9 inhibitory activity, or mixtures of such forms.

[0197] 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.

[0198] Therapy, prophylaxis and related terms

[0199] The term "therapy" is intended to have its normal meaning of treating a disease in order to relieve one, some, or all of its symptoms, either completely or partially, or in order to correct or compensate for an underlying pathology. The term "therapy" also includes "prevention", unless specifically indicated to the contrary. The terms "treatment" and "therapeutically" shall be construed correspondingly.

[0200] 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 already 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.

[0201] The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" can be considered "application of therapy", where "therapy" is as defined herein.

[0202] The "subject" to whom administration is contemplated includes, but is 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.

[0203] As used herein, "effective amount" means an amount sufficient to achieve a desired biological effect. As used herein, "therapeutically effective amount" means an amount sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can mean an amount sufficient to improve at least one sign or symptom of a disease to be treated.

[0204] Pharmaceutical composition

[0205] The compounds of formula (I) and their pharmaceutically acceptable salts can be administered as a pharmaceutical composition, which comprises one or more pharmaceutically acceptable excipients.

[0206] Accordingly, in one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0207] The excipients selected 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, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickening agents, and coating agents. As will be understood by those skilled in the art, certain pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions, depending on how much excipient is present in the composition and what other excipients are present in the composition.

[0208] 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.

[0209] In the therapeutic treatment of humans, a suitable daily dose of the compounds described herein or their pharmaceutically acceptable salts is from about 0.0001 mg / kg body weight to 100 mg / kg body weight. The pharmaceutical formulations 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.

[0210] The pharmaceutical compositions described herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof and are thus expected to be useful in therapy.

[0211] Accordingly, 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.

[0212] In one embodiment, there is provided a pharmaceutical composition for use in treating 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 treating 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 treating 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.

[0213] Method of use

[0214] 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 a patient. Such benefit can be, at least, amelioration of at least one symptom. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment (e.g., decisions regarding dosage) is within the responsibility of general practitioners and other physicians.

[0215] The compound can be administered alone or in combination with other treatments, either concomitantly or sequentially, depending on the condition to be treated.

[0216] 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).

[0217] 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 that its putative role is to reduce the LDLR at the cell surface, independent of its catalytic activity (Abifadel 2010). The binding of PCSK9 to the LDLR leads to their lysosomal degradation. This enhanced LDLR degradation results in 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 LDL-C lowering result. Accordingly, methods for treating a variety of cardiovascular diseases and conditions that benefit from inhibiting PCSK9 to lower LDL-C are disclosed herein.

[0218] In certain embodiments, methods of inhibiting PCSK9 are carried out in a subject in need thereof to treat a PCSK9-mediated disease or disorder. Methods of treating or preventing a PCSK9-mediated disease or disorder are also disclosed herein, the method comprising 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, the method comprising 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, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, preventing cardiovascular events by inhibiting PCSK9 has been described in Robinson 2015.

[0219] 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.

[0220] 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.

[0221] In certain embodiments, the disclosed methods of treatment can reduce elevated levels of circulating serum cholesterol, such as LDL-C and VLDL-cholesterol. Additionally, the disclosed methods 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 that counteract the mutation by inhibiting PCSK9.

[0222] Combination therapy

[0223] 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, co-administration of one or more additional therapeutic agents with the compounds described herein provides a synergistic effect. In certain embodiments, co-administration of one or more additional therapeutic agents provides an additive effect.

[0224] In some embodiments in which combination therapy is used, the amounts of the compounds or salts and the amounts of the other pharmaceutically active agents described in this specification are therapeutically effective for treating the targeted condition in an animal patient when combined. In this context, they are "therapeutically effective amounts" if the combined amounts are sufficient, when combined, to meet one or more of the following conditions: reducing or completely alleviating the symptoms or other adverse effects of the condition; curing the condition; reversing, completely halting, or slowing the progression of the condition; or reducing the risk of exacerbation of the condition. Generally, such amounts can be determined by one of ordinary skill in the art starting, for example, from the dosage ranges described for the compounds or salts in this specification and from the approved or otherwise publicly available dosage ranges for the other pharmaceutically active compounds.

[0225] The pharmaceutical compositions of the present specification may comprise one or more additional active ingredients, and examples of combinations of the compounds (or their pharmaceutically acceptable salts) of the present specification and one or more additional active ingredients are described herein when appropriate.

[0226] The present specification further relates to a combination therapy, wherein the compound of the present specification or its pharmaceutically acceptable salt and a second active ingredient are administered simultaneously, sequentially or in admixture for the treatment of one or more of the conditions listed above. Such combinations may be used in combination with one or more other active ingredients.

[0227] In one aspect, there is provided a combination (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 of the present specification or its pharmaceutically acceptable salt and at least one active ingredient selected from the following:

[0228] i) Statins;

[0229] ii) Cholesterol absorption inhibitors;

[0230] iii) SGLT2 inhibitors;

[0231] iv) P2Y12 inhibitors;

[0232] v) Citrate lyase inhibitors; and

[0233] vi) Antihypertensive drugs.

[0234] In another aspect of the present specification, there is provided a pharmaceutical composition (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 of the present specification or its pharmaceutically acceptable salt and at least one active ingredient selected from the following:

[0235] i) Statins;

[0236] ii) Cholesterol absorption inhibitors;

[0237] iii) SGLT2 inhibitors;

[0238] iv) P2Y12 inhibitors;

[0239] v) Citrate lyase inhibitors;

[0240] vi) Antihypertensive drugs.

[0241] 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 the statins, where the statins are selected from atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, or Simvastatin. In another aspect, the statin is Rosuvastatin (Crestor).

[0242] 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 cholesterol absorption inhibitors, where the cholesterol absorption inhibitor is Ezetimibe (Ezetrol).

[0243] 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 SGLT2 inhibitors, where the SGLT2 inhibitors are selected from Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin etabonate, Sergliflozin etabonate, Sotagliflozin, or Tofogliflozin. In some aspects, the SGLT2 inhibitors are selected from Dapagliflozin (Farxiga or Forxiga).

[0244] 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, where the P2Y12 inhibitors are selected from Ticagrelor and Clopidogrel (Plavix).

[0245] 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, where the citrate lyase inhibitor is Bempedoic acid (Nexletol).

[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 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.

[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 antihypertensive agents. In some aspects, the antihypertensive agents are selected from valsartan (Diovan), metoprolol (Metoprolol) (Lopressor), HCTZ (hydrochlorothiazide), olmesartan (Olmesartan) (Benicar), lisinopril (Lisinopril) (Prinivil, Zestril), amlodipine besylate (Norvasc), candesartan, or calcium channel blockers, or combinations thereof. In another aspect, there is provided a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with:

[0248] i) valsartan;

[0249] ii) metoprolol;

[0250] iii) valsartan and HCTZ;

[0251] iv) olmesartan;

[0252] v) olmesartan and HCTZ;

[0253] vi) lisinopril;

[0254] vii) amlodipine;

[0255] viii) candesartan;

[0256] ix) a calcium channel blocker; or

[0257] x) HCTZ.

[0258] 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.

[0259] 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.

[0260] Further embodiments

[0261] 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.

[0262] X 1

[0263] In some embodiments, X 1 is N.

[0264] R A2

[0265] In some embodiments, R A2 is selected from the group consisting of:

[0266] (i) H;

[0267] (ii) a halogen group;

[0268] (iii) CN;

[0269] (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;

[0270] (v) C 1-6 alkoxy, which is optionally substituted with OH, alkylamido or one or more halogen groups;

[0271] (vi) C 1-6 acylamido (wherein the acyl substituent is H or Me);

[0272] (vii) C 1-6 Thioalkyl

[0273] (viii) C 1-6 Alkyl ester

[0274] (ix) C 1-6 Alkyl acyl

[0275] (x) C 4-5 Heterocyclic group

[0276] (xi) C-5 heteroaryl

[0277] (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, optionally substituted by one or more halogen groups or OH groups;

[0278] (xiii) OH; and

[0279] (xiv) C 1-6 Alkylamino

[0280] In some embodiments, R A2 is selected from the group consisting of:

[0281] (i) H;

[0282] (ii) Halogen group;

[0283] (iii) CN;

[0284] (iv) C 1-6 Hydrocarbon, optionally substituted by OH, CN, C 1-6 Acyl, C 1-6 Alkoxy or one or more halogen groups;

[0285] (v) C 1-6 Alkoxy, optionally substituted by OH, alkyl acylamino or one or more halogen groups;

[0286] (vi) C 1-6 Acyl acylamino (where the acyl substituent is H or Me);

[0287] (vii) C 1-6 Thioalkyl

[0288] (viii) C 1-6 Alkyl ester

[0289] (ix) C 1-6Alkyl acyl

[0290] (x)C 4-5 Heterocyclic group

[0291] (xi)C-5 heteroaryl

[0292] (xii)C 1-6 Alkyl acylamino, optionally substituted by C 1-3 Alkyl acylamino, CN, C 2-3 Alkynyl, C 4-6 Heterocyclic group, C 1-3 Alkyl substituted, the alkyl optionally substituted by one or more halogen groups or OH groups; and

[0293] (xiii)OH

[0294] In some embodiments, R A2 Is selected from the group consisting of

[0295] (i)H

[0296] (ii)Halogen group

[0297] (iii)CN

[0298] (iv)C 1-6 Hydrocarbon, optionally substituted by OH, CN, C 1-6 Acyl, C 1-6 Alkoxy or one or more halogen groups

[0299] (v)OH

[0300] (vi)C 1-6 Alkoxy, optionally substituted by OH, C 1-6 Alkyl acylamino or one or more halogen groups

[0301] (vii)C 1-6 Alkyl ester

[0302] (viii)C 1-6 Alkyl acyl

[0303] (ix)C 1-6 Alkyl acylamino, optionally substituted by C 1-3 Alkyl acylamino, CN, C 2-3 Alkynyl, C 4-6 Heterocyclic group or C 1-3 Alkyl substituted, the alkyl optionally substituted by one or more halogen groups or OH groups; and

[0304] (x)C 1-6 Alkylamino

[0305] In a further embodiment, R A2 is selected from the group consisting of:

[0306] (i) H;

[0307] (ii) a halogenated group;

[0308] (iii) CN;

[0309] (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 groups;

[0310] (v) OH;

[0311] (vi) C 1-6 alkoxy, which is optionally substituted by OH, C 1-6 alkylamido or one or more halogenated groups;

[0312] (vii) C 1-6 alkyl ester;

[0313] (viii) C 1-6 alkyl acyl; and

[0314] (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, and the alkyl is optionally substituted by one or more halogenated groups or OH groups.

[0315] In a further embodiment, R A2 is selected from the group consisting of:

[0316] (i) H;

[0317] (ii) a halogenated group;

[0318] (iii) CN;

[0319] (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 groups;

[0320] (v) C 1-6 alkoxy, which is optionally substituted by OH, C 1-6 alkylamido or one or more halogenated groups;

[0321] (vi) C 1-6 Thioalkyl;

[0322] (viii) C 1-6 Alkyl ester; and

[0323] (ix) C 1-6 Alkylamido, optionally substituted by C 1-3 alkylamido, CN, C 2-3 alkynyl, C 4-6 heterocyclic group or C 1-3 alkyl, said alkyl optionally substituted by one or more halogen groups or OH groups.

[0324] In a further embodiment, R A2 is selected from the group consisting of:

[0325] (i) H;

[0326] (ii) Halogen group;

[0327] (iii) C 1-6 alkyl ester;

[0328] (iv) C 1-6 hydrocarbon;

[0329] (v) C 1-6 alkylamido, optionally substituted by C 1-3 alkylamido, C 2-3 alkynyl, C 4-6 heterocyclic group or C 1-3 alkyl, said alkyl optionally substituted by one or more halogen groups or OH groups;

[0330] (vi) C 1-6 thioalkyl;

[0331] (vii) C 1-6 alkyl acyl;

[0332] (viii) C5 heteroaryl; or

[0333] (ix) C 1-6 alkylamino.

[0334] When R A2 is a halogen group, in some embodiments, it is Br or Cl. In a further embodiment, it is Cl.

[0335] In some embodiments, R A2 is selected from CN, Cl, OMe, methyl, cyclopropyl, -OCHF2, -OCF3 and optionally substituted C 1-6 alkylamido.

[0336] In some embodiments, R A2 is selected from C 1-6 alkyl esters,

[0337] In some embodiments, R A2 is CN.

[0338] In some embodiments, R A2 is H.

[0339] In some embodiments, R A2 is OH.

[0340] In some embodiments, R A2 is -C(=O)CH3.

[0341] In some embodiments, R A2 is -OCHF2.

[0342] In some embodiments, R A2 is cyclopropyl.

[0343] In some embodiments, R A2 is Cl.

[0344] In some embodiments, R A2 is methyl.

[0345] In some embodiments, R A2 is S-ethyl.

[0346] In some embodiments, R A2 is pyrazole.

[0347] In some embodiments, R A2 is N(CH3)2.

[0348] In some embodiments, R A2 is C(=O)NH(CH2C(=O)NH2, C(=O)NHCH2C≡CH, C(=O)NH(oxetane), C(=O)NH(CH2CHF2), C(=O)NH(CH2CH3), C(=O)NH2, C(=O)NH(CH2), C(=O)N(CH3)2, C(=O)N(CH3)(CH2CH2OH), C(=O)N(CH3)(CH2C≡CH or C(=O)NH(CH2CH2OH).

[0349] When R A2 is C 1-6 hydrocarbon, it is optionally substituted C 1-6Alkyl. 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.

[0350] 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.

[0351] When R A2 is an optionally substituted C 1-6 alkoxy, in some embodiments, it is an optionally substituted OMe or ethoxy.

[0352] 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, when R A2 is an optionally substituted C 1-6 alkoxy, it is difluoromethoxy (OCHF2).

[0353] When R A2 is C 1-6 alkyl ester, in some embodiments, it is -C(=O)OCH2CH3.

[0354] When R A2 is C 1-6 alkylamido, in some embodiments, the optional substituents are selected from one or more methyl groups, an oxetane ring, C2 alkylamido, ethyl, which ethyl is optionally substituted by OH or one or more halo groups. In other embodiments, when R A2 is C 1-6 alkylamido, 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 C 1-6 alkylamido, in some embodiments, the optional substituent is OH.

[0355] When R A2 is C1-6 When it is an alkylamino group, in some embodiments, it is NHCH3, NHC(CH3)2, N(CH2CH3)2 or N(CH3)2. In some embodiments, when R A2 is C 1-6 alkylamino group, it is N(CH3)2.

[0356] 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 or -OMe.

[0357] In further embodiments, R A2 is selected from methyl, -OCHF2, Cl and cyclopropyl.

[0358] In further embodiments, R A2 is selected from H, -COOH, -CH2OH, methyl, CN, cyclopropyl, -C(=O)CH3, -OCHF2, Cl, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH - oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3.

[0359] In some embodiments, R A2 is selected from the group consisting of: -CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH - oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCHF2, H, -OMe and -OCF3.

[0360] In some embodiments, R A2Selected from C(=O)OCH2CH3, cyclopropyl, methyl, C(=O)NH(CH2C(=O)NH2, C(=O)NHCH2C≡CH, C(=O)NH(oxetane), C(=O)NH(CH2CHF2), C(=O)NH(CH2CH3), C(=O)NH2, C(=O)NH(CH3), C(=O)N(CH3)2, H, C(=O)N(CH3)(CH2CH2OH), C(=O)N(CH3)(CH2C≡CH, Cl, N(CH3)2, pyrazole, S-ethyl, C(=O)CH3 or C(=O)NH(CH2CH2OH).

[0361] In some embodiments, R A2 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, -OCHF2, H, -OMe, -OCF3. These groups are shown in the following table:

[0362]

[0363] In some embodiments, R A2 Selected from the following groups:

[0364]

[0365] In some embodiments, R A2 Selected from the following groups:

[0366]

[0367]

[0368] R A3

[0369] In some embodiments, R A3 Selected from the group consisting of:

[0370] (i) H;

[0371] (ii) a halogenated group;

[0372] (iii) CN;

[0373] (iv) C 1-6Hydrocarbons, 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;

[0374] (v) OH;

[0375] (vi) C 1-6 alkoxy, optionally substituted by OH, NH2, C4 heterocyclic or one or more halo groups;

[0376] (vii) C 1-6 acyloxy;

[0377] (viii) C4 heterocyclic;

[0378] (ix) -NH2;

[0379] (x) C 1-6 alkylamino, optionally substituted by CN, OH or C4 heterocyclic;

[0380] (xi) C 1-6 dialkylamino, optionally substituted by -NH2;

[0381] (xii) C 1-6 acylacylamino (where the acyl substituent is H or Me);

[0382] (xiii) amidino or methyl-amidino;

[0383] (xiv) carboxylamino;

[0384] (xv) C 1-6 thioalkyl, optionally substituted by OH or NH2;

[0385] (xvi) C 1-6 alkylsulfinyl;

[0386] (xvi) C 1-6 alkylsulfonyl, optionally substituted by one or more halo groups;

[0387] (xvii) C 1-6 sulfonimido;

[0388] (xviii) C 1-6 Alkylphosphinyl;

[0389] (xix) Carboxyl;

[0390] (xx) C(=O)NH2

[0391] (xxi) C 1-6 Alkyl ester;

[0392] (xxii) C 1-6 Alkyl acyl, optionally substituted by one or more halo groups; and (xxiii) C 1-6 Alkyl acylamino.

[0393] In some embodiments, R A3 is selected from the group consisting of:

[0394] (i) H;

[0395] (ii) Halo group;

[0396] (iii) CN;

[0397] (iv) C 1-6 Hydrocarbon, optionally substituted by OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyl oxy, carboxyl, C 1-6 Alkyl ester, C 1-6 Alkylamino; -C(=O)NH2, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl acylamino, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl or one or more halo groups;

[0398] (v) OH; and

[0399] (vi) C 1-6 Alkoxy, optionally substituted by OH, NH2, C4 heterocyclic group or one or more halo groups.

[0400] In some embodiments, R A3 is selected from the group consisting of:

[0401] (i) H;

[0402] (ii) Halo group;

[0403] (iii) CN;

[0404] (iv) C 1-6A 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;

[0405] (v) OH;

[0406] (vi) C 1-6 alkoxy, optionally substituted by OH, NH2, a C4 heterocyclic group or one or more halo groups.

[0407] When 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.

[0408] When R A3 is C 1-6 hydrocarbon, it is optionally substituted C 1-6 alkyl. In some embodiments, it is optionally substituted methyl or optionally substituted ethyl. In a further embodiment, it is optionally substituted methyl. In a further embodiment, it is unsubstituted methyl.

[0409] When R A3 is optionally substituted C 1-6 alkyl, 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.

[0410] In some embodiments, R A3 is OH.

[0411] When R A3 is optionally substituted C 1-6 alkoxy, in some embodiments, it is optionally substituted OMe or ethoxy. In a further embodiment, it is OMe.

[0412] When R A3 is optionally substituted C 1-6When it is an alkoxy group, in some embodiments, the optional substituent is selected from alkylamido or one or more halogenated groups. In another embodiment, the optional substituent is selected from one or more Fs.

[0413] In some embodiments, R A3 is selected from H, CF3, CN, C 1-2 alkyl, NH2, and halogenated groups. In other embodiments, R A3 is selected from H, methyl, CN, and Cl.

[0414] In some embodiments, R A3 is selected from H, OMe, CF3, CN, C 1-2 alkyl, NH2, and halogenated groups.

[0415] In some embodiments, R A3 is CN.

[0416] In some embodiments, R A3 is H.

[0417] In some embodiments, R A3 is methyl.

[0418] In some embodiments, R A3 is OMe. In some embodiments, R A3 is selected from methyl, H, and CN.

[0419] In some embodiments, R A3 is selected from H, methyl, or OH.

[0420] R A2 and R A3

[0421] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C6 carbon aromatic ring or a C 5-7 heteroaromatic ring, they form an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0422] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C6 carbon aromatic ring or a C 5-7 heteroaromatic ring, the optional substituent is selected from NH2, C 1-6 alkyl, C 1-6 alkoxy, and halogenated groups. In other embodiments, the optional substituent is selected from methyl, ethyl, OMe, NH2, F, Cl, and Br. In other embodiments, the optional substituent is selected from methyl, NH2, Cl, F, and OMe. In other embodiments, the optional substituent is methyl.

[0423] 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.

[0424] 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 substituent is selected from C 1-6 alkyl, C 1-6 alkoxy, NH2 and halo group. In other embodiments, the optional substituent is selected from methyl, ethyl, OMe, ethoxy, NH2 and halo group. In other embodiments, the optional substituent is selected from NH2 and methyl.

[0425] When R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C 5-7 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.

[0426] 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 substituent is selected from NH2, C 1-6 alkyl, C 1-6 alkoxy and halo group. In other embodiments, the optional substituent is selected from methyl, ethyl, OMe, ethoxy, NH2, F, Cl and Br. In other embodiments, the optional substituent is methyl.

[0427] In other embodiments, RA2 and R A3 together with the carbon atom to which they are attached form:

[0428] (i) an optionally substituted C6 heteroaromatic ring; wherein the optional substituent is NH2;

[0429] (ii) an optionally substituted C6 carbocyclic aromatic ring; wherein the optional substituent is F, OMe, Cl;

[0430] (iii) an optionally substituted C5 heteroaromatic or C5 heterocyclic ring, wherein the optional substituent is methyl.

[0431] 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 substituent is selected from C 1-6 alkyl and halo groups.

[0432] 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.

[0433] In some embodiments, R A2 and R A3 together form a ring selected from:

[0434]

[0435] B

[0436] In some embodiments, B has the formula (B-1):

[0437]

[0438] 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.

[0439] In other embodiments, R B1 is H, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0440] In other embodiments, R B1 is -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0441] In other embodiments, RB1 It is H.

[0442] In another embodiment, B has the formula (B-1a):

[0443]

[0444] In a further embodiment, B has the formula (B-1b):

[0445]

[0446] Thus, in some embodiments, the compound of formula (I) is the S,S-enantiomer.

[0447] In some embodiments, B has the formula (B-2):

[0448]

[0449] where the wavy line indicates the attachment points to A and C;

[0450] R B2 is C 1-2 alkyl-OH, CH2CONHMe or C 1-3 alkyl.

[0451] In some of these embodiments, R B2 is C 1-2 alkyl-OH or C 1-3 alkyl.

[0452] In some embodiments, when B has the formula (B-2), it has the following formula (B-2a), 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;

[0453]

[0454] In some embodiments, B has the following formula:

[0455]

[0456] In a further embodiment, B has the following formula:

[0457]

[0458] C

[0459] C is selected from C 6-10 carbon aryl, C 5-6 heteroaryl and C 5-10A group consisting of a heterocyclic group, said group being optionally substituted by:

[0460] (i) C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocyclic group, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[0461] which are themselves optionally substituted by one or more of the following groups;

[0462] a) one or two =O groups;

[0463] b) one or more halo groups;

[0464] c) CN, NH2, OH;

[0465] d) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH or one or more halo groups;

[0466] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0467] f) C 1-6 alkyl ester;

[0468] g) C 5-6 heterocyclic group, which has optional methyl, OH or =O substituents;

[0469] h) C 5-6 heteroaryl;

[0470] i) C 4-10 carbocyclic group, which has optional methyl or =O substituents;

[0471] j) C 6-10 carbaryl, which has optional substituents of one or more halo groups;

[0472] l) P(=O)Me2;

[0473] m) carboxyl or CH2-carboxyl;

[0474] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[0475] (ii) one or more selected from carboxyl, CN, halo, nitro, C 1-6 alkyl, C 1-6Thioalkyl, 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.

[0476] 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 with one or more of the following groups:

[0477] a) One or two ═O groups;

[0478] b) One or more halo groups;

[0479] c) CN, NH2 or OH;

[0480] 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;

[0481] e) C 1-6 Alkoxy, which has optional substituents of one or more halo groups;

[0482] f) C 1-6 Alkyl esters;

[0483] g) C 5-6 Heterocyclic, which has optional methyl, OH or ═O substituents;

[0484] h) C 5-6 Heteroaryl;

[0485] i) C 4-10 Carbocyclic, which has optional methyl or ═O substituents;

[0486] j) C 6-10 Carboaryl, which has optional substituents of one or more halo groups;

[0487] l) P(═O)Me2;

[0488] m) Carboxyl or CH2-carboxyl; and / or

[0489] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0490] 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, pyrazinyl or pyrimidinyl. In other embodiments, it is an optionally substituted pyridyl.

[0491] When C is an optionally substituted C 5-6 heteroaryl, it may be optionally substituted with:

[0492] (i) C 6-10 carbaryl, 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,

[0493] which are themselves optionally substituted with one or more groups selected from the following:

[0494] a) one or two ═O groups;

[0495] b) one or more halo groups;

[0496] c) CN, NH2, OH;

[0497] d) C 1-6 alkyl group, which includes branched and cyclic and has optional substituents selected from OH or one or more halo groups;

[0498] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0499] f) C 1-6 alkyl ester;

[0500] g) C 5-6 heterocyclic group, which has optional methyl, OH or ═O substituents;

[0501] h) C 5-6 heteroaryl;

[0502] i) C 4-10 carbocyclic group, which has optional methyl or ═O substituents;

[0503] j) C 6-10 carbaryl, which has optional substituents of one or more halo groups;

[0504] l) P(=O)Me2;

[0505] m) carboxyl or CH2-carboxyl; and / or

[0506] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[0507] (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.

[0508] When C is replaced 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:

[0509] a) one or two =O groups;

[0510] b) one or more halo groups, CN, NH2;

[0511] 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;

[0512] d) C 5-6 heterocyclic group or C 5-6 heteroaryl having an optional methyl substituent;

[0513] e) C 6-10 carbaryl which is optionally substituted by one or more halo atoms;

[0514] f) P(=O)Me2; or

[0515] g) carboxyl or CH2-carboxyl.

[0516] In some embodiments, one of the substituents of C is in the para position.

[0517] In some embodiments, when C is an optionally substituted C 5-6 heteroaryl, the optional substituents are selected from C1-6 Alkyl and halo groups. In further embodiments, the optional substituent is methyl. In further embodiments, C is substituted with a methyl group at the meta position.

[0518] In other embodiments, when C is optionally substituted C 6-10 carbon aryl, C 5-10 heteroaryl or C 5-10 heterocyclic group substituted, it may be substituted with 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 imidazopyridyl group. These groups themselves may optionally be substituted with one or two ═O groups, halo groups, CN, one or more C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl ester, C 5-6 heterocyclic group (having an optional methyl substituent), phenyl substituted with F at the para position, carboxyl, CH2-carboxyl, tetrazolyl, pyrazolyl, triazolyl or P(═O)Me2.

[0519] In other embodiments, when C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl group, it may carry a number of substituent groups. The substituents are selected from optionally substituted C 5-10 heteroaryl and C 5-10 heterocyclic group, which itself is optionally substituted with one or two ═O groups, one or more halo groups, CN, one or more C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl ester, C 5-6 heterocyclic group (having an optional methyl substituent), phenyl optionally substituted with one or two halo groups, carboxyl, CH2-carboxyl, tetrazolyl, pyrazolyl, triazolyl, pyridine ring, NH2 or OH. In some embodiments, the substituents are an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted imidazolidine, an optionally substituted dihydroquinoline, an optionally substituted benzimidazolyl group or an optionally substituted imidazopyridyl group.

[0520] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl group, wherein the optional substituents are selected from:

[0521] i)C 6-10 carbon aryl, C 5-10 heteroaryl, C 5-10 heterocyclic group, which itself is optionally substituted with one or more of the following groups;

[0522] a) One or two ═O groups;

[0523] b) One or more halo groups;

[0524] c) CN, NH2, OH;

[0525] d) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH or one or more halo groups;

[0526] e) C 1-6 alkoxy groups, which have optional substituents of one or more halo groups;

[0527] f) C 1-6 alkyl esters;

[0528] g) C 5-6 heterocyclic groups, which have optional methyl, OH or =O substituents;

[0529] h) C 5-6 heteroaryl groups;

[0530] i) C 4-10 carbocyclic groups, which have optional methyl or =O substituents;

[0531] j) C 6-10 carboaryl groups, which have optional substituents of one or more halo groups;

[0532] l) P(=O)Me2;

[0533] m) carboxyl, CH2-carboxyl; and / or

[0534] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[0535] 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.

[0536] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl group, wherein the optional substituents are selected from C 6-10 carboaryl, C 5-10 heteroaryl, C 5-10 heterocyclic groups, which are themselves optionally substituted by one or more groups selected from:

[0537] a) One or two ═O groups;

[0538] b) One or more halo groups;

[0539] c) CN, NH2, OH;

[0540] d) One or more C 1-6 alkyl groups, which include branched and cyclic ones and have optional substituents selected from OH or one or more halo groups;

[0541] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0542] f) C 1-6 alkyl esters;

[0543] g) C 5-6 heterocyclic groups, which have optional methyl, OH or ═O substituents;

[0544] h) C 5-6 heteroaryl;

[0545] i) C 4-10 carbocyclic groups, which have optional methyl or ═O substituents;

[0546] j) C 6-10 carboaryl, which has optional substituents of one or more halo groups;

[0547] l) P(═O)Me2;

[0548] m) Carboxyl, CH2 - carboxyl; and / or

[0549] n) Tetrazolyl, CH2 - tetrazolyl, 5 - oxo - 4H - 1,2,4 - oxadiazol - 3 - yl.

[0550] 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 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:

[0551] a) One or two ═O groups;

[0552] b) One or more halo groups;

[0553] c) CN, NH2 or OH;

[0554] d) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have substituents selected from OH or one or more halo groups;

[0555] e) C 1-6 alkoxy, which has an optional substituent of one or more halo groups;

[0556] f) C 1-6 alkyl esters;

[0557] g) C 5-6 heterocyclic groups, which have optional methyl, OH or ═O substituents;

[0558] h) C 5-6 heteroaryl;

[0559] i) C 4-10 carbocyclic groups, which have optional methyl or ═O substituents;

[0560] j) C 6-10 carbaryl, which has an optional substituent of one or more halo groups;

[0561] l) P(═O)Me2;

[0562] m) carboxyl or CH2-carboxyl; and / or

[0563] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0564] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl, 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 with one or more of the following groups:

[0565] a) one or more halo groups;

[0566] b) CN, NH2 or OH;

[0567] c) one or more C 1-6 alkyl groups, which include branched and cyclic ones and have an optional substituent selected from OH or one or more halo groups;

[0568] d) C 1-6An alkoxy group having an optional substituent of one or more halogenated groups;

[0569] e)C 1-6 An alkyl ester;

[0570] f)C 5-6 A heterocyclic group having optional methyl, OH or ═O substituents;

[0571] g)C 5-6 A heteroaryl group;

[0572] h)C 4-10 A carbocyclic group having optional methyl or ═O substituents;

[0573] i)C 6-10 A carboaryl group having an optional substituent of one or more halogenated groups;

[0574] j)P(═O)Me2;

[0575] k)A carboxyl group or CH2-carboxyl; and / or

[0576] l)A tetrazolyl group, CH2-tetrazolyl group, 5-oxo-4H-1,2,4-oxadiazol-3-yl group.

[0577] In some embodiments, C is an optionally substituted pyridyl group, pyrazinyl group or pyrimidinyl group, wherein the optional substituent is selected from C 6-10 A carboaryl group, C 4-10 A carbocyclic group, C 5-10 A heteroaryl group, C 5-10 A heterocyclic group, C 5-10 A bridged heterocyclic group, spiro C 6-12 A heterocyclic group or spiro C 6-12 A carbocyclic group, which is optionally substituted by one or two ═O groups and substituted by one or more groups selected from the following groups:

[0578] a) One or more halogenated groups;

[0579] b) CN, NH2 or OH;

[0580] c) One or more C 1-6 An alkyl group, which includes branched and cyclic ones and has a substituent selected from OH or one or more halogenated groups;

[0581] d)C 1-6 An alkoxy group having an optional substituent of one or more halogenated groups;

[0582] e)C 1-6 An alkyl ester;

[0583] f)C 5-6A heterocyclic group having an optional methyl, OH or ═O substituent;

[0584] g)C 5-6 A heteroaryl;

[0585] h)C 4-10 A carbocyclic group having an optional methyl or ═O substituent;

[0586] i)C 6-10 A carboaryl having an optional substituent of one or more halo groups;

[0587] j)P(═O)Me2;

[0588] k)A carboxyl or CH2-carboxyl; and / or

[0589] l)A tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl.

[0590] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl, wherein the optional substituent is selected from a C6 heteroaryl or a C6 heterocyclic group, which are themselves optionally substituted with one or more groups selected from:

[0591] i)One or two ═O groups;

[0592] ii)Methyl;

[0593] iii)OMe;

[0594] iv)Cl;

[0595] v)CN;

[0596] vi)CF3;

[0597] vii)F;

[0598] viii)A triazolyl, tetrazolyl, pyrazolyl optionally substituted with methyl;

[0599] ix)O-CF3;

[0600] x)O-CHF2.

[0601] In some embodiments, C is a substituted pyridyl, which is substituted with a C6 heterocyclic group or a C6 heteroaryl, and the heterocyclic group or heteroaryl each contains one or two N atoms and is substituted with ═O and another group selected from methyl, Cl, OMe, CN and OCHF2.

[0602] In some embodiments, C is a substituted pyridyl group, which is substituted by a pyridyl group, which pyridyl group itself is substituted by at least one ═O group and another group selected from CF3, OCF3, Cl, CN, OMe, tetrazole, F, OCHF2 or triazole, a pyrazole optionally substituted by methyl.

[0603] In further embodiments, C is an optionally substituted pyridyl group, wherein the optional substituents are selected from phenyl and pyridyl, which are themselves optionally substituted by methyl or CN.

[0604] In some embodiments, C is an optionally substituted pyridyl, pyrazinyl or pyrimidinyl group, wherein the optional substituents are selected from pyridine, pyridazine and pyrimidine, which are themselves optionally substituted by one or more groups selected from:

[0605] a) one or two ═O groups;

[0606] b) one or more halo groups;

[0607] c) methyl;

[0608] d) OMe;

[0609] e) CN; or

[0610] f) OCHF2.

[0611] In some embodiments, C is an optionally substituted pyridyl group, wherein the optional substituents are phenyl or pyridyl, which are themselves optionally substituted by one or more groups selected from:

[0612] a) one or more OMe groups;

[0613] b) one or more F groups;

[0614] c) CN;

[0615] d) tetrazole; or

[0616] e) carboxyl.

[0617] In some embodiments, C is an optionally substituted pyridyl group, wherein the optional substituents are a C5 heteroaryl or C5 heterocyclic group, which are themselves optionally substituted by one or more substituents selected from methyl and CN. In some embodiments, C is an optionally substituted pyridyl group, wherein the optional substituents are pyrazole, triazole, imidazole or oxazole, which are themselves optionally substituted by one or more substituents selected from methyl and CN. In further embodiments, the pyrazole, triazole, imidazole or oxazole is substituted by two methyl groups and optionally one CN group.

[0618] In some embodiments, C is an optionally substituted pyridyl group, wherein the optional substituent is an unsubstituted C9 heteroaryl group containing two or three nitrogen atoms.

[0619] In another embodiment, C has the formula (C-1):

[0620]

[0621] wherein D is C 6-10 carboaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, which is itself optionally substituted by: ═O, halo, CN, NH2, OH, one or more C 1-6 alkyl groups (the alkyl is optionally substituted by halo), C optionally substituted by halo 1-6 alkoxy, C 1-6 alkyl ester, C 5-6 heterocyclic group (having an optional methyl substituent), carboxyl, CH2-carboxyl, P(═O)Me2, tetrazolyl, pyrazolyl or triazolyl. In some embodiments, the optional substituents are selected from ═O, CN, F, Cl, Br, CN, methyl, ethyl, OMe, ethoxy, O-CF3, OMe, CF3, P(═O)Me2 and C 1-2 alkyl ester.

[0622] 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 having 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 pyridin-2-one is pyridin-2(1H)-one.

[0623] 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 by ═O in the ortho position, and the other optional substituents are selected from methyl, OMe, piperazine substituted by methyl, C(═O)OH (carboxyl), Cl, phenyl substituted by fluorine, CN, CF3, F, pyrazolyl, triazolyl, tetrazolyl or O-CF3.

[0624] In some embodiments, C has the formula (C-1):

[0625]

[0626] wherein D is C 6-10 carboaryl, C5-10 Heteroaryl or C 5-10 heterocyclic group, each of which is optionally substituted by the following:

[0627] i) one or two ═O groups;

[0628] ii) one or two C 1-4 alkyl groups, which can be branched;

[0629] iii) OMe;

[0630] iv) piperazinyl, which is optionally substituted by methyl;

[0631] v) C(═O)OH (carboxyl);

[0632] vi) Cl;

[0633] vii) F;

[0634] viii) phenyl, which is optionally substituted by one or more fluorines;

[0635] ix) CN;

[0636] x) CF3;

[0637] xi) O-CF3;

[0638] xii) tetrazolyl, pyrazolyl, triazolyl, each of which is optionally substituted by methyl;

[0639] xiii) NH2;

[0640] xiv) pyridinyl;

[0641] xv) CH2OH;

[0642] xvi) OH;

[0643] xvii) P(═O)Me2; or

[0644] xviii) OCHF2.

[0645] In some embodiments, C has the formula (C-1):

[0646]

[0647] 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:

[0648] i) one or two ═O groups;

[0649] ii) one or two C 1-4 alkyl groups, which can be branched;

[0650] i) OMe;

[0651] ii) piperazinyl, which is optionally substituted with methyl;

[0652] iii) C(=O)OH (carboxyl);

[0653] iv) Cl;

[0654] v) F;

[0655] vi) phenyl, which is optionally substituted with one or more fluorines;

[0656] vii) CN;

[0657] viii) CF3;

[0658] ix) O-CF3;

[0659] x) OMe;

[0660] xi) tetrazolyl, pyrazolyl, triazolyl;

[0661] xii) NH2;

[0662] xiii) (CH3)2;

[0663] xiv) pyridyl;

[0664] xv) CH2OH;

[0665] xvi) OH; or

[0666] xvii) P(=O)Me2.

[0667] In some embodiments, D is an optionally substituted 6-membered heteroaryl containing 1 or 2 N atoms, wherein one N atom is bonded to the (C-1) substituted with =O at the ortho position, and the optional substituents are selected from:

[0668] i) methyl;

[0669] ii) OMe;

[0670] iii) piperazinyl substituted with methyl;

[0671] iv) C(=O)OH (carboxyl);

[0672] v) Cl;

[0673] vi) phenyl substituted with fluorine;

[0674] vii) CN;

[0675] viii) CF3;

[0676] ix) O-CF3;

[0677] x) F; or

[0678] xi) pyrazolyl, triazolyl or tetrazolyl.

[0679] 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:

[0680] i) methyl;

[0681] ii) OMe;

[0682] iii) piperazinyl substituted by methyl;

[0683] iv) C(═O)OH (carboxyl);

[0684] v) Cl;

[0685] vi) F;

[0686] vii) phenyl substituted by fluorine;

[0687] viii) CN;

[0688] ix) CF3;

[0689] x) O-CF3;

[0690] xi) O-CHF2;

[0691] xii) pyrazole, triazole, tetrazole, each of which is optionally substituted by methyl.

[0692] In some embodiments, 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:

[0693] i) methyl;

[0694] ii) OMe;

[0695] iii) Cl;

[0696] iv) F;

[0697] v) CN;

[0698] vi) CF3;

[0699] vii) O-CF3;

[0700] viii) O-CHF2; or

[0701] ix) pyrazolyl, triazolyl or tetrazolyl, each of which is optionally substituted with methyl.

[0702] In some embodiments, D is a substituted 6-membered heteroaryl containing 1 or 2 N atoms, wherein one N atom is bonded to the (C-1) substituted with =O at the ortho position, and the substituents are selected from:

[0703] i) OMe;

[0704] ii) Cl;

[0705] iii) F;

[0706] iv) CN;

[0707] v) CF3;

[0708] vi) O-CF3;

[0709] vii) O-CHF2; or

[0710] viii) pyrazolyl, triazolyl or tetrazolyl, each of which is optionally substituted with methyl.

[0711] In some embodiments, C has the formula (C-1), wherein D is C 6-10 carboaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, each of which is optionally substituted by itself with the following:

[0712] i) one or two =O groups;

[0713] ii) one or two C 1-4 alkyl groups, which can be branched and are optionally substituted with one or more halo groups;

[0714] iii) one or more OMe groups;

[0715] iv) C(=O)OH (carboxyl);

[0716] v) halo;

[0717] vi) CN;

[0718] vii) C 1-4 alkoxy, which is optionally substituted with one or more halo groups;

[0719] viii) tetrazolyl, pyrazolyl, triazolyl, wherein each of them is optionally substituted with methyl;

[0720] ix) P(=O)Me2.

[0721] In some embodiments, C has formula (C-1) and D is C. 6-10 carbaryl, C 5-10 heteroaryl or C 5-10 heterocyclic group, each of which is optionally substituted by itself with: one or two ═O groups; methyl, CF3; OCF3; Cl, CN, OMe, tetrazole, F, OCHF2, triazole, C(═O)OH, P(═O)Me2, pyrazole optionally substituted with methyl.

[0722] In some embodiments, D is optionally substituted with 1, 2 or 3 substituents.

[0723] In some embodiments, D is optionally substituted with 1 substituent.

[0724] In some embodiments, D is optionally substituted with 2 or 3 substituents.

[0725] 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 at the ortho position, and the optional substituents are selected from:

[0726] i) methyl;

[0727] ii) OMe;

[0728] iii) piperazinyl substituted with methyl;

[0729] iv) C(═O)OH (carboxyl);

[0730] v) Cl;

[0731] vi) F;

[0732] vii) phenyl substituted with fluorine;

[0733] viii) CN;

[0734] ix) CF3;

[0735] x) O-CF3;

[0736] xi) triazole, tetrazole, pyrazole optionally substituted with methyl.

[0737] In some embodiments, C has 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. In some embodiments, C has formula (C-1) and D is an optionally substituted phenyl or pyridinyl, wherein there is one or two optional substituents selected from F, OMe, and CN.

[0738] In some embodiments, D is an optionally substituted C5 heterocyclic group or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN. In a further embodiment, D is an optionally substituted pyrazole, imidazole, triazole, or oxazole, wherein the optional substituents are selected from methyl and CN. In a further embodiment, D is a triazole substituted with two methyl groups. In a further embodiment, D is a pyrazole substituted with two methyl groups. In a further embodiment, D is an imidazole substituted with two methyl groups and CN. In a further embodiment, D is an oxazole substituted with two methyl groups.

[0739] In some embodiments, D is a C9 heterocyclic group or C9 heteroaryl containing 2 or 3 nitrogen atoms. In a further embodiment, D is 1H-pyrazolo[3,4-b]pyridinyl, indazol-1-yl, or indazol-2-yl.

[0740] In some embodiments, D is optionally substituted with one, two, or three substituents.

[0741] In another embodiment, D has formula (D-1):

[0742]

[0743] 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 heterocyclic group or C 5-6 heteroaryl having an optional methyl substituent, carboxyl, ═O, halo, NH2, CN, or phenyl optionally substituted with one or more halo atoms; 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, halo, CN, P(═O)Me2, and C(═O)OH; or wherein R D1 , R D2 , R D3 , and R D4 are all H.

[0744] In another embodiment, R D1 , R D2 , R D3 and R D4 one or both of which 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, halo, CN, or phenyl optionally substituted with one or more halo atoms, and the rest are H.

[0745] In some embodiments, D has formula (D-1) and R D1 , R D2 , R D3 and R D4 one or both of which are selected from:

[0746] i) methyl;

[0747] ii) OMe;

[0748] iii) piperazine substituted with methyl;

[0749] iv) C(=O)OH (carboxyl);

[0750] v) Cl;

[0751] vi) phenyl substituted with fluorine;

[0752] vii) CN;

[0753] viii) CF3;

[0754] ix) F;

[0755] x) pyrazolyl, triazolyl, tetrazolyl;

[0756] xi) O-CF3

[0757] and R D1 , R D2 , R D3 and R D4 the remaining ones are H.

[0758] In some embodiments, D has formula (D-1) and R D1 , R D2 , R D3 and R D4 one or both of which are selected from:

[0759] i) methyl;

[0760] ii) OMe;

[0761] iii) Cl;

[0762] iv) CN;

[0763] v) CF3;

[0764] vi) F;

[0765] vii) Triazolyl, tetrazolyl, pyrazolyl optionally substituted with methyl;

[0766] viii) O-CF3

[0767] ix) O-CHF2

[0768] and R D1 , R D2 , R D3 and R D4 and the remainder of R

[0769] are H. D1 , R D2 , R D3 and R D4 are each independently selected from methyl, -OMe, halo, -C(=O)OH, CN, CF3, -OCF3, -OCHF2, and the remainder of R D1 , R D2 , R D3 and R D4 are H.

[0770] In one embodiment, all of R D1 , R D2 , R D3 and R D4 are H.

[0771] In another embodiment, R D3 is selected from H, phenyl optionally substituted (where the optional substituent is halo), methyl, OMe, -C(=O)OH, -OCHF2Cl, CN, and piperazinyl optionally substituted with methyl, where R D1 , R D2 and R D4 are all H. In some embodiments, R D3 is selected from H, CN, OMe, Cl, tetrazole, methyl, OCHF2, or triazole, pyrazolyl optionally substituted with methyl, and where R D1 , R D2 and R D4 are all H. In some embodiments, R D3Selected from H, CN, OMe, Cl, pyrazole, tetrazole, methyl, OCHF2 or triazole and wherein R D1 R D2 and R D4 are both H.

[0772] In some embodiments, R D2 is selected from H, OMe, Cl and CN, and wherein R D1 , R D3 and R D4 are both H.

[0773] In other embodiments, R D1 is selected from H, methyl, OMe, Cl, CF3, OCF3, OCHF2 and CN and R D2 , R D3 and R D4 are both H. In some embodiments, R D1 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole and pyrazole optionally substituted with methyl, and R D2 , R D3 and R D4 are both H.

[0774] 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 substituents are selected from OH, CN, P(=O)Me2, methyl, OMe, halo and C(=O)OH.

[0775] In some embodiments, R D3 and R D4 form an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0776] In some embodiments, R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0777] In another embodiment, D has the formula (D-2):

[0778]

[0779] wherein X D is NR D5a or CR D5a R D5b ;

[0780] R D5a is selected from H or methyl;

[0781] R D5band R D6b Each is H or together they are -CH2-;

[0782] R D6a is selected from H, =O, methyl, -CH2OH or -C(=O)OH, where when R D6a is =O, R D6b does not exist;

[0783] R D7a is selected from H, =O, methyl, -CH2OH or -C(=O)OH;

[0784] R D7b is H, where when R D7a is =O, R D7b does not exist;

[0785] 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 do not exist.

[0786] In some embodiments, C has formula (C-1) and D has formula (D-2), and X D is N and R D5a is methyl.

[0787] In some embodiments, C has formula (C-1) and D has formula (D-2), and R D6a and R D6b are each H, and R D7a is selected from =O, -CH2OH or -C(=O)OH and R D7b is H, or when R D7a is =O, R D7b does not exist.

[0788] 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 R D7b does not exist, and where R D6a is =O, R D7a and R D7b are H and R D6b does not exist.

[0789] In some embodiments, C has formula (C-1) and D has formula (D-2), R D7a is ═O, and R D7b is absent, X D is C, and R D5b and R D6b together are -CH2-, and R D6a and R D5a are methyl.

[0790] 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 are absent.

[0791] In some embodiments, R D6a and R D7a together form a benzene ring or a pyridine ring optionally substituted with CN, P(═O)Me2 or C(═O)OH, and R D6b and R D7b are absent.

[0792] In some embodiments, R D6a and R D7a form an unsubstituted benzene ring and R D6b and R D7b are absent. In some embodiments, R D6a and R D7a form an unsubstituted pyridine ring and R D6b and R D7b are absent.

[0793] In some embodiments, X D is N and R D5a is H or methyl.

[0794] In some embodiments, X D is C and R D5a is H or methyl, and R D5b is H. In a further embodiment, R D5a and R D5b are both H.

[0795] 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 is absent.

[0796] In some embodiments, R D6a is H or =O. In some embodiments, R D6a is =O and R D6b is absent.

[0797] In some embodiments, when R D7a is =O, R D6a and R D6b are H and R D7b is absent, and when R D6a is =O, R D7a and R D7b are H and R D6a is absent.

[0798] 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 are absent.

[0799] In some embodiments, D is selected from the following table:

[0800]

[0801]

[0802]

[0803] In some embodiments, D is selected from the following table:

[0804]

[0805]

[0806]

[0807]

[0808] In some embodiments, D is selected from the following table:

[0809]

[0810]

[0811]

[0812]

[0813] In another embodiment, C has the formula (C-2):

[0814]

[0815] wherein R C7 、R C8 、R C9 and R C10 one or both of which are selected from methyl, OMe, halo, C(=O)OH, piperazine optionally substituted with methyl, phenyl optionally substituted (where the optional substituent is methyl or halo), CN, CF3, -O-CF3, O-CHF2, tetrazolyl, triazolyl, pyrazolyl optionally substituted with methyl, and the remaining ones 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, heterocyclic or heteroaromatic ring, wherein the optional substituent is selected from OH, methyl, OMe, halo, CN, P(=O)Me2 or -C(=O)OH; or

[0816] wherein R C7 、R C8 、R C9 and R C10 are all H.

[0817] In some embodiments, one or both of R C7 、R C8 、R C9 and R C10 are selected from methyl, OMe, halo, C(=O)OH, piperazine optionally substituted with methyl, phenyl optionally substituted (where the optional substituent is methyl or halo), CN, CF3, -O-CF3, tetrazolyl, pyrazolyl, or triazolyl, and the remaining ones 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, heterocyclic or heteroaromatic ring, wherein the optional substituent is selected from OH, methyl, OMe, halo, CN, P(=O)Me2 or -C(=O)OH; or

[0818] wherein R C7 、R C8 、R C9 and RC10 All are H.

[0819] In one embodiment, C has the formula (C-1) and R C7 , R C8 , R C9 and R C10 All are H.

[0820] In another embodiment, one or both of R C7 , R C8 , R C9 and R C10 are each independently selected from 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 remaining ones 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 each independently selected from methyl, OMe, Cl, CN, CF3, F; triazolyl, tetrazolyl, pyrazolyl optionally substituted with methyl; O-CF3, O-CHF2, and the remaining ones of R D1 , R D2 , R D3 and R D4 are H.

[0821] 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, -OMe, Cl, -C(=O)OH, CN, CF3, O-CHF2, -O-CF3, F, pyrazolyl, triazolyl or tetrazolyl and the other is H, and R C10 and R C8 are H.

[0822] In another embodiment, R C9Selected from H, optionally substituted phenyl (where the optional substituent is a halogen group), methyl, OMe, C(=O)OH, Cl, CN, pyrazolyl, triazolyl, tetrazolyl, and piperazinyl optionally substituted by methyl, and R C7 , R C8 and R C10 are all H. In some embodiments, R C9 is selected from H, CN, OMe, Cl, tetrazole, methyl, OCHF2, or triazole, and R C7 , R C8 and R C10 are all H.

[0823] 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 some embodiments, R C7 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole, and pyrazolyl optionally substituted by methyl, and R C7 , R C8 and R C10 are all H.

[0824] In some embodiments, R C8 is selected from H, OMe, Cl, and CN, and wherein R C7 , R C9 and R C10 are all H.

[0825] In another embodiment, C is selected from the group consisting of groups 1 to 48 listed in the following table:

[0826]

[0827]

[0828]

[0829] In another embodiment, C is selected from the group consisting of 49 to 80 listed in the following table:

[0830]

[0831]

[0832]

[0833] In another embodiment, C is selected from the group consisting of the groups listed in the following table:

[0834]

[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 N.

[0842] In some embodiments, R A2 is selected from the group consisting of:

[0843] (i) H;

[0844] (ii) a halogen group;

[0845] (iii) C 1-6 alkyl ester;

[0846] (iv) C 1-6 hydrocarbon;

[0847] (v) C 1-6 alkylamido, optionally substituted by C 1-3 alkylamido, C 2-3 alkynyl, C 4-6 heterocyclic group or C 1-3 alkyl, said alkyl optionally substituted by one or more halogen groups or OH groups;

[0848] (vi) C 1-6 thioalkyl;

[0849] (vii) C 1-6 alkylacyl;

[0850] (viii) C5 heteroaryl; or

[0851] (ix) alkylamino.

[0852] In some embodiments, R A2 is selected from the group consisting of: Br, Cl, CN, H, -C(=O)CH3, C 1-6 alkylamido (said alkylamido optionally substituted by C 1-3alkylacylamino substitution), CN, C 2-3 alkynyl, C 4-6 heterocyclic group, C 1-3 alkyl (the alkyl is optionally substituted with one or more halogen groups or OH groups), optionally substituted methoxy, methyl, ethyl or cyclopropyl (wherein the optional substituents are selected from OH, CN or one or more halogen groups), optionally substituted methoxy or ethoxy (wherein the optional substituents are selected from alkylacylamino or one or more halogen groups). In a further embodiment, R A2 is selected from CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCHF2, H, -OMe, -OCF3. In some embodiments, R A2 is selected from -C(=O)OCH2CH3 cyclopropyl, methyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, C(=O)N(CH3)2, H, -C(=O)N(CH3)CH2CH2OH, -C(=O)N(CH3)CH2CCH, Cl, N(CH3)2, pyrazole, -SCH2CH3, -C(=O)CH3 and -C(=O)NHCH2CH2OH.

[0853] 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 a further embodiment, R A3 is selected from H, methyl and CN. In some embodiments, R A3 is selected from H, methyl or OH.

[0854] In other embodiments, R A3 and R A2 together with the carbon atom to which they are attached form an optionally substituted C6 carbon aromatic ring or C 5-7 heteroaromatic ring, the optional substituents being selected from NH2, C 1-6 alkyl, C 1-6Alkoxy and halo groups. In other embodiments, the optional substituents are selected from NH2, methyl, ethyl, OMe, F, Cl, and Br.

[0855] 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, 2-pyrrole substituted with methyl, pyridine optionally substituted with NH2, or benzene optionally substituted with Cl, F, or OMe.

[0856] In some embodiments, C is an optionally substituted pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the optional substituents are selected from:

[0857] (i) C 6-10 carbaryl, C 4-10 carbocyclic, C 5-10 heteroaryl, C 5-10 heterocyclic, or C 5-10 bridged heterocyclic, 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:

[0858] a) one or two ═O groups;

[0859] b) one or more halo groups;

[0860] c) CN, NH2, OH;

[0861] 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;

[0862] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[0863] f) C 1-6 alkyl esters;

[0864] g) C 5-6 heterocyclic, which has optional methyl, OH, or ═O substituents;

[0865] h) C 5-6 heteroaryl;

[0866] i) C 4-10 carbocyclic, which has optional methyl or ═O substituents;

[0867] j)C 6-10 a carbon aryl group having an optional substituent of one or more halo groups;

[0868] k) a carboxyl group, CH2-carboxyl;

[0869] l) P(=O)Me2;

[0870] (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 alkyl acyl, C 1-6 alkyl acylamino, di-C 1-6 alkyl acylamino, C 1-6 alkyl sulfinylamino, di-C 1-6 alkyl sulfinylamino.

[0871] In other embodiments, the compound of formula A-B-C has formula (I-B):

[0872]

[0873] wherein X 1 , R A2 and R A3 are as defined in (I-A).

[0874] In some embodiments, formula (I-B) can be formula (I-Ba) or (I-Bb) shown below:

[0875]

[0876]

[0877] In some embodiments, D is a C 6-10 carbon aryl, C 4-10 carbocyclic, C 5-10 heteroaryl or C 5-10 heterocyclic group, which is itself optionally substituted by one or more groups selected from:

[0878] a) one or two =O groups;

[0879] b) one or more halo groups;

[0880] c) CN, NH2, OH;

[0881] 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 halo groups;

[0882] e)C 1-6 an alkoxy group having an optional substituent of one or more halogenated groups;

[0883] f)C 1-6 an alkyl ester;

[0884] g)C 5-6 a heterocyclic group having optional methyl, OH or ═O substituents;

[0885] h)C 5-6 a heteroaryl;

[0886] i)C 4-10 a carbocyclic group having optional methyl or ═O substituents;

[0887] j)C 6-10 a carboaryl having an optional substituent of one or more halogenated groups;

[0888] l) carboxyl, CH2-carboxyl

[0889] m) P(═O)Me2.

[0890] 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 having an optional 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 pyridin-2-one is pyridin-2(1H)-one.

[0891] 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 atom substituted by ═O at the ortho position, and the other optional substituents are selected from methyl, OMe, piperazinyl substituted by methyl, C(═O)OH (carboxyl), Cl, F, pyrazolyl, triazolyl, tetrazolyl, phenyl substituted by fluorine, CN, CF3 or O-CF3. 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 atom substituted by ═O at the ortho position, and the other optional substituents are selected from methyl, OMe, piperazinyl substituted by methyl, C(═O)OH (carboxyl), Cl, F, triazolyl, tetrazolyl, pyrazolyl optionally substituted by methyl, phenyl substituted by fluorine, CN, CF3, OCHF2 or O-CF3.

[0892] In some embodiments, D is an optionally substituted C5 heterocycle or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments, D is an optionally substituted pyrazole, imidazole, triazole or oxazole, wherein the optional substituents are selected from methyl. In further embodiments, D is a triazole substituted with two methyl groups. In further embodiments, D is a pyrazole substituted with two methyl groups. In further embodiments, D is an imidazole substituted with two methyl groups and CN. In further embodiments, D is an oxazole substituted with two methyl groups.

[0893] In some embodiments, D is a C9 heterocyclic group or C9 heteroaryl containing 2 or 3 nitrogen atoms. In further embodiments, D is 1H-pyrazolo[3,4-b]pyridinyl, indazol-1-yl or indazol-2-yl.

[0894] In other embodiments, the compound of formula A-B-C has formula (I-C):

[0895]

[0896] wherein X 1 , R A2 and R A3 are as defined in (I-A).

[0897] 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 or C 5-6 heteroaryl having an optional methyl substituent, carboxyl, =O, halo, NH2, CN or phenyl optionally substituted with one or more halo atoms; or

[0898] wherein R D3 and R D4 form an optionally substituted 6-membered carbocyclic aromatic ring, heterocycle or heteroaromatic ring, wherein the optional substituents are selected from OH, methyl, OMe, halo, C(=O)OH.

[0899] In another embodiment, R D1 , R D2 , R D3 and R D4One or both of them are selected from methyl, OMe, halo, C(=O)OH, CN, CF3, OCF3, OCHF2, pyrazolyl, triazolyl, tetrazolyl, and the rest are H. In another embodiment, R D1 , R D2 , R D3 and R D4 One or both of them are selected from methyl, OMe, halo, C(=O)OH, CN, CF3, OCF3, OCHF2, triazolyl, tetrazolyl, pyrazolyl optionally substituted with methyl, and the rest are H.

[0900] In one embodiment, all R D1 , R D2 , R D3 and R D4 are H.

[0901] In some embodiments, R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.

[0902] In other embodiments, the compound of formula A-B-C has formula (I-D):

[0903]

[0904] In some embodiments, X 1 , R A2 and R A3 are as defined in (I-A).

[0905] In some embodiments, X D is NR D5a or CR D5a R D5b ;

[0906] R D5a is selected from H or methyl;

[0907] R D5b and R D6b are both H or together they are -CH2-;

[0908] R D6a is selected from H, =O, methyl, CH2OH or C(=O)OH;

[0909] R D7a is selected from H, =O, methyl, CH2OH or C(=O)OH;

[0910] R D7b is H, where when R D7a is =O, R D7b does not exist;

[0911] or 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 a carboxyl group, and R D6b and R D7b are absent.

[0912] In some embodiments, R D6a and R D7a together form a benzene ring or a pyridine ring optionally substituted with CN, P(=O)Me2 or a carboxyl group, and R D6b and R D7a are absent.

[0913] In other embodiments, the compound of formula A-B-C has formula (I-E):

[0914]

[0915] In some embodiments, R A2 is selected from:

[0916] (i) H;

[0917] (ii) a halogen group;

[0918] (iii) CN;

[0919] (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;

[0920] (v) OH

[0921] (vi) C 1-6 alkoxy, which is optionally substituted with OH, C 1-6 alkylacylamino or one or more halogen groups;

[0922] (vii) a carboxyl group;

[0923] (viii) C 1-6 alkylacylamino, which is optionally substituted with C 1-3 alkylacylamino, CN, C 2-3 alkynyl, C 4-6 heterocyclic group, C 1-3 alkyl, and the alkyl is optionally substituted with one or more halogen or OH groups.

[0924] In some embodiments, R A2 is selected from the group consisting of:

[0925] (i) H;

[0926] (ii) Halo group;

[0927] (iii) C 1-6 Alkyl ester;

[0928] (iv) C 1-6 Hydrocarbon;

[0929] (v) C 1-6 Alkylcarbonylamino, optionally substituted by C 1-3 Alkylcarbonylamino, C 2-3 Alkynyl, C 4-6 Heterocyclic group or C 1-3 alkyl substituted, the alkyl optionally substituted by one or more halo groups or OH groups;

[0930] (vi) C 1-6 Thioalkyl;

[0931] (vii) C 1-6 Alkylcarbonyl;

[0932] (viii) C5 heteroaryl; or

[0933] (ix) Alkylamino.

[0934] In some embodiments, R A2 is selected from CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCHF2, H, -OMe, -OCF3, or

[0935] R A2 and R A3 together form unsubstituted 2 - pyrazole, 2 - pyrrole substituted by methyl, pyridine optionally substituted by NH2, or benzene optionally substituted by Cl, F or OMe.

[0936] In some embodiments, R A2Selected from -C(=O)OCH2CH3, cyclopropyl, methyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, C(=O)N(CH3)2, H, -C(=O)N(CH3)CH2CH2OH, -C(=O)N(CH3)CH2CCH, Cl, N(CH3)2, pyrazole, -SCH2CH3, -C(=O)CH3 and -C(=O)NHCH2CH2OH.

[0937] In some embodiments, R A3 is selected from:

[0938] (i) H;

[0939] (ii) a halogenated group;

[0940] (iii) CN;

[0941] (iv) C 1-6 hydrocarbon, which is optionally substituted by OH, CN, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1-6 acyloxy, carboxyl, C 1-6 alkyl ester, C 1-6 alkyl amino; -C(=O)NH2, C 1-6 alkyl acyl amino, C 1-6 alkyl acyl acyl amino, C 1-6 alkyl sulfinyl, C 1-6 alkyl sulfonyl or one or more halogenated group substituents;

[0942] (v) OH;

[0943] (vi) C 1-6 alkoxy, which is optionally substituted by OH, NH2, C4 heterocyclic group or one or more halogenated group substituents.

[0944] In some embodiments, R A3 is selected from:

[0945] (i) H;

[0946] (ii) a halogenated group;

[0947] (iii) CN;

[0948] (iv) C 1-6 hydrocarbon, which is optionally substituted by OH, CN, C 1-6 thioalkyl, C1-6 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 substituted by one or more halo groups;

[0949] (v) OH;

[0950] (vi) C 1-6 alkoxy, which is optionally substituted by OH, NH2, C4 heterocyclic group or one or more halo groups.

[0951] In some embodiments, the compound has formula (I-E) and R A3 is H, methyl or OH. In further embodiments, the compound has formula (I-E) and R A3 is H.

[0952] In some embodiments, the compound has formula (I-E) and D is C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl or C 5-10 heterocyclic group, which are themselves optionally substituted by: =O; halo group; CN; NH2; OH; one or more C 1-6 alkyl groups, the alkyl being optionally substituted by halo groups; C 1-6 alkoxy optionally substituted by halo groups; C 1-6 alkyl ester; C 5-6 heterocyclic group having an optional methyl substituent; carboxyl; CH2-carboxyl; tetrazolyl; pyrazolyl or triazolyl. In some embodiments, the optional substituents are selected from =O, CN, F, Cl, Br, methyl, ethyl, OMe, ethoxy, O-CF3, CF3, C 1-2 alkyl ester. In some embodiments, the compound has formula (I-E) and D is C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl or C 5-10 heterocyclic group, which are themselves optionally substituted by: =O; methyl; OMe; piperazinyl substituted by methyl; C(=O)OH (carboxyl); Cl; F; phenyl substituted by fluorine; CN; CF3; OCHF2, O-CF3; triazole, tetrazole, pyrazole optionally substituted by methyl.

[0953] In some embodiments, the compound has formula (I-E) and D is an optionally substituted pyridin-2-one. In some embodiments, the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF3), OCF3, carboxyl (C(=O)OH), CN, phenyl optionally having an F substituent at the para position, or piperazinyl having a methyl substituent. In some embodiments, the compound has formula (I-E), and D is an optionally substituted pyridin-2-one or pyridin-2(1H)-one. In some embodiments, the optional substituents are selected from OMe, Cl, F, pyrazole, triazole, tetrazole, methyl, trifluoromethyl (CF3), OCHF2, OCF3, carboxyl (C(=O)OH), CN, phenyl optionally having an F substituent at the para position, or piperazinyl having a methyl substituent. In some embodiments, the pyridin-2-one is unsubstituted. In some embodiments, the pyridin-2-one is pyridin-2(1H)-one.

[0954] In some embodiments, the compound has formula (I-E) and D is an optionally substituted C5 heterocycle or C5 heteroaryl, wherein the optional substituents are selected from methyl and CN. In further embodiments, D is an optionally substituted pyrazole, imidazole, triazole, or oxazole, wherein the optional substituents are selected from methyl. In further embodiments, D is a triazole substituted with two methyl groups. In further embodiments, D is a pyrazole substituted with two methyl groups. In further embodiments, D is an imidazole substituted with two methyl groups and CN. In further embodiments, D is an oxazole substituted with two methyl groups. In some embodiments, D is a C9 heterocyclic group or C9 heteroaryl containing 2 or 3 nitrogen atoms. In further embodiments, D is 1H-pyrazolo[3,4-b]pyridinyl, indazol-1-yl, or indazol-2-yl.

[0955] In some embodiments, D is optionally substituted with 1, 2, or 3 substituents.

[0956] In another embodiment, the compound has formula (I-Ea):

[0957]

[0958] wherein D and R A3 are as defined above for formula (I-E).

[0959] In another embodiment, the compound has formula (I-Eb):

[0960]

[0961] wherein D and R A3 are as defined above for formula (I-E).

[0962] In one embodiment, the compound has the formula (I)

[0963] A - B - C (I)

[0964] or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof,

[0965] wherein A has the formula:

[0966]

[0967] wherein the wavy line indicates the point of attachment to B;

[0968] X 1 is N;

[0969] R A2 is selected from the group consisting of:

[0970] (i) H;

[0971] (ii) a halogenated group;

[0972] (iii) CN;

[0973] (iv) C 1-6 hydrocarbon, optionally substituted with OH, CN, C 1-6 acyl, C 1-6 alkoxy or one or more halogenated groups;

[0974] (v) C 1-6 alkoxy, optionally substituted with OH, alkylamido or one or more halogenated groups;

[0975] (vi) C 1-6 acylamido (wherein the acyl is optionally substituted with H or methyl);

[0976] (vii) C 1-6 thioalkyl;

[0977] (viii) C 1-6 alkyl ester;

[0978] (ix) C 1-6 alkyl acyl;

[0979] (x) C 4-5 heterocyclic group;

[0980] (xi) C - 5 heteroaryl;

[0981] (xii) C 1-6 alkylamido, optionally substituted with C 1-3 alkylamido, CN, C 2-3 alkynyl, C4-6 heterocyclic group or C 1-3 alkyl substituted, wherein said C 1-3 alkyl is optionally substituted by one or more halogen groups or OH groups; and

[0982] (xiii) OH;

[0983] R A3 is selected from the group consisting of:

[0984] (i) H;

[0985] (ii) halogen group;

[0986] (iii) CN;

[0987] (iv) C 1-6 hydrocarbon, which is optionally substituted by OH, CN, C 1-6 thioalkyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1-6 acyloxy, carboxyl, C 1-6 alkyl ester, C 1-6 alkylamino, -C(=O)NH2, C 1-6 alkyl acylamino, C 1-6 alkyl acyl acylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or one or more halogen groups;

[0988] (v) OH;

[0989] (vi) C 1-6 alkoxy, which is optionally substituted by OH, NH2, C4 heterocyclic group or one or more halogen groups;

[0990] (vii) C 1-6 acyloxy;

[0991] (viii) C4 heterocyclic group;

[0992] (ix) -NH2;

[0993] (x) C 1-6 alkylamino, which is optionally substituted by CN, OH or C4 heterocyclic group;

[0994] (xi) C 1-6 dialkylamino, which is optionally substituted by -NH2;

[0995] (xii) C 1-6 acyl acylamino (wherein the acyl substituent is H or Me);

[0996] (xiii) Amidino or methyl - amidino;

[0997] (xiv) Carboxylamino;

[0998] (xv) C 1-6 Thioalkyl, optionally substituted by OH or NH2;

[0999] (xvi) C 1-6 Alkylsulfinyl;

[1000] (xvi) C 1-6 Alkylsulfonyl, optionally substituted by one or more halogen groups;

[1001] (xvii) C 1-6 Sulfonimido;

[1002] (xviii) C 1-6 Alkylphosphinyl;

[1003] (xix) Carboxyl;

[1004] (xx) C(=O)NH2

[1005] (xxi) C 1-6 Alkyl ester;

[1006] (xxii) C 1-6 Alkyl acyl, optionally substituted by one or more halogen groups; and (xxiiv) C 1-6 Alkyl acylamino;

[1007] Or wherein R A3 and R A2 together with the carbon atom to which they are attached form:

[1008] (i) Optionally substituted C 5-7 Heterocycle;

[1009] (ii) Optionally substituted C 5-7 Heteroaromatic ring;

[1010] (iii) Optionally substituted C6 carbon aromatic ring;

[1011] (iv) Optionally substituted C 5-7 Carbocycle

[1012] Wherein the optional substituent is selected from C 1-6 Alkyl, halogen, C 1-6 Alkoxy, NH2, C 1-6 Alkylamino, OH and CN;

[1013] Wherein B has the formula (B - 1) or (B - 2)

[1014] i)

[1015]

[1016] wherein the wavy line indicates the attachment points to A and C;

[1017] 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 with OH or OMe;

[1018] (ii)

[1019]

[1020] wherein the wavy line indicates the attachment points to A and C;

[1021] R B2 is C 1-2 alkyl-OH, CH2CONHMe or C 1-3 alkyl;

[1022] wherein C is selected from the group consisting of C 6-10 carbaryl, C 5-6 heteroaryl and C 5-10 heterocyclic group, the groups being optionally substituted with:

[1023] (i)C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocyclic group, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group,

[1024] which are themselves optionally substituted with one or more of the following groups;

[1025] a) one or two =O groups;

[1026] b) one or more halo groups;

[1027] c) CN, NH2, OH;

[1028] 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;

[1029] e) C 1-6 alkoxy, which has optional substituents of one or more halo groups;

[1030] f)C 1-6 alkyl ester;

[1031] g)C 5-6 heterocyclic group having an optional methyl, OH or =O substituent;

[1032] h)C 5-6 heteroaryl;

[1033] i)C 4-10 carbocyclic group having an optional methyl or =O substituent;

[1034] j)C 6-10 carbaryl having an optional substituent of one or more halo groups;

[1035] l)P(=O)Me2;

[1036] m) carboxyl or CH2-carboxyl; and / or

[1037] n) tetrazolyl, CH2-tetrazolyl, 5-oxo-4H-1,2,4-oxadiazol-3-yl;

[1038] (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.

[1039] In some embodiments, the compound has the formula (I)

[1040] A-B-C (I)

[1041] or a pharmaceutically acceptable salt, tautomeric form or stereoisomer thereof,

[1042] wherein A has the following formula:

[1043]

[1044] wherein the wavy line indicates the point of attachment to B;

[1045] R A2 is C 1-6 alkylamino;

[1046] X 1 、R A3, B and C are as defined above.

[1047] In some embodiments, the compounds of formula (I) are selected from Table 1 below.

[1048] Table 1.

[1049]

[1050]

[1051]

[1052]

[1053]

[1054] Additional compounds are shown in Table 2:

[1055] Table 2.

[1056]

[1057]

[1058]

[1059]

[1060] Additional compounds are shown in Table 3:

[1061] Table 3.

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072] In some embodiments, the compound is selected from 50, 57, 129, 132, and 136. In some embodiments, the compound is 132.

[1073] General synthesis

[1074] The compounds according to general formula (I-B) can be prepared according to Schemes 1, 2, 3, 4, and 5 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 Schemes 1, 2, 3, 4, and 5 can be modified in various ways. Therefore, the order of the transformations illustrated in these schemes is not intended to be limiting.

[1075] The routes for preparing the compounds of general formula (I-B) and the corresponding intermediates are described in Schemes 1, 2, 3, 4, and 5.

[1076] Scheme 1.

[1077]

[1078] Scheme 1: Route for preparing the 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).

[1079] 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 a 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, microwave heating may be beneficial.

[1080] For palladium-catalyzed Buchwald-Hartwig amination, all methods known in the art can be applied. For example, diamine (A1) can react 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.

[1081] Diamines of general formula (A1) and heteroaryls of general formula (A2a) are commercially available or can be prepared according to procedures available from the public domain. For the synthesis of diamine (A1), see, for example, WO2004004726 and the references therein.

[1082] Arylated diamines of general formula (A6) can be obtained from (A3) by copper-catalyzed Ullmann coupling with heterocycle (A4) or by palladium-catalyzed Suzuki coupling with boronic acid derivative (A5). For 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 hours - 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.

[1083] For the Suzuki coupling for (A6), all methods known in the art can be applied. For example, (A3) can react with 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 hours - 15 hours.

[1084] Heterocycles of general formula (A4) and boronic acid derivatives of general formula (A5) are commercially available or can be prepared according to procedures available from the public domain.

[1085] Primary amines of general formula (A7) can be obtained from mono-protected diamines of general formula (A6) by deprotection methods. Depending on the protecting groups applied, these methods can be, for example, acidic, basic, oxidative or hydrogenative methods. Suitable protecting moieties for amino groups and their introduction and cleavage are well known in the art. For an overview of protecting group chemistry, see, for example, Wuts 2014.

[1086] The final compound of general formula (I-B) can be synthesized from the primary amine of general formula (A7) by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination. The primary amine of general formula (A7) can be reacted with a heteroaryl of general formula (A8) in which X is a leaving group such as a halogen (such as chlorine) or -S(O)Me, applying procedures similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a). Heteroaryls of general formula (A8) are commercially available or can be prepared according to procedures available from the public domain.

[1087] An alternative route for the compounds of general formula (I-B) starts with the deprotection of the diamine of general formula (A3) to give the primary amine of general formula (A9), as depicted in Scheme 1. For the deprotection, the same procedures as described for the synthesis of (A7) from (A6) are applied.

[1088] The primary amine of general formula (A9) can in turn react with a heteroaryl of general formula (A8) by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination to give an aryl iodide of general formula (A10), applying procedures similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a).

[1089] The final compound of general formula (I-B) can be synthesized from the aryl iodide of general formula (10) by copper-catalyzed Ullmann coupling with the heterocycle H-D (A4) or by palladium-catalyzed Suzuki coupling with the boronic acid derivative (A5), applying procedures similar to those described in Scheme 1 for the synthesis of compound (A6) from (A3).

[1090] Yet another method for the compounds of general formula (I-B) starts with a mono-protected diamine (1) or its corresponding salt and a pre-assembled heteroaryl (A11a) in which X is a leaving group such as a halogen or -S(O)Me, by nucleophilic aromatic substitution (S NPalladium-catalyzed Buchwald-Hartwig amination of (Ar) or palladium gives an arylated diamine 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). The heteroaryl of general formula (A11a) is commercially available or can be prepared according to procedures available from the public domain (e.g., by Chan-Lam coupling). Specific examples of (A11a) are described in the subsequent paragraphs.

[1091] An alternative route for the preparation of the compound of general formula (I-B) and the intermediate of general formula (A10) is depicted in Scheme 2.

[1092] Scheme 2

[1093]

[1094] Scheme 2: Route for the preparation of the compound of general formula (I-B) and the 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).

[1095] 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).

[1096] Deprotection of the diamine of general formula (A12) can give a 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.

[1097] 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).

[1098] For the synthesis of the intermediate of general formula (A10), a 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 a 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).

[1099] 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 N 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 - 12 hours. The nitroaryl of general formula (A14) is commercially available or can be prepared according to procedures available from the public domain.

[1100] 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 react in the presence of a metal catalyst (such as palladium / carbon), in a hydrogen atmosphere (1 bar - 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 - 24 hours.

[1101] Scheme 3

[1102]

[1103] Scheme 3: Route for the preparation of 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).

[1104] The pyridone of general formula (A18) can be obtained by condensing an aniline (A16) with an 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 - 12 hours. The oxo-pyran of general formula (A17) is commercially available or can be prepared according to procedures available from the public domain.

[1105] The primary amine of general formula (A19) can be synthesized from (A18) by removing the protecting group. For deprotection, the same procedure as described in Scheme 1 for the synthesis of (A7) from (A6) is applied.

[1106] 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 in Scheme 1 for the synthesis of (A3) from (A1) and (A2a).

[1107] The carboxylic acid derivative of general formula (A21) can be synthesized from the carboxylic acid ester of general formula (A20) by ester hydrolysis. For saponification, 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 hours to 2 hours.

[1108] The 1,2,4-triazine of general formula (A29) can be synthesized according to the route depicted in Scheme 4. The methyl-sulfide moiety of 3-(methylthio)-1,2,4-triazine (A22) [CAS 28735-21-9] can be activated for nucleophilic displacement by oxidation, and all methods known in the art can be applied for oxidation. For example, (A22) can be reacted with mCPBA or in an inert solvent such as dichloromethane at a temperature between 0 °C and the boiling point of the solvent for 0.5 hours to 2 hours. By reacting the crude oxidation product with the primary amine of general formula (A1) in a polar solvent such as nBuOH at a temperature between room temperature and the boiling point of the solvent for 2 hours to 18 hours, the crude oxidation product can be directly converted to the monoarylated diamine of general formula (A23) in nucleophilic aromatic substitution (S N Ar).

[1109] The aryl bromide of general formula (A24) can be obtained from the triazine of general formula (A23) by bromination. For bromination, all methods known in the art can be applied. For example, the triazine (A23) can be reacted with bromine or N-bromosuccinimide (NBS) in a solvent such as methanol, water, DMF, or a mixture thereof at a temperature between 0 °C and the boiling point of the solvent for 4 hours to 15 hours.

[1110] The 3,6-disubstituted triazines of general formula (A27) can be synthesized from the aryl bromide (A24) via Suzuki coupling, and for the Suzuki coupling, all methods known in the art can be applied. For example, (A24) can be reacted with potassium trifluoroborate (A25) or trioxatriborinane (A26) in the presence of a palladium catalyst (such as CataCXium A Pd G3 [CAS 1651823-59-4] or 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium [CAS 95408-45-0]) 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 8 to 15 hours. The trifluoroborate or trioxatriborinane (A26) of general formula (A25) is commercially available or can be prepared according to procedures available from the public domain.

[1111] Scheme 4

[1112]

[1113] Scheme 4: Route for the preparation of compounds of general formula (A29), where X is a leaving group, PG is a protecting group, Alk is methyl or ethyl, X 2 and X 3 is CH or N (with the condition that when X 2 is N, X 3 is CH and vice versa), R A2 is alkyl or cycloalkyl and D has the meaning given above for general formula (I-B).

[1114] The primary amine of general formula (A28) can be obtained from (A27) by removing the protecting group. For deprotection, the same procedure as described in Scheme 1 for the synthesis of (A7) from (A6) is applied.

[1115] The final compound of general formula (A29) can be synthesized from the primary amine (A28) or its corresponding salt and the pre-assembled heteroaryl (A11) (where X is a leaving group, such as a halogen) 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 (A3) from (A1) and (A2a).

[1116] The heteroaryl of general formula (A11) is commercially available or can be prepared according to procedures available from the public domain. Specific examples of (A11) are described in the subsequent paragraphs.

[1117] In an alternative route to the triazines of general formula (A29), a primary amine (A28) or its corresponding salt can first react with a heteroaryl (A2) in which X is a leaving group such as a halogen, by nucleophilic aromatic substitution (S N Ar) or palladium-catalyzed Buchwald-Hartwig amination reaction to give an aryl iodide of general formula (A30). The procedures that can be applied are similar to those described in Scheme 1 for the synthesis of (A3) from (A1) and (A2a). The heteroaryls of general formula (A2) are commercially available or can be prepared according to procedures available from the public domain.

[1118] The final compound of general formula (A29) can be synthesized from the aryl iodide of general formula (A30) by copper-catalyzed Ullmann coupling with a heterocycle H-D (A4) or by palladium-catalyzed Suzuki coupling with a boronic acid derivative (A5), applying procedures similar to those described in Scheme 1 for the synthesis of compound (A6) from (A3).

[1119] In an alternative method for the 3,6-disubstituted triazines of general formula (A27), a ketal (A31) can be reacted with methylhydrazine thiocarbamate ester (A32) or its corresponding salt in a polar solvent (such as methanol) at a temperature between room temperature and the boiling point of the solvent for 5 hours to 12 hours to give a triazine thioether of general formula (A33) [for a similar method for triazine thioethers, see Duan 2012]. The ketal (A31) and methylhydrazine thiocarbamate ester (A32) are commercially available or can be prepared according to procedures available from the public domain.

[1120] The triazine thioether of general formula (A33) can in turn be converted to the 3,6-disubstituted triazine of general formula (A27) by a two-step method that includes oxidizing (A33) and then subjecting it to nucleophilic aromatic substitution (S N Ar) with a primary amine of general formula (A1), applying procedures similar to those described in Scheme 4 for the synthesis of compound (A23) from (A22).

[1121] The carboxylic acid ester or amide derivatives of general formula (A35) and (A37) can be synthesized according to the routes depicted in Scheme 5. The carboxylic acid ester of general formula (A35) can be obtained from a primary amine (A7) [see Scheme 1] and a triazine of general formula (A34) by nucleophilic aromatic substitution (S N(Ar) is obtained by applying procedures similar to those described for the synthesis of (A3) from (A1) and (A2a) in Scheme 1. For example, (A7) and (A34) can be reacted under microwave heating for 0.5 h to 2 h at a temperature between room temperature and the boiling point of the solvent, in the presence of an organic base such as DIPEA, in a polar solvent such as NMP. The triazines of general formula (A34) are commercially available or can be prepared according to procedures available from the public domain.

[1122] The formamide of general formula (A37) can be obtained by direct amidation of the carboxylic acid ester (A35). For the amidation reaction, all methods known in the art can be applied. For example, the ester (A35) can be reacted with the amine (A36) in a polar solvent such as methanol, ethanol or THF at a temperature between room temperature and the boiling point of the solvent for 1 h to 5 h. If an amine (A36) with limited nucleophilicity is used, the temperature can be increased and the reaction time can be extended and / or a Lewis acid such as AlMe3 can be added.

[1123] Scheme 5

[1124]

[1125] Scheme 5: Routes for the preparation of compounds of general formula (A35) and general formula (A37), where Alk is methyl or ethyl and D has the meaning given above for general formula (I-B).

[1126] Alternatively, the ester (A35) can first be hydrolyzed to the carboxylic acid of general formula (A38). For the saponification, all methods known in the art can be applied. For example, the ester (A35) can be reacted with a base (such as sodium hydroxide, lithium hydroxide or potassium hydroxide), in a polar protic solvent (such as water or methanol or a mixture thereof), at a temperature between 0 °C and the boiling point of the solvent for 0.5 h to 24 h. In some cases, it may be beneficial to add an ether such as THF or 1,4-dioxane to the reaction mixture.

[1127] The carboxamide of general formula (A37) can in turn be obtained from the carboxylic acid (A38) by amide coupling with a suitable amine (A36). For the amide coupling, all methods known in the art from peptide chemistry can be applied. For example, the acid (A38) and the amine (A36) can be reacted via an activated acid derivative in a polar aprotic solvent such as DMF, acetonitrile or NMP. These activated derivatives can be prepared from the acid A38 with reagents such as HOBt, HOAt or N-hydroxysuccinimide and a carbodiimide such as DCC or EDC or with a preformed reagent such as HATU, PyBOP or Obtained. To increase reactivity, suitable bases such as DIPEA or triethylamine can be used. In some cases, the activated acid derivative can be isolated before reacting with the amine (A36). The formation of the amide can also be achieved via acyl halides (which can be formed from carboxylic acids by reaction with, for example, oxalyl chloride, thionyl chloride or sulfuryl chloride), mixed acid anhydrides (which can be formed from carboxylic acids by reaction with, for example, isobutyl chloroformate), imidazolides (which can be formed from carboxylic acids by reaction with, for example, CDI) or azides (which can be formed from carboxylic acids by reaction with DPPA).

[1128] For the synthesis of the final compounds of general formula (B-2), routes and methods comparable to those described in Schemes 1 to 5 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.

[1129] Scheme 6

[1130]

[1131] 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 formulae (I-B) and (B-2).

[1132] Scheme 7

[1133]

[1134] 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 formulae (I-B) and (B-2).

[1135] Additional compounds of different formulae as described above can be prepared by similar methods.

[1136] Experimental section

[1137] The NMR peak forms are stated as they appear in the spectrum without considering possible higher-order effects.

[1138] 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 meanings customary to those skilled in the art.

[1139] Abbreviations

[1140] Aq Aqueous

[1141] BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[1142] Boc tert-Butoxycarbonyl

[1143] Brine Saturated aqueous sodium chloride solution

[1144] nBuOH Butan-1-ol

[1145] CataCXium A Di(adamantan-1-yl)(butyl)phosphine (CAS Registry Number 321921-71-5)

[1146] CataCXium A Pd G3 Methanesulfonic acid (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) Generation 3 precatalyst

[1147] CDI 1,1'-Carbonyldiimidazole

[1148] CHAPS 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate

[1149] m-CPBA 3-Chloroperoxybenzoic acid

[1150] DavePhos 2'-(Dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (CAS Registry Number 213697-53-1)

[1151] dba (All-E)-Dibenzylideneacetone

[1152] DCC Dicyclohexylcarbodiimide

[1153] DCM Dichloromethane

[1154] DEA Diethylamine

[1155] DIPEA N-Ethyl-N-isopropyl-propan-2-amine

[1156] DMA N,N-Dimethylacetamide

[1157] DME Dimethoxyethane

[1158] DMF N,N-Dimethylformamide

[1159] DMSO Dimethyl sulfoxide

[1160] DPPA Diphenylphosphoryl azide

[1161] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[1162] EDC 2-(((Ethylimino)methylene)amino)-N,N-dimethylethan-1-aminium hydrochloride

[1163] ESI Electrospray ionization

[1164] EtOAc Ethyl acetate

[1165] EtOH Ethanol

[1166] FA Formic acid

[1167] G3 Generation 3

[1168] Gmean Geometric mean

[1169] HATU (1-(Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[1170] HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)

[1171] HOAt 3H-[1,2,3]Triazolo[4,5-b]pyridin-3-ol

[1172] HOBt 1H-Benzotriazol-1-ol

[1173] HPLC High performance liquid chromatography

[1174] HRMS High resolution mass spectrometry

[1175] i-PrOH Propan-2-ol

[1176] IC 50 Half maximal inhibitory concentration

[1177] K D Dissociation constant

[1178] MeCN Acetonitrile

[1179] MeOH Methanol

[1180] MS Mass spectrometry

[1181] MTBD 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[1182] MTBE Methyl tert-butyl ether

[1183] MW Microwave

[1184] NBS N-Bromosuccinimide

[1185] NCS 1-Chloropyrrolidine-2,5-dione

[1186] NIS 1-Iodopyrrolidine-2,5-dione

[1187] NMP 1-Methylpyrrolidin-2-one

[1188] NMR Nuclear magnetic resonance

[1189] O.n Overnight

[1190] Otf Trifluoromethanesulfonate

[1191] Pd-118 / PdCl2(dtbpf) Palladium(II) dichloride [1,1'-bis(di-tert-butylphosphino)ferrocene] complex

[1192] Pd2(dba)3 Tris(dibenzylideneacetone) dipalladium(0)

[1193] Pd2(dba)3·CHCl3 Tris(dibenzylideneacetone) dipalladium(0) chloroform adduct

[1194] Pd(dppf)Cl2·DCM Palladium(II) dichloride [1,1'-bis(diphenylphosphino)ferrocene] complex CH2Cl2 (1:1)

[1195] PdCl2(dppf) Palladium(II) dichloride [1,1'-bis(diphenylphosphino)ferrocene] complex

[1196] Pd-PEPPSI-IpentCl 2-Methylpyridine (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-yl] dichloro(2-methylpyridine)palladium (CAS Registry Number 1612891-29-8)

[1197] PE Petroleum ether

[1198] PG Protecting group

[1199] prep. Preparative

[1200] PyBOP ((1H-Benzotriazol-1-yl)oxy)tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate

[1201] qToF Quadrupole time-of-flight

[1202] RockPhos Di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine

[1203] rt Room temperature

[1204] sat. Saturated

[1205] SFC Supercritical fluid chromatography

[1206] S N Ar Nucleophilic aromatic substitution

[1207] T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide

[1208] TEA Triethylamine

[1209] TFA Trifluoroacetic acid

[1210] TFAA 2,2,2-Trifluoroacetic anhydride

[1211] THF Tetrahydrofuran

[1212] TLC Thin layer chromatography

[1213] TMEDA N 1 ,N 1 ,N 2 ,N 2 -Tetramethylethane-1,2-diamine

[1214] t R Retention time

[1215] UPLC Ultra performance liquid chromatography

[1216] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

[1217] XPhos Dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine

[1218] Units

[1219] atm Atmosphere

[1220] C Celsius

[1221] g Gram

[1222] h Hour

[1223] Hz Hertz

[1224] L liter

[1225] M mole per liter

[1226] mg milligram

[1227] MHz megahertz

[1228] min minute

[1229] mL milliliter

[1230] mm millimeter

[1231] mM millimole per liter

[1232] mol mole

[1233] mmol millimole

[1234] nA nanoampere

[1235] nL nanoliter

[1236] μm micrometer

[1237] μL microliter

[1238] N equivalent per liter

[1239] nm nanometer

[1240] ppm parts per million

[1241] angstrom

[1242] The various embodiments described in the present application are illustrated by the following examples, which are not meant to limit the compounds of formula (I) in any way.

[1243] The exemplary test experiments described herein are used to illustrate the present embodiment and are not limited to the examples given.

[1244] Experimental section - General part

[1245] General conditions

[1246] (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.

[1247] (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 nitrogen stream for a suitable period of time (e.g., 5 minutes to 10 minutes) or by repeatedly evacuating the vessel and backfilling it with an appropriate inert atmosphere (e.g., nitrogen (g) or argon (g));

[1248] (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;

[1249] (iv) Generally, the progress of the reaction is monitored by thin-layer chromatography (TLC) and / or analytical high-performance liquid chromatography (HPLC or UPLC) usually coupled with a mass spectrometer (LCMS);

[1250] (v) To remove excess water, the organic solution is dried over anhydrous MgSO4 or Na2SO4, or by using a phase separator, and the work-up procedure is carried out using conventional phase separation techniques;

[1251] (vi) Evaporation is carried out by rotary evaporation under vacuum or in a Genevac TM HT-4 / EZ-2 or V10;

[1252] (vii) Unless otherwise stated, flash column chromatography is 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 The X2 rapid system or a similar system is carried out manually or automatically;

[1253] (viii) Using an isocratic or gradient mobile phase as described in the experimental section, preparative reverse-phase HPLC and preparative reverse-phase SFC are carried out using standard HPLC and SFC instruments equipped with MS and / or UV-triggered fraction collection instruments, respectively;

[1254] Collect the relevant fractions, combine and lyophilize or evaporate to obtain the purified compound, or collect the relevant fractions, combine and concentrate under reduced pressure, extract with DCM or EtOAc, and dry the organic phase over Na2SO4 or by using a phase separator, then concentrate under reduced pressure to obtain the purified compound;

[1255] (ix) Chiral preparative chromatography is carried out using HPLC or SFC on a standard HPLC or SFC instrument and using an isocratic or gradient run with a mobile phase as described in the experimental section;

[1256] (x) Preparative thin-layer chromatography (TLC) is carried out using TLC glass plates and applying a suitable solvent or solvent mixture;

[1257] (xi) The yield (if present) is not necessarily the maximum achievable, and if a larger amount of the reaction product is required, some reactions are repeated;

[1258] (xii) In cases where certain compounds are obtained as acid addition salts (e.g., monohydrochloride or dihydrochloride), 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;

[1259] (xiii) Generally, the structure of the end product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; using Bruker Avance III 300, 400, 500, and 600 spectrometers (at 300 MHz, 400 MHz, 500 MHz, and 600 MHz, respectively) 1The proton NMR chemical shift values are measured on the δ scale while operating at H frequency. The experiments are usually recorded at 25 °C. The 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 the solvent peak 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 were obtained using 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 were obtained using a Waters XEVOqToF mass spectrometer or a similar device coupled to Waters Acquity UPLC, acquiring cationic and anionic data and usually only reporting ions related to the parent structure;

[1260] (xiv) In some cases, the intermediates were not fully purified, but their structures and purities were evaluated by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry;

[1261] (xv) Some 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 yield the corresponding free bases;

[1262] (xvi) Compounds containing asymmetric carbon and / or sulfur atoms were not resolved unless otherwise stated;

[1263] (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.

[1264] 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 existing stereocenter.

[1265] 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 into its free base or free acid form, respectively, 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.

[1266] Purification method

[1267] Preparative HPLC method :

[1268] Preparation Method A: The compound is purified by preparative HPLC on an Xbridge TM 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;

[1269] Preparation Method B: The compound is 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;

[1270] Preparation Method C: The compound is 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;

[1271] Preparation Method D: The compound is purified by preparative HPLC on an Xbridge TMPurification was carried out using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase on a C18 OBD column (5 μm, 150×30 mm ID);

[1272] Preparation method E: The compound was purified by preparative HPLC using a gradient of MeCN in a buffer system of H2O / FA (0.1%) as the mobile phase on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID);

[1273] 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;

[1274] 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;

[1275] Preparation method H: The compound was purified by preparative HPLC on an Xbridge TM C18 column (10 μm, 250×19 mm ID) using a gradient of MeCN in a buffer system of H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase;

[1276] 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 a buffer system of H2O / NH4HCO3 (10 mM, pH 9) as the mobile phase;

[1277] 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;

[1278] 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 a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) as the mobile phase;

[1279] 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 a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1280] 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 a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1281] 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 a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.1%, aqueous solution) as the mobile phase;

[1282] Preparation method O: 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 (0.05%, aqueous solution) as the mobile phase;

[1283] Preparation method P: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O as the mobile phase;

[1284] Preparation method Q: The compound was purified by preparative HPLC on an Xbridge TM Shield RP18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) as the mobile phase;

[1285] 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;

[1286] Preparation method S: 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 H2O / NH4HCO3 (10 mM) buffer system as the mobile phase;

[1287] Preparation method T: The compound was purified by preparative HPLC on an Xbridge TM C18 OBD column (5 μm, 150×30 mm ID) using a gradient of 20 mM NaOH + 10% MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1288] Preparation method U: The compound was purified by preparative HPLC on an Xbridge TM OBD phenyl column (5 μm, 250×19 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1289] Preparation method V: The compound was purified by preparative HPLC on an Xbridge TM OBD phenyl column (5 μm, 250×19 mm ID) using a gradient of MeCN in H2O / TFA (0.05%) buffer system as the mobile phase;

[1290] Preparation method X: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1291] 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 H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1292] Preparation method Z: The compound is 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;

[1293] Preparation method Z1: The compound is 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;

[1294] Preparation method Z2: The compound is 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;

[1295] Preparation method Z3: The compound is 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;

[1296] Preparation method Z4: The compound is purified by preparative HPLC on an Xbridge TM C18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN in an H2O / TFA (0.005%) buffer system as the mobile phase;

[1297] Preparation method Z5: The compound is purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeOH in an H2O / NH4HCO3 (10 mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase;

[1298] Preparation method Z6: The compound is 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 (0.1%, aqueous solution) buffer system as the mobile phase;

[1299] Preparation method Z7: The compound is purified by preparative HPLC on an Xbridge TM C18 OBD column (5 μm, 100×50 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;

[1300] Preparation method Z8: The compound is purified by preparative HPLC on an Xbridge TM RP18 OBD column (5 μm, 100×30 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.

[1301] Preparation method Z9: The compound is purified by preparative HPLC on an Xbridge TM C8 column (5 μm, 250×20 mm ID) using a gradient of MeCN in a buffer system of H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase;

[1302] Preparation method Z10: The compound is purified by preparative HPLC on an Xbridge TM C8 column (5 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.

[1303] Preparative SFC method :

[1304] Preparation method SFC-A: The compound is purified by preparative SFC on a Waters TM BEH (5 μm, 250×30 mm ID) using MeOH / H2O (NH3, 50 mM) (97 / 3) in CO2 as the mobile phase;

[1305] Preparation method SFC-B: The compound is purified by preparative SFC on a Phenomenex Luna Hilic (3.5 μm, 100×3 mm ID) using MeOH / NH3 20 mM in CO2 as the mobile phase;

[1306] Preparation method SFC-C: The compound is purified by preparative SFC on a 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;

[1307] 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;

[1308] 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.

[1309] Preparative HPLC method for parallel experimental setup :

[1310] 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;

[1311] 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;

[1312] Parallel preparation method C: The compound was purified by preparative HPLC on Waters TM Xbridge TM C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) (pH 10) buffer system (5%-95%) as the mobile phase;

[1313] Parallel preparation method D: The compound was purified by preparative HPLC on Xbridge TM C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / NH4HCO3 (10 mM) (pH 9) buffer system (5%-95%) as the mobile phase.

[1314] Synthesis method

[1315] General Method 1 (GM1): Nucleophilic Aromatic Substitution (S N Ar)

[1316] Condition A (GM1A): Conventional heating

[1317] 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 under 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.

[1318] 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.

[1319] Condition B (GM1B): Microwave heating

[1320] 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 is added NMP and a base (1 equivalent - 3 equivalents), 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.

[1321] General method 2 (GM2): Buchwald - Hartwig amination

[1322] A solution of the corresponding amine nucleophile or its salt (1 equivalent) in 1,4-dioxane is treated under nitrogen at room temperature with the corresponding heteroaryl electrophile (0.5 equivalent - 4 equivalents), Cs2CO3 (1.2 equivalents - 5 equivalents) 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 pad of Celite or silica, the filter cake is washed with EtOAc and the combined filtrates are 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.

[1323] 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 afford the desired aniline product.

[1324] General method 3 (GM3): Ullmann coupling

[1325] 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 at elevated temperature (80 °C - 100 °C) until TLC and / or LCMS indicate complete consumption of the starting material (usually 15 - 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 afford the desired coupling product.

[1326] In an alternative non-aqueous workup, the reaction mixture is filtered through a pad of Celite, the cake is washed with DCM and the combined filtrates are concentrated under reduced pressure. The obtained crude material is subjected to preparative TLC and / or preparative HPLC to afford the desired coupling product.

[1327] General method 4 (GM4): Suzuki coupling

[1328] Condition A (GM4A): Coupling with boronic acid derivative

[1329] 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 - 2 equiv) or (A26) (10 equiv), Cs2CO3 (3 equiv) or K2CO3 (3 equiv) or K3PO4 (2 - 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 - 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.

[1330] 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.

[1331] Condition B (GM4B): Coupling with trifluoroborate

[1332] 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.

[1333] General method 5 (GM5): Chan - Lam coupling

[1334] 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.

[1335] General method 6 (GM6): Boc deprotection

[1336] Condition A (GM6A): Deprotection with HCl

[1337] 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 - 3 h). The reaction mixture was concentrated under reduced pressure to give the desired amine as the (unspecified) HCl salt.

[1338] Condition B (GM6B): Deprotection with TFA

[1339] 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 - 16 h). The reaction mixture was concentrated under reduced pressure to give the desired amine as the (unspecified) TFA salt.

[1340] General method 7 (GM7): Amide formation

[1341] 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.

[1342] General method 8 (GM8): Methyl - thioether oxidation

[1343] 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 - 2 h). Use the reaction mixture directly in the next step.

[1344] Alternatively, concentrate the reaction mixture under reduced pressure and subject the obtained crude material to flash column chromatography on silica gel to give the desired oxidation product.

[1345] Intermediate

[1346] Intermediate 1

[1347] 6'-(((1S,3S)-3 - Aminocyclopentyl)amino)-2H - [1,3'-bipyridin]-2 - one

[1348] Step A.i - 1a

[1349] ((1S,3S)-3 - ((5 - Iodopyridin - 2 - yl)amino)cyclopentyl)carbamic acid tert - butyl ester

[1350]

[1351] According to GM1A, add 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (2.23 g, 9.99 mmol) to a solution of tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 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 column 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.

[1352] Step B.i - 1b

[1353] ((1S,3S)-3 - ((2 - Oxo - 2H - [1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert - butyl ester

[1354]

[1355] 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 give the title compound as a yellow solid (2.70 g, 98%). MS (ESI): m / z [M+H] + 371.2。

[1356] Step C.i - 1c

[1357] 6'-(((1S,3S)-3 - Aminocyclopentyl)amino)-2H - [1,3'-bipyridin]-2 - one

[1358]

[1359] 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 give the unspecified HCl salt of the title compound as a yellow solid (2.5 g, 100%). MS (ESI): m / z [M+H] + 270.9。

[1360] Intermediate 3

[1361] 6'-(((1S,3S)-3 - Aminocyclopentyl)amino)-3 - methoxy - 2H - [1,3'-bipyridin]-2 - one × 2 HCl

[1362] Step A.i - 3a

[1363] ((1S,3S)-3 - ((3 - Methoxy - 2 - oxo - 2H - [1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino Formic acid tert - butyl ester

[1364]

[1365] 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.

[1366] Step B.i - 3b

[1367] 6'-(((1S,3S)-3 - Aminocyclopentyl)amino)-3 - methoxy - 2H - [1,3'-bipyridin]-2 - one × 2 HCl

[1368]

[1369] 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.

[1370] Intermediate 6

[1371] i - 6a

[1372] 1 - (6 - Chloropyridin - 3 - yl)-1,8 - naphthyridin - 2(1H)-one

[1373]

[1374] 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-rapid chromatography (gradient: 5%-43% MeCN / water + 0.1% NH3 (aqueous solution)), the title compound as a pale yellow solid (252 mg, 23%) was obtained. MS (ESI): m / z [M+H] + 257.9.

[1375] Intermediate 7

[1376] 3 - (6 - Chloropyridin - 3 - yl)-1 - methylimidazolidine - 2,4 - dione

[1377] Step A.i - 7a

[1378] (6 - Chloropyridin - 3 - yl)carbamic acid 4 - nitrophenyl ester

[1379]

[1380] 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.

[1381] Step B.i - 7b

[1382] 3 - (6 - Chloropyridin - 3 - yl)-1 - methylimidazolidine - 2,4 - dione

[1383]

[1384] At 20 °C, DIPEA (3.90 mL, 22.3 mmol) was added to a solution of methyl glycine methyl ester HCl (CAS Registry No. 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 column 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。

[1385] Intermediate 8

[1386] 6'-Chloro - 2 - oxo - 2H - [1,3'-bipyridin]-5 - carbonitrile

[1387] Step A.i - 8a

[1388] 6'-Chloro - 2 - oxo - 2H - [1,3'-bipyridin]-5 - methyl formate

[1389]

[1390] At 15 °C, 6-chloropyridin-3-amine (CAS Registry No. 5350-93-6) (1.0 g, 7.8 mmol) was added to a solution of methyl 2-oxo-2H-pyran-5-carboxylate (CAS Registry No. 6018-41-3) (1.2 g, 7.8 mmol) in EtOH (20 mL), and the mixture 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。

[1391] Step B.i - 8b

[1392] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid

[1393]

[1394] 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.

[1395] Step C.i-8c

[1396] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carboxamide

[1397]

[1398] 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.

[1399] Step D.i-8d

[1400] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-5-carbonitrile

[1401]

[1402] 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 afford the title compound as a white solid (540 mg, 72%). MS (ESI): m / z [M+H] + 232.1。

[1403] Intermediate 9

[1404] 3-(Trifluoromethoxy)pyridin-2-ol

[1405] Step A.i-9a

[1406] 2-((4-Methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine

[1407]

[1408] 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 afford the title compound as a pale yellow liquid (600 mg, 66%). MS (ESI): m / z [M+H] + 300.0。

[1409] Step B.i-9b

[1410] 3-(Trifluoromethoxy)pyridin-2-ol

[1411]

[1412] At 25 °C, 2-((4-methoxybenzyl)oxy)-3-(trifluoromethoxy)pyridine compound i-9a (500 mg, 1.67 mmol) was added to TFA (10 mL), and 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

[1413] Intermediate 10

[1414] i-10a

[1415] 6'-Chloro-2-oxo-2H-[1,3'-bipyridine]-3-carbonitrile

[1416]

[1417] 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 and 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 dried solid was triturated with DMF (3 × 5 mL), the solid was filtered off and the filter cake was washed with MTBE (3 × 5 mL). The solid was dried under vacuum to give the title compound as a grey solid (105 mg, 9%). MS (ESI): m / z [M+H] + 232.1

[1418] Intermediate 11

[1419] i-11a

[1420] 2-(5-Bromopyrazin-2-yl)pyridazin-3(2H)-one

[1421]

[1422] In slightly modified GM3, 2-bromo-5-iodopyrazine (CAS Registry No. 622392-04-5) (1.00 g, 3.51 mmol), pyridazin-3(2H)-one (CAS Registry No. 504-30-3) (0.337 g, 3.51 mmol), Cs2CO3 (2.287 g, 7.02 mmol), Cu(I)I (0.669 g, 3.51 mmol) and rel-(1R,2R)-N 1 ,N 2 ,N-dimethylcyclohexane-1,2-diamine (0.499 g, 3.51 mmol) were reacted in 1,4-dioxane (25 mL) at 60 °C for 1 hour. After non-aqueous workup and subsequent preparative TLC (EtOAc:PE = 1:1), the title compound as a white solid (300 mg, 33%) was obtained. The product also contained the corresponding iodo compound. MS (ESI): m / z [M+H] + 252.9.

[1423] Intermediate 12

[1424] i-12a

[1425] 6'-Chloro-1-methyl-[3,3'-bipyridine]-2(1H)-one

[1426]

[1427] According to GM4A, (6-chloropyridin-3-yl)boronic acid (CAS Registry No. 444120-91-6) (301 mg, 1.91 mmol), 3-bromo-1-methylpyridin-2(1H)-one (81971-38-2) (200 mg, 1.06 mmol), Cs2CO3 (1.04 g, 3.19 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (CAS Registry No. 95408-45-0) (34.7 mg, 0.05 mmol) were reacted in a mixture of 1,4-dioxane (12 mL) and water (3 mL) at 80 °C for 15 hours. After non-aqueous workup and subsequent preparative TLC (100% EtOAc), the title compound as a pale yellow solid (230 mg, 98%) was obtained. MS (ESI): m / z [M+H] + 221.0.

[1428] Intermediate 13

[1429] i-13a

[1430] 3-Chloro-6'-fluoro-2H-[1,3'-bipyridine]-2-one

[1431]

[1432] 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), the organic layer was dried over Na2SO4, filtered and evaporated. The crude material was purified by flash column 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.

[1433] Intermediate 14

[1434] i-14a

[1435] 6'-Chloro-3-fluoro-[2,3'-bipyridine]-6-carbonitrile

[1436]

[1437] According to GM4A, palladium(II) dichloride-1,1'-bis(di-tert-butylphosphino)ferrocene (49 mg, 0.07 mmol) was added to 6-bromo-5-fluoropyridinecarbonitrile (CAS Registry No. 1416713-45-5) (300 mg, 1.49 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry No. 444120-91-6) (352 mg, 2.24 mmol) and K3PO4 (950 mg, 4.48 mmol) in water (2 mL) and 1,4-dioxane (8 mL). The resulting solution was stirred at 100 °C for 2 h. Aqueous work-up and purification by preparative TLC (EtOAc:PE = 2:1) gave the title compound as a white solid (214 mg, 61%) MS (ESI) m / z [M+H] + = 234.0.

[1438] Intermediate 17

[1439] (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[1440] Step A.i-17a

[1441] (1S,3S)-N 1 -(5-Iodopyridin-2-yl)cyclopentane-1,3-diamine × 3 HCl

[1442]

[1443] According to GM6A, tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (Intermediate 1, Step A) (1.29 g, 3.19 mmol) was reacted with 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。

[1444] Step B.i-17b

[1445] (1S,3S)-N 1 -(5-chloropyrazin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[1446]

[1447] According to GM1A, (1S,3S)-N 1 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine compound i-17a (1.26 g, 3.05 mmol), 2,5-dichloropyrazine (CAS Registry No. 19745-07-4) (0.910 g, 6.11 mmol) and Na2CO3 (1.62 g, 15.3 mmol) were reacted in DMSO (25 mL) at 120 °C for 15 h. The mixture was filtered through a Celite pad and the filtrate was purified by flash C18 - flash chromatography (gradient: 10% - 61% MeCN / 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。

[1448] Intermediate 21

[1449] 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[1450] Step A.i-21a

[1451] 1-(6-Chloropyridin-3-yl)quinolin-2(1H)-one

[1452]

[1453] According to GM5, quinolin-2(1H)-one (CAS Registry Number 59-31-4) (500 mg, 3.44 mmol), (6-chloropyridin-3-yl)boronic acid (CAS Registry Number 444120-91-6) (1.63 g, 10.3 mmol), Cu(Otf)2 (2.49 g, 6.89 mmol) and N,N,N',N'-tetramethylethylenediamine (1.20 g, 10.3 mmol) were reacted in 1,4-dioxane (20 mL) at 100 °C for 16 hours. After purification by C18-rapid chromatography (gradient: 5%-46% MeCN / water, containing 0.1% aqueous NH3 solution), 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one as a green solid (211 mg, 24%) was obtained. MS (ESI): m / z [M+H] + 256.95。

[1454] Step B.i-21b

[1455] ((1S,3S)-3-((5-(2-Oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert- butyl ester

[1456]

[1457] According to GM2, 1-(6-chloropyridin-3-yl)quinolin-2(1H)-one compound i-21a (90 mg, 0.35 mmol), ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (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 hours. After aqueous workup and purification by preparative TLC (MeOH:DCM = 1:40), ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester as a white solid (122 mg, 83%) was obtained. MS (ESI): m / z [M+H] + 421.00。

[1458] Step C.i-21c

[1459] 1-(6-(((1S,3S)-3-Aminocyclopentyl)amino)pyridin-3-yl)quinolin-2(1H)-one

[1460]

[1461] According to GM6A, ((1S,3S)-3-((5-(2-oxoquinolin-1(2H)-yl)pyridin-2-yl)amino)cyclopentyl) tert-butyl 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 hours to obtain 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

[1462] Intermediate 22

[1463] (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-di Amine

[1464] Step A.i-22a

[1465] ((1S,3S)-3-((1,2,4-Triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1466]

[1467] At 0 °C, m-CPBA (5.60 g, 25.95 mmol) was added portionwise to a solution of 3-(methylthio)-1,2,4-triazine (CAS Registry No. 28735-21-9) (3.0 g, 23.6 mmol) in DCM (80 mL), and the resulting suspension was stirred at 20 °C for 2 hours. The solvent was removed under reduced pressure without heating, the residue was dissolved in n-butanol (40 mL) and ((1S,3S)-3-aminocyclopentyl) tert-butyl carbamate (CAS Registry No. 645400-44-8) (5.20 g, 26.0 mmol) was added, and the resulting solution was stirred at 120 °C for 18 hours. 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

[1468] Step B.i-22b

[1469] ((1S,3S)-3-((6-Bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1470]

[1471] 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。

[1472] Step C.i-22c

[1473] ((1S,3S)-3-((6-Cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1474]

[1475] According to GM4B, ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester 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 registration number 1651823-59-4) (0.61 g, 0.84 mmol) were reacted in dioxane (70 mL) at 100 °C for 15 h. After combining with a second batch (prepared 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。

[1476] Step D.i-22d

[1477] (1S,3S)-N 1 -(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 4 TFA

[1478]

[1479] According to GM6B, ((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-22c (500 mg, 1.57 mmol) was reacted with TFA (5.0 mL, 65 mmol) in DCM (20 mL) at room temperature for 15 hours to obtain the title compound as a yellow gum (940 mg, 89%) (containing 4 molar equivalents of residual TFA). MS (ESI): m / z [M+H] + 220。

[1480] Step E.i-22e

[1481] (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1,3-di Amine

[1482]

[1483] According to GM1A, (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 4TFA compound i-22d (880 mg, 1.30 mmol), 2-fluoro-5-iodopyridine (436 mg, 1.95 mmol) and K2CO3 (900 mg, 6.51 mmol) were reacted in DMSO (10 mL) at 120 °C for 15 hours. After aqueous workup and purification by preparative TLC (EtOAc:PE = 3:1), the title compound was obtained as a light yellow solid (369 mg, 67%). MS (ESI): m / z [M+H] + 423。

[1484] Intermediate 23

[1485] i-23a

[1486] 1-(6-Chloropyridin-3-yl)-3-methylimidazolidine-2,4-dione

[1487]

[1488] 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。

[1489] Intermediate 24

[1490] i-24a

[1491] 3-(6-Chloropyridin-3-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1492]

[1493] 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 - flash chromatography (gradient: 5% - 40% MeCN / water, containing 0.1% aqueous NH3), the title compound was obtained as a white solid (0.235 g, 12%). MS (ESI): m / z [M+H] + 261。

[1494] Intermediate 25

[1495] i-25a

[1496] 6'-Chloro-3-methoxy-2H-[1,3'-bipyridine]-2-one

[1497]

[1498] 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。

[1499] Intermediate 26

[1500] i-26a

[1501] 6'-Chloro-5-methoxy-2H-[1,3'-bipyridine]-2-one

[1502]

[1503] CuI (159 mg, 0.84 mmol) and N,N-dimethylglycine hydrochloride (117 mg, 0.84 mmol) were added to a mixture of 2-chloro-5-iodopyridine (400 mg, 1.67 mmol), 5-methoxypyridin-2(1H)-one (CAS Registry 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 under nitrogen at 100 °C for 15 h. The mixture was filtered through a pad of Celite, 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 as a white solid (179 mg, 45%). MS (ESI): m / z [M+H] + 237。

[1504] Intermediate 27

[1505] i-27a

[1506] 6'-Chloro-3-methyl-2H-[1,3'-bipyridine]-2-one

[1507]

[1508] In a slightly modified GM3, 2-chloro-5-iodopyridine (600 mg, 2.51 mmol), 3-methylpyridin-2(1H)-one (CAS Reg. No. 1003-56-1) (273 mg, 2.51 mmol), K3PO4 (1.60 g, 7.52 mmol), Cu(I)I (239 mg, 1.25 mmol) and rel-(1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (178 mg, 1.25 mmol) was reacted in dioxane (20 mL) at 100°C for 1 hour, and the title compound (261 mg, 47%) was obtained as a brown solid after aqueous workup and purification by preparative TLC (DCM:MeOH=20:1). MS (ESI): m / z [M+H] + 221.

[1509] Intermediate 28

[1510] (1S,3S)-N 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 2TFA

[1511] Step A.i-28a

[1512] ((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1513]

[1514] 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.

[1515] Step B.i-28b

[1516] (1S,3S)-N 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 2 TFA

[1517]

[1518] 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 h to give the title compound as a white solid (100 mg, 95%). MS (ESI): m / z [M+H] + 194.

[1519] Intermediate 29

[1520] i-29a

[1521] 6'-Chloro-2H-[1,3'-bipyridin]-2-one

[1522]

[1523] According to GM3, 2-chloro-5-iodopyridine (3.0 g, 12.5 mmol), pyridin-2(1H)-one (CAS Registry No. 142-08-5) (3.57 g, 37.6 mmol), Cu(I)I (1.19 g, 6.26 mmol), Cs2CO3 (8.16 g, 25.1 mmol) and rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (0.891 g, 6.26 mmol) were reacted in dioxane (80 mL) at 100 °C for 15 h. After aqueous workup and trituration with PE:EtOAc (1:1, 30 mL), a solid was obtained. The solid was collected by filtration and dried in vacuo to give the title compound as a yellow solid (0.60 g, 23%). MS (ESI): m / z [M+H] + 207.

[1524] Intermediate 30

[1525] i-30a

[1526] 3-(((1S,3S)-3-((2-Oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-1,2, 4-triazine-6-carboxylic acid

[1527]

[1528] Ethyl 3-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-1,2,4-triazine-6-carboxylate compound 10 (22 mg, 0.05 mmol), finely ground NaOH (10 mg, 0.26 mmol) and water (0.5 mL) were added to a vial, and the mixture was stirred at room temperature for 0.5 h. The compound was purified by preparative HPLC (preparation method G, gradient: 5% - 45%) to give the title compound (17 mg, 86%) as an off-white solid. MS (ESI): m / z [M+H] + 394。

[1529] Intermediate 31

[1530] (1S,3S)-N 1 -(5-methylpyrazin-2-yl)cyclopentane-1,3-diamine

[1531] Step A.i-31a

[1532] ((1S,3S)-3-((5-Methylpyrazin-2-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1533]

[1534] The reaction was carried out in 3 parallel batches.

[1535] According to GM2, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS registry number 645400-44-8) (420 mg, 2.10 mmol), 2-bromo-5-methylpyrazine (CAS registry number 98006-90-7) (363 mg, 2.10 mmol), Cs2CO3 (1.03 g, 3.15 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (62 mg, 0.07 mmol) were reacted in 1,4-dioxane (20 mL) at 100 °C for 15 h. After combining the batches, non-aqueous work-up and trituration (PE:EtOAc = 2:1, 20 mL), the solid was collected by filtration and dried under vacuum to give the title compound (1.2 g, 63%) as a grey solid. 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).

[1536] Step B.i-31b

[1537] (1S,3S)-N 1 -(5-Methylpyrazin-2-yl)cyclopentane-1,3-diamine

[1538]

[1539] 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 hours to obtain 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).

[1540] Intermediate 35

[1541] Step A.i-35a

[1542] ((1S,3S)-3-((3-Cyano-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbam ic acid tert-butyl ester

[1543]

[1544] In slightly modified GM2, 6'-chloro-2-oxo-2H-[1,3'-bipyridin]-3-carbonitrile compound i-10a (560 mg, 1.89 mmol), ((1S,3S)-3-aminocyclopentyl)carbamic acid tert-butyl ester (CAS Registry No. 645400-44-8) (1.13 g, 5.66 mmol), Cs2CO3 (1.84 g, 5.66 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (79 mg, 0.09 mmol) were reacted in DMF (30 mL) at 100 °C for 15 h. The reaction mixture was filtered through a 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), and then purified 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。

[1545] Step B.i-35b

[1546] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-3-carbonitrile × 4 HCl

[1547]

[1548] According to GM6A, ((1S,3S)-3-((3-cyano-2-oxo-2H-[1,3'-bipyridin]-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。

[1549] Intermediate 36

[1550] Step A.i-36a

[1551] 6-Methyl-3-(methylthio)-1,2,4-triazine

[1552]

[1553] At room temperature, methylhydrazine thiocarbamate ester HI (CAS Registry Number 35600-34-1) (9.87 g, 42.4 mmol) was added to a stirred solution of 1,1-dimethoxypropan-2-one (CAS Registry Number 6342-56-9) (5.00 g, 42.3 mmol) in ethanol (250 mL), and the resulting solution was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the obtained residue was purified by flash chromatography on silica gel (gradient: 40%-50% EtOAc / PE) to give the title compound as a yellow solid (2.77 g, 46%). MS (ESI): m / z [M+H] + 141.9. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.56 (3H, s), 2.59 (3H, s), 8.56 (1H, s).

[1554] Step B.i-36b

[1555] 6-Methyl-3-(methylsulfinyl)-1,2,4-triazine

[1556]

[1557] According to GM8, 6-methyl-3-(methylthio)-1,2,4-triazine compound i-36a (1.99 g, 14.1 mmol) was treated with 3-chloroperoxybenzoic acid (3.65 g, 16.9 mmol) in DCM (25 mL) at room temperature for 2 h, and after purification by flash chromatography on silica gel (gradient: 10%-20% MeOH / DCM), the title compound was obtained as a yellow oil (1.36 g, 61%). MS (ESI): m / z [M+H] + 157.8. 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.71 (3H, s), 2.96 (3H, s), 8.95 (1H, s).

[1558] Intermediate 37

[1559] i-37a

[1560] 6'-Fluoro-5-methyl-2H-[1,3'-bipyridin]-2-one

[1561]

[1562] According to GM3, 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (150 mg, 0.67 mmol), 2-hydroxy-5-methylpyridine (CAS Registry No. 1003-68-5) (367 mg, 3.36 mmol), Cs2CO3 (658 mg, 2.02 mmol), Cu(I)I (128 mg, 0.67 mmol) and rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (96 mg, 0.67 mmol) were reacted in 1,4-dioxane (15 mL) at 100 °C for 15 h. The reaction mixture was filtered through a Celite pad, the filter cake was washed with EtOAc (3 × 5 mL) and the combined filtrate was diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with water (2 × 50 mL), dried over Na2SO4, filtered and evaporated, and the crude material was purified by preparative TLC (EtOAc) to give the title compound as a white solid (116 mg, 84%). MS (ESI): m / z [M+H] + 204.9. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 2.06 (3H, s), 6.47 (1H, d), 7.36 (1H, dd), 7.43 (1H, dd), 7.53–7.54 (1H, m), 8.12 (1H, ddd), 8.33 (1H, dd).

[1563] Intermediate 38

[1564] i-38a

[1565] 6'-Fluoro-3-methyl-2H-[1,3'-bipyridin]-2-one

[1566]

[1567] According to GM3, 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (105 mg, 0.47 mmol), 2-hydroxy-3-methylpyridine (CAS Registry No. 1003-56-1) (257 mg, 2.35 mmol), Cs2CO3 (460 mg, 1.41 mmol), Cu(I)I (90 mg, 0.47 mmol) and rel-(1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (67 mg, 0.47 mmol) was reacted in 1,4-dioxane (10 mL) at 100 °C for 15 h. The reaction mixture was filtered through a Celite pad, the filter cake was washed with EtOAc (3 × 5 mL) and the combined filtrate was diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (4 × 75 mL). The combined organic layers were washed with water (2 × 50 mL), dried over Na2SO4, filtered and evaporated, and the crude material was purified by preparative TLC (EtOAc) to give the title compound as a white solid (85 mg, 88%). MS (ESI): m / z [M+H] + 205.0。 1 H NMR (300 MHz, DMSO-d6) δ ppm 2.05 (3H, s), 6.29 (1H, t), 7.36 (1H, dd), 7.42–7.45 (1H, m), 7.58 (1H, dd), 8.13 (1H, ddd), 8.32–8.34 (1H, m).

[1568] Intermediate 39

[1569] i-39a

[1570] (1S,3S)-N 1 -(5-Iodopyridin-2-yl)-N 3 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[1571]

[1572] According to GM1A, 2-Fluoro-5-iodopyridine (203 mg, 0.91 mmol) was added to a mixture of (1S,3S)-N 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine dihydrochloride compound i-28b (220 mg, 0.83 mmol) and Na2CO3 (263 mg, 2.48 mmol) in DMSO (15 mL). The resulting mixture was stirred at 100 °C for 15 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the obtained material was dissolved in EtOAc (300 mL). The organic layer was washed with saturated brine (4 × 125 mL), dried over Na2SO4, filtered and evaporated, and the crude material was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound as a light yellow solid (140 mg, 43%). MS (ESI): m / z [M+H] + 396.7。 11H NMR (300 MHz, DMSO-d6) δ ppm 1.39–1.59 (2H, m), 1.79–1.95 (2H, m), 2.06–2.16 (2H, m), 2.37 (3H, s), 4.17–4.39 (2H, m), 6.37 (1H, dd), 6.83 (1H, d), 7.53–7.59 (2H, m), 8.10 (1H, d), 8.16 (1H, s).

[1573] Intermediate 42

[1574] Step A.i-42a

[1575] ((1S,3S)-3-((5-Methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino carbamic acid tert-butyl ester

[1576]

[1577] 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.

[1578] Step B.i-42b

[1579] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-methoxy-2H-[1,3'-bipyridin]-2-one

[1580]

[1581] At 25 °C, TFA (5 mL, 64.90 mmol) was added to a solution of tert-butyl ((1S,3S)-3-((5-methoxy-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-42a (400 mg, 1.00 mmol) in DCM (15 mL). The resulting suspension was stirred at 25 °C for 18 h. The solvent was removed under reduced pressure to afford the TFA salt of the crude title compound as a black gum (1.1 g, 100%). MS (ESI) m / z [M+H] + 301.0

[1582] Intermediate 44

[1583] Step A.i-44a

[1584] ((1S,3S)-3-((5-Chloro-2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1585]

[1586] 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 afford the title compound as a green solid (298 mg, 99%). MS (ESI) m / z [M+H] + 405.0

[1587] Step B.i-44b

[1588] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-5-chloro-2H-[1,3'-bipyridin]-2-one

[1589]

[1590] 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 afford the TFA salt of the crude title compound as a brown gum (432 mg, 91%). MS (ESI) m / z [M+H] + 304.9。

[1591] Intermediate 47

[1592] i-47a

[1593] (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N 3 -(5-iodopyrimidin-2-yl)cyclopentane-1,3-di Amine

[1594]

[1595] At room temperature, K2CO3 (126 mg, 0.91 mmol) was added to (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (200 mg, 0.91 mmol), 2-chloro-5-iodopyrimidine (CAS Registry No. 32779-38-7) (329 mg, 1.37 mmol) in DMSO (5 mL), and the resulting suspension was stirred at 120 °C for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with water (2 × 25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the crude product, which was purified by flash C18 flash chromatography (elution gradient: 0-60% MeCN / water) to afford the title compound as a yellow solid (150 mg, 39%). MS (ESI): m / z [M+H] + 424.0。

[1596] Intermediate 48

[1597] Step A.i-48a

[1598] Methyl 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzoate

[1599]

[1600] The reaction was carried out in 3 parallel batches (2 × 500 mg and 1 × 600 mg of 6-chloropyridin-3-amine). At room temperature, methyl 4-fluoro-3-nitrobenzoate (CAS Registry Number 329-59-9) (929 mg, 4.67 mmol) was added to 6-chloropyridin-3-amine (CAS Registry Number 5350-93-6) (500 mg, 3.89 mmol), XantPhos (338 mg, 0.58 mmol), Pd(OAc)2 (66 mg, 0.29 mmol) and K2CO3 (1.61 g, 11.7 mmol) in 1,4-dioxane (25 mL), and the resulting mixture was stirred at 80 °C under nitrogen for 18 h. The three reaction mixtures were combined, dissolved in EtOAc (200 mL), loaded onto silica gel and subjected to silica gel flash chromatography (gradient: 10%-20% EtOAc / heptane), giving the title compound (851 mg, 71% combined yield) as a yellow solid. MS (ESI): m / z [M+H] + 307.9。

[1601] Step B.i-48b

[1602] Methyl 3-amino-4-((6-chloropyridin-3-yl)amino)benzoate

[1603]

[1604] At room temperature, methyl 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzoate compound i-48a (420 mg, 1.37 mmol) was added to zinc (535 mg, 8.19 mmol) and NH4Cl (730 mg, 13.65 mmol) in EtOAc (10 mL) and EtOH (10 mL), and the resulting mixture was stirred at 60 °C for 18 h. The reaction mixture was filtered through Celite. The Celite was washed with EtOAc (3 × 25 mL). The filtrate was concentrated under reduced pressure to give the crude title compound (761 mg) (salt-containing) as a light pink solid, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 277.9。

[1605] Step C.i-48c

[1606] Methyl 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

[1607]

[1608] At room temperature, methyl 3-amino-4-((6-chloropyridin-3-yl)amino)benzoate compound i-48b (300 mg, 1.08 mmol) was added to CDI (771 mg, 4.75 mmol) in DMF (20 mL), and the resulting solution was stirred at 80 °C for 18 h. The reaction mixture was concentrated, diluted with EtOAc (200 mL) and washed successively with brine (3 × 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the crude product. The crude solid was triturated with MeCN to give a solid, which was collected by filtration and dried in vacuo to give the title compound (226 mg, 69%) as a pink solid. MS (ESI): m / z [M+H] + 303.8。

[1609] Step D.i-48d

[1610] Methyl 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

[1611]

[1612] At room temperature, CH3I (246 mg, 1.73 mmol) was added to methyl 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate compound i-48c (351 mg, 1.16 mmol) and Na2CO3 (367 mg, 3.47 mmol) in DMF (20 mL), and the resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed successively with brine (3 × 100 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the crude product (92 mg, 25%) as a pale yellow solid, which was used in the next step without further purification. MS (ESI): m / z [M+H] + 317.9。

[1613] Step E.i-48e

[1614] 1-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

[1615]

[1616] At room temperature, Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry No. 1612891-29-8) (29 mg, 0.03 mmol) was added to methyl 1-(6-chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate compound i-48d (110 mg, 0.35 mmol), Cs2CO3 (338 mg, 1.04 mmol) and (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (76 mg, 0.35 mmol) in 1,4-dioxane (20 mL), and the resulting mixture was stirred at 100 °C for 18 h under nitrogen. The reaction mixture was concentrated, diluted with EtOAc (200 mL) and washed successively with brine (3 × 75 mL). The organic layer was dried over Na2SO4, filtered and evaporated, and the obtained residue was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound (90 mg, 52%) as a pale yellow solid. MS (ESI): m / z [M+H] + 510.1.

[1617] Intermediate 49

[1618] Step A.i-49a

[1619] 6'-Chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1620]

[1621] 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 at 100 °C for 16 h under nitrogen. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound (410 mg, 100%) as a white solid. MS (ESI): m / z [M+H] + 394.0.

[1622] Step B.i-49b

[1623] 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4- methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1624]

[1625] At room temperature, Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry Number 1612891-29-8) (21 mg, 0.03 mmol) was added to 6'-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one compound i-49a (200 mg, 0.51 mmol), (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (167 mg, 0.76 mmol) and Cs2CO3 (331 mg, 1.02 mmol) in 1,4-dioxane (10 mL), and the resulting mixture was stirred at 100 °C under nitrogen for 15 h. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with water (50 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and evaporated, and the residue obtained was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound as a yellow solid (166 mg, 57%). MS (ESI): m / z [M+H] + 577.2.

[1626] Step C.i-49c

[1627] 5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-6'-(((1S,3S)-3-((6-methyl-1,2, 4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[1628]

[1629] In a similar manner to that described for compound i-49b, from 6'-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one compound i-49a (109 mg, 0.28 mmol), (1S,3S)-N 1The 4×TFA salt of (6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b (340 mg, 0.55 mmol), Cs2CO3 (451 mg, 1.38 mmol) and Pd-PEPPSI-IpentCl 2-methylpyridine (23 mg, 0.03 mmol) were prepared in 1,4-dioxane (5 mL) and purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a brown solid (22 mg, 14%). MS (ESI): m / z [M+H] + 551.0。

[1630] Intermediate 50

[1631] Step A.i-50a

[1632] 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridin-2-ol

[1633]

[1634] 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 pad of diatomaceous earth. 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。

[1635] Step B.i-50b

[1636] 6'-Chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1637]

[1638] 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 No. 69045-79-0) (128 mg, 0.53 mmol), rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (114 mg, 0.80 mmol) and Cs2CO3 (347 mg, 1.07 mmol) in 1,4-dioxane (10 mL), and the resulting suspension was stirred at 60 °C under nitrogen for 5 h. The mixture was filtered through a Celite pad. The filter cake was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure. The residue obtained 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 + 393.0.

[1639] Step C.i-50c

[1640] 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-5-(1-(4- methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1641]

[1642] At room temperature, Pd-PEPPSI-IpentCl 2-methylpyridine (CAS Registry No. 1612891-29-8) (14 mg, 0.02 mmol) was added to 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one compound i-50b (130 mg, 0.33 mmol) in 1,4-dioxane (10 mL), (1S,3S)-N 1-(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (109 mg, 0.50 mmol) and Cs2CO3 (216 mg, 0.66 mmol) were added, and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with water (50 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give the crude product, which was purified by preparative TLC (MeOH:DCM = 1:10) to give the title compound as a yellow solid (117 mg, 61%). MS (ESI): m / z [M+H] + 576.3。

[1643] Step D.i-50d

[1644] 5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin- 3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one

[1645]

[1646] In a manner similar to that described for compound i-50c, from 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one compound i-50b and (1S,3S)-N 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-28b was prepared and purified by preparative TLC (MeOH:DCM = 1:15) to give the title compound as a yellow solid (82 mg, 73%). MS (ESI): m / z [M+H]+550.0。

[1647] Step E.i-50e

[1648] 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

[1649]

[1650] In a manner similar to that described for compound i-50c, from 6'-chloro-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one compound i-50b and (1S,3S)-N 1Preparation of (5-methylpyrazin-2-yl)cyclopentane-1,3-diamine compound i-31b, and purification by preparative TLC (MeOH:DCM = 1:15) gave the title compound as a yellow solid (150 mg, 43%). MS (ESI): m / z [M+H]+ 549.0.

[1651] Intermediate 51

[1652] Step A.i-51a

[1653] 5-Bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1654]

[1655] TMEDA (1.33 mL, 8.81 mmol) was added to 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CAS Registry No. 84712-08-3) (1.0 g, 4.4 mmol), (6-fluoropyridin-3-yl)boronic acid (CAS Registry No. 351019-18-6) (1.55 g, 11.0 mmol) and Cu(OTf)2 (3.19 g, 8.81 mmol) in DCM (30 mL) at room temperature. Air was diffused through a CaCl2 tube above the flask into the reaction mixture, and the resulting mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water (150 mL) and extracted with DCM (4 × 300 mL). The combined organic layers were washed with water (2 × 200 mL), dried (Na2SO4), filtered and evaporated. The obtained material was purified by flash chromatography on silica gel (gradient: 0 - 60% EtOAc / heptane) to give the title compound as a white solid (0.38 g, 27%). MS (ESI): m / z [M+H] + 321.8 / 323.8 (Br isotope pattern).

[1656] Step B.i-51b

[1657] 5-Bromo-3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyr idin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1658]

[1659] K2CO3 (219 mg, 1.59 mmol) was added to 5-bromo-3-(6-fluoropyridin-3-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one compound i-51a (358 mg, 1.11 mmol) and (1S,3S)-N 1-(6-Cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (116 mg, 0.53 mmol), and the resulting mixture was stirred at 120 °C for 15 h. The mixture was filtered through a Celite pad and the cake was washed with DCM (4 × 5 mL). The filtrate was concentrated under reduced pressure and purified by flash C18 - flash chromatography (elution gradient: 0 - 100% MeOH / water) to give the title compound as a white solid (95 mg, 34%). MS (ESI): m / z [M+H] + 521 / 523 (Br isotope pattern).

[1660] Intermediate 52

[1661] Step A.i-52a

[1662] tert-Butyl ((1S,3S)-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate

[1663]

[1664] At room temperature, m-CPBA (733 mg, 3.40 mmol) was added portionwise to a stirred solution of 5-methyl-3-(methylthio)-1,2,4-triazine (CAS Registry No. 28735-24-2) (400 mg, 2.83 mmol) in DCM (8 mL), and the resulting solution was stirred at this temperature for 2 h. The solvent was removed under reduced pressure to give a pale yellow solid, which was dissolved in n-BuOH (8 mL). ((1S,3S)-3-Aminocyclopentyl)carbamic acid tert-butyl ester (CAS Registry No. 645400-44-8) (567 mg, 2.83 mmol) was added, and the resulting solution was stirred at 120 °C for 15 h. The reaction mixture was quenched with 1 M NaOH (aqueous solution) (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 3:1) to give the title compound as an orange solid (220 mg, 26%). MS (ESI): m / z [M+H] + 294.2.

[1665] Step Bi-52b

[1666] (1S,3S)-N 1 -(5-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[1667]

[1668] tert-Butyl ((1S,3S)-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-52a (210 mg, 0.72 mmol) was treated with DCM (6 mL) and TFA (2 mL) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated NaHCO3 (100 mL) and extracted with (7M NH3 / MeOH:DCM = 1:20) (3 × 75 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound as an orange solid (120 mg, 87%), which was used without further purification. MS (ESI): m / z [M+H] + 194.1。

[1669] Intermediate 53

[1670] Step A.i-53a

[1671] ((1S,3S)-3-((5,6-Dimethyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester

[1672]

[1673] 5,6-Dimethyl-3-(methylthio)-1,2,4-triazine (CAS Registry No. 7275-70-9) (400 mg, 2.58 mmol) was added portionwise to a stirred solution of 3-chloroperoxybenzoic acid (667 mg, 3.09 mmol) in DCM (10 mL) at room temperature and the resulting solution was stirred at this temperature for 2 h. The solvent was removed under reduced pressure to give a pale yellow solid, which was dissolved in n-BuOH (10 mL). ((1S,3S)-3-Aminocyclopentyl)carbamate tert-butyl ester (CAS Registry No. 645400-44-8) (567 mg, 2.83 mmol) was added and the resulting solution was stirred at 120 °C for 15 h. The reaction mixture was quenched with 1M aqueous NaOH (100 mL) and extracted with EtOAc (3 × 75 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated and the material obtained was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound as an orange solid (115 mg, 14%). MS (ESI): m / z [M+H] + 308.2。

[1674] Step B.i-53b

[1675] (1S,3S)-N 1 -(5,6-Dimethyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 3 TFA

[1676]

[1677] tert-Butyl ((1S,3S)-3-((5,6-dimethyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-53a (100 mg, 0.33 mmol) was treated with TFA (2 mL) and DCM (6 mL). The resulting mixture was stirred at room temperature for 3 h and the organic solvents were removed by evaporation to give the crude title compound as a brown oil (112 mg, 63%), which was used in the next step without further purification. MS (ESI): m / z [M+H] + 208.0。

[1678] Intermediate 54

[1679] Step A.i-54a

[1680] ((1S,3S)-3-((2-Oxo-3-(trifluoromethyl)-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl) Carbamic acid tert-butyl ester

[1681]

[1682] 3-(Trifluoromethyl)pyridin-2(1H)-one (CAS Registry No. 22245-83-6) (324 mg, 1.98 mmol) was added to tert-butyl ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate compound i-1a (400 mg, 0.99 mmol), Cu(I)I (94 mg, 0.50 mmol), Cs2CO3 (970 mg, 2.98 mmol) and rel-(1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (70 mg, 0.50 mmol) in 1,4-dioxane (20 mL) at room temperature and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into water (150 mL), extracted with EtOAc (5 × 100 mL) and the combined organic layers were dried (Na2SO4), filtered and evaporated to give the crude product. The residue was first purified by preparative TLC (MeOH:EtOAc = 1:1) and then by flash C18 - flash chromatography (gradient: 0 - 100% MeCN / water) to give the title compound as a pale yellow solid (235 mg, 54%). MS (ESI): m / z [M+H] + 439.2。

[1683] Step B.i-54b

[1684] 6'-(((1S,3S)-3-Aminocyclopentyl)amino)-3-(trifluoromethyl)-2H-[1,3'-bipyridin]-2-one

[1685]

[1686] At room temperature, tert-butyl ((1S,3S)-3-((2-oxo-3-(trifluoromethyl)-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate compound i-54a (220 mg, 0.50 mmol) was added to a mixture of a 4 M HCl solution in MeOH (2 mL, 8 mmol) and MeOH (8 mL), and the resulting mixture was stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure and the substance was purified by flash C18 - flash chromatography (gradient: 0 - 100% MeCN / water) to give the title compound as a yellow solid (148 mg, 87%). MS (ESI): m / z [M+H] + 339.0。

[1687] Intermediate 57

[1688] i-57a

[1689] 3-(5-Bromopyrazin-2-yl)-1-methylpyridin-2(1H)-one

[1690]

[1691] At room temperature, 2-bromo-5-iodopyrazine (CAS Registry Number 622392-04-5) (1.68 g, 5.88 mmol) was added to (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (CAS Registry Number 1454558-46-3) (300 mg, 1.96 mmol), KOAc (578 mg, 5.88 mmol) and PdCl2(dppf)×DCM (160 mg, 0.20 mmol) in 1,4-dioxane (16 mL) and water (4 mL), and the resulting mixture was stirred at 100 °C for 2 hours under nitrogen. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (4 × 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated and the obtained substance was purified by flash silica gel chromatography (gradient: 0 - 100% EtOAc / n-heptane) to give the title compound as a brown solid (360 mg, 69%). MS (ESI): m / z [M+H] + 265.8 / 267.8。

[1692] Intermediate 58

[1693] i-58a

[1694] 3-(6-Chloropyridin-3-yl)pyrimidin-4(3H)-one

[1695]

[1696] At room temperature, TMEDA (0.942 mL, 6.24 mmol) was added to (6-chloropyridin-3-yl)boronic acid (CAS Registry No. 444120-91-6) (983 mg, 6.24 mmol), pyrimidin-4(3H)-one (CAS Registry No. 4562-27-0) (300 mg, 3.12 mmol) and Cu(OTf)₂ (2.26 g, 6.24 mmol) in DCM (35 mL). Air was diffused through a CaCl₂ tube above the flask into the reaction mixture. The resulting suspension was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (150 mL) and washed successively with water (2 × 50 mL). The organic layer was dried (Na₂SO₄), filtered and evaporated, and the residue was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound as a white solid (243 mg, 37%). MS (ESI): m / z [M+H] + 207.9。

[1697] Intermediate 59

[1698] i-59a

[1699] 3-(2-Chloropyrimidin-5-yl)-1-methylpyridin-2(1H)-one

[1700]

[1701] At room temperature, 3-bromo-1-methylpyridin-2(1H)-one (CAS Registry No. 81971-38-2) (300 mg, 1.60 mmol) was added to (2-chloropyrimidin-5-yl)boronic acid (CAS Registry No. 1003845-06-4) (505 mg, 3.19 mmol), K₂CO₃ (662 mg, 4.79 mmol) and Pd-118 / PdCl₂(dtbpf) (104 mg, 0.16 mmol) in 1,4-dioxane (8 mL) and water (2 mL), and the resulting mixture was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was poured into water (150 mL) and the aqueous layer was extracted with EtOAc (5 × 150 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated, and the residue was purified by preparative TLC (MeOH:DCM = 1:20) to give the title compound as a yellow solid (105 mg, 30%). MS (ESI): m / z [M+H] + 221.9。

[1702] Intermediate 60

[1703] Step A.i-60a

[1704] 3-((6-Chloropyridin-3-yl)amino)-4-nitrobenzonitrile

[1705]

[1706] 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 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。

[1707] Step B.i-60b

[1708] 4-Amino-3-((6-chloropyridin-3-yl)amino)benzonitrile

[1709]

[1710] 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 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。

[1711] Step C.i-60c

[1712] 3-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1713]

[1714] 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。

[1715] Step D.i-60d

[1716] 3-(6-Chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1717]

[1718] 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。

[1719] Intermediate 61

[1720] Step A.i-61a

[1721] 4-((6-Chloropyridin-3-yl)amino)-3-nitrobenzonitrile

[1722]

[1723] 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

[1724] Step B.i-61b

[1725] 3-Amino-4-((6-chloropyridin-3-yl)amino)benzonitrile

[1726]

[1727] At room temperature, zinc (1.33 g, 20.4 mmol) was added to a solution of NH4Cl (1.09 g, 20.4 mmol) and 4-((6-chloropyridin-3-yl)amino)-3-nitrobenzonitrile compound i-61a (0.70 g, 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。

[1728] Step C.i-61c

[1729] 1-(6-Chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1730]

[1731] 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。

[1732] Step D.i-61d

[1733] 1-(6-Chloropyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

[1734]

[1735] 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 the mixture 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。

[1736] Intermediate 62

[1737] i-62a

[1738] 2-(6-Fluoropyridin-3-yl)pyridazin-3(2H)-one

[1739]

[1740] At room temperature, 2-fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (300 mg, 1.35 mmol) was added to pyridazin-3(2H)-one (CAS Registry No. 504-30-3) (259 mg, 2.69 mmol), Cu(I)I (128 mg, 0.67 mmol), Cs2CO3 (1315 mg, 4.04 mmol) and rel-(1R,2R)-N 1 ,N 2A mixture of (96 mg, 0.67 mmol) of rel-(1R,2R)-N,N-dimethylcyclohexane-1,2-diamine in 1,4-dioxane (20 mL) was stirred at 100 °C for 15 h under nitrogen. The reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (8 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated, and the residue was purified by preparative TLC (EtOAc) to give the title compound as a brown solid (242 mg, 94%). MS (ESI): m / z [M+H] + 191.9.

[1741] Intermediate 63

[1742] Step A.i-63a

[1743] 5-((tert-Butyldimethylsilyl)ethynyl)-6'-chloro-2H-[1,3'-bipyridin]-2-one

[1744]

[1745] At room temperature, Cs2CO3 (2.23 g, 6.86 mmol) was added to a solution of 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 ,N-dimethylcyclohexane-1,2-diamine (731 mg, 5.14 mmol) in 1,4-dioxane (20 mL), and the resulting suspension was stirred at 60 °C for 5 h under nitrogen. The mixture was combined with a second batch prepared in the same manner 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 crude product was purified by flash column 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.

[1746] Step B.i-63b

[1747] 6'-Chloro-5-ethynyl-2H-[1,3'-bipyridin]-2-one

[1748]

[1749] 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 afford the title compound as a beige solid (290 mg, 74%). MS (ESI): m / z [M+H] + 231.0。

[1750] Intermediate 67

[1751] Step A.i-67a

[1752] 5-(1-Methyl-1H-pyrazol-4-yl)pyridin-2-ol

[1753]

[1754] 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 silica gel chromatography (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。

[1755] Step B.i-67b

[1756] 6'-Chloro-5-(1-methyl-1H-pyrazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1757]

[1758] 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 hours. After non-aqueous work-up (EtOAc) and flash column 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 isotope pattern).

[1759] Intermediate 68a

[1760] i-68a

[1761] 6'-(((1S,3S)-3-((6-Methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-3-(2-(tetrahydro- 2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)-2H-[1,3'-bipyridin]-2-one

[1762]

[1763] Under nitrogen, 3-chloro-6'-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl))amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one Example 129 (280 mg, 0.70 mmol) was added to 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) (393 mg, 1.41 mmol), Cs2CO3 (688 mg, 2.11 mmol), XPhos (CAS Registry Number 564483-18-7) (34 mg, 0.07 mmol) and XPhos Pd G3 (CAS Registry Number 1445085-55-1) (59 mg, 0.07 mmol) in a mixture of 1,4-dioxane (16 mL) and water (4 mL). The resulting reaction mixture was stirred at 100 °C for 15 h, then poured into saturated brine (150 mL). It was extracted with EtOAc (4 × 150 mL), and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a pale yellow solid (335 mg, 93%). MS (ESI): m / z [M+H] + 515.1。

[1764] Intermediate 76

[1765] i-76a

[1766] (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boron ic acid

[1767]

[1768] Dissolve tert-butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-28a (1.32 g, 4.50 mmol) in DCM (15 mL) and TFA (5 mL). After stirring for 1 hour, add toluene and concentrate the resulting mixture. Dissolve the residue in DMSO (10 mL) and treat with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS Registry No. 444120-95-0) (1.81 g, 8.11 mmol) and K2CO3 (2.25 g, 16.3 mmol), and stir the resulting mixture at 80 °C for 20 hours. Cool the mixture to room temperature, filter off the solid and purify the filtrate by preparative HPLC (preparation method G, gradient 0 - 50%) to give the title compound as a red solid (1.07 g, 66%), MS (ESI) m / z [M+H] + 315.

[1769] Intermediate 77

[1770] Step Ai-77a

[1771] (1S,3S)-N 1 -(5-(2,4-Dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-N 3 -(6-Methyl-1,2,4-tri -3-yl)cyclopentane-1,3-diamine

[1772]

[1773] A mixture of (6-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)boronic acid compound i-76a (0.126 g, 0.40 mmol), 2,4-dimethyl-1H-imidazole (CAS Registry No. 930-62-1), Cu(OAc)2 (0.175 g, 0.96 mmol) and pyridine (0.178 mL, 2.21 mmol) in DCM (4 mL) and DMF (0.8 mL) was stirred at room temperature for 24 hours. Filter off the solid and wash with MeOH. Concentrate the combined filtrates and purify by preparative HPLC (preparation method F, gradient 20% - 60%) to give the title compound as a beige solid (52 mg, 36%). MS (ESI) m / z [M+H] + 365.

[1774] Step Bi-77b

[1775] (1S,3S)-N 1 -(5-(5-Iodo-2,4-dimethyl-1H-imidazol-1-yl)pyridin-2-yl)-N 3 -(6-methyl-1,2, 4-triazin-3-yl)cyclopentane-1,3-diamine

[1776]

[1777] A mixture of compound i-77a (0.051 g, 0.14 mmol) and NIS (0.063 g, 0.28 mmol) in MeCN (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated, and the residue was dissolved in DCM and washed with water. The organic layer was concentrated and purified by preparative HPLC (preparation method H, gradient 20%-60%) to give the title compound as a beige solid (55 mg, 80%). MS (ESI) m / z [M+H] + 491.

[1778] Intermediate 80

[1779] i-80a

[1780] 6-methyl-3-(methylsulfinyl)-1,2,4-triazin-5(4H)-one

[1781]

[1782] According to GM8, 6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (CAS Registry No. 1566-32-1) (300 mg, 1.91 mmol) was treated portionwise with 3-chloroperoxybenzoic acid (494 mg, 2.29 mmol) in DCM (25 mL) at room temperature for 2 h. After purification by preparative TLC (DCM:MeOH = 10:1), the title compound was obtained as a white solid (200 mg, 61%). MS (ESI): m / z [M+H] + 174. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (3H, s), 2.71 (3H, s).

[1783] Intermediate 81

[1784] Step A.i-81a

[1785] N-(6-chloropyridin-3-yl)-6-methyl-3-nitropyridin-2-amine

[1786]

[1787] At room temperature under nitrogen, XantPhos (CAS Registry Number 161265-03-8) (34 mg, 0.06 mmol) was added to a mixture of 2-chloro-6-methyl-3-nitropyridine (CAS Registry Number 56057-19-3) (1.00 g, 8.69 mmol), 6-chloropyridin-3-amine (CAS Registry Number 5350-93-6) (1.12 g, 7.8 mmol), Na2CO3 (1.84 g, 17.4 mmol) and Pd(OAc)2 (13 mg, 0.06 mmol) in THF (15 mL), and the mixture was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (250 mL). The organic layer was washed with saturated brine (4 × 125 mL), dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography on silica gel (gradient: 0-10% EtOAc / PE) to give the title compound as a yellow solid (1.43 g, 93%). MS (ESI): m / z [M+H] + 265.0 / 267 (Cl isotope pattern).

[1788] Step B.i-81b

[1789] N 2 -(6-chloropyridin-3-yl)-6-methylpyridine-2,3-diamine

[1790]

[1791] At room temperature, the N-(6-chloropyridin-3-yl)-6-methyl-3-nitropyridin-2-amine compound i-81a (1.4 g, 5.3 mmol) was added to a mixture of zinc (2.08 g, 31.7 mmol) and NH4Cl (2.83 g, 52.9 mmol) in a mixture of EtOH (8 mL) and EtOAc (8 mL), and the mixture was stirred at 60 °C for 15 h. The reaction mixture was filtered through a Celite pad, the filtrate was concentrated under reduced pressure, and the crude material was purified by preparative TLC (EtOAc) to give the title compound as a yellow solid (1.2 g, 97%). MS (ESI): m / z [M+H] + 235.0 / 237 (Cl isotope pattern).

[1792] Step C.i-81c

[1793] 3-(6-chloropyridin-3-yl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1794]

[1795] N in DMF (5 mL) 2-(6-Chloropyridin-3-yl)-6-methylpyridine-2,3-diamine compound i-81b (65 mg, 0.28 mmol) was treated with CDI (CAS Registry No. 530-62-1) (225 mg, 1.38 mmol) under nitrogen at room temperature and stirred at 80 °C for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3 × 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated, and the crude material was purified by preparative HPLC to give the title compound as a pale yellow powder (42 mg, 58%). MS (ESI): m / z [M+H] + 260.9 / 263 (Cl isotope pattern).

[1796] Step D.i-81d

[1797] 3-(6-chloropyridin-3-yl)-1,5-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1798]

[1799] In a vial, a mixture of 3-(6-chloropyridin-3-yl)-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-81c (340 mg, 1.30 mmol) and K2CO3 (541 mg, 3.01 mmol) in DMF (25 mL) was treated with methyl iodide (1.85 g, 13.0 mmol) under nitrogen at room temperature and stirred at 80 °C for 1 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (3 × 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated, and the crude material was purified by flash chromatography on silica gel (gradient: 0-50% EtOAc / PE) to give the title compound as a pink film (305 mg, 85%). MS (ESI): m / z [M+H] + 275.0 / 277 (Cl isotope pattern).

[1800] Step E.i-81e

[1801] 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonitrile

[1802]

[1803] The reaction was carried out in 3 parallel batches (2 batches starting from 100 mg of compound i-81d and 1 batch starting from 150 mg of compound i-81d). In a vial, a mixture of 3-(6-chloropyridin-3-yl)-1,5-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one compound i-81d (150 mg, 0.55 mmol), phthalimide (CAS Registry No. 524-38-9) (45 mg, 0.27 mmol) and tert-butyl nitrite (CAS Registry No. 540-80-7) (169 mg, 1.64 mmol) in MeCN (4 mL) was treated with Pd(OAc)2 (12 mg, 0.05 mmol) under nitrogen at room temperature and the mixture was stirred at 80 °C for 24 h. The reaction mixtures of the three parallel batches were combined, poured into water (200 mL) and the mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the crude material was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound as a brown solid (180 mg, 44% average yield). MS (ESI): m / z [M+H] + 286.2 / 288 (Cl isotopic pattern).

[1804] Intermediate 82

[1805] Step A.i-82a

[1806] 6-((6-chloropyridin-3-yl)amino)-5-nicotinonitrile

[1807]

[1808] Under nitrogen, at room temperature, Na2CO3 (1.73 g, 16.3 mmol) was added to a mixture of 6-chloro-5-nicotinonitrile (CAS Registry No. 160906-98-9) (1.00 g, 5.45 mmol), 6-chloropyridin-3-amine (CAS Registry No. 5350-93-6) (1.40 g, 10.9 mmol), XantPhos (CAS Registry No. 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 h. The reaction mixture was filtered through a membrane, 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 isotopic pattern).

[1809] Step B.i-82b

[1810] 5-amino-6-((6-chloropyridin-3-yl)amino)nicotinonitrile

[1811]

[1812] At room temperature, 6-((6-chloropyridin-3-yl)amino)-5-nitronicotinonitrile compound i-82a (1.28 g, 4.64 mmol) was added to a mixture of zinc (1.52 g, 23.2 mmol) and acetic acid (2.79 g, 46.4 mmol) in EtOH (15 mL), and it 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).

[1813] Step C.i-82c

[1814] 3-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[1815]

[1816] 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 it was stirred at 80 °C for 2 hours. The reaction mixture was poured into water (100 mL) and the mixture was extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over 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).

[1817] Step D.i-82d

[1818] 3-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile

[1819]

[1820] 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 afford the title compound as a brown oil (401 mg, 66%). MS (ESI): m / z [M+H] + 285.9 / 288 (Cl isotopic pattern).

[1821] Intermediate 83

[1822] Step A.i-83a

[1823] (1S,3S)-N 1 -(1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[1824]

[1825] At 20 °C, HCl (4 M solution in MeOH, 4 mL, 16 mmol) was slowly added to ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-22a (200 mg, 0.72 mmol) in MeOH (10 mL) and the resulting solution was stirred at 60 °C for 1 h. The solvent was removed under reduced pressure to afford the crude title compound as an unspecified HCl salt as a brown gum (265 mg, 100%) which was used directly in the next step. MS (ESI): m / z [M+H] + 179.8.

[1826] Step B.i-83b

[1827] 6'-(((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]- 2-one

[1828]

[1829] At 25 °C, (1S,3S)-N 1-(1,2,4-Triazin-3-yl)cyclopentane-1,3-diamine compound i-83a (255 mg, 0.69 mmol) was added to 6'-fluoro-2H-[1,3'-bipyridin]-2-one compound i-100a (197 mg, 1.04 mmol) and K2CO3 (477 mg, 3.45 mmol) in DMSO (5 mL). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 15 h. The crude product was purified by C18-rapid chromatography (gradient: 40%-55% MeCN / water) to give the title compound as a brown gum (175 mg, 72%). MS (ESI): m / z [M+H] + 349.9。

[1830] Intermediate 84

[1831] Step A.i-84a

[1832] (1S,3S)-N 1 -(6-bromo-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[1833]

[1834] At 30 °C, TFA (2.2 mL, 29 mmol) was added to ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-22b (1.2 g, 3.4 mmol) in DCM (20 mL), and the resulting mixture was stirred at this temperature for 5 h. The reaction mixture was concentrated, diluted with MeOH:DCM = 1:10 (300 mL) and washed successively with saturated NaHCO3 (3 × 125 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the crude title compound as a black gum (0.563 g, 65%), which was used directly in the next step. MS (ESI): m / z [M+H] + 259.8。

[1835] Step B.i-84b

[1836] 6'-(((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyr idine]-2-one

[1837]

[1838] At 30 °C, (1S,3S)-N 1-(6-Bromo-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-84a (530 mg, 2.05 mmol) was added to 6'-fluoro-2H-[1,3'-bipyridin]-2-one compound i-100a (781 mg, 4.11 mmol) and Na2CO3 (653 mg, 6.16 mmol) in DMSO (20 mL), and the resulting mixture was stirred at 120 °C for 15 h. The reaction mixture was concentrated, diluted with EtOAc (250 mL) and washed successively with saturated brine (3 × 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated, and the residue obtained was purified by preparative TLC (EtOAc) to give the title compound as a yellow solid (117 mg, 13%). MS (ESI): m / z [M+H] + 427.8。

[1839] Intermediate 85

[1840] Step A.i-85a

[1841] ((1S,3S)-3-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1,2,4-triazin-3-yl) amino)cyclopentyl)tert-butyl carbamate

[1842]

[1843] At 20 °C, Cs2CO3 (819 mg, 2.51 mmol) was added to a mixture of ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-22b (300 mg, 0.84 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS Registry No. 903550-26-5) (466 mg, 1.67 mmol) and PdCl2(dtbpf) (55 mg, 0.08 mmol) in 1,4-dioxane (5 mL), and the resulting suspension was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the residue was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a brown solid (273 mg, 76%). MS (ESI): m / z [M+H] + 430.1。

[1844] Step B.i-85b

[1845] (1S,3S)-N 1 -(6-(1H-pyrazol-5-yl)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[1846]

[1847] At 20 °C, tert-butyl ((1S,3S)-3-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-85a (263 mg, 0.61 mmol) was added to TFA (2 mL) and DCM (2 mL), and the resulting solution was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a brown gum (431 mg, 100%). MS (ESI): m / z [M+H] + 245.9。

[1848] Intermediate 86

[1849] Step A.i-86a

[1850] ((1S,3S)-3-((6-(ethylthio)-1,2,4-triazin-3-yl)amino)cyclopentyl)tert-butyl carbamate

[1851]

[1852] At 20 °C, sodium ethanethiolate (141 mg, 1.67 mmol) was added to tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-22b (200 mg, 0.56 mmol) in EtOH (5 mL), and the resulting solution was stirred at 60 °C for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as an orange solid (84 mg, 44%). MS (ESI): m / z [M+H] + 339.9。

[1853] Step B.i-86b

[1854] (1S,3S)-N 1 -(6-(ethylthio)-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine × 3.3 TFA

[1855]

[1856] At 20 °C, TFA (2 mL, 26 mmol) was added to ((1S,3S)-3-((6-(ethylthio)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-86a (73.8 mg, 0.22 mmol) in DCM (2 mL), and the resulting solution was stirred at this temperature for 16 h. The solvent was removed under reduced pressure to give the title compound as a brown gum (133 mg, 99%). This compound was used directly in the next step. MS (ESI): m / z [M+H] + 239.9。

[1857] Intermediate 87

[1858] Step A.i-87a

[1859] rel-((1R,3R)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)tert-butyl carbamate

[1860]

[1861] DIPEA (0.94 mL, 5.4 mmol) and rel-((1R,3R)-3-aminocyclopentyl)carbamic acid tert-butyl ester (CAS Registry No. 947732-58-3) (0.446 g, 2.23 mmol) were added to a solution of crude 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (0.283 g, 1.8 mmol) in MeCN (6 mL), and the resulting mixture was stirred at 50 °C for 5 days. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in DCM and washed with 1 M NaOH (aqueous solution). The phases were separated and the aqueous phase was extracted again with DCM (3×). The organic phases were combined, passed through a phase separator and concentrated. The brown solid obtained was further purified by flash column chromatography on silica gel (gradient: 0 - 100% EtOAc:MeOH = 95:5 in n-heptane) to give the title compound as a yellow solid (0.280 g, 53%). MS (ESI): m / z [M+H] + 294.1。

[1862] Step B.i-87b

[1863] rel-(1R,3R)-N 1 -(6-Methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine 3HCl

[1864]

[1865] A solution of tert-butyl rel-((1R,3R)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate compound i-87a (280 mg, 0.95 mmol) in dioxane (4 mL) was treated with HCl (4 M in dioxane, 5 mL, 20 mmol) at room temperature, and the resulting slurry was stirred at room temperature for 20 h. The mixture was concentrated to dryness to afford the crude title compound (312 mg) as a pale yellow solid. MS (ESI): m / z [M+H] + 194.1。

[1866] Intermediate 90

[1867] Step A.i-90a

[1868] 6-bromo-3-(methylthio)-1,2,4-triazine

[1869]

[1870] tert-Butyl nitrite (10.6 g, 103 mmol) was added dropwise to a mixture of 6-bromo-1,2,4-triazin-3-amine (CAS Registry Number 58-4-028-01) (3.0 g, 17 mmol) and 1,2-dimethyldisulfane (16.2 g, 171 mmol) in MeCN (60 mL) under air at room temperature over 10 min, and the resulting solution was stirred at this temperature for 16 h. The solvent was removed under reduced pressure. The crude product was combined with three other equal batches prepared in the same manner and purified by flash column chromatography on silica gel (gradient: 0 - 20% EtOAc in n-heptane) to afford the title compound (8.60 g, 60%) as a yellow solid. MS (ESI): m / z [M+H] + 205.8 / 207.8 (Br isotope pattern).

[1871] Step B.i-90b

[1872] Ethyl 3-(methylthio)-1,2,4-triazine-6-carboxylate

[1873]

[1874] At room temperature under air, Pd(OAc)2 (0.142 g, 0.63 mmol) and XantPhos (0.584 g, 1.01 mmol) were added to a mixture of 6-bromo-3-(methylthio)-1,2,4-triazine compound i-90a (2.6 g, 12.6 mmol) and TEA (5.3 mL, 38 mmol) in EtOH (26 mL). The resulting suspension was placed under a carbon monoxide atmosphere (20 atm) and stirred at 85 °C for 16 h. The mixture was combined with three other equal batches prepared in the same manner 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 obtained material was purified by flash chromatography on silica gel (gradient: 0 - 20% EtOAc / heptane) to give the title compound as a yellow oil (6.10 g, 73%). MS (ESI): m / z [M+H] + 200.

[1875] Step C.i-90c

[1876] 3-(Methylthio)-1,2,4-triazine-6-carboxylic acid

[1877]

[1878] At 0 °C, NaOH (1 M aqueous solution) (18 mL, 18 mmol) was added dropwise to 3-(methylthio)-1,2,4-triazine-6-carboxylic acid ethyl ester compound i-90b (3.0 g, 15 mmol) in THF (20 mL) and water (10 mL), and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water / ice (150 mL), the aqueous layer was adjusted to pH 2 with 2 M HCl (aqueous solution) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound as a brown gum (2.5 g, 97%), which was used without further purification. MS (ESI): m / z [M+H] + 172.

[1879] Step D.i-90d

[1880] 3-(Methylthio)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide

[1881]

[1882] At room temperature, T3P (50% w / w) (18.6 g, 29.2 mmol) in EtOAc was added to a mixture of crude 3-(methylthio)-1,2,4-triazine-6-carboxylic acid compound i-90c (2.5 g, 14.6 mmol), oxetan-3-amine (2.14 g, 29.2 mmol), and DIPEA (7.65 mL, 43.8 mmol) in EtOAc (75 mL), and the resulting solution was stirred at 60 °C for 15 h. The reaction mixture was poured into saturated NaHCO3 (aqueous solution) (150 mL) and extracted with EtOAc (3 × 125 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give a yellow gum. The material was triturated with EtOAc:PE = 1:3 (10 mL) to give the title compound as a pale yellow solid (1.0 g, 30%). MS (ESI): m / z [M+H] + 227.1。

[1883] Step E.i-90e

[1884] 3-(((1S,3S)-3-((5-Iodopyridin-2-yl)amino)cyclopentyl)amino)-N-(oxetan-3-yl)- 1,2,4-triazine-6-carboxamide

[1885]

[1886] m-CPBA (1.05 g, 4.86 mmol) was added dropwise to 3-(methylthio)-N-(oxetan-3-yl)-1,2,4-triazine-6-carboxamide compound i-90d (1.0 g, 4.42 mmol) in DCM (10 mL), and the resulting solution was stirred at room temperature for 30 min. (1S,3S)-N 1 -(5-iodopyridin-2-yl)cyclopentane-1,3-diamine × 2HCl compound i-17a (1.08 g, 2.87 mmol) and TEA (3.1 mL, 22 mmol) were added to the reaction mixture, and it was stirred at room temperature for an additional 8 h. The reaction mixture was poured into 1 M aqueous NaOH (150 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to give a yellow oil, which was allowed to stand and solidify. The material was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a yellow solid (0.50 g, 23%). MS (ESI): m / z [M+H] + 481.7。

[1887] Intermediate 91

[1888] Step A.i-91a

[1889] Methyl 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzoate

[1890]

[1891] At room temperature under nitrogen, CataCXium A Pd G3 (55 mg, 0.08 mmol) was added to a mixture of methyl 3-bromo-4-fluoro-2-methoxybenzoate (CAS Registry No. 1935415-04-05) (200 mg, 0.76 mmol), 2-chloropyridine-5-boronic acid (CAS Registry No. 444120-91-6) (179 mg, 1.14 mmol), K2CO3 (210 mg, 1.52 mmol) and water (2 mL) in 1,4-dioxane (8 mL), and the mixture was stirred at 80 °C for 8 h. The reaction mixture was poured into water (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was extracted with EtOAc (3 × 25 mL), and the combined organic layers were dried over Na2SO4, filtered and evaporated. The obtained material was purified by preparative TLC (PE:EtOAc = 3:1) to give the title compound as a yellow solid (160 mg, 71%). MS (ESI): m / z [M+H] + 296.0。

[1892] Step B.i-91b

[1893] Methyl 3-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3- yl)-4-fluoro-2-methoxybenzoate

[1894]

[1895] At room temperature under nitrogen, (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine compound i-22d (133 mg, 0.61 mmol) was added to a mixture of methyl 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzoate compound i-91a (150 mg, 0.51 mmol), Pd-PEPPSI-IPentCl2-methylpyridine (43 mg, 0.05 mmol) and Cs2CO3 (496 mg, 1.52 mmol) in 1,4-dioxane (10 mL), and the mixture was stirred at 100 °C for 8 h. The reaction mixture was poured into water (20 mL) and filtered through a pad of diatomaceous earth. The filtrate was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried (Na2SO4), filtered and evaporated. The obtained material was purified by preparative TLC (EtOAc:PE = 1:1) to give the title compound as a white solid (90 mg, 37%). MS (ESI): m / z [M+H]+ 479.2。

[1896] Intermediate 92

[1897] Step A.i-92a

[1898] 3-Bromo-4-fluoro-2-methoxybenzamide

[1899]

[1900] Sodium methoxide (30% w / w in MeOH, 458 mg, 2.54 mmol) was added dropwise to 3-bromo-2,4-difluorobenzamide (CAS Registry No. 1518200-63-9) (500 mg, 2.12 mmol) in DMSO (30 mL) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (3 × 50 mL), dried (Na2SO4), filtered and evaporated, and the residue was purified by preparative TLC (DCM:MeOH = 30:1) to give the title compound as a white solid (400 mg, 76%). MS (ESI): m / z [M+H] + 249.8。

[1901] Step B.i-92b

[1902] 3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide

[1903]

[1904] 3-Bromo-4-fluoro-2-methoxybenzamide compound i-92a (320 mg, 1.29 mmol) was added to a mixture of PdCl2(dppf) DCM adduct (105 mg, 0.13 mmol), Na2CO3 (273 mg, 2.58 mmol) and 2-chloropyridine-5-boronic acid (CAS Registry No. 444120-91-6) (305 mg, 1.94 mmol) in 1,4-dioxane (15 mL) and water (2.5 mL), and it was stirred at 80 °C for 8 hours. The reaction mixture was poured into water (50 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3 ×), and the combined organic layers were dried (Na2SO4), filtered and evaporated. The obtained material was purified by preparative TLC (EtOAc:PE = 1:2) to give the title compound as a white solid (130 mg, 36%). MS (ESI): m / z [M+H] + 281。

[1905] Step C.i-92c

[1906] 3-(6-Chloropyridin-3-yl)-4-fluoro-2-methoxybenzonitrile

[1907]

[1908] TFAA (0.13 mL, 0.93 mmol) was added to a mixture of TEA (0.258 mL, 1.85 mmol) and 3-(6-chloropyridin-3-yl)-4-fluoro-2-methoxybenzamide compound i-92b (130 mg, 0.46 mmol) in DCM (10 mL) at 0 °C. The reaction was brought to room temperature and stirred at room temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated, and the obtained material was purified by preparative TLC (PE:EtOAc = 3:1) to give the title compound as a yellow solid (100 mg, 82%). MS (ESI): m / z [M+H] + 263。

[1909] Intermediate 100

[1910] i-100a

[1911] 6'-Fluoro-2H-[1,3'-bipyridin]-2-one

[1912]

[1913] 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 flash column chromatography on silica gel (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。 1¹H 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).

[1914] Intermediate 104

[1915] Step A.i-104a

[1916] ((1S,3S)-3-((6-(1-Ethoxyvinyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic tert-butyl ester

[1917]

[1918] At 20 °C under a nitrogen atmosphere, bis(triphenylphosphine)palladium(II) dichloride (CAS Registry Number 13965-03-2) (59 mg, 0.08 mmol) was added to a mixture of ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-22b (300 mg, 0.84 mmol), tributyl(1-ethoxyvinyl)tin (CAS Registry Number 97674) (605 mg, 1.67 mmol), and lithium chloride (177 mg, 4.19 mmol) in 1,4-dioxane (20 mL), and the mixture was stirred at 100 °C for 6 hours. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (gradient: 2%-25% EtOAc / PE) to give the title compound as a yellow solid and tin impurities (500 mg). MS (ESI): m / z [M+H] + 350.1.

[1919] Step B.i-104b

[1920] 1-(3-(((1S,3S)-3-Aminocyclopentyl)amino)-1,2,4-triazin-6-yl)ethan-1-one

[1921]

[1922] At 20 °C, a solution of 4 M HCl in dioxane (4.0 mL, 16 mmol) was added to ((1S,3S)-3-((6-(1-ethoxyvinyl)-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamic acid tert-butyl ester compound i-104a (250 mg, 1.05 mmol) in EtOAc (3 mL), and the resulting suspension was stirred at 20 °C for 18 hours. The solvent was removed under reduced pressure to give the undesignated HCl salt of the title compound as a yellow gum (200 mg), which was used without further purification. MS (ESI) m / z [M+H]+ 222。

[1923] Intermediate 107

[1924] Step A.i-107a

[1925] 4-Bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1926]

[1927] 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 pad of Celite, the filter 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).

[1928] Step B.i-107b

[1929] 6-Chloro-4-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1930]

[1931] At 15 °C, RockPhos Pd G3 (CAS Registry Number 2009020-38-4) (1.97 g, 2.35 mmol) was added to a mixture of 4-bromo-6-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one compound i-107a (7.75 g, 23.5 mmol), (E)-benzaldoxime (3.70 g, 30.6 mmol), and Cs2CO3 (15.6 g, 47.8 mmol) in a mixture of 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).

[1932] Step C.i-107c

[1933] 6-Chloro-4-(difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1934]

[1935] 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).

[1936] Step D.i-107d

[1937] 4-(Difluoromethoxy)-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[1938]

[1939] 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。

[1940] Step E.i-107e

[1941] 4-(Difluoromethoxy)pyridazin-3(2H)-one

[1942]

[1943] 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。

[1944] Intermediate 108

[1945] Step A.i-108a

[1946] 2-Bromo-1-(6-fluoropyridin-3-yl)propan-1-one

[1947]

[1948] A solution of 1-(6-fluoropyridin-3-yl)propan-1-one (CAS Registry No. 949154-27-2) (201 mg, 1.31 mmol) in HOAc (2 mL) was treated with HBr (CAS Registry No. 10035-10-6) (33 wt% in HOAc, 238 μL, 1.31 mmol) and bromine (67 μL, 1.3 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude title compound (410 mg), which was used in the next step without further purification.

[1949] Step B.i-108b

[1950] 4-(6-Fluoropyridin-3-yl)-2,5-dimethyl-oxazole

[1951]

[1952] The mixture of the crude 2-bromo-1-(6-fluoropyridin-3-yl)propan-1-one compound i-108a (270 mg, 1.2 mmol) in xylene (4 mL) was treated with acetamide (593 mg, 11.6 mmol) and stirred at 135 °C for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by preparative HPLC (preparation method Z9, gradient: 20%-60%) to give the title compound as a brown solid (83 mg, 37%). MS (ESI): m / z [M+H] + 193.0。 1 H NMR (500 MHz, CDCl3) δ ppm 2.44 (3H, s), 2.47 (3H, s), 6.96 (1H, dd), 8.04 (1H, dt), 8.42 (1H, d).

[1953] Intermediate 109

[1954] Step A.i-109a

[1955] 2-(2-(Benzyloxy)ethyl)malonamide

[1956]

[1957] The reaction was carried out in 10 identical-sized parallel batches.

[1958] Diethyl 2-(2-(benzyloxy)ethyl)malonate (CAS Registry No. 41478-45-9) (2.0 g, 6.8 mmol) was treated with NH3 (7 M solution in MeOH, 25 mL, 140 mmol) at room temperature and the mixture was stirred at 60 °C for 16 h. Ten portions of the reaction mixture were combined and concentrated under reduced pressure. The material obtained was triturated with EtOAc (50 mL), the solid was separated by filtration and dried under reduced pressure to give the title compound as a white solid (14.7 g, 92%). MS (ESI): m / z [M+H] + 237.3。

[1959] Step B.i-109b

[1960] Di-tert-butyl (2-(2-(benzyloxy)ethyl)propane-1,3-diyl)dicarbonate

[1961]

[1962] A solution of 2-(2-(benzyloxy)ethyl)malonamide compound i-109a (13.5 g, 57.1 mmol) in THF (250 mL) was treated with BH3xSMe2 (10 M solution in SMe2, 45.7 mL, 457 mmol) at 20 °C and the reaction mixture was stirred at 60 °C for 16 h. The mixture was quenched with MeOH (400 mL) and concentrated under reduced pressure to give a pale yellow gum. The material was dissolved in 1,4-dioxane (250 mL) at 20 °C and treated with Na2CO3 (18.2 g, 171 mmol) in water (250 mL), followed by treatment with Boc2O (39.8 mL, 171 mmol), and the resulting suspension was stirred at 20 °C for 15 h. The reaction mixture was poured into saturated brine (500 mL) and the aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the material obtained was purified by flash chromatography on silica gel (gradient: 2%-20% EtOAc / PE) to give the title compound as a colorless gum (9.0 g, 39%). MS (ESI): m / z [M+H] + 409.3。

[1963] Step C.i-109c

[1964] Di-tert-butyl (2-(2-hydroxyethyl)propane-1,3-diyl)dicarbonate

[1965]

[1966] Pd(OH)2-C (15%, 928 mg, 0.99 mmol) was added to a mixture of (2-(2-(benzyloxy)ethyl)propane-1,3-diyl)bis(tert-butyl carbamate) compound i-109b (9.0 g, 22 mmol) and TFA (3.0 mL, 39 mmol) in MeOH (50 mL) at 20 °C. The resulting suspension was evacuated and backfilled with hydrogen 3 times, and stirred at 20 °C under a hydrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure to give the title compound as a colorless gum (7.0 g, quantitative), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 319.2。

[1967] Step D.i-109d

[1968] (±)-tert-Butyl (2-(aminomethyl)-4-hydroxybutyl)carbamate

[1969]

[1970] At 20 °C, a solution of crude bis(tert-butyl) (2-(2-hydroxyethyl)propane-1,3-diyl) dicarbamate compound i-109c (7.0 g, 22 mmol) in MeOH (20 mL) was treated with a MeOH solution of HCl (4 M, 20 mL, 80 mmol), and the reaction mixture was stirred at 60 °C for 5 h. The mixture was concentrated under reduced pressure and the obtained material was triturated with EtOAc (20 mL). The solid formed (fully deprotected title compound) was filtered off and the filtrate was concentrated under reduced pressure to give the undesignated HCl salt of the title compound as a pale yellow gum (1.4 g, purity 70%), which was used directly in the next step without further purification. MS (ESI): m / z [M+H] + 219.2。

[1971] Step E.i-109e

[1972] tert-Butyl (4-hydroxy-2-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butyl)carbamate Butyl ester

[1973]

[1974] At 20 °C, a suspension of crude racemic tert-butyl (2-(aminomethyl)-4-hydroxybutyl)carbamate compound i-109d (1.4 g) and K2CO3 (1.55 g, 11.2 mmol) in i-PrOH (40 mL) was treated with 6-methyl-3-(methylsulfinyl)-1,2,4-triazine compound i-36b (0.283 g, 1.8 mmol), and the reaction mixture was stirred at 100 °C for 15 h. The mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained material was purified by flash column chromatography on silica gel (gradient: 0 - 5% 7M NH3 / MeOH:DCM) to give the title compound as a pale yellow gum (700 mg, 10% over three steps). MS (ESI): m / z [M+H] + 312。

[1975] Step F.i-109f

[1976] (4-Amino-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl)butan-1-ol

[1977]

[1978] A solution of racemic - tert - butyl (4 - hydroxy - 2 - (((6 - methyl - 1,2,4 - triazin - 3 - yl)amino)methyl)butyl)carbamate compound i - 109e (700 mg, 2.25 mmol) in MeOH (15 mL) was treated with a MeOH solution of HCl (4 M, 3.0 mL, 12 mmol) at 20 °C, and the reaction mixture was stirred at 60 °C for 15 h. The mixture was concentrated under reduced pressure to give the undesignated HCl salt of the title compound as a yellow gum (530 mg), which was used directly in the next step without further purification. MS (ESI): m / z [M + H] + 212.1。

[1979] Step G.i-109g

[1980] (4-((5-Iodopyridin-2-yl)amino)-3-(((6-methyl-1,2,4-triazin-3-yl)amino)methyl) Butan-1-ol

[1981]

[1982] According to GM1A, 2 - fluoro - 5 - iodopyridine (CAS Registry No. 171197 - 80 - 1) (499 mg, 2.24 mmol) was added to the crude racemic - 4 - amino - 3 - (((6 - methyl - 1,2,4 - triazin - 3 - yl)amino)methyl)butan - 1 - ol compound i - 109f (530 mg, 1.86 mmol) and K2CO3 (515 mg, 3.73 mmol) in DMSO (10 mL) at 20 °C. The resulting mixture was stirred at 120 °C for 15 h, cooled to room temperature and poured into saturated brine (250 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried over Na2SO4, filtered and evaporated to give a brown gum. The material obtained was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:20) to give the title compound as a yellow gum (230 mg, 25%). MS (ESI): m / z [M + H] + 415.1。 1 H NMR (300 MHz, DMSO - d6) δ ppm 1.49 (2H, q), 1.99 (1H, quint), 2.38 (3H, s), 3.23–3.39 (4H, m), 3.49 (2H, t), 5.75 (1H, s), 6.41 (1H, d), 6.78 (1H, brs), 7.44 (1H, brs), 7.56 (1H, dd), 8.06 (1H, d), 8.14 (1H, s).

[1983] Example

[1984] Example 10

[1985] Ethyl 3-(((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)amino)-1,2, 4-triazine-6-carboxylate - Compound 10

[1986]

[1987] According to GM1B, the 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one compound i-1c (226 mg, 0.84 mmol), ethyl 3-bromo-1,2,4-triazine-6-carboxylate (CAS Registry No. 2091717-09-6) (194 mg, 0.84 mmol) and DIPEA (0.437 mL, 2.51 mmol) were reacted in NMP (2 mL) under microwave irradiation at 100 °C for 1 h. After purification by preparative HPLC (preparation method F, gradient: 15% - 55%), the title compound as a colored solid was obtained (182 mg, 52%). HRMS (ESI) m / z [M+H] + C 21 H 24 Calculated for C H N7O3: 422.1936, found: 422.1924. 1 H NMR (500 MHz, DMSO-d6, a mixture of two rotamers approximately 1.4 / 1) δ ppm 1.32 (3H, t), 1.5–1.58 (1H, m), 1.58–1.67 (1H, m), 1.87–2.04 (2H, m), 2.11–2.24 (2H, m), 4.29–4.44 (4H, m), 6.27 (1H, td), 6.44 (1H, dt), 6.53 (1H, d), 6.94–7.02 (1H, m), 7.40 (1H, dd), 7.44–7.51 (1H, m), 7.57–7.63 (1H, m), 7.93 (1H, d), 8.58 (d, minor rotamer), 8.63–8.71 (1H, m), 9.09 (1H, d, major rotamer).

[1988] Example 50

[1989] 6'-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)-2H-[1,3'- Bipyridin]-2-one - Compound 50

[1990]

[1991] K3PO4 (60 mg, 0.28 mmol) was added to (1S,3S)-N 1 -(6-cyclopropyl-1,2,4-triazin-3-yl)-N3 -(5-...

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: wherein the wavy line indicates the point of attachment to B; X 1 is N; R A2 selected from the group consisting of: (i) H; (ii) a halogen substituent; (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, optionally substituted by OH, alkylamido or one or more halogen groups; (vi) C 1-6 Acylamino (wherein the acyl group is optionally substituted by H or methyl); (vii) C 1-6 Thioalkyl; (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 substituted, wherein the C 1-3 Alkyl is optionally substituted by one or more halogen groups or OH groups; and (xiii) OH; and (xiv)C 1-6 alkylamino; R A3 selected from the group consisting of: (i) H; (ii) a halogen substituent; (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 by CN, OH or a C4 heterocyclic group; (xi) C 1-6 Dialkylamino, optionally substituted by -NH2; (xii)C 1-6 Acylamino (wherein the acyl substituent is H or Me); (xiii) an amidino or methyl - amidino group; (xiv) a carboxylamino group; (xv)C 1-6 Thioalkyl group, which is 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 sulfonylimide group; (xviii)C 1-6 Alkylphosphinyloxy group; (xix) a carboxyl group; (xx) -C(=O)NH2 (xxi)C 1-6 alkyl ester; (xxii)C 1-6 alkyl acyl, optionally substituted by one or more halo groups; (xxiii)C 1-6 alkyl acylamino; or wherein R A3 and R A2 together with the carbon atom 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 formula (B - 1) or (B - 2) i) wherein 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, wherein said C 1-4 alkyl is optionally substituted by OH or OMe; (ii) wherein the wavy line indicates the points of attachment to A and C; R B2 is C 1-2 alkyl-OH, CH2C(=O)NHMe 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 the group is optionally substituted with the following: (i) C 6-10 carbaryl, C 4-10 carbocyclic group, C 5-10 heteroaryl, C 4-10 heterocyclic group or C 5-10 bridged heterocyclic group, spiro C 6-12 heterocyclic group or spiro C 6-12 carbocyclic group, which are themselves optionally substituted with one or more of the following groups; a) one or two =O groups; b) one or more halogen substituent 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 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 heteroaryl; 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 halogenated groups; l) P(=O)Me2; m) a carboxyl group or CH2 - carboxyl group; n) a tetrazolyl, CH2 - tetrazolyl, 5 - oxo - 4H - 1,2,4 - oxadiazol - 3 - yl group; (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.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R A2 is selected from the group consisting of: (i) H; (ii) a halogen substituent; (iii) C 1-6 alkyl ester; (iv)C 1-6 Hydrocarbons; (v)C 1-6 Alkylamido, which is optionally substituted by C 1-3 Alkylamido, 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 substituents or OH groups; (vi) C 1-6 Thioalkyl; (vii) C 1-6 alkyl acyl; (viii) a C5 heteroaryl; or (ix) C 1-6 alkylamino 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R A2 is selected from the group consisting of: -C(=O)OCH2CH3, cyclopropyl, methyl, H, Cl, -C(=O)CH3, -S-ethyl, pyrazole, -N(CH3)2, -C(=O)NH(CH2C(=O)NH2, - C(=O)NHCH2C≡CH, -C(=O)NH(oxetane), - C(=O)NH(CH2CHF2), -C(=O)NH(CH2CH3), -C(=O)NH2, - C(=O)NH(CH3), -C(=O)N(CH3)2, -C(=O)N(CH3)(CH2CH2OH), - C(=O)N(CH3)(CH2C≡CH) or -C(=O)NH(CH2CH2OH).

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R A3 is selected from the group consisting of: (i) H; (ii) a halogen substituent; (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, which is optionally substituted by OH, NH2, a C4 heterocyclic group or one or more halo groups.

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

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein B has the formula: a) or b) 7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein C is an optionally substituted pyridinyl, pyrazinyl or pyrimidinyl, and the optional substituent is 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 is itself optionally substituted by one or more groups selected from the following groups: a) one or two =O groups; b) one or more halogen substituent 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 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 heteroaryl; i)C 4-10 a carbocyclic group which has 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) a carboxyl group or CH2 - carboxyl group; and / or n) a tetrazolyl, CH2 - tetrazolyl, 5 - oxo - 4H - 1,2,4 - oxadiazol - 3 - yl group.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein C is: a) an optionally substituted pyridyl, pyrazinyl or pyrimidinyl group, wherein the optional substituent is selected from a C6 heteroaryl or a C6 heterocyclic group, which are themselves optionally substituted with one or more of the following groups: i) one or two =O groups; ii) methyl; iii) OMe; iv) Cl; v) CN; vi) CF3; vii) F; viii) a triazolyl, tetrazolyl, pyrazolyl optionally substituted with methyl; ix) O - CF3; x) O - CHF2; or b) an optionally substituted pyridyl group, wherein the optional substituent is a phenyl or a pyridyl group, which are themselves optionally substituted with one or more of the following groups: f) one or more OMe groups; g) one or more F groups; h) CN; i) tetrazole; or j) carboxyl; or c) an optionally substituted pyridyl group, wherein the optional substituent is a C5 heteroaryl group or a C5 heterocyclic group, which is itself optionally substituted by one or more groups selected from methyl and CN.

9. The compound according to any one of claims 1 to 6 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; iii) OMe; iv) piperazinyl, which is optionally substituted by methyl; v) C(═O)OH (carboxyl); vi) Cl; vii) F; viii) phenyl, which is optionally substituted by one or more fluorines; ix) CN; x) CF3; xi) O-CF3; xii) tetrazolyl, pyrazolyl, triazolyl, each of which is optionally substituted by methyl; xiii) NH2; xiv) pyridyl; xv) CH2OH; xvi) OH; xvii) P(═O)Me2; or xviii) OCHF2.

10. The compound according to claim 9 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 one or more halo groups; ii)C 1-6 an alkoxy group, optionally substituted by one or more halogen groups; iii)C 5-6 heterocyclic group or C 5-6 heteroaryl, which has an optional methyl substituent; iv) carboxyl or CH2-carboxyl; v) ═O, halo, NH2 or CN; vi) phenyl, which is optionally substituted by one or more halogen atoms; and the rest 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, halo and C(=O)OH; Or wherein R D1 、R D2 、R D3 and R D4 are all H.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein: a) R D1 、R D2 、R D3 and R D4 One or both of them are selected from: i) methyl; ii) OMe; iii) Cl; iv) CN; v) CF3; vi) F; vii) triazolyl, tetrazolyl, pyrazolyl optionally substituted by methyl; viii) O-CF3 ix) O-CHF2 and R D1 、R D2 、R D3 and R D4 and the remainder of R b) R D1 , R D2 , R D3 and R D4 All are H; c) R D3 is selected from H, CN, OMe, Cl, tetrazole, methyl, OCHF2 or triazole, and a pyrazole optionally substituted with methyl, and wherein R D1 , R D2 and R D4 are all H; d) R D1 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole or pyrazole optionally substituted by methyl, and R D2 , R D3 and R D4 are all H; or e) R D3 and R D4 form an unsubstituted benzene ring or an unsubstituted pyridine ring.

12. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein D has the formula (D-2): wherein 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, wherein 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 by CN, P(=O)Me2 or carboxyl, and R D6b and R D7b are absent.

13. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein 14. The compound according to any one of claims 1 to 6 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; OMe; a piperazinyl optionally substituted by methyl; C(=O)OH (carboxyl); Cl; F; a pyrazolyl optionally substituted by methyl; a triazolyl; a tetrazole; an optionally substituted phenyl (wherein the optional substituent is methyl or a halogenated group); CN; CF3; O-CHF2, O-CF3; and R C7 , R C8 , R C9 , and R C10 the remainder of are H; or R C9 and R C10 form a benzene or 6-membered heteroaromatic ring, and R C7 and R C8 are both H; or wherein R C7 , R C8 , R C9 and R C10 are all H.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein: a) R C7 、R C8 、R C9 and R C10 are all H; or b) R C9 selected from H, CN, OMe, Cl, tetrazole, methyl, OCHF2 or triazole, pyrazole optionally substituted with methyl, and R C7 , R C8 and R C10 are all H; or c) R C7 is selected from H, OMe, Cl, CF3, OCF3, OCHF2, CN, F, triazole or pyrazole optionally substituted by methyl, and R C7 , R C8 and R C10 are both H.

16. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein C is selected from the group consisting of:

17. 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), (I-D), (I-E), (I-Ea) or (I-Eb): wherein X 1 、R A2 、R A3 、C, D, R D1 、R D2 、R D3 、R D4 、R D1a 、R D2a 、R D3a 、R D4a 、X D 、R D6a 、R D6b and R D7a are defined as in any one of the preceding claims.

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

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

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

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, or the pharmaceutical composition according to claim 20, 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.

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

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