PCSK9 inhibitors and methods of using the same

Abstract

A compound of formula (I): A-B-C (I) or a pharmaceutically acceptable salt and tautomeric form or stereoisomer thereof, wherein A has one of the following formulae: B has the following formula: (B-1); C has the following formula: (C-1a).

Description

[0001] This application claims priority to European Patent Application No. 24164963.1, filed on 20 March 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to compounds that inhibit PCSK9 and their use in therapeutic applications. Background Technology

[0003] PCSK9 (also known as "proprotein convertase subtilisin / kexin 9") is a member of the secretory proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases circulating LDL cholesterol (LDL-C) levels by enhancing LDLR degradation independently of its catalytic activity. Secreted PCSK9 binds to the epidermal growth factor domain A (EGFA) of the LDL receptor (LDLR) on the cell surface, and the PCSK9 / LDLR complex is internalized into the endosome / lysosome compartment. The enhanced affinity of PCSK9 for LDLR binding at the acidic pH of the late endosome / lysosome reduces LDLR receptor recycling and instead targets LDLR for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with lower plasma LDL-C levels and a reduced incidence of adverse cardiovascular events.

[0004] For cardiovascular disease, there are virtually no options for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and human primary hepatocytes by increasing the expression of SREBP-2 (a transcription factor that upregulates both LDLR and PCSK9 genes). Because elevated PCSK9 levels reduce the abundance of LDLR on the cell surface, increased statin doses fail to achieve a proportional reduction in LDL-C.

[0005] Two monoclonal antibodies (mAbs) that selectively bind to extracellular PCSK9 and prevent its interaction with the LDLR alirocumab and evolocumab have recently been approved by the FDA for lowering LDL-C levels. In clinical trials, alirocumab showed a reduction in LDL levels of approximately 50% compared to placebo (Elbitar 2016). Patients taking evolocumab showed a reduction in LDL levels of approximately 60%–75%. The efficacy of these drugs demonstrates the potential of PCSK9 inhibitors as an effective treatment for 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.

[0006] Unlike infections that may occur incidentally, cardiovascular diseases typically require lifelong management. Therefore, ease of administration and delivery is a crucial factor in patient adherence to and maintenance of medication. There is a need for PCSK9 inhibitors that offer increased efficacy and are easier to administer, achievable with small molecule PCSK9 inhibitors.

[0007] WO 2020 / 150473 A2 relates to heteroaryl compounds and pharmaceutical preparations thereof. It also relates to methods of treating or preventing cardiovascular diseases using the described novel heterocyclic compounds, and methods of treating sepsis or septic shock.

[0008] WO 2020 / 15474 A1 relates to pharmacophores that inhibit PCSK9 and heteroaryl compounds that bind to the PCSK9 protein.

[0009] WO 2023 / 084449 A1 relates to diaminocyclopentylpyridine derivatives as modulators of PCKS9. Summary of the Invention

[0010] The first aspect of this article provides a compound of formula (I).

[0011] ABC (I)

[0012] Or its pharmaceutically acceptable salts and tautomers or stereoisomers.

[0013] Where A has one of the following properties:

[0014] (A1a)

[0015]

[0016] The wavy line indicates the attachment point with B;

[0017] X 1 Is it N or CR? A3 ,

[0018] R A1 Choose from the following groups:

[0019] (i)H;

[0020] (ii) Halogenated groups;

[0021] (iii)CN;

[0022] (iv)C 1-6 Hydrocarbons, optionally reacted with one or more OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0023] (v)C1-6 alkoxy group, optionally surrounded by OH, one or more halogroups, C 1-6 Alkyl amide substitution;

[0024] (vi)C 1-6 Alkyl esters;

[0025] (vii)C 1-6 Alkyl acyl; and

[0026] (viii)OH;

[0027] R A2 Choose from the following groups:

[0028] (i)H;

[0029] (ii) Halogenated groups;

[0030] (iii)CN;

[0031] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0032] (v)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[0033] (vi)C 1-6 Acylamide (wherein the acyl group is optionally substituted with H or methyl);

[0034] (vii)C 1-6 Thioalkyl;

[0035] (viii)C 1-6 Alkyl esters;

[0036] (ix)C 1-6 Alkyl acyl;

[0037] (x)C 4-5 Heterocyclic groups;

[0038] (xi)C5 heteroaryl;

[0039] (xii)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, OH, C 2-3 alkynyl group, C 4-6 Heterocyclic group, C 1-3 Alkyl substitution, wherein C 1-3The alkyl group may optionally be substituted with one or more halogroups or OH groups;

[0040] (xiii)OH; and

[0041] (xiv)C 1-6 Alkylamino;

[0042] R A3 Choose from the following groups:

[0043] (i)H;

[0044] (ii) Halogenated groups;

[0045] (iii)CN;

[0046] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[0047] (v)OH;

[0048] (vi)C 1-6 Alkoxy groups, which may optionally be substituted with OH, NH2, C4 heterocyclic groups or one or more halogroups;

[0049] (vii)C 1-6 Acyloxy group;

[0050] (viii) C4 heterocyclic group;

[0051] (ix)NH2;

[0052] (x)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups;

[0053] (xi)C 1-6 Dialkylamino, which is optionally substituted with -NH2;

[0054] (xii)C 1-6 Acylamide (where the acyl substituent is H or Me);

[0055] (xiii) amidoyl or methyl-amidinyl;

[0056] (xiv) carboxylamino;

[0057] (xv)C 1-6 Thioalkyl groups, which are optionally substituted with OH or NH2;

[0058] (xvi)C 1-6 alkylsulfinyl;

[0059] (xvii)C 1-6 Alkyl sulfonyl group, which is optionally substituted with one or more haloyl groups;

[0060] (xviii)C 1-6 sulfonylimide group;

[0061] (xix)C 1-6 Alkyloxyphosphine group;

[0062] (xx) carboxyl group;

[0063] (xxi)C(=O)NH2;

[0064] (xxii)C 1-6 Alkyl esters;

[0065] (xxiii)C 1-6 An alkyl acyl group, optionally substituted with one or more halogroups; and

[0066] (xxiv)C 1-6 Alkyl amide;

[0067] Or R A3 and R A2 Together with the carbon atoms they are bonded to, they form:

[0068] (i) C can be arbitrarily substituted 5-7 Heterocyclic rings;

[0069] (ii) C can be arbitrarily substituted 5-7 Mixed aromatic rings;

[0070] (iii) Optionally substituted C6-carbon aromatic rings;

[0071] (iv) Optional substitution of C 5-7 carbon ring

[0072] Wherein, when present, one, two, three, or four optional substituents are independently selected from C. 1-6 Alkyl, Halogenated, C 1-6 Alkoxy, NH2, C 1-6 Alkylamino, OH, and CN;

[0073] (A2a)

[0074] (A2a)

[0075] The wavy line indicates the attachment point with B;

[0076] Z 1 Selected from O or S;

[0077] R A5 Choose from the following groups:

[0078] (i)H;

[0079] (ii) Halogenated groups;

[0080] (iii)CN;

[0081] (iv) A C1 alkyl group, optionally substituted with one or more OH, CN, or one or more halogroups; and

[0082] (v)C1 alkoxy group, which is optionally substituted with one or more halogroups;

[0083] R A6 Choose from the following groups:

[0084] (i)H;

[0085] (ii) Halogenated groups;

[0086] (iii)CN;

[0087] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0088] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[0089] (vi)C 1-6 Alkylamino;

[0090] (vii)C 1-6 Thioalkyl;

[0091] (viii)C 1-6 Alkyloxyphosphine; and

[0092] (ix)C 1-6 Alkylphosphonoyl;

[0093] R A7 Choose from the following groups:

[0094] (i)H;

[0095] (ii) Halogenated groups;

[0096] (iii)CN;

[0097] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[0098] (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups and one or more halogenated groups;

[0099] (vi) C4 heterocyclic group;

[0100] (vii)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups;

[0101] (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and

[0102] (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2;

[0103] (A2b)

[0104]

[0105] The wavy line indicates the attachment point with B;

[0106] Z 6 Is it N or CH?

[0107] Z 7 Is it N or CR? A8

[0108] Z 8 and Z 9Choose independently from the following groups:

[0109] (i)H;

[0110] (ii) Halogenated groups;

[0111] (iii)CN;

[0112] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0113] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[0114] (vi)C 1-6 Alkylamino

[0115] (vii)C 1-6 Thioalkyl,

[0116] (viii)C 1-6 Alkyloxyphosphine; and

[0117] (ix)C 1-6 Alkylphosphonoyl;

[0118] R A8 Choose from the following groups:

[0119] (i)H;

[0120] (ii) Halogenated groups;

[0121] (iii)CN;

[0122] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[0123] (v)C 1-6Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups and one or more halogenated groups;

[0124] (vi) C4 heterocyclic group;

[0125] (vii)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups;

[0126] (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and

[0127] (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2;

[0128] (A3a)

[0129] ;or

[0130] (A3b)

[0131]

[0132] Where R A9 Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 1-methylcyclopropyl, and 2-methylcyclopropyl;

[0133] (A4)

[0134] (A4)

[0135] Where R A4 Selected from H, CN, -OCF2H, cyclopropyl, Cl, and methyl;

[0136] Where B has the following formula

[0137] (B-1)

[0138] (B-1)

[0139] The wavy line indicates the attachment points to A and C;

[0140] R B1 It is -H, -OH, =CHCH2-OH, -C 1-4 Alkyl or -C 1-4 Alkyl, the C 1-4 Alkyl groups may optionally be substituted with -OH or OMe;

[0141] Where C has the following formula:

[0142] (C-1a)

[0143]

[0144] Where X is hydrogen or fluorine;

[0145] Where R N It is H, methyl, or optionally C 1-3 Benzyl groups substituted with alkoxy groups;

[0146] R C1 and R C2 Together with the carbon atoms they are bonded to, they form fused benzene rings or C6 heteroaromatic rings, which are optionally separated by one or more R atoms. C3 Group substitution;

[0147] Where R C3 Selected from

[0148] (i)CN;

[0149] (ii)P(=O)Me2;

[0150] (iii)C(=O)OH;

[0151] (iv)C 1-6 Hydrocarbons, which are optionally C 1-6 Alkyl substitution;

[0152] (v)C 1-6 Alkoxy;

[0153] (vi)C 1-6 Alkyl amide;

[0154] (vii)C 5-6 Mixed aromatics;

[0155] (viii) Halogenated group;

[0156] (ix)C 1-6 Alkyl acyl; and

[0157] (x)Oxide group.

[0158] The second aspect provides a pharmaceutical composition comprising the compound of the first aspect and a pharmaceutically acceptable diluent, carrier, or excipient.

[0159] The third aspect provides the compound of the first aspect for use in a treatment method. The third aspect also provides the use of the compound of the first aspect in the manufacture of a medicament for treating cardiovascular diseases. The third aspect further 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 a therapeutically effective amount of the compound of the first aspect or the composition according to the second aspect to a patient in need.

[0160] The fourth aspect provides compounds selected from the following compounds:

[0161] ;

[0162] ;

[0163] ;

[0164] ;and

[0165] .

[0166] This disclosure includes combinations of the described aspects and preferred features, unless such combinations are obviously not permitted or explicitly avoided. Attached Figure Description

[0167] Figure 1 The structure of mouse GalNAc ASO used in in vivo experiments to determine 6 is shown. Detailed Implementation

[0168] The various aspects and implementation schemes will now be discussed. Further aspects and implementation schemes will be apparent to those skilled in the art. All references in this text are incorporated herein by reference.

[0169] This document describes compounds of formula (I) and their use in the treatment of cardiovascular diseases. The compounds disclosed herein are PCSK9 inhibitors. The compounds may possess higher PCSK9 inhibition, lower hERG activity, improved secondary pharmacological characteristics (including GSK3β and / or other kinases), good stability, and / or improved activity in the treatment of cardiovascular diseases. The compounds may possess improved secondary pharmacological characteristics or improved off-target characteristics.

[0170] definition

[0171] Substituents

[0172] As used herein, the phrase “optionally substituted” refers to a parent group that may be unsubstituted or substituted.

[0173] Unless otherwise stated, as used herein, the term "substituted" refers to a parent group having one or more substituents. The term "substituent" is used herein in its conventional sense and refers to a chemical part that is covalently attached to or, if appropriate, fused to a parent group. Various substituents are well known, as are methods for their formation and introduction into various parent groups.

[0174] Examples of substituents are described in more detail below.

[0175] Unless otherwise stated, the halogen group is selected from chlorine (Cl), fluorine (F), bromine (Br) and iodine (I).

[0176] Cyano group (nitriles, formonitriles): -CN.

[0177] Hydroxyl group: -OH.

[0178] Oxide group: =O (oxygen is bonded to the rest of the molecule via a double bond).

[0179] C 1-6 Hydrocarbons: As used herein, the term "C" 1-6 "Hydrocarbon" refers to the monovalent portion obtained by removing hydrogen atoms from the carbon atoms of a hydrocarbon compound having 1 to 6 carbon atoms, which may be aliphatic or alicyclic, saturated or unsaturated (e.g., partially unsaturated, fully unsaturated), and may also be branched. Therefore, the term "hydrocarbon" includes the terms alkyl, alkenyl, alkynyl, cycloalkyl, etc., discussed below.

[0180] C 1-6 Alkyl: As used herein, the term "C" 1-6 "Alkyl" refers to the monovalent moiety obtained by removing hydrogen atoms from the carbon atoms of a hydrocarbon compound having 1 to 6 carbon atoms, which is saturated and may also be branched. As used herein, the term "C" refers to... 1-4 "Alkyl" refers to the monovalent portion obtained by removing hydrogen atoms from the carbon atoms of a hydrocarbon compound having 1 to 4 carbon atoms, wherein the hydrocarbon compound is saturated.

[0181] Examples of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), and hexyl (C6).

[0182] 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 (C5), and n-hexyl (C6).

[0183] Examples of saturated branched alkyl groups include isopropyl (C3), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), isopentyl (C5), and neopentyl (C5).

[0184] 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.

[0185] Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl (allyl, CHCH=CH2), isopropenyl (1-methyl vinyl, C(CH3)=CH2), butenyl (C4), pentenyl (C5), and hexenyl (C6).

[0186] C 2-6 Alkyne group: As used herein, the term "C" 2-6 "Alkyne" refers to a hydrocarbon group having one or more carbon-carbon triple bonds.

[0187] Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and 2-propynyl (propynyl, -CH2C≡CH).

[0188] C 1-6 Alkoxy: As used herein, the term C 1-6 The alkoxy group involves an OR group, where R is C. 1-6 Hydrocarbon group. C 1-6 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).

[0189] C 1-6 Acyloxy group: As used herein, the term C 1-6 Acyloxy group (reverse ester) involves OC(=O)R, where R is C 1-6 Hydrocarbon groups. Examples of acyloxy groups include, but are not limited to, OC(=O)CH3 (acetoxy), OC(=O)CH2CH3 or OC(=O)C(CH3)3.

[0190] Amino: NR 1 R 2 , where R 1 and R 2 Independently, it is an amino substituent, such as hydrogen, C 1-6 Hydrocarbon group (also known as C) 1-6 Alkylamino or C 1-6 Dialkylamino, where both groups are C14. 1-6 (hydrocarbon group), or in the case of a "cyclic" amino group, R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form heterocycles with 4 to 6 ring atoms. The amino groups can be primary amino (-NH2), secondary amino (-NHR), or other types of amino groups. 1 ) or tertiary amino (-NR) 1R 2 ), and in cationic form, it can be a quaternary ammonium group (- + NR 1 R 2 R 3 Examples of amino groups include, but are not limited to, NH2, NHCH3, NHCH(CH3)2, N(CH3)2, N(CH2CH3)2, and NHPh. Examples of cyclic amino groups include, but are not limited to, aziridinyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholino, and thiomorpholino.

[0191] C 1-6 Acylamide: Acylamide (acylamino): NR 1 C(=O)R 2 , where R 1 It is an amide substituent, such as hydrogen or C. 1-6 Hydrocarbon group, and R 2 It is an acyl substituent, such as C 1-6 Hydrocarbon groups. 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 They can be combined to form cyclic or bicyclic structures and form cyclic acylamino groups. Examples of such groups include succinimide, maleimide, phthalimide, 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.

[0192]

[0193] Amino group: -C(=NH)NH2.

[0194] Methyl-amidinyl: -C(=N-CH3)NH2.

[0195] Carboxylamino group: -N(H)(C(=O)OH).

[0196] C 1-6 Thioalkyl: As used herein, the term C 1-6 Thioalkyl groups involve SR, where R is C 1-6 Hydrocarbon group. C 1-6 Examples of alkylthio groups include, but are not limited to, SCH3 and SCH2CH3.

[0197] C 1-6 Alkyl sulfinyl group: Term C 1-6Alkyl sulfinyl groups relate to sulfinyl groups (sulfinyl groups, sulfoxides) having the structure S(=O)R-, where R is C 1--6 Hydrocarbon group. C 1-6 Examples of alkyl sulfinyl groups include, but are not limited to, S(=O)CH3 and S(=O)CH2CH3.

[0198] C 1-6 Alkyl sulfonyl: As used herein, the term C 1-6 alkylsulfonyl groups involve -S(=O)2R groups, where R is C. 1--6 Hydrocarbon groups, including, for example, fluorinated or perfluorinated C 1--6 Alkyl group. C 1-6 Examples of alkyl sulfonyl groups include, but are not limited to, -S(=O)2CH3 (methanesulfonyl / mesyl), -S(=O)2CF3 (trifluoromethanesulfonyl), -S(=O)2CH2CH3 (ethanesulfonyl), -S(=O)2C4F9 (perfluorobutylsulfonyl) and -S(=O)2CH2CF3 (trifluoroethanesulfonyl).

[0199] C 1-6 sulfonamide group: term C 1-6 The sulfonylimide group is also called sulfinylamino (aminosulfinyl; sulfonic acid amide; sulfonamide or di-C). 1-6 (alkylsulfinylamino) and has the structure S(=O)2NR 1 R 2 , where R 1 and R 2 Independently, it is an amino substituent, as defined for an amino group. Examples of sulfinylamino 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.

[0200] sulfonamide: NR 1 S(=O)2R, where R 1 R is an amino substituent, as defined for an amino group, and R is a sulfonamide substituent, such as C. 1-6 alkyl groups, C 3-20 Heterocyclic groups or C 5-20 Aryl group, preferably C 1-6 Alkyl groups. Examples of sulfonamide groups include, but are not limited to, NHS(=O)2CH3 and N(CH3)S(=O)2C6H5.

[0201] C 1-6Alkyloxyphosphine group: Term C 1-6 Alkyloxyphosphine (phosphine oxide) has the structure -P(=O)R2, where each R is independently C. 1-6 Hydrocarbon group. C 1-6 Examples of alkyloxyphosphine groups include, but are not limited to, P(=O)Me2, P(=O)(CH2CH3)2, and P(=O)(tBu)2. Each R group may be the same or different groups.

[0202] C 1-6 Alkylphosphonoyl: Term C 1-6 Alkylphosphonoyl groups have the structure -P(=O)2R, where R is C. 1-6 Hydrocarbon group. C 1-6 Examples of alkylphosphonoyl groups include, but are not limited to, P(=O)2(CH3), P(=O)2(CH2CH3) and P(=O)2(tBu).

[0203] Carboxyl group (carboxylic acid): -C(=O)OH.

[0204] C 1-6 Alkyl ester: Term C 1-6 Alkyl esters (carboxylate / carboxylic acid esters, oxycarbonyl groups) have the structure C(=O)OR, where R is C. 1-6 Hydrocarbon groups. Examples of ester groups include, but are not limited to, C(=O)OCH3, C(=O)OCH2CH3 and C(=O)OC(CH3)3.

[0205] C 1-6 Alkyl acyl group: also known as acyl (ketone) group. 1-6 Alkyl acyl groups have 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-butyryl).

[0206] C 1-6 Alkylamide: Term C 1-6 Alkylamino (also known as carbamoyl, aminocarbonyl, or formamide) has the structure C(=O)NR 1 R 2 , where R 1 and R 2 Independently, it is an amino substituent, as defined with respect to the amino group, such as hydrogen, C 1-6 Hydrocarbon group (also known as C) 1-6 Alkyl amide or C 1-6Dialkylamide), or in the case of a "cyclic" amide group, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form heterocycles with 4 to 6 ring atoms. Examples of amide groups include, but are not limited to, C(=O)NH2, C(=O)NHCH3, C(=O)N(CH3)2, C(=O)NHCH2CH3 and C(=O)N(CH2CH3)2, and R in which 1 and R 2 Acylamino groups that form heterocyclic structures together with the nitrogen atoms to which they are attached, such as acylamino groups in piperidinyl carbonyl, morpholino carbonyl, thiomorpholino carbonyl, and piperazine carbonyl.

[0207] C 3-12 Cycloalkyl: As used herein, the term "C" refers to cycloalkyl groups. 3-12 "Cycloalkyl" refers to an alkyl group that is also a cycloalkyl group; that is, a monovalent portion obtained by removing hydrogen atoms from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, the portion having 3 to 7 carbon atoms, including 3 to 7 ring atoms. The carbocyclic ring can be saturated or unsaturated and can be bridged or unbridged. The ring can be fused or monocyclic.

[0208] Examples of cycloalkyl groups include, but are not limited to, those derived from:

[0209] Saturated monocyclic hydrocarbon compounds:

[0210] 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);

[0211] Unsaturated monocyclic hydrocarbon compounds:

[0212] Cyclopropene (C3), cyclobutene (C4), cyclopentene (C5), cyclohexene (C6), methylcyclopropene (C4), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (C6), methylcyclopentene (C6), dimethylcyclopentene (C7), and methylcyclohexene (C7); and

[0213] Saturated polycyclic hydrocarbons:

[0214] Norcarbazine (C7), Norpinene (C7), Norcamphene (C7).

[0215] C 3-10 Heterocyclic group: As used herein, the term "C" 3-10A "heterocyclic group" refers to a monovalent moiety obtained by removing hydrogen atoms from the ring atoms of a heterocyclic compound, having 3 to 10 ring atoms, of which 1 to 5 are cyclic heteroatoms. In some embodiments, each ring has 3 to 7 ring atoms, of which 1 to 4 are cyclic heteroatoms. The ring can be saturated or unsaturated and can be bridged or unbridged. The ring can be fused or monocyclic. To avoid confusion, substituents on the heterocyclic ring can be connected by carbon atoms or heteroatoms.

[0216] In this context, the term "heteroatom" refers to O, S, N, Si, or B (boron). More generally, in a pharmaceutical context, the term "heteroatom" refers to O, S, or N.

[0217] In this context, prefixes (e.g., C) 3-10 C 3-7 C 5-6 (etc.) indicates the number of ring atoms or a range of ring atoms, regardless of whether they are carbon atoms or heteroatoms. For example, as used herein, the term "C 5-6 "Heterocyclic group" refers to a heterocyclic group having 5 or 6 ring atoms.

[0218] Examples of monocyclic heterocyclic groups include, but are not limited to, those derived from:

[0219] N1: Aziprodine (C3), aziridine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrrololine (e.g., 2,5-dihydro-1H-pyrrole) (C5), 2H-pyrrole or 3H-pyrrole, isoxazole (C5), piperidine (C6), dihydropyridine (C6), tetrahydropyridine (C6), aziridine (C7);

[0220] O1: Oxycyclopropane (C3), Oxycyclobutane (C4), Oxycyclopentane (tetrahydrofuran) (C5), Oxycyclopentadiene (dihydrofuran) (C5), Oxycyclohexane (tetrahydropyran) (C6), Dihydropyran (C6), Pyran (C6), Oxycycloheptatriene (C7);

[0221] S1: Thionicyclopropane (C3), Thionicyclobutane (C4), Thionicyclopentane (tetrahydrothiophene) (C5), Thionicyclohexane (tetrahydrothiaran) (C6), Thionicycloheptane (C7);

[0222] O2: dioxolane (C5), dioxane (C6) and dioxane-heptane (C7);

[0223] O3: Trioxane (C6);

[0224] N2: Imidazolidine (C5), pyrazolidine (diazoline) (C5), imidazoline (C5), pyrazolidine (dihydropyrazole) (C5), piperazine (C6);

[0225] N1O1: Tetrahydrooxazole (C5), Dihydrooxazole (C5), Tetrahydroisoxazole (C5), Dihydroisoxazole (C5), Morpholine (C6), Tetrahydrooxazine (C6), Dihydrooxazine (C6), Oxazine (C6);

[0226] N1S1: Thiazoline (C5), Thiazolidine (C5), Thiomorpholine (C6);

[0227] N2O1: Oxadiazine (C6);

[0228] O1S1: oxothiacyclopentadiene (C5) and oxothiacyclohexane (thiaxane) (C6); and,

[0229] N1O1S1: Oxythiazide (C6).

[0230] Examples of bicyclic heterocyclic groups include, but are not limited to, those derived from:

[0231]

[0232] C 6-10 Carbon aryl: As used herein, the term "C" refers to... 6-10 "Carbonaryl" refers to a monovalent moiety obtained by removing hydrogen atoms from an aromatic ring atom of an aromatic compound, having 6 to 10 ring atoms, all of which are carbon atoms, as in "carbonaryl group". The ring can be fused or monocyclic. Examples of carbonaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C4), etc. 10 ) and azurite (C 10 Those.

[0233] In this context, prefixes (e.g., C) 5-7 C 5-6 C 5-10 (etc.) indicates the number of ring atoms or a range 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.

[0234] Examples of carbon aryl groups containing fused rings (at least one of which is an aromatic ring) include, but are not limited to, those derived from indene (e.g., 2,3-dihydro-1H-indene) (C9), indene (C9), isoindene (C9), and tetrahydronaphthalene (1,2,3,4-tetrahydronaphthalene) (C9). 10 ) group.

[0235] C 5-10 heteroaryl: as used herein, the term "C 5-10"Heteroaryl" refers to a monovalent moiety obtained by removing hydrogen atoms from an aromatic ring atom of an aromatic compound, having 5 to 10 ring atoms, of which 1 to 5 are cyclic heteroatoms. In some embodiments, each ring has 5 to 7 ring atoms, of which 1 to 4 are cyclic heteroatoms. To avoid confusion, substituents on the heteroaryl ring can be connected by carbon atoms or heteroatoms. The ring can be a fused ring or a monocyclic ring.

[0236] In this context, the term "heteroatom" refers to O, S, N, Si, or B (boron). More generally, in a pharmaceutical context, the term "heteroatom" refers to O, S, or N.

[0237] Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from:

[0238] N1: Pyrrole (azole) (C5), Pyridine (acrazine) (C6);

[0239] O1: Furan (oxacyclopentadiene) (C5);

[0240] S1: Thiophene (thiacyclopentadiene) (C5);

[0241] N1O1: Oxazole (C5), Isoxazole (C5), Isoxazine (C6);

[0242] N2O1: Oxadiazole (furazan) (C5);

[0243] N3O1: Oxadiazole (C5);

[0244] N1S1: Thiazole (C5), Isothiazole (C5);

[0245] N2: 1H-imidazolium (1,3-diazole) (C5), 1H-pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C6), pyrimidine (1,3-diazine) (C6) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6);

[0246] N3: triazole (C5), triazine (C6); and,

[0247] N4: Tetraazole (C5).

[0248] Examples of heteroaryl groups containing fused rings include, but are not limited to, those derived from the following C9 heteroaryl groups (having two fused rings):

[0249]

[0250] Examples of heteroaryl groups containing fused rings include, but are not limited to, those derived from the following C 10 Heteroaryl (with 2 fused rings):

[0251]

[0252] Examples of heteroaryl or heterocyclic compounds include, but are not limited to, those derived from:

[0253]

[0254] Screw C 6-12 Carbocyclic group: As used herein, the term spirocyclohexane is used in this context. 6-12 A carbocyclic group involves a portion having at least two molecular rings (with only one common atom). The simplest spiro compounds are bicyclic (having only two rings), or have a bicyclic portion as part of a larger ring system, in either case, the two rings being connected by a defined single common atom. SpiroC6- 12 A carbocyclic group refers to a cyclic group; that is, a monovalent portion obtained by removing hydrogen atoms from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which has 6 to 12 carbon atoms, including 3 to 7 ring atoms, wherein the rings share a common atom.

[0255] Screw C 6-12 Heterocyclic groups: As used herein, the term spiroC 6-12 Heterocyclic groups involve a portion having at least two molecular rings (with only one common atom). The simplest spiro compounds are bicyclic (having only two rings), or have a bicyclic portion as part of a larger ring system, in either case the two rings are connected by a defined single common atom. SpiroC 6-12 The heterocyclic moiety relates to a monovalent moiety obtained by removing hydrogen atoms from the ring atoms of a heterocyclic compound, having 8 to 12 ring atoms, of which 1 to 3 are cyclic heteroatoms, wherein the rings share a common atom. In some embodiments, each ring has 9 to 11 ring atoms, of which 1 to 2 are cyclic heteroatoms. To avoid confusion, substituents on the heteroaryl ring can be connected by carbon atoms or heteroatoms.

[0256] To avoid confusion, when multiple substituents are independently selected from a given group, the selected substituents may include the same substituents or different substituents from within the given group.

[0257] Pharmaceutically acceptable salts

[0258] The term "pharmaceutical acceptable" is used to indicate that an object (e.g., 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 PH Stahl and CG Wermuth, Weinheim / Zürich: Wiley-VCH / VHCA, 2002.

[0259] Suitable pharmaceutically acceptable salts of compounds of formula (I) are, for example, acid addition salts. Acid addition salts of compounds of formula (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to a 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.

[0260] Another suitable pharmaceutically acceptable salt of a compound of formula (I) is, for example, a base addition salt. A base addition salt of a compound of formula (I) can be formed by contacting the compound with a suitable inorganic or organic base under conditions known to a person skilled in the art. The base addition salt can be formed, for example, using an inorganic base selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. The base addition salt can also be formed using an organic base selected from the group consisting of L-arginine, choline, L-lysine, tert-butylamine, ethylenediamine, ammonia, dimethylaminoethanol, N-methylglucosamine, tromethamine, and hydroxyethylmorpholine.

[0261] Therefore, in one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, citrate, maleate, oxalate, acetate, formate, benzoate, fumarate, succinate, tartrate, lactate, pyruvate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.

[0262] Therefore, in another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the pharmaceutically acceptable salt is a lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, L-arginine salt, choline salt, L-lysine salt, tert-butylamine salt, ethylenediamine salt, ammonium salt, dimethylaminoethanol salt, N-methylglucosamine salt, tromethamine salt, or hydroxyethylmorpholine salt.

[0263] Other forms

[0264] The compounds and salts described in this specification may exist in solvated and non-solvated forms. For example, the solvated form may be a hydrated form, such as a hemihydrate, monohydrate, dihydrate, trihydrate, or alternative amounts thereof. Compounds of formula (I) encompass all such solvated and non-solvated forms of compounds of formula (I), particularly with respect to the presence of PCSK9 inhibitory activity in such forms, as measured, for example, using the tests described herein.

[0265] The compounds and salts described in this specification include one or more chiral (i.e., asymmetric) centers. Where the structure or chemical name in this specification does not indicate chirality, the structure or name is intended to cover any single stereoisomer (i.e., any single chiral isomer) corresponding to that 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., racemates) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by direct synthesis from, for example, a chiral starting material.

[0266] The specific enantiomers of the compounds described in this article may be more active than other enantiomers of the same compound.

[0267] According to one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which is a single enantiomer with an enantiomer excess (%ee) of ≥95%, ≥98%, or ≥99%. Conveniently, the single enantiomer is present with an enantiomer excess (%ee) of ≥99%.

[0268] According to another embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients, wherein the compound is a single enantiomer with an enantiomer excess (%ee) of ≥95%, ≥98%, or ≥99%. Conveniently, the single enantiomer is present with an enantiomer excess (%ee) of ≥99%.

[0269] isotope

[0270] 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 their isotopes are substituted (e.g., where one or more carbon atoms are...). 11 C or 13 C carbon isotopes, or one or more of the hydrogen atoms are 2 H or 3 Compounds of formula (I) with H isotope.

[0271] tautomer

[0272] The compounds and salts described in this specification may exist as mixtures of tautomers. A “tautomer” is a structural isomer that exists in equilibrium due to the migration of hydrogen atoms. Compounds of formula (I) include all tautomers of compounds of formula (I), particularly in relation to the PCSK9 inhibitory activity of such tautomers.

[0273] Therapy, prevention and related terminology

[0274] The term "therapy" is intended to have its normal meaning, namely, treating a disease to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for the underlying pathological condition. Unless specifically indicated to the contrary, the term "therapy" also includes "prevention." The terms "treatment" and "in treatment" should be interpreted accordingly.

[0275] The term “prevention” is intended to have its normal meaning and includes: primary prevention, which is used to prevent the development of disease; and secondary prevention, which involves taking temporary or permanent protective measures for patients after the disease has developed to prevent the disease from worsening or deteriorating or new symptoms related to the disease from appearing.

[0276] The term “treatment” is used synonymously with “therapeutic therapy.” Similarly, the term “treatment” can be considered as “the application of a therapeutic therapy,” where “therapeutic therapy” is as defined herein.

[0277] The term "subject" intended for application includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) 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. Humans are preferred subjects.

[0278] As used herein, "effective amount" means an amount sufficient to achieve the desired biological effect. As used herein, "therapeutic effective amount" means an amount sufficient to achieve the desired therapeutic effect. For example, a therapeutic effective amount may refer to an amount sufficient to improve at least one sign or symptom of the disease to be treated.

[0279] Pharmaceutical Composition

[0280] Compounds of formula (I) and their pharmaceutically acceptable salts may be administered as pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients.

[0281] Therefore, in one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0282] The excipients selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, 6th Edition, Pharmaceutical Press, edited by Ray C. Rowe, Paul J. Sheskey, and Marian Quinn. Pharmaceutically acceptable excipients can function as, for example, adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, flow aids, thickeners, and coating agents. As those skilled in the art will understand, some pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions, depending on the amount of excipient present in the composition and what other excipients are present in the composition.

[0283] Pharmaceutical compositions may be in the form suitable for oral administration (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable for topical administration (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), suitable for inhalation administration (e.g., as fine powders or liquid aerosols), suitable for inhalation administration (e.g., as fine powders), or suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or suitable for rectal administration as suppositories. The compositions can be obtained through conventional procedures well known in the art. Compositions intended for oral use may contain additional components, such as one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0284] In human therapeutic treatment, a suitable daily dose of the compounds disclosed herein or pharmaceutically acceptable salts thereof is about 0.0001 mg / kg body weight to 100 mg / kg body weight.

[0285] The pharmaceutical formulations described herein can be formulated using methods known to those skilled in the art to provide doses of the active compound ranging from 0.1 mg to 1000 mg. Daily doses must vary depending on the host being treated, the specific route of administration, any co-administered therapies, and the severity of the disease being treated. Therefore, the optimal dose can be determined by the physician treating any particular patient.

[0286] The pharmaceutical compositions described herein comprise compounds of formula (I) or pharmaceutically acceptable salts thereof, and are therefore expected to be useful in therapeutic applications.

[0287] Therefore, in one embodiment, a pharmaceutical composition for use in a therapy is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0288] In one embodiment, a pharmaceutical composition is provided 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, a pharmaceutical composition is provided 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, a pharmaceutical composition is provided 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.

[0289] How to use

[0290] The compounds described herein can be used in treatment methods. A treatment method is also provided, comprising administering a therapeutically effective amount of a compound of formula (I) to a subject requiring treatment. The term "therapeutically effective amount" is an amount sufficient to demonstrate benefit to the patient. Such benefit may be improvement in at least one symptom. The actual amount administered, as well as the rate and duration of administration, will depend on the nature and severity of the disease being treated. Treatment prescriptions (e.g., dosage determination) are within the responsibility of general practitioners and other physicians.

[0291] The compound can be administered alone or in combination with other treatments, either simultaneously or sequentially, depending on the condition to be treated.

[0292] In one embodiment, 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 a therapy. In another embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), is provided for manufacture of a medicament. In yet another embodiment, a treatment method is provided comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0293] The compounds described in this article are PCSK9 inhibitors. The PCSK9 gene was identified using genetic mapping techniques from DNA of subjects with autosomal dominant hypercholesterolemia (Abifadel 2003). The encoded protein is a serine protease primarily expressed in the liver, intestine, kidneys, and nervous system and circulating in plasma. While not wishing to be bound by any particular theory, studies of mutations in the gene suggest its putative role is the reduction of LDLR at the cell surface, independent of its catalytic activity (Abifadel 2010). The binding of PCSK9 to 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 downregulated by dietary cholesterol, glucagon, ethinyl estradiol, chenodeoxycholic acid, and bile acid-activated farnesyl X receptor (FXR) (Maxwell 2003; Persson 2009; Langhi 2008). Because elevated PCSK9 levels reduce the abundance of LDLR on the cell surface, increased statin doses do not achieve a proportional reduction in LDL-C. Therefore, this article discloses methods for treating various cardiovascular diseases and conditions that benefit from PCSK9 inhibition, thereby reducing LDL-C.

[0294] In some embodiments, the method of inhibiting PCSK9 is performed in a subject in need, thereby treating a PCSK9-mediated disease or condition. This document also discloses methods for treating or preventing PCSK9-mediated diseases or conditions, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, this document discloses methods for treating PCSK9-mediated diseases or conditions, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the prevention of cardiovascular events by inhibiting PCSK9 has been described in Robinson 2015.

[0295] In some embodiments, a method of treating 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 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 cardiovascular disease.

[0296] Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalpha-lipoproteinemia, 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 some embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease. In some embodiments, the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In some embodiments, the disease is hyperlipidemia. In some embodiments, the disease is coronary artery disease.

[0297] In some embodiments, the disclosed treatment methods can lower high levels of circulating serum cholesterol, such as LDL-C and VLDL-cholesterol. Furthermore, the disclosed methods can be used to lower circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL-C, and atherogenic lipoproteins. In some embodiments, the diseases or conditions treated with the disclosed compounds and compositions include atherosclerosis and atherosclerotic plaque formation. Subjects with gain-of-function mutations in the PCSK9 gene also benefit from treatment with the disclosed compounds and compositions that counteract the mutation by inhibiting PCSK9.

[0298] In some embodiments, a method of treating kidney 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 kidney 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 kidney disease. In some embodiments, the kidney disease is chronic kidney disease.

[0299] Combination therapy

[0300] The disclosed compounds and compositions can be administered in combination with other therapeutic agents, such as other agents suitable for treating high levels of LDL-C and triglycerides. In some embodiments, administration of one or more additional therapeutic agents in combination with the compounds described herein provides a synergistic effect. In some embodiments, administration of one or more additional therapeutic agents in combination provides an additive effect.

[0301] In some embodiments where combination therapy is used, the amounts of the compounds or salts described in this specification and other pharmaceutically active agents, when combined, are therapeutically effective in treating the targeted disease in animal patients. In this context, these are “therapeuticly effective amounts” if the combined amounts, when combined, are sufficient to satisfy: reduce or completely alleviate symptoms or other adverse effects of the disease; cure the disease; reverse, completely stop, or slow the progression of the disease; or reduce the risk of disease exacerbation. Typically, such amounts can be determined by those skilled in the art by, for example, starting with a dose range of the compounds or salts described in this specification and with approved or otherwise disclosed dose ranges for other pharmaceutically active compounds.

[0302] The pharmaceutical compositions described herein may contain one or more additional active ingredients. Where appropriate, examples of combinations of the compounds described herein (or pharmaceutically acceptable salts thereof) and one or more additional active ingredients are described herein.

[0303] This specification further relates to a combination therapy in which the compounds of this specification or their pharmaceutically acceptable salts and a second active ingredient are administered simultaneously, sequentially, or in combination 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.

[0304] In one aspect, a combination is provided (e.g., as a medicine for treating one of the diseases or conditions listed herein, such as cardiovascular diseases), the combination comprising a compound of the present specification or a pharmaceutically acceptable salt thereof and at least one active ingredient selected from:

[0305] i) Statins;

[0306] ii) Cholesterol absorption inhibitors;

[0307] iii) SGLT2 inhibitors;

[0308] iv) P2Y12 inhibitors;

[0309] v) ATP-citrate lyase inhibitors; and

[0310] vi) Antihypertensive drugs.

[0311] In another aspect of this specification, a pharmaceutical composition (e.g., a medicament for treating one of the diseases or conditions listed herein, such as cardiovascular diseases) is provided, the pharmaceutical composition comprising a compound of this specification or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from:

[0312] i) Statins;

[0313] ii) Cholesterol absorption inhibitors;

[0314] iii) SGLT2 inhibitors;

[0315] iv) P2Y12 inhibitors;

[0316] v) ATP-citrate lyase inhibitors; and

[0317] vi) Antihypertensive drugs.

[0318] 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 statins, wherein the statin is selected from atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In another aspect, the statin is rosuvastatin (Crestor).

[0319] 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, wherein the cholesterol absorption inhibitor is selected from ezetimibe (Ezetrol).

[0320] 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, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin, or tofogliflozin. In some aspects, the SGLT2 inhibitor is selected from dapagliflozin (Farxiga or Forxiga).

[0321] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with at least one additional active ingredient selected from P2Y12 inhibitors, wherein the P2Y12 inhibitor is selected from Brilinta (Ticagrelor) and Clopidogrel (Plavix).

[0322] 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 ATP-citrate lyase inhibitors, wherein the ATP-citrate lyase inhibitor is bempedoic acid (Nexletol).

[0323] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with at least one additional active ingredient selected from ezetimibe, rosuvastatin, dapagliflozin, and ticagrelor. In one embodiment, one additional active ingredient is present. In another embodiment, two additional active ingredients are present. 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.

[0324] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with at least one additional active ingredient selected from antihypertensive drugs. In some aspects, the antihypertensive drug is selected from valsartan (Diovan), metoprolol (Lopressor), HCTZ (hydrochlorothiazide), olmesartan (Benicar), lisinopril (Prinivil, Zestril), amlodipine besylate (Norvasc), candesartan, or calcium channel blockers, or combinations thereof. In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided in combination with the following:

[0325] i) Valsartan;

[0326] ii) Metolor;

[0327] iii) Valsartan and HCTZ;

[0328] iv) Olmesartan;

[0329] v) Olmesartan and HCTZ;

[0330] vi) Lisinopril;

[0331] vii) Amlodipine;

[0332] viii) Candesartan;

[0333] ix) Calcium channel blockers; or

[0334] x)HCTZ.

[0335] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, along with at least one additional active ingredient, for use in the simultaneous, separate, or sequential treatment of cardiovascular disease. In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cardiovascular disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with at least one additional active substance selected from ezetimibe, rosuvastatin, dapagliflozin, and ticagrelor.

[0336] In another embodiment, a method for treating cardiovascular disease in a subject is provided, 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 the at least one additional active substance is selected from ezetimibe, rosuvastatin, dapagliflozin and ticagrelor.

[0337] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating a subject with cardiovascular disease, wherein the treatment comprises administering to the subject alone, sequentially or simultaneously i) the compound of formula (I) or a pharmaceutically acceptable salt thereof, and ii) at least one additional active ingredient.

[0338] In one embodiment, a method for treating cardiovascular disease is provided, the method comprising administering to a subject in need a first amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second amount of at least one additional active ingredient, wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0339] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for manufacturing a medicament for treating cardiovascular disease, wherein the treatment comprises administering to the subject alone, sequentially or simultaneously i) the medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and ii) at least one additional active ingredient.

[0340] In the above embodiments, at least one additional active ingredient may be selected from (a) statins or pharmaceutically acceptable salts thereof, (b) ezetimibe or pharmaceutically acceptable salts thereof, and / or (c) bepedoconic acid or pharmaceutically acceptable salts thereof.

[0341] Therefore, in some embodiments, at least one additional active ingredient is a statin or a pharmaceutically acceptable salt thereof. In some embodiments, at least one additional active ingredient is ezetimibe or a pharmaceutically acceptable salt thereof. In some embodiments, at least one additional active ingredient is bepedocoxel or a pharmaceutically acceptable salt thereof. In some embodiments, at least one additional active ingredient is a statin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof.

[0342] statins

[0343] Statins include atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, velostatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, rosuvastatin, and simvastatin; and their pharmaceutically acceptable salts.

[0344] US4231938 discloses certain compounds isolated after culturing microorganisms belonging to the genus *Aspergillus*, such as lovastatin. Furthermore, US4444784 discloses synthetic derivatives of the above compounds, such as simvastatin. Additionally, US4739073 discloses certain substituted indoles, such as fluvastatin. Furthermore, US4346227 discloses ML-236B derivatives, such as pravastatin. Furthermore, EP0491226A and US5502199 disclose certain pyridyl dihydroxyheptenic acid, such as cerivastatin. Furthermore, US5273995 discloses certain 6-[2-(substituted -pyrrolo-1-yl)alkyl]pyran-2-ones, such as atorvastatin and any pharmaceutically acceptable form thereof (i.e., LIPITOR). ® Atorvastatin calcium (i.e., atorvastatin hemicalcium), disclosed in US5273995, is currently marketed as Lipitor. ®Sales. US RE37,314 E discloses rosuvastatin and rosuvastatin calcium. EP0304063 and US5011930 disclose pitavastatin. US3983140 discloses mevastatin. US4448784 and US4450171 disclose velotasamine. US4804770 discloses compaltine. EP0738510A2 discloses davastatin. EP0363934A1 discloses fluindolstatin. US4450171 discloses dihydrocomaltine.

[0345] In some implementations, the statins are selected from atorvastatin, rosuvastatin, lovastatin, pravastatin, simvastatin, and fluvastatin; and pharmaceutically acceptable salts thereof.

[0346] In some embodiments, the statin is rosuvastatin or a pharmaceutically acceptable salt thereof. In some of these embodiments, the statin is rosuvastatin or rosuvastatin calcium.

[0347] dose level

[0348] In some implementations, the statin dosing regimen is a moderate-intensity dosing regimen according to the ACC (American College of Cardiology) / AHA (American Heart Association) (Grundy 2018).

[0349] This moderate-intensity administration can be:

[0350]

[0351] Rosuvastatin can be administered in the form of rosuvastatin calcium, wherein the dose given is calculated based on the free form of rosuvastatin.

[0352] Atorvastatin can be administered in the form of atorvastatin calcium or atorvastatin calcium trihydrate, wherein the dose given is calculated based on the free form of atorvastatin.

[0353] Pravastatin can be administered in the form of pravastatin calcium, wherein the dose given is calculated based on the free form of pravastatin.

[0354] Pitavastatin can be administered in the form of pitavastatin calcium, wherein the dose given is calculated based on the free form of pitavastatin.

[0355] In some implementations, statin dosing regimens are high-intensity dosing according to ACC (American College of Cardiology) / AHA (American Heart Association) (Grundy 2018).

[0356] This high-intensity dose can be:

[0357]

[0358] As mentioned above, rosuvastatin can be administered in the form of rosuvastatin calcium, wherein the dose given is calculated based on the free form of rosuvastatin.

[0359] As above, atorvastatin can be administered in the form of atorvastatin calcium or atorvastatin calcium trihydrate, wherein the dose given is calculated based on the free form of atorvastatin.

[0360] In some implementations, statin dosing regimens are suitable for patients from, for example, Japan:

[0361]

[0362] As mentioned above, rosuvastatin can be administered in the form of rosuvastatin calcium, wherein the dose given is calculated based on the free form of rosuvastatin.

[0363] As above, atorvastatin can be administered in the form of atorvastatin calcium or atorvastatin calcium trihydrate, wherein the dose given is calculated based on the free form of atorvastatin.

[0364] As mentioned above, pitavastatin can be administered in the form of pitavastatin calcium, wherein the dose given is calculated based on the free form of pitavastatin.

[0365] Ezetimibe

[0366] Ezetimibe refers to the compound with the chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azacyclobutane-2-one and the structure shown below:

[0367]

[0368] Ezetimibe inhibits cholesterol absorption in the small intestine and reduces the amount of cholesterol normally available to hepatocytes. Lower cholesterol levels in hepatocytes cause them to absorb more cholesterol from the circulation, thus lowering circulating cholesterol levels. It blocks key mediators of cholesterol absorption, namely the gastrointestinal epithelium.

[0369] Niemann-Pick C1-like 1 (NPC1L1) protein on cells and in hepatocytes; it blocks aminopeptidase N and disrupts the caveolin 1-annexin A2 complex involved in cholesterol transport (Phan 2012).

[0370] Awad reported in 2018 that ezetimibe reduced plasma LDL-C levels by up to 20% when used alone, and reduced plasma lipoprotein(a) levels by about 7%.

[0371] In some implementations, ezetimibe is administered at doses of 5 mg to 15 mg daily. Daily doses can be up to 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, or 15 mg. Daily doses can be at least 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0372] In some implementations, ezetimibe is administered at a dose of 10 mg daily.

[0373] In some implementations, ezetimibe is administered as a free base, i.e., not as a salt.

[0374] In some embodiments, ezetimibe is administered in the form of its pharmaceutically acceptable salt, wherein the dose is the same as that of ezetimibe in non-salt form. Unless otherwise stated, any reference in this disclosure to the amount of ezetimibe or its pharmaceutically acceptable salt is based on the free base equivalent of ezetimibe. For example, "wt%" means % based on the free base equivalent of ezetimibe.

[0375] Bepedioxanone

[0376] Bepedoconic acid refers to a compound also known as 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid with the structure shown below:

[0377] .

[0378] Bepedocoxel targets the cholesterol biosynthesis pathway in the liver. Bepedocoxel inhibits two steps upstream of ATP-citrate lyase (ACL), HMG CoA reductase. Bepedocoxel is converted to its active coenzyme A form via an enzyme found only in the liver and not in muscle (Agarwala and Goldberg 2020).

[0379] Bepedocoxel has been approved for use alone or in combination with other lipid-lowering therapies in patients who cannot achieve their LDL-C target at the maximum tolerated dose of statins, or in patients who are intolerant to or have contraindications to statins.

[0380] In some implementations, bepedioxic acid is administered at a dose of 150 mg to 200 mg daily. The daily dose can be up to 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. The daily dose can be at least 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, or 180 mg.

[0381] In some implementations, bepedocoxel is administered at a dose of 180 mg per day.

[0382] In some implementations, bepedocoxel is applied in the form of a free acid, i.e., not as a salt.

[0383] In some embodiments, bepedocoxel is administered in the form of its pharmaceutically acceptable salt, wherein the dose is the dose of bepedocoxel in its non-salt form. Unless otherwise stated, any reference in this disclosure to the amount of bepedocoxel or its pharmaceutically acceptable salt is based on the free base equivalent of bepedocoxel. For example, "wt%" means % based on the free acid equivalent of bepedocoxel.

[0384] Salts of bepedoconic acid are described in WO 2020 / 257573.

[0385] Other implementation plans

[0386] The following implementation schemes can be applied to all aspects described above or may relate to a single aspect. These implementation schemes can be combined in any combination.

[0387] (A1a)

[0388] In some implementations, A is (A1a).

[0389] (A1a)

[0390] In some implementations of formula A1a, X 1 It is N.

[0391] In some implementations of formula A1a, X 1 It is CR A3 .

[0392] In some implementations, A has the formula (A1):

[0393] .

[0394] R A1

[0395] In some implementation schemes, R A1 Choose from the following groups:

[0396] (i)H

[0397] (ii) Halogenated groups;

[0398] (iii)CN;

[0399] (iv)C 1-6 Hydrocarbons, optionally reacted with one or more OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0400] (v)C 1-6 alkoxy group, optionally surrounded by OH, one or more halogroups, C 1-6 Alkyl amide substitution;

[0401] (vi)C 1-6 Alkyl esters;

[0402] (vii)C 1-6 Alkyl acyl; and

[0403] (viii)OH.

[0404] In some implementation schemes, R A1 Choose from the following groups:

[0405] (i)H

[0406] (ii) Halogenated groups;

[0407] (iii)CN;

[0408] (iv)C 1-6 Hydrocarbons, optionally reacted with one or more OH, CN, C 1-6 Alkyl acyl, C 1-6 Substitution with an alkoxy group or one or more halogroups; and

[0409] (v)C 1-6 alkoxy groups, optionally surrounded by OH, halogroups, or C groups. 1-6 Alkyl amide substitution.

[0410] In some implementation schemes, R A1 Choose from the following groups:

[0411] (i)H

[0412] (ii) Halogenated groups;

[0413] (iii)CN;

[0414] (iv)C 1-6 Hydrocarbons, optionally reacted with one or more OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0415] (v)C 1-6 alkoxy groups, optionally surrounded by OH, one or more halogroups, or C 1-6 Alkylamide substitution; and

[0416] (vi)OH.

[0417] When R A1 C is an optional substitute1-6 In hydrocarbons, it is an optional substituted C. 1-6 Alkyl group. In some embodiments, it is an optionally substituted methyl or optionally substituted ethyl group. In further embodiments, it is an optionally substituted methyl group. In still further embodiments, it is an unsubstituted methyl group.

[0418] When R A1 C is an optional substitute 1-6 In the case of alkyl groups, in some embodiments, the optional substituents are selected from OH, CN, and one or more halogroups. In further embodiments, the optional substituents are selected from OH, F, and Br.

[0419] When R A1 C is an optional substitute 1-6 When alkoxy is used, in some embodiments it is optionally substituted with OMe or ethoxy. In some embodiments, R A1 It is the unreplaced OMe.

[0420] When R A1 C is an optional substitute 1-6 In the case of alkoxy, in some embodiments, the optional substituent is selected from C. 1-6 Alkyl amide or one or more halogroups. In another embodiment, the optional substituent is selected from one, two or three F atoms.

[0421] When R A1 When it is a halogenated group, in some embodiments it is F, Br, or Cl. In other embodiments it is Br or Cl.

[0422] In some implementation schemes, R A1 It's H.

[0423] In some implementation schemes, R A1 It is OH.

[0424] In some implementation schemes, R A1 It's CN.

[0425] In some implementation schemes, R A1 It is a methyl group.

[0426] In some implementation schemes, R A1 It is -OCF2H.

[0427] In some implementation schemes, R A1 Selected from H, Br, Cl, CN, OMe, ethoxy, methyl, and ethyl. In a further embodiment, R A1 Selected from H, -OCF2H, Br, and Cl. In a further embodiment, R A1Selected from H, Br, and Cl. In other embodiments, R A1 It is H or -OCF2H.

[0428] In some implementation schemes, R A1 The following groups are selected: H, OH, Br, Cl, CN, OCF2H, OMe, ethoxy, methyl, and ethyl. In some embodiments, R A1 The following groups are selected: H, Br, Cl, CN, OCF2H, OMe, ethoxy, methyl, and ethyl. In some embodiments, R A1 Choose from the following groups: H, OH, -OCF2H, Br, and Cl. In some implementations, R A1 Choose from the following groups: H, -OCF2H, Br, and Cl.

[0429] In some implementation schemes, R A1 It's H.

[0430] In some implementation schemes, R A1 It is OH or H.

[0431] R A2

[0432] In some implementation schemes, R A2 Choose from the following groups:

[0433] (i)H;

[0434] (ii) Halogenated groups;

[0435] (iii)CN;

[0436] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0437] (v)C 1-6 Alkoxy groups, which are optionally substituted with OH, alkylamide or one or more halogroups;

[0438] (vi)C 1-6 Acylamide (where the acyl substituent is H or Me);

[0439] (vii)C 1-6 Thioalkyl,

[0440] (viii)C 1-6 Alkyl esters;

[0441] (ix)C 1-6 Alkyl acyl,

[0442] (x)C 4-5 Heterocyclic groups;

[0443] (xi)C5 heteroaryl;

[0444] (xii)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, OH, C 2-3 alkynyl group, C 4-6 Heterocyclic group, C 1-3 Alkyl substitution, wherein the alkyl group is optionally substituted with one or more halogroups or OH groups;

[0445] (xiii)OH; and

[0446] (xiv)C 1-6 Alkylamino.

[0447] In some implementation schemes, R A2 Choose from the following groups:

[0448] (i)H;

[0449] (ii) Halogenated groups;

[0450] (iii)CN;

[0451] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0452] (v)C 1-6 Alkoxy groups, which are optionally substituted with OH, alkylamide or one or more halogroups;

[0453] (vi)C 1-6 Acylamide (where the acyl substituent is H or Me);

[0454] (vii)C 1-6 Thioalkyl,

[0455] (viii)C 1-6 Alkyl esters;

[0456] (ix)C 1-6 Alkyl acyl,

[0457] (x)C 4-5 Heterocyclic groups;

[0458] (xi)C5 heteroaryl;

[0459] (xii)C1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, C 2-3 alkynyl group, C 4-6 Heterocyclic group, C 1-3 Alkyl substitution, wherein the alkyl group is optionally substituted with one or more halogroups or OH groups; and

[0460] (xiii)OH.

[0461] In some implementation schemes, R A2 Choose from the following groups:

[0462] (i)H;

[0463] (ii) Halogenated groups;

[0464] (iii)CN;

[0465] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Acyl group, C 1-6 Alkoxy or one or more halogroups are substituted;

[0466] (v)OH;

[0467] (vi)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[0468] (vii)C 1-6 Alkyl esters;

[0469] (viii)C 1-6 Alkyl acyl;

[0470] (ix)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, C 2-3 alkynyl group, C 4-6 Heterocyclic group or C 1-3 Alkyl substitution, wherein the alkyl group is optionally substituted with one or more halogroups or OH groups; and

[0471] (x)C 1-6 Alkylamino.

[0472] In a further implementation scheme, R A2 Choose from the following groups:

[0473] (i)H;

[0474] (ii) Halogenated groups;

[0475] (iii)CN;

[0476] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Acyl group, C 1-6 Alkoxy or one or more halogroups are substituted;

[0477] (v)OH;

[0478] (vi)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[0479] (vii)C 1-6 Alkyl esters;

[0480] (viii)C 1-6 Alkyl acyl; and

[0481] (ix)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, C 2-3 alkynyl group, C 4-6 Heterocyclic group or C 1-3 Alkyl substitution, wherein the alkyl group is optionally substituted with one or more halogroups or OH groups.

[0482] In a further implementation scheme, R A2 Choose from the following groups:

[0483] (i)H;

[0484] (ii) Halogenated groups;

[0485] (iii)CN;

[0486] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0487] (v)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[0488] (vi)C 1-6 Thioalkyl;

[0489] (viii)C 1-6 Alkyl esters; and

[0490] (ix)C 1-6Alkylamide, which is optionally C 1-3 Alkyl amide, CN, C 2-3 alkynyl group, C 4-6 Heterocyclic group or C 1-3 Alkyl substitution, wherein the alkyl group is optionally substituted with one or more halogroups or OH groups.

[0491] In a further implementation scheme, R A2 Choose from the following groups:

[0492] (i)H;

[0493] (ii) Halogenated groups;

[0494] (iii)C 1-6 Alkyl esters;

[0495] (iv)C 1-6 hydrocarbon;

[0496] (v)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, C 2-3 alkynyl group, C 4-6 Heterocyclic group or C 1-3 Alkyl substitution, wherein the alkyl group is optionally substituted with one or more halogroups or OH groups;

[0497] (vi)C 1-6 Thioalkyl;

[0498] (vii)C 1-6 Alkyl acyl;

[0499] (viii) C5 heteroaryl; and

[0500] (ix)C 1-6 Alkylamino.

[0501] In some implementation schemes, R A2 Choose from the following groups:

[0502] (i)H;

[0503] (ii) Halogenated groups;

[0504] (iii)C 1-3 Alkyl groups, which are optionally substituted with OH or one or more halogroups;

[0505] (v)C 1-3 An alkoxy group, optionally substituted with OH or one or more halogroups; and

[0506] (vi) Cyclopropyl.

[0507] When RA2 When it is a halogenated group, in some embodiments it is Br or Cl. In a further embodiment, it is Cl.

[0508] In some implementation schemes, R A2 Selected from CF3, CN, Cl, OMe, methyl, cyclopropyl, -OCHF2, -OCF3 and optionally substituted C 1-6 Alkyl amide. In some embodiments, R A2 Selected from CN, Cl, OMe, methyl, cyclopropyl, -OCHF2, -OCF3 and optionally substituted C 1-6 Alkyl amide.

[0509] In some implementation schemes, R A2 Selected from C 1-6 Alkyl esters

[0510] In some implementation schemes, R A2 It's CN.

[0511] In some implementation schemes, R A2 It's H.

[0512] In some implementation schemes, R A2 It is OH.

[0513] In some implementation schemes, R A2 It is -C(=O)CH3.

[0514] In some implementation schemes, R A2 Yes, it is -OCHF2.

[0515] In some implementation schemes, R A2 It is cyclopropyl.

[0516] In some implementation schemes, R A2 It is Cl.

[0517] In some implementation schemes, R A2 It is a methyl group.

[0518] In some implementation schemes, R A2 It is S-ethyl.

[0519] In some implementation schemes, R A2 It is pyrazole.

[0520] In some implementation schemes, R A2 It is N(CH3)2.

[0521] In some implementation schemes, R A2It is C(=O)NH(CH2C(=O)NH2, C(=O)NHCH2C≡CH, C(=O)NH(oxacyclobutane), 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).

[0522] In some implementation schemes, R A2 It is -S-CH3.

[0523] In some implementation schemes, R A2 It is -S-CH2CH3.

[0524] In some implementation schemes, R A2 It is -S-CH2-C(=O)-O-CH3.

[0525] In some implementation schemes, R A2 It is C(=O)NH(CH)3.

[0526] In some implementation schemes, R A2 It's CF3.

[0527] When R A2 C is an optional substitute 1-6 In hydrocarbons, it is an optional substituted C. 1-6 Alkyl group. In some embodiments, it is an optionally substituted methyl, optionally substituted ethyl, or optionally substituted cyclopropyl group. In further embodiments, it is an optionally substituted methyl group. In further embodiments, it is an unsubstituted methyl group. In other embodiments, it is an unsubstituted cyclopropyl group.

[0528] When R A2 C is an optional substitute 1-6 In the case of alkyl groups, in some embodiments, the optional substituents are selected from OH, CN, or one or more halogroups. In further embodiments, the optional substituents are selected from OH, F, and Br.

[0529] When R A2 C is an optional substitute 1-6 In the case of an alkoxy group, in some embodiments it is optionally substituted with OMe or ethoxy.

[0530] When R A2 C is an optional substitute 1-6In the case of an alkoxy group, in some embodiments, the optional substituent is selected from alkylamide and one or more halogroups. In another embodiment, the optional substituent is selected from one or more F groups. In yet another embodiment, in R... A2 C is an optional substitute 1-6 In the case of alkoxy groups, it is difluoromethoxy (-OCHF2).

[0531] When R A2 It is C 1-6 In some embodiments, when it is an alkyl ester, it is -C(=O)OCH2CH3.

[0532] When R A2 It is C 1-6 In the case of alkylamides, in some embodiments, the optional substituent is selected from one or more methyl groups, oxetane rings, C2 alkylamides, and ethyl groups, wherein the ethyl group is optionally substituted with OH or one or more halogroups. In other embodiments, when R A2 It is C 1-6 When R is an alkylamide, it is C(=O)NHCH2C(=O)NH2, C(=O)NHCH2CHCH, -C(=O)NH-oxetane, C(=O)NHCH2CHF2, C(=O)NHCH2CH2OH, C(=O)NHCH2CH3, C(=O)NH2, C(=O)NHCH3, and C(=O)N(CH3)2. A2 It is C 1-6 In the case of alkylamides, in some embodiments, the optional substituent is OH.

[0533] When R A2 It is C 1-6 In some embodiments, when R is an alkylamino group, it is NHCH3, NHCH(CH3)2, N(CH2CH3)2, or N(CH3)2. In some embodiments, when R... A2 It is C 1-6 When it is an alkylamino group, it is N(CH3)2.

[0534] In other implementations, R A2 Selected from -OCHF2, Cl, -OMe, methyl, C(=O)CH3, CN, -CH2OH, H, and cyclopropyl. In a further embodiment, R A2 Selected from methyl, -OCHF2, Cl, -CH2OH, H, CN, -C(=O)CH3 and -OMe.

[0535] In a further implementation scheme, R A2 Selected from methyl, -OCHF2, Cl and cyclopropyl.

[0536] In a further implementation scheme, R A2 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-oxacyclobutane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH and -C(=O)NHCH2CH3.

[0537] In some implementation schemes, R A2 Choose from the following groups: -CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxacyclobutane, -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.

[0538] In some implementation schemes, R A2 Selected 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 and C(=O)NH(CH2CH2OH).

[0539] In some implementation schemes, R A2Selected 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, and -OCF3. These groups are shown in the table below:

[0540]

[0541]

[0542] In some implementation schemes, R A2 Selected from the following groups:

[0543]

[0544] In some implementation schemes, R A2 Selected from the following groups:

[0545]

[0546] In some implementation schemes, R A2 Selected from the following groups:

[0547]

[0548] In some implementation schemes, R A2 Selected from the following groups:

[0549]

[0550] In some implementation schemes, R A2 Selected from halogenated groups, C 1-6 Hydrocarbons and C2Cs optionally substituted with one or more halogenated groups 1-6 Alkyl group.

[0551] In some implementation schemes, R A2 Selected from chlorine, bromine, C 1-6 Alkyl groups and C groups optionally substituted with one, two, or three halogen groups 1-6 Alkyl group.

[0552] In some implementation schemes, R A2 Selected from H, chloro, methyl, OCF2H, CF3 and cyclopropyl.

[0553] In some implementation schemes, R A2Selected from chlorine, methyl, OCF2H, and CF3. In some embodiments, R A2 Selected from methyl, CF3, and OCF2H. In some embodiments, R A2 Selected from OCF2H and methyl.

[0554] In some implementation schemes, R A2 Selected from chlorine, methyl and OCF2H.

[0555] In some implementation schemes, R A2 Selected from chlorine and OCF2H.

[0556] R A3

[0557] In some implementation schemes, R A3 Choose from the following groups:

[0558] (i)H;

[0559] (ii) Halogenated groups;

[0560] (iii)CN;

[0561] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[0562] (v)OH;

[0563] (vi)C 1-6 Alkoxy groups, which may optionally be substituted with OH, NH2, C4 heterocyclic groups or one or more halogroups;

[0564] (vii)C 1-6 Acyloxy group;

[0565] (viii) C4 heterocyclic group;

[0566] (ix)-NH2;

[0567] (x)C 1-6 Alkylamino groups, which may optionally be substituted with CN, OH or C4 heterocyclic groups;

[0568] (xi)C 1-6 Dialkylamino, which is optionally substituted with -NH2;

[0569] (xii)C 1-6 Acylamide (where the acyl substituent is H or Me);

[0570] (xiii) amidoyl or methyl-amidinyl;

[0571] (xiv) carboxylamino;

[0572] (xv)C 1-6 Thioalkyl groups, which are optionally substituted with OH or NH2;

[0573] (xvi)C 1-6 alkylsulfinyl;

[0574] (xvi)C 1-6 Alkyl sulfonyl group, which is optionally substituted with one or more haloyl groups;

[0575] (xvii)C 1-6 sulfonylimide group;

[0576] (xviii)C 1-6 Alkyloxyphosphine group;

[0577] (xix) carboxyl group;

[0578] (xx)C(=O)NH2

[0579] (xxi)C 1-6 Alkyl esters;

[0580] (xxii)C 1-6 An alkyl acyl group, optionally substituted with one or more halogroups; and

[0581] (xxiii)C 1-6 Alkyl amide.

[0582] In some implementation schemes, R A3 Choose from the following groups:

[0583] (i)H;

[0584] (ii) Halogenated groups;

[0585] (iii)CN;

[0586] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino; -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[0587] (v)OH; and

[0588] (vi)C 1-6 An alkoxy group, which may optionally be substituted with an OH, NH2, C4 heterocyclic group or one or more halogenated groups.

[0589] In some implementation schemes, R A3 Choose from the following groups:

[0590] (i)H;

[0591] (ii) Halogenated groups;

[0592] (iii)CN;

[0593] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino; -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[0594] (v)OH;

[0595] (vi)C 1-6 An alkoxy group, which may optionally be substituted with an OH, NH2, C4 heterocyclic group or one or more halogenated groups.

[0596] In R A3 In the case of a halogenated group, in some embodiments it is Br or Cl. In some embodiments it is Cl. In further embodiments, R A3 It is Br.

[0597] When R A3 C is an optional substitute 1-6In hydrocarbons, it is an optional substituted C. 1-6 Alkyl group. In some embodiments, it is an optionally substituted methyl or optionally substituted ethyl group. In further embodiments, it is an optionally substituted methyl group. In still further embodiments, it is an unsubstituted methyl group.

[0598] When R A3 C is an optional substitute 1-6 In the case of alkyl groups, in some embodiments, the substituents are optionally selected from OH, CN, or one or more halogroups. In further embodiments, the optional substituents are optionally selected from OH, F, and Br.

[0599] In some implementation schemes, R A3 It is OH.

[0600] When R A3 C is an optional substitute 1-6 When alkoxy is used, in some embodiments it is optionally substituted OMe or ethoxy. In further embodiments, it is OMe.

[0601] When R A3 C is an optional substitute 1-6 In the case of an alkoxy group, in some embodiments, the optional substituent is selected from alkylamide or one or more halogroups. In another embodiment, the optional substituent is selected from one or more F groups.

[0602] In some implementation schemes, R A3 Selected from H, CF3, CN, C 1-2 Alkyl groups, NH2 groups, and halogenated groups. In other embodiments, R A3 Selected from H, methyl, CN and Cl.

[0603] In some implementation schemes, R A3 Selected from H, OMe, CF3, CN, C 1-2 Alkyl groups, NH2 groups, and halogen groups.

[0604] In some implementation schemes, R A3 Choose from the following groups: H, methyl, and OH.

[0605] In some implementation schemes, R A3 It's CN.

[0606] In some implementation schemes, R A3 It's H.

[0607] In some implementation schemes, R A3 It is a methyl group.

[0608] In some implementation schemes, R A3 It's OMe.

[0609] In some implementation schemes, R A3 Selected from methyl, H and CN.

[0610] In some implementation schemes, R A3 Selected from H, methyl and OH.

[0611] R A2 and R A3

[0612] When R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted C6 carbon aromatic rings or C6 carbon aromatic rings. 5-7 When they are heteroaromatic rings, they form either a benzene ring with optional substitution or a pyridine ring with optional substitution.

[0613] When R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted C6 carbon aromatic rings or C6 carbon aromatic rings. 5-7 When using a heteroaromatic ring, the optional substituents are selected from NH2, C... 1-6 Alkyl, C 1-6 Alkoxy and halogroups. 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.

[0614] In one implementation, when R A2 and R A3 Together with the carbon atoms they are bonded to, they form optionally substituted C atoms. 5-7 When a heteroaromatic ring is formed, they form optionally substituted pyridines. In some embodiments, the optional substituent is NH2. In another embodiment, R A2 and R A3 Together with the carbon atoms they are bonded to, they form unsubstituted pyridine. In another embodiment, R A2 and R A3 Together they form optionally substituted pyrazoles, optionally substituted pyrroles, or optionally substituted thiazoles. In some embodiments, the optional substituent is methyl.

[0615] When R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted C atoms. 5-7 In heteroaryrheic rings, the optional substituents are selected from C10 and C20. 1-6 Alkyl, C 1-6Alkoxy, NH2, and halogroups. In other embodiments, optional substituents are selected from methyl, ethyl, OMe, ethoxy, NH2, and halogroups. In other embodiments, optional substituents are selected from NH2 and methyl.

[0616] When R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted C atoms. 5-7 When heterocyclic, they form a 5-membered ring containing one or two atoms selected from N, O, and S. In some embodiments, the 5-membered ring contains one N and one S. In other embodiments, the 5-membered ring contains one N. In other embodiments, the 5-membered ring contains one N and one O. In other embodiments, the 5-membered ring contains two N atoms. In some embodiments, R... A3 and R A2 Together with the carbon atoms they bind to, they form optionally substituted pyrroles or pyrazoles.

[0617] When R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted C atoms. 5-7 In the case of heterocyclic compounds, the optional substituents are selected from NH2, C 1-6 alkyl,

[0618] C 1-6 Alkoxy and halogroups. 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.

[0619] In other implementations, R A2 and R A3 Together with the carbon atoms they are bonded to, they form:

[0620] (i) An optional substituted C6 heteroaromatic ring; wherein the optional substituent is NH2;

[0621] (ii) An optionally substituted C6-carbon aromatic ring; wherein the optional substituents are F, OMe, or Cl;

[0622] (iii) An optional substituted C5 heteroaromatic or C5 heterocyclic compound, wherein the optional substituent is methyl.

[0623] In some implementation schemes, R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted C6 carbon aromatic rings or C6 carbon aromatic rings. 5-7 A heteroaryrheic ring, wherein the optional substituents are selected from C. 1-6 Alkyl and halogenated groups.

[0624] In some implementation schemes, RA2 and R A3 Together they form unsubstituted 2-pyrazole, methyl-substituted 2-pyrrole, optionally NH2-substituted pyridine, or optionally substituted Cl, F, or OMe phenyl.

[0625] In some implementation schemes, R A2 and R A3 Together they form a ring selected from the following:

[0626]

[0627] In some implementations, A is selected from one of the following:

[0628]

[0629] In some implementations, A is selected from one of the following:

[0630]

[0631] In some implementations, A1a is selected from one of the following:

[0632]

[0633] In some implementations, A is selected from one of the following:

[0634]

[0635] In some implementations, A is selected from one of the following:

[0636]

[0637] In some implementations, A is selected from one of the following:

[0638]

[0639] In some implementations, A is selected from one of the following:

[0640]

[0641] In some implementations, A is selected from one of the following:

[0642]

[0643] (A2a)

[0644] In some implementations, A is (A2a).

[0645] (A2a)

[0646] The wavy line indicates the attachment point to B.

[0647] Z 1 Choose from O or S.

[0648] In some implementation schemes, Z 1 It is O.

[0649] In some implementation schemes, Z 1 It is S.

[0650] R A5

[0651] R A5 Choose from the following groups:

[0652] (i)H;

[0653] (ii) Halogenated groups;

[0654] (iii)CN;

[0655] (iv) A C1 alkyl group, optionally substituted with one or more OH, CN, or one or more halogroups; and

[0656] (v)C1 alkoxy group, which is optionally substituted with one or more halogroups;

[0657] In some implementation schemes, R A5 The methyl group is selected from H, a halogroup, CN, or optionally substituted with one or more OH groups or one or more halogroups.

[0658] In some implementation schemes, R A5 It's H.

[0659] R A6

[0660] R A6 Choose from the following groups:

[0661] (i)H;

[0662] (ii) Halogenated groups;

[0663] (iii)CN;

[0664] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0665] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[0666] (vi)C 1-6 Alkylamino;

[0667] (vii)C 1-6 Thioalkyl;

[0668] (viii)C 1-6 Alkyloxyphosphine; and

[0669] (ix)C 1-6 Alkylphosphonoyl;

[0670] In some implementation schemes, R A6 Choose from the following groups:

[0671] (i)H;

[0672] (ii) Halogenated groups;

[0673] (iii)C 1-6 Alkyl groups, which are optionally substituted with one or more OH groups or one or more halogroups;

[0674] (iv)C 1-6 Alkoxy groups, which are optionally substituted with one or more halogroups;

[0675] (v)C 3-5 cycloalkyl;

[0676] (vi)C 1-6 Thioalkyl; and

[0677] (vii)C 1-6 Alkyloxyphosphine group.

[0678] In some implementation schemes, R A6 Choose from the following groups:

[0679] (i)H;

[0680] (ii) Halogenated groups;

[0681] (iii)C 1-3 Alkyl groups, optionally substituted with one or more OH groups or one or more halogroups; and

[0682] (iv)C 1-3 Alkoxy groups, which are optionally substituted with one or more halogenated groups.

[0683] In some implementation schemes, R A6 It's H.

[0684] RA7

[0685] R A7 Choose from the following groups:

[0686] (i)H;

[0687] (ii) Halogenated groups;

[0688] (iii)CN;

[0689] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[0690] (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups and one or more halogenated groups;

[0691] (vi) C4 heterocyclic group;

[0692] (vii)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups;

[0693] (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and

[0694] (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2;

[0695] In some implementation schemes, R A7 It's H.

[0696] In some implementation schemes, R A7 It's CN.

[0697] In some implementations, when R A7 When it is a halogenated group, it is selected from Cl, Br, and F.

[0698] In some implementations, when R A7 C is an optional substitute 1-6When alkoxy is present, it is OCF3, OCF2H, or OMe.

[0699] In some implementation schemes, R A7 Selected from H, Cl, Br, OMe, CH=CH2, OCF3, OCF2H, F, CH2-CF2H, CF3, CF2H, CN, propargyl, and CH2-cyclopropyl. In a further embodiment, R A3 Selected from H, Cl, Br and OMe.

[0700] In some implementations, A is selected from one of the following:

[0701]

[0702] The wavy line indicates the attachment point to B, and R... A5 R A6 and R A7 As defined in any other implementation thereof.

[0703] In some implementations, A is selected from one of the following:

[0704]

[0705] The wavy line indicates the attachment point to B.

[0706] In some implementations, A has the formula A2a7:

[0707] (A2a7).

[0708] In some implementations, A is selected from one of formulas A2a1, A2a3, and A2a5. In some implementations, A2a is formula A2a5.

[0709] (A2b)

[0710] In some implementations, A is A2b:

[0711] (A2b).

[0712] Z 6

[0713] In some implementation schemes, Z 6 It is N.

[0714] In some implementation schemes, Z 6 It is CH.

[0715] Z 7

[0716] In some implementation schemes, Z7 It is N.

[0717] In some implementation schemes, Z 7 It is CR A8 .

[0718] Z 6 and Z 7

[0719] In some implementation schemes, Z 6 For CH, and Z 7 It is CR A8 In some of these implementation schemes, R A8 It's H.

[0720] In some implementation schemes, Z 6 It is N, and Z 7 It is CH.

[0721] Z 8 and Z 9

[0722] In some implementation schemes, Z 8 and Z 9 Choose independently from the following groups:

[0723] (i)H;

[0724] (ii) Halogenated groups;

[0725] (iii)CN;

[0726] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0727] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[0728] (vi)C 1-6 Alkylamino

[0729] (vii)C 1-6 Thioalkyl,

[0730] (viii)C 1-6 Alkyloxyphosphine; and

[0731] (ix)C 1-6 Alkylphosphonoyl group.

[0732] In some implementation schemes, Z 8 and Z 9 Choose independently from the following groups:

[0733] (i)H;

[0734] (ii) Halogenated groups;

[0735] (iii)CN;

[0736] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0737] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide or one or more halogroups are substituted;

[0738] (vi)C 1-6 Alkylamino;

[0739] (vii)C 1-6 Thioalkyl, and

[0740] (viii)C 1-6 Alkyloxyphosphine group.

[0741] In some implementation schemes, Z 8 and Z 9 Selected independently from:

[0742] (i)H;

[0743] (ii) Halogenated groups;

[0744] (iii)C 1-6 Alkyl groups, which are optionally substituted with one or more OH groups or one or more halogroups;

[0745] (iv)C 1-6 Alkoxy groups, which are optionally substituted with one or more halogroups;

[0746] (v)C 3-5 cycloalkyl;

[0747] (vi)C 1-6 Thioalkyl; and

[0748] (vii)C 1-6 Alkyloxyphosphine group.

[0749] In some implementation schemes, Z 8 and Z 9 It is H. In some implementations, Z6 and Z 7 It is CH, and Z 8 and Z 9 It's H.

[0750] In some implementation schemes, when Z 8 and Z 9 When one or both of them are halogenated groups, it is F, Cl, or Br.

[0751] In some implementation schemes, when Z 8 and Z 9 One or both of them are optional substitutes for C 1-6 When alkyl, it is methyl, ethyl, propyl, CH2OH, CH2F, CHF2, or CF3. In a further embodiment, it is methyl, ethyl, CH2OH, or CF3.

[0752] In some implementation schemes, when Z 8 and Z 9 One or both of them are optional substitutes for C 1-6 When alkoxylated, it is OMe, O-ethyl, O-propyl, OCF2H, OCF3, or OCFH2. In a further embodiment, it is OMe, OCF3, or OCF2H.

[0753] In some implementation schemes, when Z 8 and Z 9 When one or both of them are cycloalkyl, it is cyclopropyl or cyclobutyl. In some embodiments, it is cyclopropyl.

[0754] In some implementation schemes, when Z 8 and Z 9 One or both of them are C 1-6 When thioalkyl, it is S-CH3, S-CH2CH3, or S-CH2CH2CH3. In some embodiments, it is S-CH3.

[0755] In some implementation schemes, when Z 8 and Z 9 One or both of them are C 1-6 When alkyloxyphosphine is used, it is P(=O)Me2, P(=O)(CH2CH3)2, or P(=O)(CH3)(CH2CH3). In some embodiments, it is P(=O)Me2.

[0756] In a further implementation plan, Z 8 and Z 9One or both of them are selected from H, CH2OH, OCF2H, OCF3, CF3, F, Cl, Br, ethyl, cyclopropyl, methyl, P(=O)Me2, S-CH3 and OMe.

[0757] R A8

[0758] In some implementation schemes, R A8 Selected from:

[0759] (i)H;

[0760] (ii) Halogenated group

[0761] (iii)CN;

[0762] (iv)C 1-6 Alkyl groups, which are optionally substituted with OH or one or more halogroups;

[0763] (v)C 2-6 Alkenyl group, which may optionally be substituted with OH or one or more halogroups;

[0764] (vi)C 2-6 An alkynyl group, optionally substituted with OH or one or more haloyl groups; and

[0765] (vii)C 1-6 Alkoxy groups, which are optionally substituted with one or more halogenated groups.

[0766] In some implementation schemes, R A8 It's H.

[0767] In some implementation schemes, R A8 It's CN.

[0768] In some implementations, when R A8 When it is a halogenated group, it is selected from Cl, Br, or F.

[0769] In some implementations, when R A8 C is an optional substitute 1-6 When alkyl, it is methyl, ethyl, propyl, CF3, CF2H, CH2-CF2H, or CH2-cyclopropyl. In a further embodiment, it is CF3, CH2-CF2H, CF2H, or CH2-cyclopropyl.

[0770] In some implementations, when R A8 It is C 2-6 When it is alkenyl, it is CH=CH2, CH=CHCH3, or CH2CH=CH2. In some embodiments, it is CH=CH2.

[0771] In some implementations, when R A8 It is C 2-6 When it is alkynyl, it is propynyl, acetylene, or 1-butyne. In some embodiments, it is propynyl.

[0772] In some implementations, when R A8 C is an optional substitute 1-6 When alkoxy is present, it is OCF3, OCF2H, or OMe.

[0773] In some implementation schemes, R A8 Selected from H, Cl, Br, OMe, CH=CH2, OCF3, OCF2H, F, CH2-CF2H, CF3, CF2H, CN, propargyl, and CH2-cyclopropyl. In a further embodiment, R A8 Selected from H, Cl, Br and OMe.

[0774] In some implementations, A is selected from one of the following:

[0775]

[0776] The wavy line indicates the attachment point to B, and Z... 7 Z 8 and Z 9 As defined in any other implementation thereof.

[0777] In some implementations, A is selected from one of the following:

[0778]

[0779] The wavy line indicates the attachment point to B, and Z... 6 As defined in any other embodiment herein. In some embodiments, A is formula A2b7.

[0780] In some implementations, A is selected from one of the following:

[0781]

[0782] (A3a) and (A3b)

[0783] In some implementations, A is (A3a) or (A3b):

[0784] (A3a) or (A3b).

[0785] In some implementations, A is (A3a). In some implementations, A is (A3b).

[0786] RA9

[0787] In some implementation schemes, R A9 It is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 1-methylcyclopropyl and 2-methylcyclopropyl.

[0788] In some implementation schemes, R A9 It is selected from methyl, cyclopropyl, 1-methylcyclopropyl and 2-methylcyclopropyl.

[0789] In some implementation schemes, R A9 Selected from methyl and 1-methylcyclopropyl.

[0790] In some implementation schemes, R A9 It is a methyl group.

[0791] In some implementation schemes, A is:

[0792] .

[0793] (A4)

[0794] In some implementations, A is A4.

[0795] (A4)

[0796] R A4

[0797] R A4 Choose from the following groups:

[0798] (i)H;

[0799] (ii) Halogenated groups;

[0800] (iii)CN;

[0801] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[0802] (v)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[0803] (vi)C 1-6 Acylamide (wherein the acyl group is optionally substituted with H or methyl);

[0804] (vii)C 1-6 Thioalkyl;

[0805] (viii)C 1-6 Alkyl esters;

[0806] (ix)C 1-6 Alkyl acyl;

[0807] (x)C 4-5 Heterocyclic groups;

[0808] (xi)C5 heteroaryl;

[0809] (xii)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, OH, C 2-3 alkynyl group, C 4-6 Heterocyclic group, C 1-3 Alkyl substitution, wherein C 1-3 The alkyl group may optionally be substituted with one or more halogroups or OH groups;

[0810] (xiii)OH; and

[0811] (xiv)C 1-6 Alkylamino;

[0812] In some implementation schemes, R A4 Choose from the following groups:

[0813] (i)H;

[0814] (ii) Halogenated groups;

[0815] (iii)C 1-3 Alkyl groups, which are optionally substituted with OH or one or more halogroups;

[0816] (v)C 1-3 An alkoxy group, optionally substituted with OH or one or more halogroups; and

[0817] (vi) Cyclopropyl.

[0818] In some implementation schemes, R A4 It's CN.

[0819] In some implementation schemes, R A4 It's H.

[0820] In some implementation schemes, R A4 Yes, it is -OCHF2.

[0821] In some implementation schemes, R A4 It is cyclopropyl.

[0822] In some implementation schemes, R A4 It is Cl.

[0823] In some implementation schemes, R A4 It is a methyl group.

[0824] In some implementation schemes, R A4 Selected from H, CN, -OCF2H, cyclopropyl, Cl and methyl.

[0825] In some implementations, A is one of (A1a), (A2b), (A3a), and (A3b).

[0826] In some implementations, A has formula (A1a) or (A2b).

[0827] In some implementations, A is selected from one of the following:

[0828]

[0829] In some implementations, A is selected from one of the following:

[0830]

[0831] In some implementations, A is selected from one of the following:

[0832]

[0833] In some implementations, A is selected from one of the following:

[0834]

[0835] In some implementations, A is selected from one of the following:

[0836]

[0837] (B-1)

[0838] In some implementations, B has the formula (B-1):

[0839] (B-1),

[0840] The wavy line indicates the attachment points to A and C; where R... B1 It is -H, -OH, -OMe, -O-ethyl, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0841] In other implementations, R B1 It is H, -CH2OH, -CH2CH2OH or =CHCH2-OH.

[0842] In other implementations, R B1It is -CH2OH, -CH2CH2OH, or =CHCH2-OH.

[0843] In other implementations, R B1 It's H.

[0844] In another implementation, B has formula (B-1a):

[0845] (B-1a).

[0846] In a further embodiment, B has the formula (B-1b):

[0847] (B-1b).

[0848] Therefore, in some embodiments, the compound of formula (I) is an S,S-enantiomer.

[0849] Alternatively, it is disclosed that B may have the formula (B-2):

[0850] (B-2)

[0851] The wavy line indicates the attachment points to A and C;

[0852] R B2 It is C 1-2 Alkyl-OH, CH2CONHMe or C 1-3 alkyl,

[0853] Where R A1 When it is an H or halogenated group, R B2 It is C 1-2 Alkyl-OH or CH2C(=O)NHMe,

[0854] Among these alternatives, R B2 It is C 1-2 Alkyl-OH or C 1-3 alkyl.

[0855] Among these alternatives, R B2 It is C 1-2 Alkyl-OH or CH2C(=O)NHMe.

[0856] In some of these alternatives, when X 1 It is O or S and R A1 When it is an H or halogenated group, R B2 It is C 1-2 Alkyl-OH or CH2C(=O)NHMe.

[0857] In some of these alternatives, when B has equation (B-2), it has the following equation (B-2a):

[0858] (B-2a)

[0859] The wavy line indicates the attachment points to A and C; and R B2 It is C 1-2 Alkyl-OH, CH2CONHMe or C 1-2 Alkyl, wherein when R A1 When it is an H or halogenated group, R B2 It is C 1-2 Alkyl-OH or CH2C(=O)NHMe.

[0860] (C-1a)

[0861] In some implementations, C is (C-1a).

[0862] (C-1a).

[0863] In some implementations, X is H. In some implementations, X is F.

[0864] In some implementations, C is (C-1):

[0865] (C-1)

[0866] In some implementation schemes, R N It is H, methyl, or optionally C 1-3 An alkoxy-substituted benzyl group. In some embodiments, R N It is H, methyl, or C 1-3 An alkoxy-substituted benzyl group. In some embodiments, R N It is H, methyl, or p-methoxybenzyl. In some embodiments, R N It is H or methyl. In some embodiments, R N Is H or optionally C 1-3 Benzyl groups substituted with alkoxy groups.

[0867] In some implementation schemes, R N It is arbitrarily C 1-3 An alkoxy-substituted benzyl group. In some embodiments, R N It was C 1-3 Benzyl groups substituted with alkoxy groups.

[0868] In some implementation schemes, R N It is p-methoxybenzyl.

[0869] In some implementation schemes, R N It's H.

[0870] In some implementation schemes, R N It is a methyl group.

[0871] In some implementation schemes, R C1 and R C2 Together with the carbon atoms they are bonded to, they form benzene rings or pyridine rings, which are optionally separated by one or more R atoms. C3 Group substitution.

[0872] In some implementation schemes, R C1 and R C2 Together with the carbon atoms they bond to, they form a benzene ring, which is optionally bounded by one or more R atoms. C3 Group substitution.

[0873] In some implementation schemes, R C1 and R C2 Together with the carbon atoms they are bonded to, they form a pyridine ring, which is optionally bound by one or more R atoms. C3 Group substitution.

[0874] In some implementation schemes, R C1 and R C2 Together with the carbon atoms they are bonded to, they form unsubstituted benzene rings or unsubstituted pyridine rings.

[0875] In some implementation schemes, R C1 and R C2 Together with the carbon atoms they are bonded to, they form an unsubstituted benzene ring.

[0876] In some implementation schemes, R C1 and R C2 Together with the carbon atoms they are bonded to, they form an unsubstituted pyridine ring.

[0877] In some implementation schemes, R C3 Selected from CN and P(=O)Me2.

[0878] In some implementation schemes, R C3 It's CN.

[0879] In some implementation schemes, R C3 It is P(=O)Me2.

[0880] In some implementations, C has the following formula:

[0881] (C-2a)

[0882] Where X is hydrogen or fluorine, and where Q is... 1 Q2 Q 3 and Q 4 Both are CH, or Q 1 Q 2 Q 3 and Q 4 One of them is selected from N, C-CN, C-CONMe2 and CP(=O)Me2, and the other three are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is N-Me, and the adjacent Q 1 Q 2 Q 3 Or Q 4 One of them is C=O, and the other two are CH.

[0883] In some implementation schemes, Q 1 Q 2 Q 3 and Q 4 Both are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is N-Me, and the adjacent Q is... 1 Q 2 Q 3 Or Q 4 One of them is C=O, and the other two are CH.

[0884] In some implementation schemes, Q 1 Q 2 Q 3 and Q 4 Both are CH; or Q 1 and Q 2 One of them is N-Me, and the other is C=O, and Q 3 and Q 4 For CH.

[0885] In some implementations, C has the following formula:

[0886] (C-2)

[0887] Q 1 Q 2 Q 3 and Q 4 Both are CH, or Q 1 Q 2 Q 3 and Q 4One of them is selected from N, C-CN and CP(=O)Me2, and the other three are CH.

[0888] In another implementation, C is selected from one of the formulas listed in the table below:

[0889]

[0890] The wavy line indicates the attachment point to B, and X is hydrogen or fluorine. In some embodiments of these implementations, X is H. In some embodiments of these implementations, X is F.

[0891] In some implementations, C is selected from one of the following:

[0892]

[0893] The wavy line indicates the attachment point with B, R. N As defined in any other embodiment herein, and X is hydrogen or fluorine. In some embodiments of these embodiments, X is H. In some embodiments of these embodiments, X is F.

[0894] In some implementations, C is selected from one of the following:

[0895]

[0896] Where X is hydrogen or fluorine. In some embodiments of these implementations, X is H. In some embodiments of these implementations, X is F.

[0897] In some implementations, C is selected from one of the following:

[0898]

[0899] In some implementations, C is:

[0900] .

[0901] A and C

[0902] In some implementation schemes, A is:

[0903] ;

[0904] And C is selected from:

[0905] and .

[0906] In some implementations, X is hydrogen.

[0907] In some implementation schemes, A is selected from:

[0908]

[0909] And C is selected from:

[0910]

[0911] The wavy line indicates the attachment point to B, and R... A9 R A1 R A2 Z 8 Z 9 X and R N As defined in any other embodiment herein. In some embodiments of these embodiments, X is H. In some embodiments of these embodiments, X is F.

[0912] In some implementation schemes, A is selected from:

[0913]

[0914] And C is selected from:

[0915]

[0916] The wavy line indicates the attachment point to B.

[0917] In some implementation schemes, A is selected from:

[0918]

[0919] And C is selected from:

[0920]

[0921] The wavy line indicates the attachment point to B.

[0922] ABC (A1a)

[0923] In other embodiments, the compound of formula ABC has the formula (I-Ax):

[0924] (I-Ax),

[0925] Where R A1 R A2 X 1 X, R C1 R C2 and R N As defined in any other implementation thereof.

[0926] In some implementation schemes, R A1 It is H, OH, CN, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl, or ethyl, wherein the optional substituent on the -OMe, -O-ethyl, methyl, or ethyl group is selected from OH, CN, and one or more halogroups. In some embodiments, R A1 It is H, CN, OH, Br, Cl, optionally substituted -OMe, -O-ethyl, methyl, or ethyl, wherein the optional substituent on the -OMe, -O-ethyl, methyl, or ethyl group is selected from OH, CN, or one or more halogroups. In a further embodiment, R A1 It is an optionally substituted O-methyl group, wherein the optional substituent is one or more F groups. In a further embodiment, R A1 It is H. In a further implementation, R A1 It is OH.

[0927] In some implementation schemes, R A2 Choose from the following groups: Br, Cl, CN, H, -C(=O)CH3, C 1-6 Alkyl amide (which is optionally C 1-3 Alkylamide substitution), optionally C 1-3 Alkyl ester-substituted thioalkyl, CN, C 2-3 alkynyl group, C 4-6 Heterocyclic group, C 1-3 Alkyl group (optionally substituted with one or more halogroups or OH groups), optionally substituted methoxy, methyl, ethyl, or cyclopropyl groups (wherein the optional substituents are selected from OH, CN, and one or more halogroups), and optionally substituted methoxy or ethoxy groups (wherein the optional substituents are selected from alkylamide and one or more halogroups). In some embodiments, R A2 Choose from the following groups: Br, Cl, CN, H, -C(=O)CH3, C 1-6 Alkyl amide (which is optionally C 1-3 Alkylamide substitution), CN, C 2-3 alkynyl group, C 4-6 Heterocyclic group, C 1-3 Alkyl group (optionally substituted with one or more halogroups or OH groups), optionally substituted methoxy, methyl, ethyl, or cyclopropyl groups (wherein the optional substituents are selected from OH, CN, or one or more halogroups), and optionally substituted methoxy or ethoxy groups (wherein the optional substituents are selected from alkylamide or one or more halogroups). In a further embodiment, R A2Selected from CN, methyl, Cl, -C(=O)CH3, -C(=O)OCH2CH3, cyclopropyl, -C(=O)NHCH2C(=O)NH2, -C(=O)NHCH2CHCH, -C(=O)NH-oxetane, -C(=O)NHCH2CHF2, -C(=O)NHCH2CH2OH, -C(=O)NHCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OCF2H, H, -OMe, and -OCF3. In some embodiments, R A2 Choose from the following groups: CN, methyl, Cl, -C(=O)CH3, OCHF2, cyclopropyl, OCF3, OCH3, H, -C(=O)NH(CH3), S-CH3, -S-CH2CH3 and -S-CH2-C(=O)-O-CH3.

[0928] In some implementation schemes, R A3 Choose from the following groups: CN, Br, Cl, OH, H, CF3, C 1-2 Alkyl, C 1-2 Alkyl groups and NH2. In a further embodiment, R A3 Selected from H, methyl and CN.

[0929] In other implementations, R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted C6 carbon aromatic rings or C6 carbon aromatic rings. 5-7 The heteroaromatic ring, with optional substituents selected from NH2, C 1-6 Alkyl, C 1-6 Alkoxy and halogroups. In other embodiments, optional substituents are selected from NH2, methyl, ethyl, OMe, F, Cl, and Br.

[0930] In some implementation schemes, R A3 and R A2 Together with the carbon atoms they are bonded to, they form optionally substituted pyridines, optionally substituted benzenes, pyrroles, or pyrazoles. In some embodiments, R A2 and R A3 Together they form unsubstituted 2-pyrazole, methyl-substituted 2-pyrrole, optionally NH2-substituted pyridine, or optionally substituted benzene with Cl, F, or OMe.

[0931] In other embodiments, the compound of formula ABC has the formula (I-Bx) or (I-By):

[0932] (I-Bx),

[0933] (I-By),

[0934] Where R A2 X, R C1 R C2 and R N As defined in any other implementation thereof.

[0935] In some implementations, formula (I-Bx) can be formula (I-Bax), (I-Bbx), or (I-Bcx) as shown below:

[0936] (I-Bax),

[0937] (I-Bbx),

[0938] (I-Bcx),

[0939] Among them, X and R C1 R C2 and R N As defined in any other implementation thereof.

[0940] In some implementations, formula (I-By) can be formula (I-Bay) as shown below:

[0941] (I-Bay),

[0942] Where X and R C1 R C2 and R N As defined in any other implementation thereof.

[0943] In other embodiments, the compound of formula ABC has the formula (I-Cx):

[0944] (I-Cx),

[0945] Where R A1 R A2 X 1 X and R N As defined in any other implementation thereof, and Q 1 Q 2 Q 3 and Q 4 Both are CH, or Q 1 Q 2 Q 3 and Q 4One of them is selected from N, C-CN, CC(=O)NMe2 and CP(=O)Me2, and the other three are CH; Q 1 Q 2 Q 3 and Q 4 One of them is N-Me, and the adjacent Q 1 Q 2 Q 3 Or Q 4 One of them is C=O.

[0946] In some implementation schemes, Q 1 Q 2 Q 3 and Q 4 Both are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is N-Me, and the adjacent Q is... 1 Q 2 Q 3 Or Q 4 One of them is C=O, and the other two are CH.

[0947] In some implementation schemes, Q 1 Q 2 Q 3 and Q 4 Both are CH; or Q 1 and Q 2 One of them is N-Me, and the other is C=O, and Q 3 and Q 4 For CH.

[0948] In some embodiments of formula (I-Cx), X is hydrogen, and Q 1 Q 2 Q 3 and Q 4 Both are CH, or Q 1 Q 2 Q 3 and Q 4 One of them is selected from N, C-CN and CP(=O)Me2, and the other three are CH.

[0949] In some implementations, R in equation (I-Cx) A2 Selected from fluorine, chlorine, bromine and iodine.

[0950] In some implementations, formula (I-Cx) can be any of formulas (I-Cax) to (I-Cgx) as shown below:

[0951] (I-Cax),

[0952] (I-Cbx),

[0953] (I-Ccx),

[0954] (I-Cdx),

[0955] (I-Cex),

[0956] (I-Cfx),

[0957] (I-Cgx).

[0958] ABC (A2a)

[0959] In other embodiments, the compound of formula ABC has formula (IV-A):

[0960] (IV-A)

[0961] Z 1 R A5 R A6 R A7 X, R C1 R C2 and R N As defined in any other implementation thereof.

[0962] In some implementations, when ABC has formula (IV-A), Z 1 It is S. In other implementations, Z 1 It is O.

[0963] In some implementations, when ABC has formula (IV-A), R A5 The group selected is from the group consisting of: H, halogroup, CN, C1 alkyl (optionally substituted with one or more OH, CN, or one or more halogroups), and C1 alkoxy (optionally substituted with one or more halogroups). In some embodiments, R A5 Selected from H, a halogroup, CN, or a methyl group optionally substituted with one or more OH groups or one or more halogroups. In some embodiments, R A5 It's H.

[0964] In some implementations, when ABC has formula (IV-A), R A6Choose from the following groups: H, halogenated group, CN, C 1-6 Hydrocarbons (which may optionally be converted by OH, CN, C) 1-6 alkyl acyl,

[0965] C 1-6 (alkoxy or one or more halogenated groups substituted), C 1-6 Alkoxy groups (which are optionally C 1-6 Alkyl amide, C 1-6 alkylphosphonoyl or one or more halogen groups substituted), C 1-6 Alkylamino, C 1-6 Thioalkyl, C 1-6 Alkyloxyphosphine and C 1-6 Alkylphosphonoyl group. In some embodiments, R A6 Choose from the following groups: H, halogenated group, C 1-3 Alkyl groups (optionally substituted with one or more OH groups or one or more halogroups) or C 1-3 Alkoxy group (which is optionally substituted with one or more halogroups). In some embodiments, R A6 It's H.

[0966] In some implementations, when ABC has formula (IV-A), R A7 Choose from the following groups: H, halogenated group, CN, C 1-6 Hydrocarbons (which may optionally be converted by OH, CN, C) 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl group or one or more halogenated groups substituted), C 1-6 alkoxy groups (optionally substituted with NH2, C4 heterocyclic groups, and one or more halogenated groups), C4 heterocyclic groups, C 1-6 Alkylamino groups (optionally substituted with CN, OH, or C4 heterocyclic groups), C 1-6 Dialkylamino (which may optionally be substituted with -NH2) and 1-6 Thioalkyl groups (optionally substituted with OH or -NH2). In some embodiments, R A7Selected from H, Cl, Br, OMe, CH=CH2, OCF3, OCF2H, F, CH2-CF2H, CF3, CF2H, CN, propargyl, and CH2-cyclopropyl. In a further embodiment, R A7 From H, Cl, Br, and OMe. In some implementations, R A7 It's H.

[0967] In some implementations, formula (IV-A) can be any of the following formulas: (IV-Aa), (IV-Ab), (IV-Ac), (IV-Ad), (IV-Ae), or (IV-Af):

[0968] (IV-Aa)

[0969] (IV-Ab),

[0970] (IV-Ac),

[0971] (IV-Ad),

[0972] (IV-Ae),

[0973] (IV-Af),

[0974] Where R A5 R A6 R A7 X, R C1 R C2 and R N As defined in any other implementation thereof.

[0975] In other embodiments, the compound of formula ABC has formula (IV-B):

[0976] (IV-B)

[0977] Z 1 R A5 R A6 X, Q 1 Q 2 Q 3 Q 4 and R N As defined in any other implementation thereof.

[0978] In some implementations, formula (IV-B) can be any of the following formulas: (IV-Ba), (IV-Bb), (IV-Bc), (IV-Bd), and (IV-Be):

[0979] (IV-Ba),

[0980] (IV-Bb),

[0981] (IV-Bc),

[0982] (IV-Bd),

[0983] (IV-Be).

[0984] ABC (A2b)

[0985] In other embodiments, the compound of formula ABC has formula (II-Ax):

[0986] (II-Ax),

[0987] Z 6 Z 7 Z 8 Z 9 X, R C1 R C2 and R N As defined in any other implementation thereof.

[0988] In some implementations, when ABC has the formula (II-Ax), Z 8 and Z 9 Independently selected from the group consisting of: H, one or more halogroups, CN, C 1-6 Hydrocarbons (which may optionally be converted by OH, CN, C) 1-6 Alkyl acyl, C 1-6 (alkoxy or one or more halogenated groups substituted), C 1-6 Alkoxy groups (which are optionally C 1-6 Alkyl amide or one or more halogenated groups substituted), C 1-6 Alkylamino, C 1-6 Thioalkyl and C 1-6 Alkyloxyphosphine group. In a further embodiment, Z 8 and Z 9Selected from H, CH2OH, OCF2H, OCF3, CF3, F, Cl, Br, ethyl, cyclopropyl, methyl, P(=O)Me2, S-CH3, CN and OMe.

[0989] In some implementations, when ABC has the formula (II-Ax), R A8 Selected from H, halogenated group, CN, C 1-6 Alkyl groups (optionally substituted with OH or one or more halogroups), C 2-6 Alkenyl (which may optionally be substituted with OH or one or more halogroups), C 2-6 Alkyne group (which may optionally be substituted with OH or one or more halogenated groups) or C 1-6 Alkoxy group (which is optionally substituted with one or more halogroups). In a further embodiment, R A8 Selected from H, Cl, Br, OMe, CH=CH2, OCF3, OCF2H, F, CH2-CF2H, CF3, CF2H, CN, propargyl, and CH2-cyclopropyl. In a further embodiment, R A8 Selected from H, Cl, Br and OMe.

[0990] In some implementations, formula (II-Ax) can be any of the following formulas: (II-Aax), (II-Abx), (II-Acx), and (II-Adx):

[0991] (II-Aax),

[0992] (II-Abx),

[0993] (II-Acx),

[0994] (II-Adx),

[0995] Z 7 Z 8 Z 9 X, R C1 R C2 and R N As defined in any other implementation thereof.

[0996] In other embodiments, the compound of formula ABC has formula (II-Bx):

[0997] (II-Bx),

[0998] Z 6X, R C1 R C2 and R N As defined in any other implementation thereof.

[0999] In some implementations, formula (II-Bx) can be either formula (II-Bax) or (II-Bbx) as shown below:

[1000] (II-Bax),

[1001] (II-Bbx),

[1002] Where X and R C1 R C2 and R N As defined in any other implementation thereof.

[1003] In other embodiments, the compound of formula ABC has formula (II-Cx):

[1004] (II-Cx),

[1005] Z 6 Z 7 Z 8 Z 9 X and R N As defined in any other implementation thereof, and

[1006] Q 1 Q 2 Q 3 and Q 4 Both are CH, or Q 1 Q 2 Q 3 and Q 4 One of them is selected from N, C-CN and C-PO(Me)2, and the other three are CH.

[1007] In some implementations, Z in formula (II-Cx) 8 and / or Z 9 Selected from fluorine, chlorine, bromine or iodine.

[1008] In some implementations, formula (II-Cx) can be any of formulas (II-Cax) to (II-Cgx) as shown below:

[1009] (II-Cax),

[1010] (II-Cbx),

[1011] (II-Ccx),

[1012] (II-Cdx),

[1013] (II-Cex),

[1014] (II-Cfx),

[1015] (II-Cgx),

[1016] Z 6 Z 7 Z 8 Z 9 X and R N As defined in any other implementation thereof.

[1017] ABC (A3a) and (A3b)

[1018] In other embodiments, the compound of formula ABC has the formula (III-Ax):

[1019] (III-Ax),

[1020] Where R A9 X, R C1 R C2 and R N As defined in any other implementation thereof.

[1021] In other embodiments, the compound of formula ABC has formula (III-Bx):

[1022] (III-Bx),

[1023] Where X and R C1 R C2 and R N As defined in any other implementation thereof.

[1024] In other embodiments, the compound of formula ABC has the formula (III-Cx):

[1025] (III-Cx),

[1026] Where R A9 X and R N As defined in any other implementation thereof, and

[1027] Q 1 Q 2 Q 3 and Q 4 Both are CH, or Q 1 Q 2 Q 3 and Q 4 One of them is selected from N, C-CN and CP(=O)Me2, and the other three are CH.

[1028] In some implementations, R in formula (III-Cx) A9 Selected from fluorine, chlorine, bromine and iodine.

[1029] In some implementations, formula (III-Cx) can be any of formulas (III-Cax) to (III-Cgx) as shown below:

[1030] (III-Cax),

[1031] (III-Cbx),

[1032] (III-Ccx),

[1033] (III-Cdx),

[1034] (III-Cex),

[1035] (III-Cfx),

[1036] (III-Cgx),

[1037] Where R A9 X and R N As defined in any other implementation thereof.

[1038] In some implementations, the above ABC formulas are: (I-Ax), (I-Bx), (I-By), (I-Bax), (I-Bbx), (I-Bcx), (I-Bay), (I-Cx), (I-Cax), (I-Cbx), (I-Ccx), (I-Cdx), (I-Cex), (I-Cfx), (I-Cgx), (IV-A), (IV-Aa), (IV-Ab), (IV-Ac), (IV-Ad), (IV-Ae), (IV-Af), (IV-B), (IV-Ba), (IV-Bb), (IV-Bc), (IV-Bd), (IV-Be), (II-Ax), (II-Aax), (II-Abx), (II-Acx), (II-Adx), (II-Bx). The stereochemistry of the B group in any of (II-Bax), (II-Bbx), (II-Cx), (II-Cax), (II-Cbx), (II-Ccx), (II-Cdx), (II-Cex), (II-Cfx), (II-Cgx), (III-Ax), (III-Bx), (III-Cx), (III-Cax), (III-Cbx), (III-Ccx), (III-Cdx), (III-Cex), (III-Cfx), and (III-Cgx) is as follows:

[1039] .

[1040] In some embodiments, the compounds of formula (I) are selected from Table 1 below. In some embodiments, the compounds are pharmaceutically acceptable salts selected from the compounds in Table 1 below.

[1041] Table 1. Examples 1 to 19

[1042]

[1043]

[1044]

[1045] In some embodiments, the compounds of formula (I) are selected from Table 2 below. In some embodiments, the compounds are pharmaceutically acceptable salts selected from the compounds in Table 2 below.

[1046] Table 2: Examples 20 to 32 .

[1047]

[1048]

[1049] In some embodiments, the compound is selected from Examples 1, 2, 3, 5, 8, 10, and 12. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 1, 2, 3, 5, 8, 10, and 12.

[1050] In some embodiments, the compound is selected from Examples 3, 8, 10, and 12. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 3, 8, 10, and 12.

[1051] In some embodiments, the compound is selected from Examples 3 and 12. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 3 and 12.

[1052] In some embodiments, the compound is selected from Examples 12, 16, 23, 28, 30, and 32. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 12, 16, 23, 28, 30, and 32.

[1053] In some embodiments, the compounds are selected from Examples 12 and 16. In some embodiments, the compounds are pharmaceutically acceptable salts of the compounds selected from Examples 12 and 16.

[1054] In some embodiments, the compound is selected from Examples 16 and 23. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 16 and 23.

[1055] In some embodiments, the compound is selected from Examples 12, 19, 23, 28, 30, and 32. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 12, 19, 23, 28, 30, and 32.

[1056] In some embodiments, the compound is selected from Examples 12 and 19. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 12 and 19.

[1057] In some embodiments, the compound is selected from Examples 19 and 23. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 19 and 23.

[1058] In some embodiments, the compound is selected from Examples 3 to 8, 10 to 19, and 23 to 27. In some embodiments, the compound is a pharmaceutically acceptable salt of the compound selected from Examples 3 to 8, 10 to 19, and 23 to 27.

[1059] Any definitions of formula (A1a) and its substituents in this document are to be understood to apply equally to formula (A1) and vice versa.

[1060] In some embodiments, compounds of formula (I) are provided.

[1061] ABC (I)

[1062] Or its pharmaceutically acceptable salts and tautomers or stereoisomers.

[1063] Where A has one of the following properties:

[1064] (A1)

[1065]

[1066] The wavy line indicates the attachment point with B;

[1067] R A1 Choose from the following groups:

[1068] (i)H;

[1069] (ii) Halogenated groups;

[1070] (iii)CN;

[1071] (iv)C 1-6 Hydrocarbons, optionally reacted with one or more OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1072] (v)C 1-6 alkoxy group, optionally surrounded by OH, one or more halogroups, C 1-6 Alkyl amide substitution;

[1073] (vi)C 1-6 Alkyl esters;

[1074] (vii)C 1-6 Alkyl acyl; and

[1075] (viii)OH;

[1076] R A2 Choose from the following groups:

[1077] (i)H;

[1078] (ii) Halogenated groups;

[1079] (iii)CN;

[1080] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6Alkoxy or one or more halogroups are substituted;

[1081] (v)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[1082] (vi)C 1-6 Acylamide (wherein the acyl group is optionally substituted with H or methyl);

[1083] (vii)C 1-6 Thioalkyl;

[1084] (viii)C 1-6 Alkyl esters;

[1085] (ix)C 1-6 Alkyl acyl;

[1086] (x)C 4-5 Heterocyclic groups;

[1087] (xi)C5 heteroaryl;

[1088] (xii)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, OH, C 2-3 alkynyl group, C 4-6 Heterocyclic group, C 1-3 Alkyl substitution, wherein C 1-3 The alkyl group may optionally be substituted with one or more halogroups or OH groups;

[1089] (xiii)OH; and

[1090] (xiv)C 1-6 Alkylamino;

[1091] R A3 Choose from the following groups:

[1092] (i)H;

[1093] (ii) Halogenated groups;

[1094] (iii)CN;

[1095] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[1096] (v)OH;

[1097] (vi)C 1-6 Alkoxy groups, which may optionally be substituted with OH, NH2, C4 heterocyclic groups or one or more halogroups;

[1098] (vii)C 1-6 Acyloxy group;

[1099] (viii) C4 heterocyclic group;

[1100] (ix)NH2;

[1101] (x)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups;

[1102] (xi)C 1-6 Dialkylamino, which is optionally substituted with -NH2;

[1103] (xii)C 1-6 Acylamide (where the acyl substituent is H or Me);

[1104] (xiii) amidoyl or methyl-amidinyl;

[1105] (xiv) carboxylamino;

[1106] (xv)C 1-6 Thioalkyl groups, which are optionally substituted with OH or NH2;

[1107] (xvi)C 1-6 alkylsulfinyl;

[1108] (xvii)C 1-6 Alkyl sulfonyl group, which is optionally substituted with one or more haloyl groups;

[1109] (xviii)C 1-6 sulfonylimide group;

[1110] (xix)C 1-6 Alkyloxyphosphine group;

[1111] (xx) carboxyl group;

[1112] (xxi)C(=O)NH2;

[1113] (xxii)C1-6 Alkyl esters;

[1114] (xxiii)C 1-6 An alkyl acyl group, optionally substituted with one or more halogroups; and

[1115] (xxiv)C 1-6 Alkyl amide;

[1116] Or R A3 and R A2 Together with the carbon atoms they are bonded to, they form:

[1117] (i) C can be arbitrarily substituted 5-7 Heterocyclic rings;

[1118] (ii) C can be arbitrarily substituted 5-7 Mixed aromatic rings;

[1119] (iii) Optionally substituted C6-carbon aromatic rings;

[1120] (iv) Optional substitution of C 5-7 carbon ring

[1121] Wherein, when present, one, two, three, or four optional substituents are independently selected from C. 1-6 Alkyl, Halogenated, C 1-6 Alkoxy, NH2, C 1-6 Alkylamino, OH, and CN;

[1122] (A2b)

[1123]

[1124] The wavy line indicates the attachment point with B;

[1125] Z 6 Is it N or CH?

[1126] Z 7 Is it N or CR? A8

[1127] Z 8 and Z 9 Choose independently from the following groups:

[1128] (i)H;

[1129] (ii) Halogenated groups;

[1130] (iii)CN;

[1131] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C1-6 Alkoxy or one or more halogroups are substituted;

[1132] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[1133] (vi)C 1-6 Alkylamino

[1134] (vii)C 1-6 Thioalkyl,

[1135] (viii)C 1-6 Alkyloxyphosphine; and

[1136] (ix)C 1-6 Alkylphosphonoyl;

[1137] R A8 Choose from the following groups:

[1138] (i)H;

[1139] (ii) Halogenated groups;

[1140] (iii)CN;

[1141] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[1142] (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups and one or more halogenated groups;

[1143] (vi) C4 heterocyclic group;

[1144] (vii)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups;

[1145] (viii)C 1-6Dialkylamino, optionally substituted with -NH2; and

[1146] (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2;

[1147] (A3a)

[1148] ;or

[1149] (A3b)

[1150]

[1151] Where R A9 Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 1-methylcyclopropyl, and 2-methylcyclopropyl;

[1152] Where B has the following formula

[1153] (B-1)

[1154] (B-1)

[1155] The wavy line indicates the attachment points to A and C;

[1156] R B1 It is -H, -OH, =CHCH2-OH, -C 1-4 Alkyl or -C 1-4 Alkyl, the C 1-4 Alkyl groups may optionally be substituted with -OH or OMe;

[1157] Where C has the following formula:

[1158] (C-1)

[1159]

[1160] Where R N It is H or methyl;

[1161] R C1 and R C2 Together with the carbon atoms they are bonded to, they form fused benzene rings or C6 heteroaromatic rings, which are optionally separated by one or more R atoms. C3 Group substitution;

[1162] Where R C3 Selected from

[1163] (i)CN;

[1164] (ii)P(=O)Me2;

[1165] (iii)C(=O)OH;

[1166] (iv)C 1-6 Hydrocarbons, which are optionally C 1-6 Alkyl substitution;

[1167] (v)C 1-6 Alkoxy;

[1168] (vi)C 1-6 Alkyl amide;

[1169] (vii)C 5-6 Mixed aromatics;

[1170] (viii) Halogenated groups; and

[1171] (ix)C 1-6 Alkyl acyl group.

[1172] In some embodiments, the compound of formula (I) is not one or more of the specific compounds described in WO 2024078620 A1.

[1173] In some embodiments, the compound of formula (I) is not one or more of the specific compounds described in WO 2025021188 A1.

[1174] In some embodiments, the compound of formula (I) is not one or more of the specific compounds described in WO 2025007915 A1.

[1175] General Synthesis

[1176] Compounds of general formulas (IG), (G9), and (G17) can be prepared according to schemes 1, 2, 3, 4, 5, and 6 below. The schemes and procedures described below illustrate synthetic routes for compounds of general formulas (IG), (G9), and (G17) and are not intended to be limiting. It is obvious that the sequences of transformations illustrated in schemes 1, 2, 3, 4, 5, and 6 can be modified in various ways. Therefore, the sequences of transformations illustrated in these schemes are not intended to be limiting.

[1177] Routes for the preparation of compounds and corresponding intermediates of general formulas (IG), (G9), and (G17) are described in schemes 1, 2, 3, 4, 5, and 6.

[1178] In each of schemes 1 to 6, D has the following equation:

[1179]

[1180] Where R C1 R C2 and R NAs defined for (C-1).

[1181] Option 1

[1182]

[1183] Scheme 1: A route for preparing compounds of general formula (IG), where X is a leaving group, PG is a protecting group, and R A1 R A2 and R A3 It has the meaning given above for the general formula (A1a). D is as defined above.

[1184] Monoaryl diamines of general formula (G3) can be substituted by nucleophilic aromatics (S N The S group is obtained by palladium-catalyzed Buchwald-Hartwig amination of a monoprotected diamine (G1) or its corresponding salt with a heteroaryl group (G2a) (where X is a leaving group, such as a halogen or -S(O)Me), as described in Scheme 1. N In the Ar method (where X is a group, such as fluorine or -S(O)Me), diamine (G1) can react with (G2a) in the presence of an inorganic base (such as K2CO3 or Na2CO3), an organic base (such as triethylamine or DIPEA), or without any additional base, in a polar solvent (such as DMSO, NMP, or nBuOH), at a temperature between 100°C and 130°C. The reaction time can vary between 1 hour and 24 hours. In some cases, microwave heating may be beneficial.

[1185] For palladium-catalyzed Buchwald-Hartwig amination, all methods known in the art can be applied. For example, diamine (G1) can be reacted with (G2a) in the presence of a palladium catalyst (such as Pd PEPPSI-IpentCl [CAS Registry No. 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 to 24 hours.

[1186] The diamines of general formula (G1) and the heteroaryl groups of general formula (G2a) are commercially available or can be prepared according to procedures available from the public domain. For the synthesis of diamines (G1), see, for example, WO2004004726 and its references.

[1187] Aryl diamines of general formula (G6) can be obtained by copper-catalyzed Ullmann coupling of (G3) with a heterocyclic (G4) or palladium-catalyzed Suzuki coupling with a boric acid derivative (G5). For Ullmann coupling, all methods known in the art can be applied. For example, (G3) can be reacted with (G4) in the presence of a copper catalyst (such as Cu(I)I, Cu(Otf)2 or Cu(Oac)2) and a base (such as Cs2CO3 or K2CO3) in a polar aprotic solvent (such as 1,4-dioxane, DMF or pyridine) at a temperature between room temperature and 120°C, preferably at 100°C, for 15 to 20 hours. In some cases, a ligand (such as N) can be added. 1 N 2 -Dimethylcyclohexane-1,2-diamine, TMEDA, N 1 N 2 (1,2-dimethylethane or N,N-dimethylglycine) is added to the reaction mixture.

[1188] For Suzuki coupling targeting (G6), all methods known in the art can be applied. For example, (G3) can be reacted with a boric acid derivative (G5) in the presence of a palladium catalyst (such as 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride [CAS Registry No. 95408-45-0] or 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride [CAS Registry No. 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 mixtures thereof) at a temperature between room temperature and 120°C for 2 to 15 hours.

[1189] The heterocyclic compounds of general formula (G4) and the boric acid derivatives of general formula (G5) are commercially available or can be prepared according to procedures available from the public domain.

[1190] Primary amines of general formula (G7) can be obtained from monoprotected diamines of general formula (G6) by deprotection methods. These methods can be, for example, acidic, basic, oxidative, or hydrogenation methods, depending on the protecting group applied. The appropriate protecting moiety of the amino group and its introduction and cleavage are well known in the art. For an overview of protecting group chemistry, see, for example, Wuts 2014.

[1191] The final compound of general formula (IG) can be obtained by nucleophilic aromatic substitution of primary amines of general formula (G7) (S). NThe synthesis is achieved by Buchwald-Hartwig amination catalyzed by Ar or palladium. Primary amines of general formula (G7) can be reacted with heteroaryl groups of general formula (G8) (where X is a leaving group, such as a halogen (e.g., chlorine) or -S(O)Me), using procedures similar to those described in Scheme 1 for the synthesis of (G3) from (G1) and (G2a). Heteroaryl groups of general formula (G8) are commercially available or can be prepared according to procedures available from the public domain. Similar general schemes involve oxadiazoles of general formula (G8a) and their isomers.

[1192] An alternative route for compounds of general formula (IG) begins with the deprotection of the diamine of general formula (G3) to obtain the primary amine of general formula (G9), as depicted in Scheme 1. For deprotection, the same procedure as described for the synthesis of (G7) from (G6) is applied.

[1193] Primary amines of general formula (G9) can further react with heteroaryl groups of general formula (G8) through nucleophilic aromatic substitution (S... N The Buchwald-Hartwig amination reaction, catalyzed by Ar or palladium, yields an aryl iodide of general formula (G10), which is similar to the procedure described in Scheme 1 for the synthesis of (G3) from (G1) and (G2a).

[1194] The final compound of general formula (IG) can be synthesized from aryl iodides of general formula (G10) via copper-catalyzed Ullmann coupling with heterocyclic HD (G4) or via palladium-catalyzed Suzuki coupling with boric acid derivative (G5), using a procedure similar to those described in Scheme 1 for the synthesis of compound (G6) from (G3).

[1195] Another approach to compounds of the general formula (IG) begins with a monoprotected diamine (G1) or its corresponding salt and a pre-assembled heteroaryl group (G11a) (where X is a leaving group, such as a halogen or -S(O)Me), and proceeds via nucleophilic aromatic substitution (S N Aryl diamines of general formula (G6) are obtained by Buchwald-Hartwig amination catalyzed by Ar or palladium. The applicable procedures are similar to those described in Scheme 1 for the synthesis of (G3) from (G1) and (G2a). The heteroaryl group of general formula (G11a) is commercially available or can be prepared according to procedures available from the public domain (e.g., via Chan-Lam coupling). Specific examples of (G11a) are described in subsequent paragraphs.

[1196] Scheme 2 outlines alternative routes for the preparation of compounds of general formula (IG) and intermediates of general formula (G10).

[1197] Option 2

[1198]

[1199] Option 2: A route for preparing compounds and intermediates (G10) of general formula (IG), where X is a leaving group, PG is a protecting group, and R... A1 R A2 and R A3 It has the meaning given above for the general formula (A1a). D is as defined above.

[1200] Monoaryl diamines of general formula (G12) can be substituted by nucleophilic aromatics (S... N The G3 is obtained by palladium-catalyzed Buchwald-Hartwig amination of a monoprotected diamine (G1) or its corresponding salt with a heteroaryl group (G8) (where X is a leaving group, such as a halogen or -S(O)Me). The applicable procedures are similar to those described in Scheme 1 for the synthesis of (G3) from (G1) and (G2a). Similar general schemes involve oxadiazoles of the general formula (G8a) and their isomers.

[1201] Deprotection of the diamine of general formula (G12) yields the primary amine of general formula (G13). For deprotection, the same procedure described in Scheme 1 for the synthesis of (G7) from (G6) is applied.

[1202] The final compound of general formula (IG) can be formed by a primary amine (G13) or its corresponding salt and a pre-assembled heteroaryl group (G11a) (where X is a leaving group, such as a halogen or -S(O)Me), through nucleophilic aromatic substitution (S N The synthesis is carried out by Buchwald-Hartwig amination catalyzed by Ar or palladium. The applicable procedures are similar to those described in Scheme 1 for the synthesis of (G6) from (G1) and (G11a).

[1203] For the synthesis of intermediates of general formula (G10), the primary amine (G13) or its corresponding salt can be reacted with a heteroaryl group (G2a) (where X is a leaving group, such as a halogen or -S(O)Me) in a nucleophilic aromatic substitution (S N The reaction is carried out in Buchwald-Hartwig amination catalyzed by Ar or palladium. The applicable procedures are similar to those described in Scheme 1 for the synthesis of (G3) from (G1) and (G2a).

[1204] Option 3

[1205]

[1206] Scheme 3: The route for preparing compounds of general formula (G9) is described in this scheme, where LG is the leaving group, PG is the protecting group, and Z is the protecting group. 6 Z 7 Z 8 and Z 9 It has the meaning given above for the general formula (A2b). D is as defined above.

[1207] Monoaryl diamines of general formula (G3) can be substituted by nucleophilic aromatics (S N Ar) or a monoprotected diamine (G1) or its corresponding salt with a heteroaryl group (G2) (where LG is a leaving group, such as a halogen (e.g., fluorine, chlorine, or bromine) or -S(O). 1-2 Palladium-catalyzed Buchwald-Hartwig amination between Me and S was obtained, as described in Scheme 3. N In the Ar method (where LG is a group such as, for example, fluorine, chlorine, or -S(O)Me), diamine (G1) reacts with (G2) in the presence of an inorganic base (such as K2CO3, Na2CO3, or Cs2CO3), or in the presence of an organic base (such as TEA or DIPEA), or in the absence of any additional base, in a polar solvent (such as DMSO, NMP, nBuOH, or 1,4-dioxane), 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.

[1208] For palladium-catalyzed Buchwald-Hartwig amination, all methods known in the art can be applied. For example, diamine (G1) can react with (G2) in the presence of a palladium catalyst (such as Pd PEPPSI-IpentCl [CAS Registry No. 1612891-29-8], Pd2(dba)3, tBuXPhos Pd G3 [1447963-75-8] or tBuBrettPhos G3) and a base (such as Cs2CO3, NaOtBu or MTBD) in an aprotic solvent (such as 1,4-dioxane, DMF, toluene, NMP or DMA) at a temperature between room temperature and 130°C, preferably at 65°C-100°C for 15 to 24 hours.

[1209] The diamine of general formula (G1) and the heteroaryl group of general formula (G2) are commercially available or can be prepared according to procedures available from the public domain. For the synthesis of the diamine (G1), see, for example, WO2004004726 and its references.

[1210] Aryl diamines of general formula (G6) can be obtained by copper-catalyzed Ullmann coupling of (G3) with a heterocyclic (G4) or palladium-catalyzed Suzuki coupling with a boric acid derivative (G5). For Ullmann coupling, all methods known in the art can be applied. For example, (G3) can be reacted with (G4) in the presence of a copper catalyst (such as Cu(I)I, Cu(OTf)2, or Cu(Oac)2) and a base (such as Cs2CO3 or K2CO3) in a polar aprotic solvent (such as 1,4-dioxane, DMF, or pyridine) at a temperature between room temperature and 120°C, preferably at 100°C, for 15 to 20 hours. In some cases, ligands (such as DMCDA, TMEDA, N) can be added. 1 N 2 (1,2-dimethylethane or N,N-dimethylglycine) is added to the reaction mixture.

[1211] For Suzuki coupling of (G6), all methods known in the art can be applied. For example, (G3) can be reacted with boric acid derivatives (G5) in the presence of a palladium catalyst (such as Pd(dtbpf)Cl2 [CAS Registry No. 95408-45-0] or Pd(dppf)Cl2 [CAS Registry No. 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 mixtures thereof) at a temperature between room temperature and 120°C for 2 to 15 hours.

[1212] The heterocyclic compounds of general formula (G4) and the boric acid derivatives of general formula (G5) are commercially available or can be prepared according to procedures available from the public domain.

[1213] Primary amines of general formula (G7) can be obtained from monoprotected diamines of general formula (G6) by deprotection methods. These methods can be, for example, acidic, basic, oxidative, or hydrogenation methods, depending on the protecting group applied. The appropriate protecting moiety of the amino group and its introduction and cleavage are well known in the art. For an overview of protecting group chemistry, see, for example, PGMWuts, TWGreene, Greene's Protective Groups in Organic Synthesis 4. th ed., J. Wiley & Sons, 2006.

[1214] The final compound of general formula (G9) can be obtained from a primary amine of general formula (G7) via S NAr or palladium-catalyzed Buchwald-Hartwig amination is used for synthesis. Primary amines of general formula (G7) can be reacted with heteroaryl groups of general formula (G8) (where LG is a leaving group, such as a halogen (e.g., chlorine or bromine) or -S(O)₂Me), using procedures similar to those described in Scheme 3 for the synthesis of (G3) from (G1) and (G2). Heteroaryl groups of general formula (G8) are commercially available or can be prepared according to procedures available from the public domain.

[1215] An alternative route for compounds of general formula (G9) begins with the deprotection of the diamine of general formula (G3) to obtain the primary amine of general formula (G10), as depicted in scheme 3. For deprotection, the same procedure as described for the synthesis of (G7) from (G6) is applied.

[1216] The primary amine of general formula (G10) can then react with the heteroaryl group of general formula (G8) via S N Ar or palladium-catalyzed Buchwald-Hartwig amination reactions yield aryl iodides of general formula (G11), which are similar to those procedures described in Scheme 3 for the synthesis of (G3) from (G1) and (G2).

[1217] The final compound of general formula (G9) can be synthesized from the aryl iodide of general formula (G11) via copper-catalyzed Ullmann coupling with the heterocyclic HD (G4) or via palladium-catalyzed Suzuki coupling with the boric acid derivative (G5), using procedures similar to those described in Scheme 3 for the synthesis of compound (G6) from (G3).

[1218] Another method for compounds of general formula (G9) is from a monoprotected diamine (G1) or its corresponding salt and a pre-assembled heteroaryl group (G12) (where LG is a leaving group, such as a halogen (e.g., fluorine, chlorine, or bromine) or -S(O). 1-2 Me) via S N Ar or palladium-catalyzed Buchwald-Hartwig amination begins to yield an arylated diamine of general formula (G6). The applicable procedures are similar to those described in Scheme 3 for the synthesis of (G3) from (G1) and (G2). The heteroaryl group of general formula (G12) is commercially available or can be obtained according to procedures available from the public domain (e.g., via Chan-Lam coupling, see, for example, Chen 2020).

[1219] Scheme 4 outlines alternative routes for the preparation of compounds of general formula (G9) and intermediates of general formula (G11).

[1220] Option 4

[1221]

[1222] Scheme 4: The route for preparing compounds and intermediates (G11) of general formula (G9) is described in this scheme, where LG is the leaving group, PG is the protecting group, and Z... 6 Z 7 Z 8 and Z 9 It has the meaning given above for the general formula (A2b). D is as defined above.

[1223] Monoaryl diamines of general formula (G13) can be obtained through S N Ar or a monoprotected diamine (G1) or its corresponding salt with a heteroaryl group (G8) (where LG is a leaving group, such as a halogen (e.g., chlorine or bromine)) is obtained by palladium-catalyzed Buchwald-Hartwig amination between -S(O)2Me. The procedures that can be applied are similar to those described in Scheme 3 for the synthesis of (G3) from (G1) and (G2).

[1224] Deprotection of the diamine of general formula (G13) yields the primary amine of general formula (G14). For deprotection, the same procedure described in Scheme 3 for the synthesis of (G7) from (G6) is applied.

[1225] The final compound of general formula (G9) can then be formed from a primary amine (G14) or its corresponding salt and a pre-assembled heteroaryl group (G12) (where LG is a leaving group, such as a halogen (e.g., fluorine, chlorine, or bromine) or -S(O). 1-2 Me), through S N The synthesis is carried out by Ar or palladium-catalyzed Buchwald-Hartwig amination. Applicable procedures are similar to those described in Scheme 3 for the synthesis of (G6) from (G1) and (G12).

[1226] For the synthesis of intermediates of general formula (G11), the primary amine (G14) or its corresponding salt can be reacted with a heteroaryl group (G2) (where LG is a leaving group, such as a halogen (e.g., fluorine, chlorine, or bromine) or -S(O). 1-2 Me) in S N Ar or palladium catalyzed reactions in Buchwald-Hartwig amination. Applicable procedures are similar to those described in Scheme 3 for the synthesis of (G3) from (G1) and (G2).

[1227] The final compound of general formula (G17) can be synthesized according to the route described in Scheme 5. The primary amine of general formula (G7) or its corresponding salt (prepared according to Scheme 3) can be reacted with a carbon equivalent such as CDI or TCDI in the presence of an inorganic base such as sodium hydroxide, or an organic base such as TEA or DIPEA, or without any additional base, in a polar aprotic solvent such as DMF, at a temperature between room temperature and the boiling point of the solvent, preferably at 100°C, for 1 to 2 hours, to give an acylimidazole intermediate. This intermediate can be reacted in situ with 1,2-diphenylamine (G15) in the presence of a carbodiimide reagent such as EDC, at a temperature between room temperature and the boiling point of the solvent, preferably at 100°C, for 15 to 24 hours, to give (G17).

[1228] Option 5

[1229]

[1230] Option 5: A route for preparing compounds of general formula (G17), where Z 6 Z 7 Z 8 and Z 9 It has the meaning given above for the general formula (A2b). D is as defined above.

[1231] Alternatively, the protected intermediate of general formula (G16) prepared according to the route described in scheme 3 or 4 can be deprotected to obtain a compound of general formula (G17). Depending on the protecting group used, these methods can be, for example, acidic, basic, oxidative, or hydrogenation methods. Suitable protecting groups can be groups such as p-methoxybenzyl (PMB), 4-methylbenzenesulfonyl (Ts), or benzyl (Bn). Deprotection of the PMB group can be achieved, for example, by reacting with an acid such as TFA in a solvent such as DCM, or without any additional solvent, at a temperature between room temperature and the boiling point of the solvent, preferably at 60°C–100°C, for 15 minutes to 18 hours. Deprotection of the Ts group can be carried out by reacting with a base such as K₂CO₃ or Na₂CO₃ in a polar protic solvent such as MeOH or EtOH, at a temperature between room temperature and the boiling point of the solvent, preferably at 60°C, for 1 hour to 4 hours.

[1232] Scheme 6 describes another method for compounds of general formula (G9). The aryl bromides of general formula (G18) prepared according to the procedures described in Schemes 3 to 5 can be functionalized, for example by late functionalization, with nucleophiles of general formula (G19) (see, for example, Ley and Thomas 2003), boric acid derivatives (G20) (see, for example, Miyaura and Suzuki 1995), or stananes (G21) (see, for example, Cordovilla 2015) under metal or metal photoredox catalysis to obtain the final compound of general formula (G9). All methods known in the art can be applied for metal or metal photoredox catalysis.

[1233] The nucleophile of general formula (G19), the boric acid derivative of general formula (G20), and the stanane (G21) are commercially available or can be prepared according to procedures available from the public domain.

[1234] Option 6

[1235]

[1236] Option 6: A route for preparing compounds of general formula (G9), where Z 6 Z 7 Z 8 and Z 9 It has the meaning given above for the general formula (A2b) (provided that R is...) A6 (Not halogen). D is as defined above.

[1237] Other compounds with different formulations as described above can be prepared by similar methods.

[1238] Those skilled in the art will understand that, in order to obtain the compounds disclosed herein in an alternative manner and in some cases more conveniently, the various method steps mentioned above may be performed in a different order, and / or the various reactions may be carried out at different stages of the overall route (i.e., substituents may be added to and / or chemically transformed into those different intermediates mentioned above in conjunction with specific reactions). This may eliminate the need for protecting groups, or make such a need necessary.

[1239] Those skilled in the art will understand that the chiral isomers of the compounds described herein can be resolved at any stage of the synthesis using chiral resolving agents described in the literature and known to those skilled in the art, or using chiral chromatographic methods described in the literature and known to those skilled in the art. Stereocenters can also be introduced via asymmetric synthesis. All stereoisomers are included within the scope of this disclosure.

[1240] Those skilled in the art should understand that the raw materials used in any of the above methods are commercially available in some cases.

[1241] Those skilled in the art should understand that the preparation methods for some of the above-mentioned raw materials may be common knowledge.

[1242] It should also be understood that some compounds described in the above methods may exhibit tautomerism, and the above methods include any tautomerism.

[1243] All novel intermediates constitute another aspect of this disclosure.

[1244] Experimental Section

[1245] NMR peaks are presented in the form they appear in the spectrum, without considering possible higher-order effects.

[1246] The following table lists the abbreviations used in this paragraph and the Examples section, unless otherwise explained in the text. Other abbreviations have their own meanings as commonly understood by those skilled in the art.

[1247] abbreviation

[1248]

[1249]

[1250]

[1251]

[1252] unit

[1253]

[1254] The various embodiments described in this application are illustrated by the following examples, which are not intended to limit the compound of formula (I) in any way.

[1255] The exemplary test experiments described herein are for illustrative purposes only and are not limited to the given embodiments.

[1256] Experimental Section - General Section

[1257] General conditions

[1258] (i) The operation shall be carried out at room temperature (rt) (i.e., in the range of 17°C to 28°C) and, if necessary, in an atmosphere of inert gas such as N2 or Ar; the reaction may optionally be carried out using an MBRAUN UNILab Plus ECO or MBRAUN UNILab SP Eco glove box workstation, which is recommended in this case;

[1259] (ii) In cases where the reaction involves degassing or purging, this can be done, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (e.g., 5 to 10 minutes) or by repeatedly evacuating the container and backfilling it with a suitable inert atmosphere (e.g., N2(g) or Ar(g)).

[1260] (iii) In cases where the reaction involves the use of a microwave reactor, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer;

[1261] (iv) Generally, reaction progress is tracked by thin-layer chromatography (TLC) and / or analytical high-performance liquid chromatography (HPLC or UPLC), which is usually coupled with a mass spectrometer (LCMS).

[1262] (v) If necessary, dry the organic solution with anhydrous MgSO4 or Na2SO4, or by using ISOLUTE. ® The phase separator is dried, and a post-processing procedure is performed using conventional phase separation techniques. When a desiccant such as MgSO4 or Na2SO4 is used to dry the organic layer, it should be understood that the organic layer is filtered before concentration.

[1263] (vi) It should be understood that, unless otherwise stated, the washing solutions used in the post-treatment process or the reagents used for acidification, such as brine (saturated NaCl aqueous solution), NaHCO3, NH4Cl, HCl, NaH2PO4, are considered to be aqueous solutions;

[1264] (vii) Evaporation is carried out by vacuum rotary evaporation or in Genevac HT-4 / EZ-2 or Biotage V10;

[1265] (viii) Unless otherwise stated, rapid column chromatography is performed on normal-phase silica using Merck silica gel (Art. 9385) or pre-packed small columns such as Biotage. ® SNAP columns (40μm-63μm silica, 4g-330g), Biotage ®Sfär silica HC D column (20µm, 10g-100g), Interchim puriFlash ™ Small column (25µm, 4g-120g), Interchim puriFlash ™ Small column (50µm, 25g-330g), Grace ™ GraceResolv ™ The procedure can be performed using rapid silica columnar ingots (4g-120g) or Agela rapid columnar silica-CS columnar ingots (80g-330g), or using Agela Technologies C-18 spherical columnar ingots (20µm-35µm, 100A, 80g–330g) on ​​reversed silica using Grace Reveleris. ® The X2 Fast System or similar systems can be operated manually or automatically.

[1266] (ix) Purification using an ion exchange column is performed on a standard ion exchange column (e.g., an ISOLUTESCX-2 column from Biotage);

[1267] (x) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using a mobile phase of isocratic or gradient as described in the Experimental Section and using one of the following methods, respectively, with standard HPLC and SFC instruments equipped with MS and / or UV-triggered fractionation collection instruments:

[1268] Preparation Method A: The compound was prepared by preparative HPLC on XBridge. ™ Purification was performed using a gradient of MeCN in an H2O / NH4HCO3 (10mM) / NH3 (0.1%, aqueous solution) buffer system as the mobile phase on a C18 OBD column (5µm, 150×30mm ID).

[1269] Preparation method B: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5µm, 150×30mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10mM) / NH3 (0.05%, aqueous solution) as the mobile phase.

[1270] Preparation method C: The compound was prepared by preparative HPLC on XBridge. ™ Purification was performed using a gradient of MeCN in an H2O / MeCN / NH3 (95 / 5 / 0.2) buffer system as the mobile phase on a C18 column (10 μm, 250 × 50 mm ID).

[1271] Preparation method D: The compound was purified by preparative HPLC on an XBridge C18 OBD column (5µm, 250×19mm ID) using a gradient of MeCN in an H2O / FA ​​(0.1%) buffer system as the mobile phase;

[1272] Preparation method E: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (8µm, 150×30mm ID) using a gradient of MeCN in an H2O / FA ​​(0.1%) buffer system as the mobile phase;

[1273] Preparation method F: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5µm, 150×30mm ID) using a gradient of MeCN in an H2O / FA ​​(0.1%) buffer system as the mobile phase.

[1274] Preparation method G: The compound was purified by preparative HPLC on a Waters Xselect CSH preparative fluorophenyl OBD column (5µm, 150×30mm ID) using a gradient of MeCN in an H2O / FA ​​(0.1%) buffer system as the mobile phase.

[1275] Preparation method H: The compound was purified by preparative HPLC on an XBridge C18 OBD column (3.5µm, 75×30mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10mM) / NH3 (0.05%, aqueous solution) as the mobile phase.

[1276] Preparation Method I: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRs column (5µm, 150×30mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10mM) / NH3 (0.05%, aqueous solution) as the mobile phase.

[1277] Preparation method J: The compound was prepared by preparative HPLC on XBridge. ™ Purification was performed using a gradient of MeCN in an H2O / NH4HCO3 (10mM) / NH3 (0.05%, aqueous solution) buffer system as the mobile phase on a C18 OBD column (5µm, 150×30mm ID).

[1278] Preparation method K: The compound was purified by preparative HPLC on a Waters Xselect CSH C18 OBD column (5µm, 250×19mm ID) using a gradient of MeCN in a buffer system of H2O / NH4HCO3 (10mM) / NH3 (0.05%, aqueous solution) as the mobile phase.

[1279] Collect the relevant fractions, combine them, and freeze-dry or evaporate them to obtain the purified compound; or collect the relevant fractions, combine them, concentrate them under reduced pressure, extract the aqueous layer with DCM or EtOAc, and dry the organic phase with Na2SO4 or by using a phase separator, then concentrate under reduced pressure and, if necessary, vacuum dry to obtain the purified compound.

[1280] (xi) The yield (in the presence of) is not necessarily the maximum obtainable value, and the reaction can be repeated if a larger amount of reaction product is required.

[1281] (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 precise stoichiometry of the salt cannot usually be determined, for example, by elemental analysis data; wherein the salt is treated according to methods known in the literature to produce the corresponding free base before use;

[1282] (xiii) Generally, the structure of the final product of formula (I) is confirmed by NMR and / or mass spectrometry; using Bruker Avance III 300, 400, 500 and 600 spectrometers (at 300 MHz, 400 MHz, 500 MHz and 600 MHz respectively). 1(Operated at H frequency) Proton NMR chemical shift values ​​are measured on the delta scale. Experiments are typically recorded at 25 °C. Chemical shifts are given in ppm, with the solvent serving as an internal reference. Protons on heteroatoms, such as NH and OH protons, are only reported if detected in the NMR and may therefore be lost. Record the 19F spectrum of the protons decoupled. In some cases, protons may be masked or partially masked by solvent peaks and thus either lost and not reported or reported as multiplets overlapping with the solvent. The following abbreviations (and their derivatives) have been used, such as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; qn, quintet; p, pentet; h, heptet; dd, doubletet, etc. It should be understood that when the NMR spectrum contains residual impurities and / or residual solvents, this situation is not reported unless it partially overlaps with the peaks of the intermediates and / or structures of formula (I). In this case, the peaks of the intermediates and / or structures of formula (I) are reported as multiplets partially overlapping with the solvent or impurity, and integration is omitted. In some cases, the compounds of formula (I) exhibit tautomerism in the NMR spectrum; in such cases, only the peaks of the major tautomer are reported.

[1283] In some cases, compounds of formula (I) appear as tautomers in a more equal relationship. In such cases, if the signal of the tautomer partially overlaps with other peaks, the peak of this tautomer is reported as a multiplet, or if the signal of the tautomer is well separated, the peak of this tautomer is reported as a single peak. The integral of such peaks is reported as the proton fraction, indicating the ratio of tautomers in the mixture.

[1284] (xiv) Electrospray mass spectrometry data were acquired using a WatersAcquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar device, acquiring both cation and anion data, and typically only reporting ions relevant to the parent structure; High-resolution electrospray mass spectrometry data were acquired using a Waters XEVO qToF mass spectrometer coupled to a Waters Acquity UPLC or similar device, acquiring both cation and anion data, and typically only reporting ions relevant to the parent structure.

[1285] (xv) Intermediates may not be completely purified, but their structure and purity are assessed by TLC, analytical HPLC / UPLC and / or NMR analysis and / or mass spectrometry.

[1286] (xvi) Generally, examples and intermediate compounds are named using ChemDraw Professional version 20.1.1.125 or version 21.0.0 from PerkinElmer. ChemDraw Professional version 20.1.1.125 or version 21.0.0 uses the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate names of chemical structures, and follows the IUPAC rules as strictly as possible when generating chemical names. Stereoisomers are distinguished from each other by the stereo descriptors referenced in their names and are assigned according to the CIP rules.

[1287] intermediate

[1288] Intermediate 1

[1289] ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1290] (i-1)

[1291] 2-Fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (2.23 g, 9.99 mmol) was added to 30 mL of DMSO containing 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). The resulting solution was stirred at 125 °C for 1 h under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 × 75 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The crude material was purified by silica gel rapid chromatography (gradient: 0%–50% EtOAc / PE) to give the title compound (2.70 g, 67%) as a pale yellow solid. MS (ESI) m / z [M+H] + 403.9.

[1292] Intermediate 2

[1293] ((1S,3S)-3-((5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)amino)ring tert-butyl pentyl carbamate

[1294] (i-2)

[1295] At room temperature, DMCDA (CAS Registry No. 67579-81-1) (0.388 g, 2.73 mmol) was added to 1,4-dioxane (15 mL) containing ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (1.10 g, 2.73 mmol), 1,3-dihydro-2H-benzo[d]imidazol-2-one (CAS Registry No. 615-16-7) (0.549 g, 4.09 mmol), Cs₂CO₃ (2.67 g, 8.18 mmol), and CuI (0.519 g, 2.73 mmol). The resulting mixture was stirred at 100 °C under nitrogen for 12 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL) and washed successively with brine (3 × 75 mL). The organic layer was dried (Na₂SO₄), filtered, and evaporated to obtain the crude product. This crude product was purified by preparative TLC (EtOAc:petroleum ether = 1:5) to give the title compound (0.84 g, 75%) as a yellow solid. MS (ESI): m / z [M+H] + 410.0.

[1296] Intermediate 3

[1297] 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol- 2-Keto.2HCl

[1298] (i-3)

[1299] At room temperature, 4 M, 5 mL, 20 mmol of MeOH containing HCl was added to 10 mL of MeOH containing ((1S,3S)-3-((5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamate intermediate 2 (840 mg, 2.05 mmol), and the resulting mixture was stirred at 60 °C for 3 hours. The solvent was removed under reduced pressure to give the title compound (560 mg, 88%) as a yellow solid. MS (ESI): m / z [M+H] + 309.9.

[1300] Intermediate 4

[1301] N-(6-chloropyridin-3-yl)-3-nitropyridin-2-amine

[1302] (i-4)

[1303] At room temperature under nitrogen atmosphere, Pd2(dba)3 (861 mg, 0.94 mmol) was added to 2-chloro-5-iodopyridine (CAS Registry No. 69045-79-0) (3.00 g, 12.5 mmol), 2-amino-3-nitropyridine (CAS Registry No. 4214-75-9) (1.74 g, 12.5 mmol), XantPhos (CAS Registry No. 161265-03-8) (1.09 g, 1.88 mmol), and Cs2CO3 (6.12 g, 18.8 mmol) dissolved in 1,4-dioxane (60 mL), and the mixture was stirred at 80 °C for 15 hours. The reaction mixture was filtered through a diatomaceous earth pad, washed with EtOAc (200 mL), and the combined filtrates were concentrated under reduced pressure. The crude material was purified by silica gel rapid chromatography (gradient: 2%-10% EtOAc / PE) to obtain the title compound (3.00 g, 96%) as a yellow solid. MS (ESI): m / z [M+H] + 251 / 253 (Cl isotope pattern).

[1304] Intermediate 5

[1305] N 2 - (6-chloropyridin-3-yl)pyridin-2,3-diamine

[1306] (i-5)

[1307] At 20 °C, zinc powder (7.83 g, 120 mmol) was added to a mixture of EtOH (50 mL) and EtOAc (50 mL) containing N-(6-chloropyridin-3-yl)-3-nitropyridin-2-amine intermediate 4 (5 g, 20 mmol) and NH4Cl (10.7 g, 200 mmol), and the mixture was stirred at 60 °C for 15 hours. The reaction mixture was filtered through a diatomaceous earth mat, the filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel rapid chromatography (gradient: 50% EtOAc / PE) to give the title compound (1.70 g, 39%) as a red solid. MS (ESI): m / z [M+H] + 221 / 223 (Cl isotope pattern).

[1308] Intermediate 6

[1309] 3-(6-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1310] (i-6)

[1311] At 25℃, N 2Intermediate 5 (464 mg, 2.10 mmol) of 6-chloropyridin-3-yl)pyridine-2,3-diamine was added to 10 mL of MeCN containing CDI (CAS Registry No. 530-62-1) (341 mg, 2.10 mmol), and the mixture was stirred at this temperature for 3 hours. The reaction mixture was diluted with 15 mL of MeCN, and the solid formed was collected by filtration. The material was dried under vacuum to give the title compound (362 mg, 70%) as a gray solid, which was used directly for the next step without further purification. MS (ESI): m / z [M+H] + 247 / 249 (Cl isotope pattern).

[1312] Intermediate 7

[1313] 3-(6-chloropyridin-3-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1314] (i-7)

[1315] 1-(chloromethyl)-4-methoxybenzene (453 mg, 2.89 mmol) was added to DMF (4 mL) containing 3-(6-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 6 (357 mg, 1.45 mmol) and K₂CO₃ (600 mg, 4.34 mmol) at 25 °C, and the mixture was stirred at this temperature for 2 hours. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (3 × 35 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated, and the crude material was purified by preparative TLC (EtOAc:PE = 2:1) to give the title compound (523 mg, 99%) as a brown solid. MS (ESI): m / z [M+H] + 367 / 369 (Cl isotope pattern).

[1316] Intermediate 8

[1317] ((1S,3S)-3-((5-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyrene) (Pyridin-3-yl)pyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1318] (i-8)

[1319] At 25°C, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 645400-44-8) (328 mg, 1.64 mmol) was added to 1,4-dioxane (5 mL) containing 3-(6-chloropyridin-3-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 7 (300 mg, 0.82 mmol), Cs₂CO₃ (799 mg, 2.45 mmol), and Pd-PEPPSI-IpentCl 2-methylpyridine (34 mg, 0.04 mmol). The resulting suspension was stirred at 100°C for 18 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM (2 × 5 mL) and the combined filtrates were concentrated under reduced pressure. The crude product was purified by preparative TLC (EtOAc) to give the title compound (434 mg, 100%) as a white solid. MS (ESI): m / z [M+H] + 531.4.

[1320] Intermediate 9

[1321] 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1-(4-methoxybenzyl)-1,3-di Hydrogen-2H-imidazo[4,5-b]pyridin-2-one

[1322] (i-9)

[1323] At 25 °C, TFA (5 mL, 65 mmol) was added to 30 mL of DCM containing intermediate 8 (425 mg, 0.80 mmol) of ((1S,3S)-3-((5-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyridin-2-yl)amino)cyclopentyl)carbamate tert-butyl carbamate (TFA) and the reaction mixture was stirred at this temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting material was purified by C18-fast chromatography (elution gradient: 0%-100% MeCN / 0.05% NH3 aqueous solution) to give the title compound (336 mg, 97%) as a brown gel. MS (ESI): m / z [M+H) + 431.1.

[1324] Intermediate 10

[1325] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- 1-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1326] (i-10)

[1327] At 25 °C, Pd-PEPPSI-IpentCl 2-methylpyridine (24 mg, 0.03 mmol) was added to 15 mL of DMF containing 3-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 9 (250 mg, 0.58 mmol), 2-chloro-5-(difluoromethoxy)pyrimidine (CAS Registry No. 1192813-64-1) (210 mg, 1.16 mmol), and Na2CO3 (369 mg, 3.48 mmol), and the resulting mixture was stirred at 100 °C for 8 hours under a nitrogen atmosphere. The reaction mixture was poured into brine (75 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried (Na₂SO₄), filtered, and evaporated to obtain the crude product. The residue was purified by preparative TLC (EtOAc:PE = 3:2) to give the title compound (200 mg, 60%) as a white solid. MS (ESI): m / z [M+H] + 575. 1 ¹H NMR (300MHz, DMSO-d6) δ ppm 1.49 – 1.62 (2H,m), 1.87 – 1.99 (2H, m), 2.06 – 2.22 (2H, m), 3.73 (3H, s), 4.30 – 4.37 (2H,m), 5.76 (2H, s), 6.60 (1H, d), 6.90 – 6.94 (3H, m), 7.04 (1H, t), 7.09 (1H,dd), 7.29 – 7.35 (2H, m), 7.49 – 7.56 (3H, m), 7.92 – 7.96 (1H, m; partially covered by residual DMF), 8.13 (1H, d), 8.25 (2H, s).

[1328] Intermediate 11

[1329] 6-Chloro-N-(2-nitropyridin-3-yl)pyridin-3-amine

[1330] (i-11)

[1331] 2-Chloro-5-iodopyridine (6.2 g, 25.9 mmol) was added to 1,4-dioxane (100 mL) containing 2-nitropyridine-3-amine (3.0 g, 22 mmol), Pd2(dba)3 (0.197 g, 0.22 mmol), Cs2CO3 (10.5 g, 32.4 mmol), and Xantphos (0.624 g, 1.08 mmol). The mixture was stirred at 80 °C for 15 hours under a N2(g) atmosphere. The reaction mixture was poured into water (250 mL) and extracted with EtOAc (4 × 200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude residue was purified by silica gel column chromatography (gradient: 0%–40% EtOAc / PE) to give the title compound (4.1 g, 76%) as a brown solid; MS (ESI) m / z [M+H] + 250.8.

[1332] Intermediate 12

[1333] N 3 - (6-chloropyridin-3-yl)pyridin-2,3-diamine

[1334] (i-12)

[1335] At 20 °C, 4,4'-bipyridine (0.012 g, 0.08 mmol) was added to 80 mL of DMF containing 6-chloro-N-(2-nitropyridin-3-yl)pyridine-3-amine intermediate 11 (2.0 g, 7.98 mmol) and diboronic acid (CAS Registry No. 13675-18-8) (2.86 g, 31.9 mmol). The mixture was stirred at 20 °C for 5 min and then filtered through diatomaceous earth. The filtrate was poured into saturated brine (250 mL) and extracted with EtOAc (6 × 200 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative TLC (100% EtOAc) to give the title compound (1.4 g, 80%) as a yellow solid. MS (ESI) m / z [M+H) + 220.9.

[1336] Intermediate 13

[1337] 1-(6-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1338] (i-13)

[1339] At 0°C, bis(trichloromethyl) carbonate (CAS Registry No. 32315-10-9) (1.936 g, 6.53 mmol) was added in portions to a solution containing N. 3Intermediate 12 (1.2 g, 5.44 mmol), Et3N (7.6 mL, 54 mmol), and DMAP (0.332 g, 2.72 mmol) were added to THF (100 mL). The solution was stirred at 60 °C for 15 hours. The reaction mixture was poured into saturated NaHCO3 (250 mL) and extracted with EtOAc (3 × 200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude solid was ground with EtOAc (20 mL), collected by filtration, and dried under vacuum to give the title compound (1 g, 74%) as a brown solid. MS (ESI) m / z [M+H] + 246.9.

[1340] Intermediate 14

[1341] 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1342] (i-14)

[1343] At 20 °C, 1-(chloromethyl)-4-methoxybenzene (stabilized with CaCO3, 0.952 g, 6.08 mmol) was slowly added to 15 mL of DMF containing 1-(6-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 13 (1.0 g, 4.05 mmol) and K2CO3 (1.12 g, 8.11 mmol). The mixture was stirred at 60 °C for 2 hours, then poured into brine (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and evaporated. The crude solid was ground with PE:EtOAc = 2:1 (20 mL), collected by filtration, and dried under vacuum to give the title compound (1.05 g, 71%) as a pale yellow solid. MS (ESI) m / z [M+H] + 366.9.

[1344] Intermediate 15

[1345] ((1S,3S)-3-((5-(3-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrene) (Pyridin-1-yl)pyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1346] (i-15)

[1347] At 20 °C, Pd-PEPPSI-IpentCl 2-methylpyridine (34.4 mg, 0.04 mmol) was added to 20 mL of 1,4-dioxane containing 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 14 (300 mg, 0.82 mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (180 mg, 0.90 mmol), and Cs₂CO₃ (533 mg, 1.64 mmol). The suspension was stirred at 100 °C for 18 hours under a N₂ (g) atmosphere. The reaction mixture was diluted with EtOAc (250 mL) and washed successively with water (3 × 125 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative TLC (7M NH3 / MeOH:DCM, 1:20) to give the title compound (310 mg, 71%) as a yellow solid. MS (ESI) m / z [M+H) + 531.3.

[1348] Intermediate 16

[1349] 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-(4-methoxybenzyl)-1,3-di Hydrogen-2H-imidazo[4,5-b]pyridin-2-one

[1350] (i-16)

[1351] At 20 °C, 2 mL (8.00 mmol) of MeOH containing HCl was added to 8 mL of MeOH containing 300 mg (0.57 mmol) of intermediate 15 of ((1S,3S)-3-((5-(3-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)amino)cyclopentyl)carbamate tert-butyl carbamate. The suspension was stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure to give an unspecified HCl salt (330 mg) of the crude title compound as a brown solid. MS (ESI) m / z [M+H] + 431.2.

[1352] Intermediate 17

[1353] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- 3-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1354] (i-17)

[1355] 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 16 (243 mg, 0.56 mmol) was added to 15 mL of DMF containing 2-chloro-5-(difluoromethoxy)pyrimidine (85 mg, 0.47 mmol), Pd-PEPPSI-IpentCl 2-methylpyridine (20 mg, 0.02 mmol), and Cs₂CO₃ (460 mg, 1.41 mmol). The resulting mixture was stirred at 100 °C for 15 hours. The reaction mixture was poured into brine (125 mL) and extracted with EtOAc (4 × 100 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative TLC (7M NH3 / MeOH:DCM = 1:15) to give the title compound (130 mg, 48%) as a yellow solid. MS (ESI) m / z [M+H) + 575.3.

[1356] Intermediate 18

[1357] ((1S,3S)-3-((1,2,4-triazin-3-yl)amino)cyclopentyl)tert-butyl carbamate

[1358] (i-18)

[1359] At 0 °C, m-CPBA (5.60 g, 25.95 mmol) was added in small portions to a solution of 3-(methylthio)-1,2,4-triazine (CAS Registry No. 28735-21-9) (3.0 g, 23.6 mmol) in 80 mL of DCM, and the resulting suspension was stirred at 20 °C for 2 hours. The solvent was removed under reduced pressure without heating, and the residue was dissolved in n-butanol (40 mL) and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 645400-44-8) (5.20 g, 26.0 mmol) was added. 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 obtain a crude product as a brown solid. This crude product was purified by silica gel rapid chromatography (gradient: 5%-60% EtOAc / PE) to give the title compound (3.7 g, 56%) as a yellow solid. MS (ESI): m / z [M+H] + 280.

[1360] Intermediate 19

[1361] ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)tert-butyl carbamate

[1362] (i-19)

[1363] 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-triazine-3-yl)amino)cyclopentyl)carbamate tert-butyl ester intermediate 18 (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 hours. 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 a crude product as a brown solid. The crude product was purified by silica gel rapid chromatography (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.

[1364] Intermediate 20

[1365] ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)tert-butyl carbamate

[1366] (i-20)

[1367] At 20 °C, intermediate 19 of ((1S,3S)-3-((6-bromo-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate (tert-butyl)carbamate (300 mg, 0.84 mmol) was added to a mixture containing 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (4 mL), K3PO4 (356 mg, 1.67 mmol), dioxane (4 mL) containing 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (CAS Registry No. 95408-45-0) (55 mg, 0.08 mmol), and water (1 mL). The resulting mixture was stirred at 100 °C for 15 hours under a nitrogen atmosphere. The reaction mixture was poured into brine (150 mL) and extracted with EtOAc (4 × 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and evaporated to give the crude product. The residue was first purified by preparative TLC (MeOH:DCM = 1:20), followed by C18-fast chromatography (gradient: 0%–49% MeOH / water solution) to give the title compound as a brown solid (103 mg, 42%). MS (ESI): m / z [M+H] + 294.

[1368] Intermediate 21

[1369] (1S,3S)-N 1 - (6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine. 2TFA

[1370] (i-21)

[1371] At 20 °C, intermediate 20 (100 mg, 0.34 mmol) of ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate tert-butyl ester was added to a mixture of TFA (5 mL) and DCM (5 mL), and the mixture was stirred at this temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg, 95%) as a white solid. MS (ESI): m / z [M+H] + 194.

[1372] Intermediate 22

[1373] (1S,3S)-N 1 -(5-Iodopyridin-2-yl)-N 3 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine

[1374] (i-22)

[1375] 2-Fluoro-5-iodopyridine (CAS Registry No. 171197-80-1) (203 mg, 0.91 mmol) was added to (1S,3S)-N1 Intermediate 21 (220 mg, 0.83 mmol) of the 2HCl salt of 6-methyl-1,2,4-triazine-3-yl)cyclopentane-1,3-diamine was reacted with 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 resulting material was dissolved in EtOAc (300 mL). The organic layer was washed with 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 (140 mg, 43%) as a pale yellow solid. MS (ESI): m / z [M+H] + 396.7. 1 HNMR (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).

[1376] Intermediate 23

[1377] ((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)tert-butyl carbamate

[1378] (i-23)

[1379] 2-Bromo-[1,2,4]triazolo[1,5-a]pyridine (CAS Registry No. 1021019-03-3) (0.7 g, 3.53 mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (CAS Registry No. 645400-44-8) (0.721 g, 3.60 mmol), Pd2(dba)3 (0.324 g, 0.35 mmol), Xantphos (0.409 g, 0.71 mmol), NaOtBu (0.679 g, 7.07 mmol), and 1,4-dioxane (15 mL) were mixed in a microwave-safe vial at room temperature. The vial was capped, and the mixture was microwaved at 145 °C for 30 min with stirring. The reaction mixture was cooled to room temperature and filtered through a small silica stopper. The stopper was washed with EtOAc:MeOH = 95:5, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel normal-phase chromatography (gradient: 60%-100% EtOAc / heptane) to give the title compound (0.36 g, 32%) as a pale yellow solid. MS (ESI) m / z [M+H + 318.3.

[1380] Intermediate 24

[1381] (1S,3S)-N 1 -([1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine. 2TFA

[1382] (i-24)

[1383] Intermediate 23 (0.91 g, 2.87 mmol) of ((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)carbamate tert-butyl ester intermediate 23 was dissolved in DCM (11 mL) and TFA (3.7 mL) was added at room temperature. The reaction mixture was stirred for 1 hour. Toluene was added, and the resulting mixture was concentrated under reduced pressure. The oily substance was dissolved in MeOH, and toluene was added. The solvent was evaporated under reduced pressure. This process was repeated once more to give the crude title compound (1.48 g) as a brown syrup. MS (ESI) m / z [M+H] + 217.0.

[1384] Intermediate 25

[1385] (1S,3S)-N 1 -([1,2,4]triazolo[1,5-a]pyridin-2-yl)-N 3 -(5-iodopyridin-2-yl)cyclopentane-1, 3-Diamine

[1386] (i-25)

[1387] (1S,3S)-N 1-([1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine 2TFA intermediate 24 (1.2 g, 2.71 mmol), 2-fluoro-5-iodopyridine (1.21 g, 5.41 mmol), K2CO3 (1.87 g, 13.5 mmol), and DMSO (9 mL) were mixed in a flask and heated at 100 °C for 20 h. The mixture was filtered through diatomaceous earth and the stopper was washed with DMSO. The filtrate was evaporated, and EtOAc (150 mL) and brine were added to the residue. The phases were separated, the organic layer was washed with brine (×2), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was further purified by silica gel rapid chromatography (gradient: 50%-100% EtOAc / heptane) to give the title compound (0.742 g, 65%) as a light beige foam. MS(ESI) m / z [M+H] + 421.2.

[1388] Intermediate 26

[1389] 1-(6-chloropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1390] (i-26)

[1391] A mixture of 1-(6-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 13 (780 mg, 3.16 mmol) and K₂CO₃ (1.31 g, 9.49 mmol) in DMF (20 mL) was treated with iodomethane (395 µL, 6.32 mmol) at 20 °C under nitrogen and stirred at 60 °C for 3 h. The reaction mixture was diluted with saturated brine (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude material was purified by preparative TLC (EtOAc) to give the title compound (802 mg, 97%) as a white solid. MS (ESI): m / z [M+H] + 261.0 / 263 (Cl isotope pattern).

[1392] Intermediate 27

[1393] ((1S,3S)-3-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1394] (i-27)

[1395] 2-Chloro-5-(trifluoromethyl)pyrimidine (1 g, 5.48 mmol) was added to DMSO (12 mL) containing Na₂CO₃ (0.871 g, 8.22 mmol) and ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (1.152 g, 5.75 mmol) at 25 °C, and the suspension was stirred at 100 °C for 3 hours. The reaction mixture was diluted with saturated brine. It was washed with saturated brine (350 mL) and then successively with EtOAc (3 × 250 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude solid was ground with EtOAc:PE 20:1 (42 mL), collected by filtration, and dried under vacuum to give the title compound (1.8 g, 95%) as a white solid. MS (ESI) m / z [M+H] + 347.15.

[1396] Intermediate 28

[1397] (1S,3S)-N 1 -(5-(trifluoromethyl)pyrimidin-2-yl)cyclopentane-1,3-diamine × HCl

[1398] (i-28)

[1399] At 30 °C, 4 M, 6.5 mL, 26 mmol of MeOH containing HCl was added dropwise to 20 mL of MeOH containing 1.8 g, 5.2 mmol of intermediate 27 ((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester. The reaction mixture was stirred at 60 °C for 3 hours. The solvent was removed under reduced pressure to give a crude title compound (0.927 g, 63%) as a white solid. MS (ESI) m / z [M+H] + 247.1.

[1400] Intermediate 29

[1401] 1-(6-chloro-5-fluoropyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1402] (i-29)

[1403] DMCDA (CAS Registry No. 67579-81-1) (442 mg, 3.11 mmol) was added to 1,4-dioxane (80 mL) containing 2-chloro-3-fluoro-5-iodopyridine (CAS Registry No. 153034-99-2) (800 mg, 3.11 mmol), 1,3-dihydro-2H-benzo[d]imidazol-2-one (CAS Registry No. 615-16-7) (834 mg, 6.22 mmol), Cs₂CO₃ (3.04 g, 9.32 mmol), and CuI (592 mg, 3.11 mmol). The resulting mixture was stirred at 100 °C for 15 hours. The reaction mixture was filtered through a diatomaceous earth pad, the filter cake was washed with DCM (3 × 50 mL), and the combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative TLC (EtOAc) to give the title compound (320 mg, 39%) as a white solid. MS (ESI): m / z [M+H] + 264.1 / 266 (Cl isotope pattern). 19 F NMR (282MHz, DMSO-d6) δ ppm -117.6.

[1404] Intermediate 30

[1405] ((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)tert-butyl carbamate

[1406] (i-30)

[1407] At 20 °C, 5.00 g (27.7 mmol) of 2-chloro-5-(difluoromethoxy)pyrimidine (CAS Registry No. 1192813-64-1) was added to 80 mL of DMSO containing tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 645400-44-8) (6.10 g, 30.5 mmol) and Na₂CO₃ (4.40 g, 41.5 mmol). The resulting mixture was stirred at 100 °C for 15 hours. The reaction mixture was poured into water (250 mL) and extracted with EtOAc (4 × 150 mL). The organic layers were combined, washed with saturated brine (4 × 100 mL), dried over Na₂SO₄, filtered, and evaporated to give the crude product. The crude product was purified by silica gel rapid chromatography (gradient: 46%-50% EtOAc / PE) to give the title compound (8.5 g, 89%) as a white solid. MS (ESI) m / z [M+H) + 345.2.

[1408] Intermediate 31

[1409] (1S,3S)-N 1 -(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[1410] (i-31)

[1411] At 20 °C, 20 mL (80 mmol) of MeOH containing 4 M HCl was added to 60 mL of MeOH containing 8.7 g (25 mmol) of intermediate 30 ((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester. The resulting mixture was stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure to give an unspecified HCl salt (9.9 g) of the crude title compound as a white solid, which could be used directly without further purification. MS (ESI) m / z [M+H] + 245.0.

[1412] Intermediate 32

[1413] N-(6-chloro-5-fluoropyridin-3-yl)-3-nitropyridin-2-amine

[1414] (i-32)

[1415] Pd2(dba)3 (267 mg, 0.29 mmol) was added to 1,4-dioxane (60 mL) containing 2-chloro-3-fluoro-5-iodopyridine (CAS Registry No. 153034-99-2) (1.00 g, 3.88 mmol), 2-amino-3-nitropyridine (CAS Registry No. 4214-75-9) (540 mg, 3.88 mmol), XantPhos (CAS Registry No. 161265-03-8) (337 mg, 0.58 mmol), and Cs2CO3 (1.90 g, 5.83 mmol) under nitrogen atmosphere at 25 °C and stirred at 80 °C for 18 hours. The reaction mixture was filtered through a diatomaceous earth pad, the filter cake was washed with DCM (5 × 15 mL), and the combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative TLC (EtOAc:PE=1:2) to obtain the title compound (635 mg, 61%) as a yellow solid. 19 F NMR (282MHz, DMSO-d6) δ ppm -118.3.

[1416] Intermediate 33

[1417] N 2 -(6-chloro-5-fluoropyridin-3-yl)pyridin-2,3-diamine

[1418] (i-33)

[1419] Tetrahydroxydiboron (CAS Registry No. 13675-18-8) (828 mg, 9.23 mmol) was added to a mixture of 4,4'-bipyridine (CAS Registry No. 553-26-4) (36 mg, 0.23 mmol) and N-(6-chloro-5-fluoropyridin-3-yl)-3-nitropyridine-2-amine intermediate 32 (620 mg, 2.21 mmol) in DMF (10 mL) at 25 °C, and the mixture was stirred at this temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the resulting material was purified by rapid silica chromatography (gradient: 0%-56% EtOAc / PE) to give the title compound (430 mg, 78%) as a yellow solid. MS (ESI): m / z [M+H] + 239.0 / 241 (Cl isotope pattern). 19 F NMR (282MHz, DMSO-d6) δ ppm -120.31.

[1420] Intermediate 34

[1421] 3-(6-chloro-5-fluoropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[1422] (i-34)

[1423] At 25°C, CDI (CAS Registry No. 530-62-1) (1.16 g, 7.12 mmol) was added to N. 2 The intermediate 33 (425 mg, 1.78 mmol) of 6-chloro-5-fluoropyridin-3-yl)pyridine-2,3-diamine was dissolved in 10 mL of THF and stirred at 60 °C for 18 hours. The reaction mixture was concentrated under reduced pressure, the residue was ground with DCM (5 mL), and the solid formed was collected by filtration. The material was dried under vacuum to give the title compound (331 mg, 70%) as a white solid. MS (ESI): m / z [M+H] + 265.0 / 267 (Cl isotope pattern). 19 F NMR (282MHz, DMSO-d6) δ ppm -118.26.

[1424] Intermediate 35

[1425] 3-Nitro-2-(2-(trimethylsilyl)ethoxy)pyridine-4-amine

[1426] (i-35)

[1427] Sodium hydride (60% in mineral oil; 2.88 g, 72.0 mmol) was added in portions at 0 °C to a mixture of 2-(trimethylsilyl)ethanol-1-ol (CAS Registry No. 2916-68-9) (8.52 g, 72.0 mmol) and 2-chloro-3-nitropyridine-4-amine (CAS Registry No. 2789-25-5) (5.00 g, 28.8 mmol) in THF (120 mL), and the mixture was stirred at this temperature for 1 hour. The reaction mixture was then heated to 70 °C and stirred for another 12 hours. The mixture was poured into saturated brine (400 mL), and the aqueous phase was extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude material was purified by silica gel rapid chromatography (gradient: 2%-10% EtOAc / PE) to obtain the title compound (1.8 g, 24%) as a yellow oil, which solidified upon standing.

[1428] Intermediate 36

[1429] 6-Chloro-N-(3-nitro-2-(2-(trimethylsilyl)ethoxy)pyridin-4-yl)pyridin-3-amine

[1430] (i-36)

[1431] Pd2(dba)3 (161 mg, 0.18 mmol) was added to a mixture of 2-chloro-5-iodopyridine (CAS Registry No. 69045-79-0) (647 mg, 2.70 mmol), 3-nitro-2-(2-(trimethylsilyl)ethoxy)pyridine-4-amine intermediate 35 (600 mg, 2.35 mmol), XantPhos (CAS Registry No. 161265-03-8) (204 mg, 0.35 mmol), and Cs2CO3 (1.15 g, 3.52 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere at 20 °C, and the mixture was stirred at 80 °C for 18 hours. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel rapid chromatography (gradient: 2%–6% EtOAc / PE) to give the title compound (1.7 g, 66%) as a yellow solid. MS (ESI): m / z [MH] - 365 / 367 (Cl isotope pattern).

[1432] Intermediate 37

[1433] 1-(6-chloropyridin-3-yl)-4-(2-(trimethylsilyl)ethoxy)-1,3-dihydro-2H-imidazo[4, [5-c]pyridin-2-one

[1434] (i-37)

[1435] At 25 °C, tetrahydroxydiboron (CAS Registry No. 13675-18-8) (1.56 g, 17.4 mmol) was added to a mixture of 4,4'-bipyridine (CAS Registry No. 553-26-4) (68 mg, 0.44 mmol) and 6-chloro-N-(3-nitro-2-(2-(trimethylsilyl)ethoxy)pyridin-4-yl)pyridine-3-amine intermediate 36 (1.60 g, 4.36 mmol) in DMF (60 mL), and the mixture was stirred at this temperature for 30 min. CDI (CAS Registry No. 530-62-1) (7.07 g, 43.6 mmol) was added to the reaction mixture, which was then heated to 60 °C and stirred for 12 h. The mixture was cooled to room temperature, and the precipitate formed was filtered off. The filtrate was poured into saturated brine (400 mL) and the aqueous phase was extracted with EtOAc (3 × 250 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The resulting residue was ground with EtOAc:PE = 1:2 (30 mL). The solid formed was collected by filtration and dried under vacuum to give the title compound (1.4 g, 88%) as a pale yellow solid. MS (ESI): m / z [MH] - 361 / 363 (Cl isotope pattern).

[1436] Intermediate 38

[1437] 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-4-(2-(trimethylsilyl)ethoxy)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one

[1438] (i-38)

[1439] At 20 °C, 1-(chloromethyl)-4-methoxybenzene (675 µL, 4.96 mmol) was added to a mixture of 1-(6-chloropyridin-3-yl)-4-(2-(trimethylsilyl)ethoxy)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one intermediate 37 (1.2 g, 3.31 mmol) and K₂CO₃ (914 mg, 6.61 mmol) in DMF (20 mL), and the mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with EtOAc (400 mL) and washed with saturated brine (3 × 200 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The resulting residue was ground with EtOAc:PE = 1:1 (30 mL), and the solid formed was collected by filtration and dried under vacuum to give the title compound (1.3 g, 81%) as a pale yellow solid. MS (ESI): m / z[M+H] + 483 / 485 (Cl isotope pattern).

[1440] Intermediate 39

[1441] 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-3,5-dihydro-1H-imidazo[4,5-c]pyridine-2,4- diketone

[1442] (i-39)

[1443] At 20 °C, 1,4-dioxane (4 M, 4.0 mL, 16 mmol) containing HCl was added to 20 mL of 1,4-dioxane containing 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-4-(2-(trimethylsilyl)ethoxy)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one intermediate 38 (1.30 g, 2.69 mmol), and stirring was continued at this temperature for 5 hours. The solvent was removed under reduced pressure to give the crude title compound (900 mg, 87%) as a white solid. MS (ESI): m / z [M+H] + 383 / 385 (Cl isotope pattern).

[1444] Intermediate 40

[1445] 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-5-methyl-3,5-dihydro-1H-imidazo[4,5-c]pyridine 2,4-Diketone

[1446] (i-40)

[1447] A mixture of 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-3,5-dihydro-1H-imidazo[4,5-c]pyridine-2,4-dione intermediate 39 (800 mg, 2.09 mmol) in DMF (20 mL) was treated with iodomethane (261 µL, 4.18 mmol) at 20 °C and stirred at 60 °C for 3 h. The reaction mixture was poured into saturated brine (50 mL) and 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 crude material was purified by preparative TLC (EtOAc) to give the title compound (100 mg, 12%) as a white solid. MS (ESI): m / z [M+H] + 397.1 / 399 (Cl isotope pattern).

[1448] Intermediate 41

[1449] 1-(6-chloropyridin-3-yl)-5-methyl-3,5-dihydro-1H-imidazo[4,5-c]pyridin-2,4-dione

[1450] (i-41)

[1451] 1-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)-5-methyl-3,5-dihydro-1H-imidazo[4,5-c]pyridine-2,4-dione intermediate 40 (150 mg, 0.38 mmol) was treated with TFA (10 mL) at 20 °C, and the mixture was stirred at 60 °C for 15 hours. The reaction mixture was poured into saturated NaHCO3 (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give a crude title compound (100 mg, 96%) as a brown solid, which was used for the next step without further purification. MS (ESI): m / z [M+H] + 277 / 279 (Cl isotope pattern).

[1452] Intermediate 42

[1453] ((1S,3S)-3-(2-hydroxyguanidinyl)cyclopentyl)tert-butyl carbamate

[1454] (i-42)

[1455] Cyanogen bromide (CAS Registry No. 506-68-3) (1.98 g, 18.7 mmol) was added to 20 mL of THF containing tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (CAS Registry No. 645400-44-8) (2.5 g, 12.5 mmol) and sodium acetate (3.07 g, 37.4 mmol). The resulting solution was stirred at 20 °C for 15 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOH (20 mL). Hydroxylamine (50%, aqueous solution) (6.60 g, 99.9 mmol) was slowly added at 20 °C. The resulting solution was stirred at 20 °C for 2 hours. The solvent was removed under reduced pressure to give the crude title compound (3.2 g, 99%) as a yellow gel, which was used directly without further purification. MS (ESI) m / z [M+H] + 259.0.

[1456] Intermediate 43

[1457] ((1S,3S)-3-((5-methyl-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)tert-butyl carbamate

[1458] (i-43)

[1459] Acetic anhydride (1.1 mL, 12 mmol) was added to 40 mL of MeCN containing ((1S,3S)-3-(2-hydroxyguanidinyl)cyclopentyl)carbamate intermediate 42 (2.5 g, 9.7 mmol) and TEA (4.1 mL, 29 mmol). The resulting solution was stirred at 60 °C for 15 hours. The solvent was removed under reduced pressure to give a pale yellow gel. The crude product was purified by silica gel chromatography (gradient: 2-25% EtOAc / PE) to give the title compound (1.9 g, 69%) as a white solid. MS (ESI) m / z [M+H] + 282.9.

[1460] Intermediate 44

[1461] (1S,3S)-N 1 -(5-methyl-1,2,4-oxadiazol-3-yl)cyclopentane-1,3-diamine

[1462] (i-44)

[1463] pTSA (1.59 g, 9.21 mmol) was added to 20 mL of MeCN containing intermediate 43 (1.3 g, 4.6 mmol) of ((1S,3S)-3-((5-methyl-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)carbamate tert-butyl ester. The resulting mixture was stirred at 60 °C for 15 hours. The solvent was removed under reduced pressure to give an unspecified TsOH salt (2.2 g) of the crude title compound as a brown solid, which could be used directly without further purification. MS (ESI) m / z [M+H + 182.9.

[1464] Intermediate 45

[1465] ethyl 3-((6-chloropyridin-3-yl)amino)-2-nitrobenzoate

[1466] (i-45)

[1467] Pd₂(dba)₃ (218 mg, 0.24 mmol) was added to a mixture of 2-chloro-5-iodopyridine (CAS Registry No. 69045-79-0) (1.37 g, 5.71 mmol), ethyl 3-amino-2-nitrobenzoate (CAS Registry No. 193014-01-6) (1.00 g, 4.76 mmol), XantPhos (CAS Registry No. 161265-03-8) (275 mg, 0.48 mmol), and Cs₂CO₃ (2.33 g, 7.14 mmol) in 1,4-dioxane (50 mL) at 15 °C under nitrogen atmosphere, and the mixture was stirred at 80 °C for 15 hours. The reaction mixture was poured into saturated brine (200 mL) and extracted with EtOAc (4 × 125 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc:PE = 1:3) to give the title compound (680 mg, 44%) as a yellow solid. MS (ESI): m / z [M+H] + 322 / 324 (Cl isotope pattern).

[1468] Intermediate 46

[1469] ethyl 2-amino-3-((6-chloropyridin-3-yl)amino)benzoate

[1470] (i-46)

[1471] At 0 °C, tetrahydroxydiboron (CAS Registry No. 13675-18-8) (747 mg, 8.33 mmol) was added to a mixture of 4,4'-bipyridine (CAS Registry No. 553-26-4) (3 mg, 0.02 mmol) and ethyl 3-((6-chloropyridin-3-yl)amino)-2-nitrobenzoate intermediate 45 (670 mg, 2.08 mmol) in DMF (30 mL), and the mixture was subsequently stirred at 20 °C for 2 h. The reaction mixture was poured into saturated brine (200 mL) and extracted with EtOAc (4 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (EtOAc) to give the title compound (590 mg, 97%) as a yellow solid. MS (ESI): m / z [M+H] + 292 / 294 (Cl isotope pattern).

[1472] Intermediate 47

[1473] 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylic acid ethyl ester

[1474] (i-47)

[1475] At 0 °C, Et3N (1.4 mL, 9.9 mmol) was added to a mixture of ethyl 2-amino-3-((6-chloropyridin-3-yl)amino)benzoate intermediate 46 (580 mg, 1.99 mmol), DMAP (12 mg, 0.10 mmol), and CDI (CAS Registry No. 530-62-1) (645 mg, 3.98 mmol) in THF (20 mL), and the mixture was subsequently stirred at 60 °C for 6 hours. The reaction mixture was milled with EtOAc (3 × 50 mL), and the resulting solid was collected by filtration. The material was dried under vacuum to give the title compound (390 mg, 62%) as a white solid, which was used directly for the next step without further purification. MS (ESI): m / z [M+H] + 318 / 320 (Cl isotope pattern).

[1476] Intermediate 48

[1477] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- Ethyl benzo[d]imidazolium-4-carboxylate (2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxylate)

[1478] (i-48)

[1479] Pd-PEPPSI-lpentCl 2-methylpyridine (27 mg, 0.03 mmol) was added as a 3HCl salt to (1S,3S)-N at 15 °C under a N2 atmosphere. 1 Intermediate 31 (267 mg, 0.76 mmol) of 5-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine, intermediate 47 (200 mg, 0.63 mmol) of 1-(6-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxylate, and intermediate 47 (200 mg, 0.63 mmol) of Cs₂CO₃ (1.23 g, 3.78 mmol) were placed in DMF (20 mL). The mixture was stirred at 100 °C for 15 h. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative TLC (7 M NH₃ / MeOH:DCM, 1:10) to give the title compound (245 mg, 74%) as a yellow solid. MS (ESI): m / z [M+H] + 526.3.

[1480] Example

[1481] Example 1

[1482] 1-(6-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)pyridin-3-yl)- 1,3-Dihydro-2H-benzo[d]imidazol-2-one-compound 1

[1483] (1)

[1484] At 25 °C, Pd-PEPPSI-IpentCl 2-methylpyridine (136 mg, 0.16 mmol) was added to 10 mL of DMF containing 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one intermediate 3 (150 mg, 0.49 mmol), 2-chlorooxazolo[5,4-b]pyridine (CAS Registry No. S159870-95-8) (50 mg, 0.32 mmol), and Na₂CO₃ (103 mg, 0.97 mmol). The resulting mixture was stirred at 100 °C for 15 hours under a nitrogen atmosphere. The reaction mixture was concentrated, diluted with EtOAc (150 mL), and washed successively with brine (3 × 50 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified by preparative HPLC (Preparation Method A, gradient: 24%-40%) to give the title compound (97 mg, 70%) as a white solid. HRMS (ESI) m / z [M+H] + C 23 H 22 Calculated value of N7O2: 428.1830, measured value: 428.1842. 1 H NMR (500MHz, DMSO-d6) δ 1.5–1.61 (1H, m), 1.61–1.72 (1H, m), 1.93–2.01 (1H, m), 2.01–2.07 (1H, m), 2.12–2.29 (2H, m), 4.25–4.34 (1H, m), 4.34–4.46 (1H, m), 6.62 (1H, d), 6.84 (1H, d), 6.89–7.11 (4H,m), 7.17 (1H, dd), 7.47 (1H, dd), 7.59 (1H, dd), 7.84 (1H, dd), 8.06 (1H, d),8.42 (1H, d), 11.05 (1H, s).

[1485] Example 2

[1486] 1-(6-(((1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)pyridin-3-yl)- 1,3-Dihydro-2H-benzo[d]imidazol-2-one-compound 2

[1487] (2)

[1488] At room temperature, Pd-PEPPSI-IpentCl 2-methylpyridine (108 mg, 0.13 mmol) was added to 10 mL of DMF containing the free base 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one intermediate 3 (119 mg, 0.38 mmol), 2-bromothiazo[5,4-b]pyridine (CAS Registry No. 412923-41-1) (55 mg, 0.26 mmol), and Na₂CO₃ (81 mg, 0.77 mmol), and the resulting mixture was stirred at 100 °C for 15 hours under nitrogen. The reaction mixture was concentrated, diluted with EtOAc (150 mL), and washed successively with brine (3 × 50 mL). The organic layer was dried (Na₂SO₄), filtered, and evaporated to give the crude product. The crude product was first purified by preparative TLC (MeOH:DCM = 1:15), followed by preparative HPLC (Preparation Method B, gradient 25%-40%), yielding the title compound as a white solid (47 mg, 41%). HRMS (ESI) m / z [M+H + C 23 H 22 Calculated value of N7OS: 444.1600, measured value: 444.1580. 1 H NMR (500MHz, DMSO-d6) δ ppm 1.52 – 1.69 (2H, m), 1.91 – 2.09 (2H,m), 2.2 – 2.3 (2H, m), 4.3 – 4.45 (2H, m), 6.62 (1H, d), 6.83 (1H, d), 6.95 –7.06 (4H, m), 7.25 (1H, dd), 7.47 (1H, dd), 7.67 (1H, dd), 7.97 – 8.16 (2H,m), 8.48 (1H, d), 10.99 (1H, s).

[1489] Example 3

[1490] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- )-1,3-dihydro-2H-benzo[d]imidazol-2-one-compound 3

[1491] (3)

[1492] At 25 °C, Pd-PEPPSI-IpentCl 2-methylpyridine (10.88 mg, 0.01 mmol) was added to 20 mL of DMF containing 1-(6-(((1S,3S)-3-aminocyclopentyl)amino)pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one intermediate 3 (80 mg, 0.26 mmol), 2-chloro-5-(difluoromethoxy)pyrimidine (51.4 mg, 0.28 mmol), and Na2CO3 (82 mg, 0.78 mmol). The mixture was stirred at 100 °C for 15 hours under a N2 (g) atmosphere. The reaction mixture was poured into brine (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (MeOH:DCM, 1:20) followed by preparative HPLC (Preparation Method A, gradient: 31%-47%) to give the title compound (50 mg, 43%) as a white solid. HRMS (ESI) m / z [M+H] + C 22 H 22 Calculated value of F2N7O2: 454.1798, measured value: 454.1822. 1 H NMR(300MHz, DMSO-d6) δ 1.4–1.69 (2H, m), 1.84–2.02 (2H, m), 2.08–2.24 (2H, m), 2.29 (3H, s), 2.39 (3H, s), 4.17–4.49 (2H, m), 5.71 (1H, s), 6.50 (1H, d), 6.80 (1H, d), 7.16 (1H, dd), 7.42–7.65 (1H, m), 7.71 (1H, d), 8.17 (1H, s).

[1493] Example 5

[1494] 1-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine-3- Compound 5 (-1,3-dihydro-2H-benzo[d]imidazol-2-one)

[1495] (5)

[1496] (1S,3S)-N 1 -(5-Iodopyridin-2-yl)-N 3Intermediate 22 (57 mg, 0.14 mmol) of 6-methyl-1,2,4-triazine-3-yl)cyclopentane-1,3-diamine, 1,3-dihydro-2H-benzo[d]imidazol-2-one (23.2 mg, 0.17 mmol), CuI (27 mg, 0.14 mmol), K₂CO₃ (60 mg, 0.43 mmol), 1,4-dioxane (1 mL), and DMCDA (0.023 mL, 0.14 mmol) were mixed in a vial. The vial was capped, evacuated, and filled with N₂ (g) (×2). The mixture was stirred at 100 °C for 20 hours under N₂ (g) atmosphere. The reaction mixture was cooled to room temperature and MeOH was added. The mixture was filtered through diatomaceous earth. The stopper was washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Preparation Method C, gradient: 20%-60%) to obtain the title compound (15 mg, 26%) as a beige solid. HRMS (ESI) m / z [M+H] + C 21 H 23 Calculated value of N8O: 403.1990, measured value: 403.1998. 1 H NMR (500MHz, MeOH-d4) δ 1.57–1.75 (2H, m), 1.99–2.16 (2H, m), 2.23–2.38 (2H, m), 2.45 (3H, s), 4.34–4.42 (1H, m), 4.42–4.5 (1H, m), 6.69(1H, d), 6.91 (1H, d), 7.03–7.15 (3H, m), 7.50 (1H, dd), 8.05 (1H, s), 8.20(1H, s).

[1497] Example 8

[1498] 1-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyridine- 3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one-compound 8

[1499] (8)

[1500] (1S,3S)-N 1 -([1,2,4]triazolo[1,5-a]pyridine-2-)-N 325 (66 mg, 0.16 mmol) of (5-iodopyridin-2-yl)cyclopentane-1,3-diamine intermediate, 1,3-dihydro-2H-benzo[d]imidazol-2-one (26 mg, 0.19 mmol), CuI (30 mg, 0.16 mmol), K₂CO₃ (66 mg, 0.48 mmol), dioxane (1 mL), and DMCDA (0.025 mL, 0.16 mmol) were mixed in a vial. The vial was capped, evacuated, and filled with N₂ (g) (×2). The mixture was stirred at 100 °C for 20 hours under N₂ (g) atmosphere. The reaction mixture was cooled to room temperature and EtOAc was added. The mixture was filtered through diatomaceous earth, the stopper was washed with EtOAc and MeOH, and the combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative HPLC (Preparation Method C, gradient: 20%-60%), and the lyophilized solid was redissolved in a mixture of EtOAc / MeOH (1:2). SiliaMetS dimercaptotriazine (e.g., Sigma catalog number 900680) (loading 0.59 mmol / g, 100 mg) was added, and the mixture was concentrated. The residue was dissolved in EtOAc / MeOH (1:2), the slurry was filtered, and the filtrate was evaporated to obtain an oil. The oil was dissolved in ACN / water (1:1) and lyophilized overnight to give the title compound as a white solid (23 mg, 34%). HRMS (ESI) m / z [M+H] + C 23 H 23 Calculated value of N8O: 427.1990, measured value: 427.1960. 1 H NMR (500MHz, MeOH-d4) δ1.58–1.78 (2H, m), 2–2.19 (2H, m), 2.24–2.38 (2H, m), 4.22–4.34 (1H, m), 4.34–4.44 (1H, m), 6.70 (1H, d), 6.88–6.97 (2H, m), 7.03–7.17 (3H, m), 7.37(1H, d), 7.46–7.55 (2H, m), 8.05 (1H, s), 8.39–8.54 (1H, m).

[1501] Example 10

[1502] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- Compound 10 (-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one)

[1503] (10)

[1504] Trifluoromethanesulfonic acid (6418 mg, 2.78 mmol) was added to 15 mL of DCM containing 10 (200 mg, 0.35 mmol) of 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 10, and the resulting mixture was stirred at this temperature for 15 hours. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative HPLC (Preparation Method D, gradient: 14%-25%) to give the title compound (34 mg, 21%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated value of F2N8O2: 455.1750, measured value: 455.1716. 1 H NMR (300MHz, DMSO-d6) δ ppm1.52 – 1.64 (2H, m), 1.94 – 2.02 (2H, m), 2.11 – 2.30 (2H, m), 4.28 – 4.39(2H, m), 6.94 (1H, brs), 7.04 (1H, t), 7.08 – 7.12 (1H, m), 7.40 (1H, dq), 7.53 (1H, d), 7.91 – 7.94 (2H, m), 8.13 – 8.25 (3H, m), 11.42 – 1.43 (1H, m). 19 F NMR (282MHz, DMSO-d6) δ ppm -81.8.

[1505] Example 12

[1506] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- Compound 12 (1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one)

[1507] (12)

[1508] At 15 °C, 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 17 (120 mg, 0.21 mmol) was added to TFA (10 mL, 129.80 mmol) and trifluoromethanesulfonic acid (2 mL, 0.21 mmol). The resulting mixture was stirred at 60 °C for 15 hours. The solvent was removed under reduced pressure. The mixture was filtered and evaporated again to give the crude product. The crude product was purified by preparative HPLC (Preparative Method E, gradient: 11%-26%) to give the title compound (25.8 mg, 27%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 21 Calculated value of F2N8O2: 455.1750, measured value: 455.1766. 1 H NMR(500MHz, DMSO-d6) δ 1.55–1.73 (2H, m), 1.96–2.12 (2H, m), 2.12–2.21 (1H, m), 2.24–2.35 (1H, m), 4.21–4.31 (1H, m), 4.31–4.42 (1H, m), 6.89–7.23 (3H, m),7.35 (1H, dd), 7.56 (1H, s), 8.02 (1H, dd), 8.03–8.09 (1H, m), 8.25 (1H, d),8.28 (2H, s), 9.07 (1H, s), 11.95 (1H, s). 19 F NMR (471MHz, DMSO-d6) δ ppm -81.9.

[1509] Example 21

[1510] 1-(4-Methoxybenzyl)-3-(6-(((1S,3S)-3-((6-methyl-1,2,4-triazine-3-yl)amino)cyclopentanyl (I)amino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one-compound 21

[1511] (twenty one)

[1512] Pd-PEPPSI-lpentCl 2-methylpyridine (19 mg, 0.02 mmol) was added as a 2TsOH salt to (1S,3S)-N 1Intermediate 21 (748 mg, 1.39 mmol) of 6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine, intermediate 7 (170 mg, 0.46 mmol), 3-(6-chloropyridin-3-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 7 (170 mg, 0.46 mmol), and K2CO3 (320 mg, 2.32 mmol) were added to 1,4-dioxane (5 mL). The mixture was stirred at 100 °C for 18 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM (2 × 5 mL) and the combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative TLC (7 M NH3 / MeOH:DCM, 1:25). A portion of the obtained product was further purified by preparative HPLC (Preparation Method J, gradient: 34%-41%) to obtain the title compound (31 mg) as a white solid. HRMS (ESI) m / z [M+H] + C 28 H 30 Calculated value of N9O2: 524.2518, measured value: 524.2470. 1 H NMR (500MHz, DMSO-d6) δ 1.49–1.62 (2H, m), 1.89–2.00 (2H, m), 2.13–2.20 (2H, m), 2.38 (3H, s), 3.72 (3H, s), 4.32–4.41 (2H, m), 5.05 (2H,s), 6.59 (1H, d), 6.89–6.94 (3H, m), 7.08 (1H, dd), 7.34–7.36 (2H, m), 7.51(1H, dd), 7.53–7.59 (2H, m), 7.92 (1H, dd), 8.13 (1H, d), 8.17 (1H, s).

[1513] Example 23

[1514] 3-Methyl-1-(6-(((1S,3S)-3-((5-methyl-1,2,4-oxadiazol-3-yl)amino)cyclopentyl)amino) pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one-compound 23

[1515] (twenty three)

[1516] Pd-PEPPSI-lpentCl 2-methylpyridine (45 mg, 0.05 mmol) was added as a 3TsOH salt to (1S,3S)-N 1The intermediates 44 (450 mg, 0.64 mmol) of 5-methyl-1,2,4-oxadiazol-3-yl)cyclopentane-1,3-diamine, 26 (140 mg, 0.54 mmol) of 1-(6-chloropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, and 223 mg, 1.61 mmol of K₂CO₃ were mixed in DMF (15 mL). The mixture was stirred at 100 °C for 15 hours. The reaction mixture was diluted with saturated brine (150 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude material was purified by preparative TLC (DCM:MeOH, 10:1) followed by preparative HPLC (Preparation Method F, gradient: 7%-16%) to obtain the title compound (12 mg, 5%) as a white solid. HRMS (ESI) m / z [M+H] + C 20 H 23 Calculated value of N8O2: 407.1938, measured value: 407.1904. 1 HNMR (500MHz, DMSO-d6) δ 1.45–1.58 (2H, m), 1.81–1.86 (1H, m), 1.92–1.97 (1H,m), 2.06–2.16 (2H, m), 2.38 (3H, s), 3.40 (3H, s), 3.90 (1H, sext), 4.32 (1H,sext), 6.59 (1H, d), 6.82 (1H, d), 6.97 (1H, d), 7.05 (1H, dd), 7.24 (1H, d),7.48 (1H, dd), 8.04 (1H, d), 8.08 (1H, d).

[1517] Example 24

[1518] 1-(6-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)- 1,3-Dihydro-2H-imidazo[4,5-b]pyridin-2-one-compound 24

[1519] (twenty four)

[1520] Pd-PEPPSI-lpentCl 2-methylpyridine (58 mg, 0.07 mmol) was added to 1-(6-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 13 (170 mg, 0.69 mmol) as a 2TFA salt in a N2 atmosphere at 20 °C.1 The intermediate 28 (392 mg, 0.83 mmol) of 5-(trifluoromethyl)pyrimidin-2-yl)cyclopentane-1,3-diamine was added to a mixture of 1,4-dioxane (20 mL). The mixture was stirred at 100 °C for 15 hours. The reaction mixture was diluted with saturated brine (150 mL), and the aqueous layer was extracted with EtOAc (3 × 125 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude material was purified by preparative TLC (DCM:MeOH, 10:1) followed by preparative HPLC (Preparation Method G, gradient: 13%–28%) to give the title compound (87 mg, 28%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 20 Calculated value of F3N8O: 457.1706, measured value: 457.1676. 1 H NMR (300MHz, DMSO-d6) δ 1.46–1.65 (2H, m), 1.86–2.01 (2H, m), 2.11–2.20 (2H, m), 4.29–4.50 (2H, m), 6.60 (1H, d), 6.97–7.01 (2H, m), 7.17(1H, dd), 7.48 (1H, dd), 7.95 (1H, dd), 8.07 (1H, d), 8.22 (1H, d), 8.59–8.63(2H, m), 11.74 (1H, brs). 19 F NMR (282MHz, DMSO-d6) δ ppm -59.24.

[1521] Example 26

[1522] 1-(6-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)pyridine- 3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one-compound 26

[1523] (26)

[1524] Pd-PEPPSI-lpentCl 2-methylpyridine (26 mg, 0.03 mmol) was added to 1-(6-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one intermediate 13 (150 mg, 0.61 mmol) as a 3HCl salt of (1S,3S)-N 1Intermediate 24 (238 mg, 0.73 mmol) of 1-([1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopentane-1,3-diamine was added to a mixture of Cs₂CO₃ (1.19 g, 3.65 mmol) in 15 mL of DMF. The mixture was stirred at 100 °C for 14 h. The reaction mixture was filtered through a syringe filter and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative TLC (7 M NH₃ / MeOH:DCM, 1:10) followed by preparative HPLC (Preparative Method H, gradient: 15%–30%) to give the title compound (81 mg, 31%) as a white solid. HRMS (ESI) m / z [M+H] + C 22 H 22 Calculated value of N9O: 428.1942, measured value: 428.1942. 1 H NMR (500MHz, DMSO-d6) δ 1.47–1.62(2H, m), 1.87–1.92 (1H, m), 1.95–2.01 (1H, m), 2.12–2.20 (2H, m), 4.16–4.22(1H, m), 4.30–4.37 (1H, m), 6.60 (1H, d), 6.64 (1H, d), 6.86 (1H, dt), 6.96(1H, d), 6.99 (1H, dd), 7.17 (1H, d), 7.36–7.38 (1H, m), 7.40–7.43 (1H, m),7.48 (1H, dd), 7.95 (1H, dd), 8.06–8.08 (1H, m), 8.58 (1H, d), 11.73 (1H, s).

[1525] Example 27

[1526] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- (N,N-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-carboxamide-compound 27)

[1527] (27)

[1528] At 20 °C, 230 mg (0.44 mmol) of ethyl 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxylate intermediate 48 was added to a 30% solution of dimethylamine in MeOH (20 mL), and the mixture was sealed in a microwave tube. The mixture was stirred at 100 °C for 2 hours, cooled to room temperature, and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Preparation Method K, gradient: 53%-63%) to give the title compound (15 mg, 6%) as a white solid. HRMS (ESI) m / z [M+H] + C 25 H 27 Calculated value of F2N8O3: 525.2168, measured value: 525.2192. 1 H NMR (300MHz, DMSO-d6) δ1.45–1.61 (2H, m), 1.83–1.98 (2H, m), 2.09–2.20 (2H, m), 2.90 (3H, brs), 3.00(3H, brs), 4.27–4.38 (2H, m), 6.60 (1H, d), 6.86 (1H, dd), 6.94–7.04 (3H, m), 7.03 (1H, t), 7.46 (1H, dd), 7.50 (1H, d), 8.05 (1H, d), 8.24 (2H, s), 11.25(1H, brs). 19 F NMR (282MHz, DMSO-d6) δ ppm -81.77.

[1529] Example 28

[1530] 1-(5-Fluoro-6-(((1S,3S)-3-((6-methyl-1,2,4-triazine-3-yl)amino)cyclopentyl)amino)pyridine- 3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one-compound 28

[1531] (28)

[1532] Pd-PEPPSI-lpentCl 2-methylpyridine (24 mg, 0.03 mmol) was added as a 3TsOH salt to (1S,3S)-N 1Intermediate 21 (485 mg, 0.68 mmol) of 1-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine, intermediate 29 (150 mg, 0.57 mmol), and K₂CO₃ (927 mg, 2.84 mmol) were added to a mixture of 1,4-dioxane (15 mL). The mixture was stirred at 100 °C for 15 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM (2 × 15 mL) and the combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative TLC (7 M NH₃ / MeOH:DCM, 1:15) followed by preparative HPLC (Preparative Method I, gradient: 26%–46%) to give the title compound (25 mg, 10%) as a white solid. HRMS (ESI)m / z [M+H] + C 21 H 22 Calculated value of FN8O: 421.1890, measured value: 421.1896. 1 H NMR (300MHz, DMSO-d6)δ 1.52–1.69 (2H, m), 1.91–2.06 (2H, m), 2.11–2.22 (2H, m), 2.38 (3H, s), 4.34–4.45 (1H, m), 4.49–4.61 (1H, m), 6.88–7.05 (5H, m), 7.56–7.60 (2H, m), 7.97 (1H, d), 8.17 (1H, s), 11.08 (1H, brs). 19 F NMR (282MHz, DMSO-d6) δ ppm -137.45.

[1533] Example 30

[1534] 3-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-fluoropyrimidin (Pinidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one-compound 30

[1535] (30)

[1536] Pd-PEPPSI-lpentCl 2-methylpyridine (48 mg, 0.06 mmol) was added as a 3HCl salt to (1S,3S)-N at 25 °C under a N2 atmosphere. 1Intermediate 31 (200 mg, 0.57 mmol) of 5-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine, intermediate 34 (150 mg, 0.57 mmol), and Cs₂CO₃ (923 mg, 2.83 mmol) were mixed in DMF (8 mL). The mixture was stirred at 100 °C for 18 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH (3 × 5 mL) and the combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative TLC (EtOAc) followed by preparative HPLC (Preparative Method J, gradient: 20%–38%) to give the title compound (55 mg, 21%) as a white solid. HRMS (ESI) m / z [M+H] + C 21 H 20 Calculated value of F3N8O2: 473.1656, measured value: 473.1672. 1 H NMR (300MHz, DMSO-d6) δ 1.48–1.67 (2H, m), 1.90–2.00 (2H, m), 2.07–2.21 (2H, m), 4.33 (1H, sext), 4.52(1H, sext), 6.88 (1H, d), 7.03 (1H, t), 7.07 (1H, dd), 7.37 (1H, dd), 7.49(1H, d), 7.63 (1H, dd), 7.91 (1H, dd), 8.05 (1H, d), 8.23 ​​(2H, s), 11.35 (1H,s). 19 F NMR (282MHz, DMSO-d6) δ ppm -81.74, -138.25.

[1537] Example 32

[1538] 1-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridine-3- )-5-methyl-3,5-dihydro-1H-imidazo[4,5-c]pyridine-2,4-dione-compound 32

[1539] (32)

[1540] Pd-PEPPSI-lpentCl 2-methylpyridine (91 mg, 0.11 mmol) was added as a 3HCl salt to (1S,3S)-N at 20 °C under a N2 atmosphere. 1Intermediate 31 (256 mg, 0.72 mmol) of 5-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine, intermediate 41 (100 mg, 0.36 mmol) of 1-(6-chloropyridin-3-yl)-5-methyl-3,5-dihydro-1H-imidazo[4,5-c]pyridine-2,4-dione, and intermediate 41 (100 mg, 0.36 mmol) and Cs₂CO₃ (589 mg, 1.81 mmol) were mixed in DMF (10 mL). The mixture was stirred at 100 °C for 20 h. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by preparative TLC (DCM:MeOH, 10:1) followed by preparative HPLC (Preparative Method J, gradient: 20%-40%) to give the title compound (1.5 mg, 1%) as a white solid. HRMS (ESI) m / z [M+H] + C 22 H 23 Calculated value of F2N8O3: 485.1850, measured value: 485.1878. 1 H NMR (300MHz, DMSO-d6) δ 1.47–1.60 (2H, m), 1.82–1.96 (2H, m), 2.07–2.18 (2H, m), 3.50 (3H, s), 4.26–4.37 (2H, m), 6.08 (1H, d), 6.58 (1H,d), 6.97 (1H,d), 7.03 (1H,t), 7.39–7.50 (3H,m), 7.99 (1H,d), 8.23 ​​(2H,s), 11.35 (1H,s). 19 F NMR (282MHz, DMSO-d6) δ ppm -81.78.

[1541] Measurements and methods used

[1542] Determination 1 - Biochemical Human PCSK9 Determination

[1543] This assay measures the binding of the compound to PCSK9 using homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET).

[1544] To determine the IC50 of inhibitors of the interaction between human PCSK9 and Alexa647-tagged small molecules. 50Fluorescent probe displacement was monitored using homogeneous TR-FRET technology. When a terbium (Tb) cavitation compound-conjugated anti-His mouse antibody (mAb anti-6HisTb cavitation compound Gold, Cisbio) binds to PCSK9-TEV-His6, probe displacement relative to PCSK9 was assessed by the reduction in proximity and the FRET signal between the Tb cavitation compound (as FRET donor) and the Alexa647 probe (as acceptor).

[1545] Recombinantly expressed and purified PCSK9-TEV-His6 (1 nM) was mixed with a fluorescent probe (5 nM) and an anti-His-Tb-caecinoid antibody (0.2 nM) in assay buffer (10 mM HEPES / NaOH, pH 7.4, 150 mM NaCl, 0.005 (v / v)% Tween 20). 6 µL was then added to a ready-to-use assay plate containing 0.06 µL of the control and a 10-dose-response serial dilution of the test compound (starting at a concentration of 10 mM (with a maximum final concentration of 100 µM and a minimum final concentration of 3.2 nM)) using a Certus flex dispenser. The plate was sealed, and the reaction mixture was incubated overnight (18 to 24 hours) in the dark at room temperature.

[1546] FRET signal quantification was achieved using a PHERAstar FSX (BMG) reader. The created data file contains the emission of the FRET acceptor channel (665 nm, probe), the FRET donor channel (620 nm, Tb-cavitation compound, excited at 337 nm), and the IC50 values ​​used to calculate the test compound. 50 FRET ratio (665nm / 620nm signal × 10.000).

[1547] Measurements of 2 and 2a - Biophysical human PCSK9 assay

[1548] These assays measured the binding of the compound to PCSK9 using SPR (“surface plasmon resonance”, a biophysical method) at plasma and representative endosome pH (7.4 and 5.6, respectively).

[1549] The SPR binding assay (pH 7.4, assay 2) was performed at 30°C on a Biacore S200 optical biosensor unit. The Series S SensorChip SA, designed to bind biotinylated molecules for interaction analysis in the Biacore system, was equilibrated at room temperature prior to use. The run buffer used for protein binding and subsequent ligand binding assays was 10 mM HEPES pH 7.4, 150 mM NaCl, and 0.05% (v / v) Tween 20 pH 7.4.

[1550] For surface binding of PCSK9, biotinylated human PCSK9 (31-692)-Avi-His6 (Charles River Laboratories) at a concentration of 0.5 mg / mL was used. Prior to surface binding, the surface was exposed to a solution of 50 mM NaOH and 500 mM NaCl (by three consecutive injections of this solution, with a contact time of 60 s and a flow rate of 10 µL / min). -1 To remove unconjugated streptavidin, PCSK9 protein was diluted to a concentration of 20 µg / mL using run buffer and incubated for 180–300 s with a contact time of 10 µL / min. -1 The flow rate is injected through a single flow channel (typically flow channel 2 or flow channel 4) to achieve a protein capture level of >5000 response units (RU). The remaining biotin binding sites are treated by two consecutive injections of 10 µM d-biotin solution in run buffer (contact time 60 s and flow rate 10 µL / min). -1 (Through all flow channels) to block. Flow channels 1 and 3 are typically used as reference surfaces throughout the subsequent bonding experiments.

[1551] All experiments were conducted at 30 µL / min. -1 The flow rate was determined using a single-cycle kinetics approach. This method involves the continuous injection of a series of compound concentrations without a regeneration step. Contact times were chosen between 90 and 150 seconds, followed by a 40-minute dissociation phase to allow for accurate estimation of the dissociation rate constant. Test compounds were delivered in DMSO at a concentration of 10 mM, and a series of compound concentrations using a digital dispenser HP D300 was established. The test concentrations were 30 nM, 100 nM, 300 nM, 1000 nM, 3000 nM, and 10000 nM. The surface was equilibrated by injecting run buffer onto the surface in three separate pulses before injecting any compound. The data collection rate was set to 10 Hz.

[1552] First, a reference subtraction was performed on the original sensor map of the compound injection (signals from flow channels 1 and / or 3 were subtracted from signals from channels 2 and / or 4, respectively), followed by a blank subtraction (signals from injected DMSO control were subtracted from the reference subtraction data). The resulting dual-reference sensor map was then fitted using a 1:1 binding interaction model with the manufacturer's software package to extract kinetic and affinity data. Active compounds were defined by producing a detectable binding signal ≥3 RU at the highest compound concentration (10 mM). The theoretical maximum binding signal (R0) for a 1:1 binding interaction ≥ 1 RU was only considered when the binding signal at the highest compound concentration (10 mM) was ≥ 1 RU. maxThose compounds (typically between 15 RU and 20 RU) provide kinetic and affinity data about the active compound in order to properly fit the data.

[1553] The SPR experiment (pH 5.6, assay 2a) was performed at 37°C on a Biacore 8K biosensor unit (Cytiva). The Series S SensorChip SA (Cytiva - lot number 10315802), designed to bind biotinylated molecules for interaction analysis in the Biacore system, was equilibrated at room temperature prior to use. Buffer A for protein binding was 10 mM Hepes, 150 mM NaCl, 0.05% (v / v) Tween 20, pH 7.4 (Cytiva, product number BR100671). Buffer B for subsequent ligand binding experiments was 20 mM dimethylarsethionate, 150 mM NaCl, 0.05% (v / v) Tween 20, pH 5.60.

[1554] Prior to surface binding of biotinylated PCSK9, the surface was exposed to a solution of 50 mM NaOH (Merck, product number 1.06469.1000) and 500 mM NaCl (Sigma-Aldrich, 71380-M) (by injecting the solution three times consecutively, with a contact time of 60 s and a flow rate of 10 µL / min). -1 To remove unconjugated streptavidin. Biotinylated human PCSK9 (31-692)-Avi-His6 (Charles River Laboratories) at a concentration of 0.5 mg / mL was diluted to 20 µg / mL using buffer A with a contact time of 600 s and 5 µL / min. -1 The target protein capture level was 6000-7000 RU injected into flow cell 2 at a flow rate of [missing information]. Remaining biotin-binding sites were [missing information] in all flow cells at a contact time of 60 s and a flow rate of 10 µL / min. -1 A single injection of 10 µM d-biotin solution (Avidity, product number BIO200) at a flow rate was used for blocking. Flow cell 1 was used as a reference surface during subsequent ligand binding experiments. The protein surface was stabilized overnight using a spare flow, and buffer A was exchanged with buffer B by starting the system the day before the ligand binding experiments.

[1555] All experiments were conducted at 30 µL / min. -1The flow rate was determined using a single-cycle kinetic method. This method involves continuous injection of compound concentration series without a regeneration step. A 120-second contact time was used, followed by a 40-minute dissociation phase to allow for accurate estimation of the dissociation rate constant. The compounds were tested in a concentration series using six concentrations: 30 nM, 100 nM, 300 nM, 1000 nM, 3000 nM, and 10000 nM.

[1556] First, a reference subtraction was performed on the raw sensor map of the compound injection (the signal from flow channel 1 was subtracted from the signal from channel 2), followed by a blank subtraction (the signal from the injected 2 DMSO control was subtracted from the data from the reference subtraction). Then, the resulting dual-reference sensor map was fitted using a 1:1 combined interaction model with the manufacturer's software package (BIAcore Insight Evaluation Software V 5.0.18.22102) to extract kinetic and affinity data.

[1557] The comparative compound used in determinations 2 and 2a is Example 493 in WO 2020 / 150473 A2.

[1558] .

[1559] Table 3: SPR Data

[1560]

[1561] Measurement of 3 and 3a-PCSK9 LDL-C intake

[1562] The profile analysis of the compound's PCSK9 antagonist activity was based on its ability to restore LDL uptake in HepG2 cells. This assay was based on exogenous PCSK9 protein (WT, assay 3; or D374Y mutant, assay 3a) and pH-sensitive dye (pHrodo). ™ Red-LDL complex LDL. Extracellularly, at neutral pH, pHrodo ™ Red-LDL fluoresces weakly, but under LDLR-mediated endocytosis, it fluoresces brightly. PCSK9 transports the LDL receptor (LDLR) into the cell for degradation and reduces LDL uptake. Inhibition of PCSK9 reduces LDLR degradation, and the increased LDL uptake can be quantified by fluorescence microscopy.

[1563] Preparation of assay reagents

[1564] Assay medium: OptiMem (Gibco#51985) + penicillin / streptomycin (Gibco#15140122, 1:100 dilution)

[1565] Labeled LDL: Low-density lipoprotein from human plasma, pHrodo ™ Red (pHrodo) ™ Red-LDL) (Invitrogen#L34356)

[1566] Cells: HepG2 (ATCC #HB-8065)

[1567] WT PCSK9 protein: Own. Sequence: MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEELVLALRSEED GLAEAPEHGT TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA QAARRGYLTKILHVFHGLLP GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPPRYRADE YQPPDGGSLVEVYLLDTSIQ SDHREIEGRV MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSSGRDAG VAKGASMRSLRVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLLPLA GGYSRVLNAA CQRLARAGVV LVTAAGNFRDDACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD LFAPGEDIIGASSDCSTCFV SQSGTSQAAAHVAGIAAMML SAEPELTLAE LRQRLIHFSA KDVINEAWFP EDQRVLTPNL VAALPPSTHG AGWQLFCRTVWSAHSGPTRM ATAIARCAPD EELLSCSSFS RSGKRRGERM EAQGGKLVCR AHNAFGGEGV YAIARCCLLPQANCSVHTAP PAEASMGTRV HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASCCHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV DNTCVVRSRD VSTTGSTSEEAVTAVAICCR SRHLAQASQE LQENLYFQGH HHHHH (SEQ ID NO.: 1)

[1568] PCSK9 protein (D374Y mutant): Human PCSK9 (D374Y) protein, His tag, MALS verification (AcroBiosystems PCY-H5225).

[1569] 3. Neutral control: DMSO (100%)

[1570] Assay for 3 inhibitor controls: 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one (10µM)

[1571] Determination of the synthesis of 3 inhibitor controls

[1572] 6'-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1, 3'-Bipyridine]-2-one

[1573]

[1574] A mixture of 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one intermediate X3 (100 mg, 0.20 mmol) was treated with TFA (3 mL) at 20 °C, and the resulting solution was stirred at 80 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with DCM (2 × 5 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residues were purified by reversed-phase rapid chromatography on a C18 column (gradient 0%–29% MeCN / water (1% TFA)), followed by preparative HPLC (MC-Actus Triart C18, 3000 μL). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: from 10% B to 40% B) purification, yielding the title compound (10 mg, 13%) as a white solid. HRMS (ESI) m / z [M+H + C 21 H 22 Calculated value of N7O: 388.1880, measured value: 388.1896. 1H NMR (300 MHz, methanol-d4) 1.55 – 1.74 (2 H,m), 2.04 – 2.13 (2 H, m), 2.22 – 2.42 (2 H, m), 4.38 (2 H, h), 6.46 (1 H,td), 6.57 – 6.67 (2 H, m), 6.96 (1 H, dd), 7.39 – 7.54 (2 H, m), 7.54 – 7.68 (2 H, m), 7.82 – 8.00 (2 H, m).

[1575] Intermediate X3

[1576] 6'-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentanol (1,3'-bipyridine)-2H-[1,3'-bipyridine]-2-one and

[1577] 6'-(((1S,3S)-3-((1-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentanol (1,3'-bipyridine)-2H-[1,3'-bipyridine]-2-one

[1578] and

[1579] At 20 °C, 1-(chloromethyl)-4-methoxybenzene (117 mg, 0.75 mmol) was added to a DMA (4 mL) solution of 2-chloro-1H-imidazo[4,5-b]pyridine (125 mg, 0.81 mmol) and MTBD (300 mg, 1.96 mmol), and the resulting solution was stirred at 20 °C for 18 hours under a nitrogen atmosphere. Pd-PEPPSI-IpentCl 2-methylpyridine (27.4 mg, 0.03 mmol) and 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one × HCl intermediate X2 (100 mg, 0.33 mmol) were added, and the resulting suspension was stirred at 100 °C for 16 hours. The crude reaction mixture was directly purified by reversed-phase rapid chromatography on a C18 column (gradient: 5%–30% MeCN / water) to give a mixture of regioisomeric title compounds (120 mg, 73%) as a yellow gel; MS (ESI) m / z [M+H + 508.35.

[1580] Intermediate X2

[1581] 6'-(((1S,3S)-3-aminocyclopentyl)amino)-2H-[1,3'-bipyridine]-2-one

[1582]

[1583] At 25°C, Et₂O (27 mL, 54 mmol) containing 2 M HCl was slowly added to 10 mL of DCM containing ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate intermediate X1 (1 g, 2.70 mmol). The resulting mixture was stirred at 25°C for 3 hours. The synthesis procedure was repeated for a second batch of ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)cyclopentyl)carbamate intermediate X1 (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 under vacuum to give an unspecified HCl salt of the title compound as a yellow solid (2.5 g, 100%); MS (ESI) m / z [M+H + 270.9.

[1584] Intermediate X1

[1585] ((1S,3S)-3-((2-oxo-2H-[1,3'-bipyridine]-6'-yl)amino)cyclopentyl)tert-butyl carbamate

[1586]

[1587] rel-(1R,2R)-N 1 N 2 Dimethylcyclohexane-1,2-diamine (0.212 g, 1.49 mmol) and Cu(I)I (0.283 g, 1.49 mmol) were added to 1,4-dioxane (20 mL) containing ((1S,3S)-3-((5-iodopyridin-2-yl)amino)cyclopentyl)carbamate intermediate 1 (3.0 g, 7.44 mmol), K₂CO₃ (3.08 g, 22.3 mmol), and pyridine-2(1H)-one (1.42 g, 14.9 mmol). The resulting solution was stirred at 110 °C for 18 hours 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 ground with EtOAc:PE (5:1) to obtain a solid. The solid was collected by filtration and dried under vacuum to obtain the title compound (2.70 g, 98%) as a yellow solid; MS (ESI) m / z [M+H] + 371.2.

[1588] Step-by-step protocol for running measurements:

[1589] Day 1

[1590] 1. Thaw the cryopreserved HepG2 cells in cell culture medium and centrifuge at 250g for 5 minutes. Discard the supernatant and resuspend the cell pellet in cell culture medium and count the cells using a Nucleocounter (ChemoMetec). Centrifuge the cells again at 250g for 5 minutes and resuspend the pellet in assay medium to a count of 500,000 cells / mL.

[1591] 2. Dispense 20 µL of the above cell mixture into a black µclear PDL-coated Greiner #781091 (Assay 3) or Greiner #781946 (Assays 3 and 3a) 384-well plate using Multidrop Combi (ThermoFisher) and incubate at room temperature for 20 minutes.

[1592] 3. Incubate the plate at 37°C and 5% CO2 for 24 hours.

[1593] Day 2

[1594] 1. (3 only) The test compound was prepared in an Echo 384 LDV plate (Labcyte LP-#0200) starting at 10 mM, with a half-log dilution factor in DMSO in response to the concentration in DMSO.

[1595] 2. Dispense 30 nL of the above test compound into cells using Echo 655 (Labcyte) at a maximum concentration of 10 µM (Assay 3) or a single concentration of 0.1 µM (Assay 3a).

[1596] 3. Assay 3: WT PCSK9 protein was diluted to 375 nM using assay medium and dispensed into cells at 10 µL / well using Multidrop Combi (ThermoFisher) to achieve a final concentration of 125 nM.

[1597] Assay 3a: PCSK9 protein (D374Y mutant) was diluted to 6 nM with assay medium and then dispensed into cells at 10 µL / well using MultidropCombi (ThermoFisher) to achieve a final concentration of 2 nM.

[1598] 4. Incubate the plate at 37°C and 5% CO2 for 24 hours.

[1599] Day 3

[1600] 1. Measure 6 µg / mL pHrodo in the culture medium. ™Red-LDL was dispensed into cells at 10 µL / well using Multidrop Combi (ThermoFisher).

[1601] 2. The plate was incubated at 37°C and 5% CO2 and imaged with an Incucyte S3 (Sartorius) after 4 hours (determination 3) and 24 hours (determination 3a).

[1602] Image data was processed using Incucyte 2022B Rev2 software (Sartorius) to identify cells and red fluorescence intensity.

[1603] Assay 3: Data were further processed using Genedata Screener (Genedata AG) by fitting the data to the normalized setting "neutral control minus inhibitor" using a four-parameter logistic fit. For compounds with efficacy exceeding the inhibitor control, manual curve fitting with adjusted sinf curve parameters must be applied. For reported efficacy % values, the average of all values ​​at the specified concentration was used, regardless of the curve fit.

[1604] Assay 3a: Data were further processed using Genedata Screener (Genedata AG) by fitting the data to the normalization setting “Neutral Controls Minus Inhibitors”. Wells without added compounds and without added PCSK9 protein served as inhibitor controls, giving a high signal in the assay due to uninhibited LDL uptake into cells. Wells without added compounds but with added PCSK9 served as neutral controls, giving a low signal in the assay due to PCSK9 inhibiting LDL uptake into cells. For reported efficacy % values, the average of all values ​​at the specified concentration was used. Unless otherwise specified, all compounds were replicated n=7.

[1605] The comparative compound used in determinations 3 and 3a is Example 493 in WO 2020 / 150473 A2.

[1606] .

[1607] Measurement of 4-hERG (human Ether-á-go-go related gene)

[1608] This assay (human Ether-á-go-go related gene) measures the activity of compounds at the potassium ion channel hERG (human Ether-á-go-go related gene).

[1609] Experiments were performed at room temperature on a SyncroPatch 384PE high-throughput patch-clamp platform and a medium-resistance chip with four patch wells per site. Chinese hamster ovary K1 (CHO) cell lines overexpressing the selected ion channels (hERGs) were used in ready-to-use assays and stored in liquid nitrogen, or the cell lines were used from live cultures. Cells were thawed and diluted in HBSS, or isolated from flasks and resuspended in HBSS. HBSS contained 140 mM NaCl, 4 mM KCl, 10 mM HEPES, and 5 mM glucose (pH 7.4). The internal patch-clamp solution consisted of 120 mM KF, 20 mM KCl, 10 mM HEPES, 10 mM EGTA, and 25 µM aescin (pH 7.2). After the sealing process was completed, the external solution was replaced with an external patch-clamp solution (pH 7.4) containing 80 mM NaCl, 4 mM KCl, 10 mM HEPES, 2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, and 60 mM NMDG. All solutions were stored at room temperature, except for aescin, which was stored at 4 °C. All test compounds were partitioned into Greiner-Bio 384-well plates and tested in a 6-point cumulative assay (final DMSO concentration 0.33%). Only wells meeting the previously agreed platform acceptance criteria (30 megohm seal resistance, Z prime > 0.4, and current magnitude > 0.2 nA) were used in this analysis.

[1610] High concentration of hERG

[1611] Experiments were performed at room temperature using single-well QChips on the QPatchII high-throughput patch-clamp platform. Chinese hamster ovary K1 (CHO) cell lines overexpressing the selected ion channels (hERGs) from live cultures were used. All solutions were stored at 4°C or -20°C. All compounds were partitioned into 96-well plates with 10 mM or 50 mM DMSO stock solution and diluted to a form allowing testing in a 6-point cumulative assay (final DMSO concentration 2% or 0.4% DMSO). Only wells meeting the previously agreed platform acceptance criteria (500 megohm seal resistance and current magnitude >0.2 nA, consistent with positive controls including verapamil and DMSO) were used in this analysis.

[1612] Determination of 5-GSK3 Measurement (ThermoFisher measurement)

[1613] This assay measures the compound in GSK3. (Glycogen synthase kinase-3) Activity at the site.

[1614] The test compounds were screened in 1% DMSO (final) in the wells. For 10-point titrations, the compounds were serially diluted 3-fold from an initial concentration of 10 µM.

[1615] Measurement scheme

[1616] Barcode-enabled Corning, low-volume NBS, black 384 perforated plate

[1617] 1.2.5µL – 4X test compound or 100nL 100X plus 2.4µL kinase buffer

[1618] 2.5µL – 2X peptide / kinase mixture

[1619] 3.2.5µL – 4X ATP solution

[1620] 4.30-second plate oscillation

[1621] 5. Kinase reaction incubation at room temperature for 60 minutes.

[1622] 6.5µL – Development reagent solution

[1623] 7.30-second plate oscillation

[1624] 8. Incubate the development reaction at room temperature for 60 minutes.

[1625] 9. Read the numbers and analyze the data using a fluorescent plate reader.

[1626] In step 2, a 2X GSK3β (GSK3β) / Ser / Thr (glycogen synthase kinase-3β / serine / threonine) O9 mixture was prepared in 50 mM HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, and 1 mM EGTA (ethacrylic acid). The final 10 µL kinase reaction consisted of 0.22 ng–0.92 ng of GSK3β (GSK3 beta) and 2 µM Ser / Thr O9 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, and 1 mM EGTA.

[1627] In step 3, the ATP solution was diluted to a 4X working concentration in kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA).

[1628] In step 6, the developing reagent is diluted 1:512 in developing buffer (10X Novel PKC lipid mixture: 2 mg / mL phosphatidylserine, 0.2 mg / mL DAG in 20 mM HEPES (pH 7.4) solution, 0.3% CHAPS).

[1629] Drawing software

[1630] SelectScreen ® The kinase analysis service uses XLfit from IDBS. The dose-response curves are curve fits to model number 205 (S-shaped dose-response model). If the bottom of the curve does not fit between -20% and 20% inhibition, it is set to 0% inhibition. If the top of the curve does not fit between 70% and 130% inhibition, it is set to 100% inhibition.

[1631] Measurement of 6-in vivo

[1632] GalNAc ASO for use in mice in vivo

[1633] Nucleobase sequence: 5'-AACTACAAAACCCTGC-3', where C = 5MeC (SEQ ID NO.: 2)

[1634] HELM:[GalNAc THA]-[AH]-{P.[LR](A)[sP].[LR](A)[sP].[LR]([5meC])[sP].[dR](T)[sP].[dR](A)[s P].[dR]([5meC])[sP].[dR](A)[sP].[dR](A)[sP].[dR](A)[sP].[dR](A)[sP].[dR]([5 meC])[sP].[dR]([5meC])[sP].[dR]([5meC])[sP].[LR](T)[sP].[LR](G)[sP].[LR]([5meC]), where LR = LNA (locked nucleosides), dR = deoxyribose, sP = thiophosphate, P = phosphate, A = adenosine, G = guanosine, C = 5-methylcytosine, T = thymine, GalNAc THA = GalNAc trihexylamine, AH = aminohexyl

[1635] Molecular formula: C 232 H 326 N 70 O 109 P 16 S 15

[1636] Molecular weight: 6816.0172 Da

[1637] The structure provides Figure 1 middle.

[1638] synthesis

[1639] The MMTr-protected oligonucleotide (MMTr-ON) with the above sequence was synthesized on an ÄKTA OligoPilot Plus 100 synthesizer (GE Healthcare) at a scale of 940 µmol using standard synthetic cycles of detriphenylmethylation (toluene containing 3% dichloroacetic acid), coupling (coupling agent: acetonitrile containing 0.25 M 5-[3,5-bis(trifluoromethyl)phenyl]-1H-tetrazole solution), end capping (cap A: 20% N-methylimidazolium and 80% acetonitrile; cap B: 20% pyridine, 20% acetic anhydride and 60% acetonitrile), oxidation (pyridine containing 0.05 M iodine and water) or thiolation (pyridine containing 0.2 M hydrogenated xanthan gum) and solid carrier (UNY primer carrier 5G approximately 353 μmol / g, GE Healthcare). Immediately before use, all fully protected β-cyanoethyl phosphoramide monomers were dissolved in anhydrous acetonitrile or anhydrous acetonitrile (0.2 M) containing 15% DMF under argon atmosphere. The phosphoramide recycling / coupling time for DNA monomers was 5 minutes, extended to 10 minutes for LNA monomers. Stepwise coupling efficiency and overall yield, determined by automated triphenylmethyl cation absorption monitoring, exceeded 98% for all synthesized oligonucleotides.

[1640] At the end of assembly, the solid-support-bound MTT-ON was treated with 40 mL of ammonia (26% aqueous solution) at 55 °C for 18 hours. The solution was filtered, and the MTT-ON product was purified by HPLC (XBridge C18, 10 µm, 50 × 250 mm column; 5%–45% acetonitrile / NH4HCO3 aqueous solution (50 mM)).

[1641] The fractions containing MMTr-ON products were combined, and volatiles were removed using a Speedvac. The residue was dissolved in water (4 mL) and the MMTr groups were removed by treating the resulting solution with 10% acetic acid (1 mL) at 40 °C for 60 min. NaOAc (3 M aqueous solution, 0.6 mL) and EtOH (95%, 20 mL) were added sequentially. The mixture was stored at -20 °C for 120 min and centrifuged at 4 °C for 15 min. The resulting supernatant was decanted, and the resulting precipitate was resuspended in EtOH (85%, 12 mL) and the procedure was repeated. Finally, the precipitate was dissolved in water (20 mL) and lyophilized to obtain the desired HA-oligonucleotide.

[1642] GalNac fusion

[1643] In a Falcon tube, HA-oligonucleotide (1074 mg) was dissolved in water (11.176 mL), TEA (0.38 mL) was added and the pH was checked immediately. Then, 765 mg of GalNAc ligand 1-OPfp ester (Kim 2024, dissolved in 2.79 mL ACN) was added to the tube. The mixture was shaken at room temperature for 4 hours. LCMS showed the desired product mass. The reaction mixture was mixed with 5 mL of NH3 aqueous solution, shaken overnight at room temperature, and lyophilized overnight. The ammonia-treated crude product and the lyophilized white foamy material were purified by preparative HPLC. Stationary phase: Waters Premier BEH C18, 1.7 μm, 2.1 × 100 mm; mobile phase: gradient 5%–30%, 10 min, 0.6 mL / min, 45 °C, 260 nm; A: 50 mM NH4HCO3 / water (pH 8); B: ACN. The purity of the purified fraction was 96.8% by area. The fraction was concentrated (ammonia buffer), and the oligonucleotides were precipitated overnight with EtOH containing NaOAc (10% NaOAc in 20 mL of 80% EtOH). The fraction was then centrifuged and immediately desalted. ASO was desalted using an ÄKTA system with a WorkBeads desalting (Cold Debye Dsalt) (50 mL) column at a flow rate of 10 mL / min for 20 minutes. The fraction was injected into 15 mL of 1 M NaCl aqueous solution and collected based on absorbance at 260 nm. The pure fraction was collected and lyophilized overnight. Samples were taken for absorbance analysis using a nanodrop.

[1644] In vivo study protocol and results

[1645] Heterozygous male human PCSK9 knock-in (hPCSK9-KI) mice (Carreras 2019) were fed a regular diet and administered mouse Pcsk9 GalNAc-ASO (prepared in PBS for in vivo use) at a dose of 5 mg / kg / week via subcutaneous injection for 4 weeks, with an additional loading dose given in week 1 to eliminate endogenous hepatic mouse Pcsk9 expression levels prior to compound administration.

[1646] The compound was formulated in 0.5% HPMC 10000 cPs containing or without 5% mannitol, and in Milli-Q containing 0.1% PS80. ®Administered in purified water (Merck Millipore) via oral tube feeding at the indicated dose twice daily for 7 days. 50 µL blood samples were drawn one day before the first dose (baseline) and at the end of day 7 (4 hours after administration) for plasma LDL-C measurement. Plasma LDL-C concentration was assessed using an enzymatic method (Crystal Chem, product numbers 79980 and 79983). The LDL-C reduction (%) was calculated as follows: = ((Post-administration LDL-C concentration) - (Baseline LDL-C)) / (Baseline LDL-C) 100%, then subtract the corresponding effect from the medium group.

[1647] The comparative compound used in determination 6 was Example 493 from WO 2020 / 150473 A2.

[1648] .

[1649] Table 4 - In vivo data

[1650]

[1651] Table 5 - Activity results for compounds 1-32, measured in 1, 2, 4, 5, 3 and 3a.

[1652]

[1653]

[1654] Features disclosed in the foregoing specific embodiments, or in the following claims, or in the accompanying drawings, either in their particular form or according to the manner in which the disclosed functions are performed or the method or process for obtaining the disclosed results, may, if appropriate, be used alone or in any combination of such features to implement this disclosure in its various forms.

[1655] While this disclosure has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when this disclosure is given. Therefore, the exemplary embodiments of this disclosure set forth above are to be considered illustrative rather than restrictive. Various changes may be made to the described embodiments without departing from the spirit and scope of this disclosure.

[1656] To avoid any doubt, any theoretical explanations provided herein are intended to enhance the reader's understanding. The inventor does not wish to be bound by any of these theoretical explanations.

[1657] Any chapter headings used in this article are for organizational purposes only and should not be construed as limiting the subject matter described.

[1658] Unless the context otherwise requires, throughout the specification (including the claims below), the words “comprise” and “include” and variations such as “comprises”, “comprising” and “including” will be understood to imply inclusion of the integer or step or group of integers or steps stated therein, but do not exclude any other integer or step or group of integers or steps.

[1659] It must be noted that, as used in the specification and appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise. A range may be expressed herein as from “about” a particular value and / or to “about” another particular value. When such a range is expressed, another embodiment includes from one particular value and / or to another particular value. Similarly, when a value is expressed as an approximation using the antecedent “about,” it should be understood that the particular value forms another embodiment. The term “about” in relation to numerical values ​​is optional and means, for example, + / - 10%.

[1660] References

[1661] The preceding text has cited numerous publications to more fully describe and disclose the compound of formula (I) and the current state of the field. The full citations of these references are provided below. The entire contents of each of these references are incorporated herein by reference.

[1662]

[1663]

[1664] For standard molecular biology techniques, see Sambrook, J., Russell, DWMolecularCloning, A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

[1665] Statement number A

[1666] A1. To provide a compound of formula (I)

[1667] ABC (I)

[1668] Or its pharmaceutically acceptable salt.

[1669] Where A has one of the following properties:

[1670] (A1)

[1671] The wavy line indicates the attachment point with B;

[1672] R A1 Choose from the following groups:

[1673] (i)H;

[1674] (ii) Halogenated groups;

[1675] (iii)CN;

[1676] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1677] (v)C 1-6 alkoxy groups, optionally surrounded by OH, one or more halogroups, or C 1-6 Alkyl amide substitution;

[1678] (vi)C 1-6 Alkyl esters;

[1679] (vii)C 1-6 Alkyl acyl; and

[1680] (viii)OH;

[1681] R A2 Choose from the following groups:

[1682] (i)H;

[1683] (ii) Halogenated groups;

[1684] (iii)CN;

[1685] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1686] (v)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[1687] (vi)C 1-6 Acylamide (wherein the acyl group is optionally substituted with H or methyl);

[1688] (vii)C 1-6 Thioalkyl;

[1689] (viii)C 1-6 Alkyl esters;

[1690] (ix)C 1-6 Alkyl acyl;

[1691] (x)C 4-5 Heterocyclic groups;

[1692] (xi)C5 heteroaryl;

[1693] (xii)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, OH, C 2-3 alkynyl group, C 4-6 Heterocyclic group or C 1-3 Alkyl substitution, wherein the C 1-3 The alkyl group may optionally be substituted with one or more halogroups or OH groups;

[1694] (xiii)OH; and

[1695] (xiv)C 1-6 Alkylamino;

[1696] R A3 Choose from the following groups:

[1697] (i)H;

[1698] (ii) Halogenated groups;

[1699] (iii)CN;

[1700] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[1701] (v)OH;

[1702] (vi)C 1-6Alkoxy groups, which may optionally be substituted with OH, NH2, C4 heterocyclic groups or one or more halogroups;

[1703] (vii)C 1-6 Acyloxy group;

[1704] (viii) C4 heterocyclic group;

[1705] (ix)NH2;

[1706] (x)C 1-6 Alkylamino groups, which may optionally be substituted with CN, OH or C4 heterocyclic groups;

[1707] (xi)C 1-6 Dialkylamino, which is optionally substituted with -NH2;

[1708] (xii)C 1-6 Acylamide (where the acyl substituent is H or Me);

[1709] (xiii) amidoyl or methyl-amidinyl;

[1710] (xiv) carboxylamino;

[1711] (xv)C 1-6 Thioalkyl groups, which are optionally substituted with OH or NH2;

[1712] (xvi)C 1-6 alkylsulfinyl;

[1713] (xvii)C 1-6 Alkyl sulfonyl group, which is optionally substituted with one or more haloyl groups;

[1714] (xviii)C 1-6 sulfonylimide group;

[1715] (xix)C 1-6 Alkyloxyphosphine group;

[1716] (xx) carboxyl group;

[1717] (xxi)C(=O)NH2;

[1718] (xxii)C 1-6 Alkyl esters;

[1719] (xxiii)C 1-6 An alkyl acyl group, optionally substituted with one or more halogroups; and

[1720] (xxiv)C 1-6 Alkyl amide;

[1721] Or RA3 and R A2 Together with the carbon atoms they are bonded to, they form:

[1722] (i) C can be arbitrarily substituted 5-7 Heterocyclic rings;

[1723] (ii) C can be arbitrarily substituted 5-7 Mixed aromatic rings;

[1724] (iii) Optionally substituted C6-carbon aromatic rings;

[1725] (iv) Optional substitution of C 5-7 carbon ring

[1726] Wherein, when present, one, two, three, or four optional substituents are independently selected from C. 1-6 Alkyl, Halogenated, C 1-6 Alkoxy, NH2, C 1-6 Alkylamino, OH, and CN;

[1727] (A2b)

[1728] The wavy line indicates the attachment point with B;

[1729] Z 6 Is it N or CH?

[1730] Z 7 Is it N or CR? A8

[1731] Z 8 and Z 9 Choose independently from the following groups:

[1732] (i)H;

[1733] (ii) Halogenated groups;

[1734] (iii)CN;

[1735] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1736] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[1737] (vi)C 1-6 Alkylamino

[1738] (vii)C 1-6 Thioalkyl,

[1739] (viii)C 1-6 Alkyloxyphosphine; and

[1740] (ix)C 1-6 Alkylphosphonoyl;

[1741] R A8 Choose from the following groups:

[1742] (i)H;

[1743] (ii) Halogenated groups;

[1744] (iii)CN;

[1745] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[1746] (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups or one or more halogenated groups;

[1747] (vi) C4 heterocyclic group;

[1748] (vii)C 1-6 Alkylamino groups, which may optionally be substituted with CN, OH or C4 heterocyclic groups;

[1749] (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and

[1750] (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2;

[1751] (A3a) or

[1752] (A3b)

[1753] Where RA9 Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 1-methylcyclopropyl, and 2-methylcyclopropyl;

[1754] Where B has the following formula

[1755] (B-1)

[1756] The wavy line indicates the attachment points to A and C;

[1757] R B1 It is H, OH, =CHCH2-OH, C 1-4 Alkoxy or C 1-4 Alkyl, the C 1-4 Alkyl groups may optionally be replaced by OH or OMe;

[1758] Where C has the following formula:

[1759] (C-1)

[1760] Where R N It is H or methyl;

[1761] R C1 and R C2 Together with the carbon atoms they are bonded to, they form fused benzene rings or C6 heteroaromatic rings, which are optionally separated by one or more R atoms. C3 Group substitution;

[1762] Where R C3 Selected from

[1763] (i)CN;

[1764] (ii)P(=O)Me2;

[1765] (iii)C(=O)OH;

[1766] (iv)C 1-6 Hydrocarbons, which are optionally C 1-6 Alkyl substitution;

[1767] (v)C 1-6 Alkoxy;

[1768] (vi)C 1-6 Alkyl amide;

[1769] (vii)C 5-6 Mixed aromatics;

[1770] (viii) Halogenated groups; and

[1771] (ix)C 1-6 Alkyl acyl group.

[1772] A2. The compound or a pharmaceutically acceptable salt thereof as described in statement A1, wherein R A2 Selected from H, chlorine, methyl and OCF2H.

[1773] A3. The compound or a pharmaceutically acceptable salt thereof as described in statement A1 or statement A2, wherein R A3 Choose from the following groups: H, methyl, and OH.

[1774] A4. The compound or a pharmaceutically acceptable salt thereof as described in statement A1, wherein A is selected from the following formula:

[1775] , , , and .

[1776] A5. A compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A4, wherein B has the formula (B-1).

[1777] (B-1)

[1778] The wavy line indicates the attachment points to A and C;

[1779] Where R B1 Choose from the following groups: -H, -OH, -OMe, -O-ethyl, -CH2OH, -CH2CH2OH and =CHCH2-OH.

[1780] A6. A compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A5, wherein B has the following formula (B-1a):

[1781] (B-1a).

[1782] A7. A compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A5, wherein B has the following formula (B-1b):

[1783] (B-1b).

[1784] A8. A compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A7, wherein C has the following formula:

[1785] (C-2)

[1786] Q 1 Q 2 Q 3 and Q4 Both are CH, or Q 1 Q 2 Q 3 and Q 4 One of them is selected from N, C-CN and CP(=O)(Me)2, and the other three are CH.

[1787] A9. A compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A8, wherein C is selected from one of the following formulas:

[1788]

[1789] A10. The compound or a pharmaceutically acceptable salt thereof as described in statement A1, wherein ABC has the formulas (IA), (IB), (I-Ba), (I-Bb), (IC), (I-Ca), (I-Cb), (I-Cc), (I-Cd), and (I-Ce), wherein all definitions are based on A1:

[1790] (IA);

[1791] (IB);

[1792] (I-Ba);

[1793] (I-Bb);

[1794] (IC);

[1795] (I-Ca);

[1796] (I-Cb);

[1797] (I-Cc);

[1798] (I-Cd); and

[1799] (I-Ce).

[1800] A11. The compound or a pharmaceutically acceptable salt thereof as described in statement A1, wherein ABC has the formula (II-A), (II-B), (II-Ba), (II-Bb), (II-C), (II-Ca), (II-Cb), (II-Cc), (II-Cd), and (II-Ce), wherein all definitions are based on A1:

[1801] (II-A);

[1802] (II-Aa);

[1803] (II-Ab);

[1804] (II-Ac);

[1805] (II-Ad);

[1806] (II-B);

[1807] (II-Ba);

[1808] (II-Bb);

[1809] (II-C);

[1810] (II-Ca);

[1811] (II-Cb);

[1812] (II-Cc);

[1813] (II-Cd); and

[1814] (II-Ce).

[1815] A12. The compound or a pharmaceutically acceptable salt thereof as described in statement A1, wherein ABC has the formula (III-A), (III-B), (III-C), (III-Ca), (III-Cb), (III-Cc), (III-Cd), and (III-Ce), wherein all definitions are based on statement A1:

[1816] (III-A);

[1817] (III-B);

[1818] (III-C);

[1819] (III-Ca);

[1820] (III-Cb);

[1821] (III-Cc);

[1822] (III-Cd); and

[1823] (III-Ce).

[1824] A13. A compound, said compound being selected from:

[1825] ;

[1826] ;

[1827] ;

[1828] ;and

[1829] Or, or a pharmaceutically acceptable salt thereof.

[1830] A14. A compound listed in Table 1 or a pharmaceutically acceptable salt thereof.

[1831] A15. A compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A14, for use in a therapeutic manner.

[1832] A16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A14, and a pharmaceutically acceptable diluent, carrier or excipient.

[1833] A17. A compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A14, or a pharmaceutical composition according to statement A16, for use in the treatment of cardiovascular diseases.

[1834] A18. The compound used according to statement A17, wherein the compound is applied simultaneously, separately, or sequentially in combination with additional active ingredients selected from the group consisting of:

[1835] i) Statins;

[1836] ii) Cholesterol absorption inhibitors;

[1837] iii) SGLT2 inhibitors;

[1838] iv) P2Y12 inhibitors;

[1839] v) ATP-citrate lyase inhibitors; and

[1840] vi) Antihypertensive drugs.

[1841] A19. The compound used according to statement A17 or A18, wherein the cardiovascular disease is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalpha-lipoproteinemia, 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.

[1842] A20. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of statements A1 to A14, or the pharmaceutical composition according to statement 16, in a method of medical treatment.

[1843] A21. A method of medical treatment comprising administering to a patient a pharmaceutical composition according to statement A16.

[1844] A22. Use of the compound according to any one of statements A1 to A14 in the manufacture of a medicament for use in a therapy.

[1845] A23. A method of treating a PCSK9-mediated disease or condition in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as described in any one of statements A1 to A14, or a pharmaceutical composition as described in statement A16.

[1846] A24. The method described in statement A23, wherein the disease or condition is a cardiovascular disease or condition.

[1847] A25. The method according to statement A24, wherein the cardiovascular disease or condition is selected from dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalpha-lipoproteinemia, 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.

[1848] Statement number B

[1849] B1. To provide a compound of formula (I)

[1850] ABC (I)

[1851] Or its pharmaceutically acceptable salt.

[1852] Where A has one of the following properties:

[1853] (A1a)

[1854] The wavy line indicates the attachment point with B;

[1855] X 1 Is it N or CR? A3 ;

[1856] R A1 Choose from the following groups:

[1857] (i)H;

[1858] (ii) Halogenated groups;

[1859] (iii)CN;

[1860] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1861] (v)C 1-6 alkoxy groups, optionally surrounded by OH, one or more halogroups, or C 1-6 Alkyl amide substitution;

[1862] (vi)C 1-6 Alkyl esters;

[1863] (vii)C 1-6 Alkyl acyl; and

[1864] (viii)OH;

[1865] R A2 Choose from the following groups:

[1866] (i)H;

[1867] (ii) Halogenated groups;

[1868] (iii)CN;

[1869] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1870] (v)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted;

[1871] (vi)C 1-6 Acylamide (wherein the acyl group is optionally substituted with H or methyl);

[1872] (vii)C 1-6 Thioalkyl;

[1873] (viii)C 1-6 Alkyl esters;

[1874] (ix)C 1-6 Alkyl acyl;

[1875] (x)C 4-5 Heterocyclic groups;

[1876] (xi)C5 heteroaryl;

[1877] (xii)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, OH, C 2-3 alkynyl group, C 4-6 Heterocyclic group or C 1-3 Alkyl substitution, wherein the C 1-3 The alkyl group may optionally be substituted with one or more halogroups or OH groups;

[1878] (xiii)OH; and

[1879] (xiv)C 1-6 Alkylamino;

[1880] R A3 Choose from the following groups:

[1881] (i)H;

[1882] (ii) Halogenated groups;

[1883] (iii)CN;

[1884] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[1885] (v)OH;

[1886] (vi)C 1-6 Alkoxy groups, which may optionally be substituted with OH, NH2, C4 heterocyclic groups or one or more halogroups;

[1887] (vii)C 1-6 Acyloxy group;

[1888] (viii) C4 heterocyclic group;

[1889] (ix)NH2;

[1890] (x)C 1-6 Alkylamino groups, which may optionally be substituted with CN, OH or C4 heterocyclic groups;

[1891] (xi)C 1-6 Dialkylamino, which is optionally substituted with -NH2;

[1892] (xii)C 1-6 Acylamide (where the acyl substituent is H or Me);

[1893] (xiii) amidoyl or methyl-amidinyl;

[1894] (xiv) carboxylamino;

[1895] (xv)C 1-6 Thioalkyl groups, which are optionally substituted with OH or NH2;

[1896] (xvi)C 1-6 alkylsulfinyl;

[1897] (xvii)C 1-6 Alkyl sulfonyl group, which is optionally substituted with one or more haloyl groups;

[1898] (xviii)C 1-6 sulfonylimide group;

[1899] (xix)C 1-6 Alkyloxyphosphine group;

[1900] (xx) carboxyl group;

[1901] (xxi)C(=O)NH2;

[1902] (xxii)C 1-6 Alkyl esters;

[1903] (xxiii)C 1-6 An alkyl acyl group, optionally substituted with one or more halogroups; and

[1904] (xxiv)C 1-6 Alkyl amide;

[1905] Or R A3 and R A2 Together with the carbon atoms they are bonded to, they form:

[1906] (i) C can be arbitrarily substituted 5-7 Heterocyclic rings;

[1907] (ii) C can be arbitrarily substituted 5-7 Mixed aromatic rings;

[1908] (iii) Optionally substituted C6-carbon aromatic rings;

[1909] (iv) Optional substitution of C 5-7 carbon ring

[1910] Wherein, when present, one, two, three, or four optional substituents are independently selected from C. 1-6 Alkyl, Halogenated, C 1-6 Alkoxy, NH2, C 1-6 Alkylamino, OH, and CN;

[1911] (A2a)

[1912] The wavy line indicates the attachment point with B;

[1913] Z 1 Selected from O or S;

[1914] R A5 Choose from the following groups:

[1915] (i)H;

[1916] (ii) Halogenated groups;

[1917] (iii)CN;

[1918] (iv) A C1 alkyl group, optionally substituted with one or more OH, CN, or one or more halogroups; and

[1919] (v)C1 alkoxy group, which is optionally substituted with one or more halogroups;

[1920] R A6 Choose from the following groups:

[1921] (i)H;

[1922] (ii) Halogenated groups;

[1923] (iii)CN;

[1924] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1925] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[1926] (vi)C 1-6 Alkylamino;

[1927] (vii)C 1-6 Thioalkyl;

[1928] (viii)C 1-6 Alkyloxyphosphine; and

[1929] (ix)C 1-6 Alkylphosphonoyl;

[1930] R A7 Choose from the following groups:

[1931] (i)H;

[1932] (ii) Halogenated groups;

[1933] (iii)CN;

[1934] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[1935] (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups and one or more halogenated groups;

[1936] (vi) C4 heterocyclic group;

[1937] (vii)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups;

[1938] (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and

[1939] (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2;

[1940] (A2b)

[1941] The wavy line indicates the attachment point with B;

[1942] Z 6 Is it N or CH?

[1943] Z 7 Is it N or CR? A8

[1944] Z 8 and Z 9 Choose independently from the following groups:

[1945] (i)H;

[1946] (ii) Halogenated groups;

[1947] (iii)CN;

[1948] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted;

[1949] (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted;

[1950] (vi)C 1-6 Alkylamino

[1951] (vii)C 1-6 Thioalkyl,

[1952] (viii)C 1-6 Alkyloxyphosphine; and

[1953] (ix)C 1-6 Alkylphosphonoyl;

[1954] R A8 Choose from the following groups:

[1955] (i)H;

[1956] (ii) Halogenated groups;

[1957] (iii)CN;

[1958] (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted;

[1959] (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups or one or more halogenated groups;

[1960] (vi) C4 heterocyclic group;

[1961] (vii)C 1-6 Alkylamino groups, which may optionally be substituted with CN, OH or C4 heterocyclic groups;

[1962] (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and

[1963] (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2;

[1964] (A3a) or

[1965] (A3b)

[1966] Where R A9 Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 1-methylcyclopropyl, and 2-methylcyclopropyl;

[1967] (A4)

[1968] Where R A4 Selected from H, CN, -OCF2H, cyclopropyl, Cl, and methyl;

[1969] Where B has the following formula

[1970] (B-1)

[1971] The wavy line indicates the attachment points to A and C;

[1972] R B1 It is H, OH, =CHCH2-OH, C 1-4 Alkoxy or C 1-4 Alkyl, the C 1-4 Alkyl groups may optionally be replaced by OH or OMe;

[1973] Where C has the following formula:

[1974] (C-1a)

[1975] Where X is hydrogen or fluorine;

[1976] Where R N It is H, methyl, or optionally C 1-3 Benzyl groups substituted with alkoxy groups;

[1977] R C1 and R C2 Together with the carbon atoms they are bonded to, they form fused benzene rings or C6 heteroaromatic rings, which are optionally separated by one or more R atoms. C3 Group substitution;

[1978] Where R C3 Selected from

[1979] (i)CN;

[1980] (ii)P(=O)Me2;

[1981] (iii)C(=O)OH;

[1982] (iv)C 1-6 Hydrocarbons, which are optionally C 1-6 Alkyl substitution;

[1983] (v)C 1-6 Alkoxy;

[1984] (vi)C 1-6 Alkyl amide;

[1985] (vii)C 5-6 Mixed aromatics;

[1986] (viii) Halogenated group;

[1987] (ix)C 1-6 Alkyl acyl; and

[1988] (x)Oxide group.

[1989] B2. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein R A4 It is a methyl group.

[1990] B3. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein A has the formula (A1a), (A2b), (A3a) and (A3b).

[1991] B4. A compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing statements, wherein (A1a) has the formula (A1):

[1992] (A1)

[1993] B5. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B3, wherein (A1a) is selected from one of the following formulas:

[1994]

[1995] B6. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing statements, wherein R A2 Selected from H, chlorine, methyl, CF3 and OCF2H.

[1996] B7. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing statements, wherein R A2 Selected from methyl, CF3 and OCF2H.

[1997] B8. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B4, wherein R A3 Choose from the following groups: H, methyl, and OH.

[1998] B9. The compound or a pharmaceutically acceptable salt thereof as described in statement B8, wherein R A3 It's H.

[1999] B10. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein R A7 It's H.

[2000] B11. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein (A2a) is selected from one of the following formulas:

[2001]

[2002] B12. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing statements, wherein Z 7 It is CH.

[2003] B13. The compound or a pharmaceutically acceptable salt thereof as described in statement B12, wherein (A2b) has the formula (A2b5):

[2004] (A2b5).

[2005] B14. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R A9 It is a methyl group.

[2006] B15. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein A is selected from the following formula:

[2007] , , , , , , , , and .

[2008] B16. A compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein A is selected from the following formula:

[2009]

[2010] B17. A compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein A is selected from the following formula:

[2011]

[2012] B18. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing statements, wherein B has the formula (B-1):

[2013] (B-1)

[2014] The wavy line indicates the attachment points to A and C;

[2015] Where R B1 Choose from the following groups: -H, -OH, -OMe, -O-ethyl, -CH2OH, -CH2CH2OH and =CHCH2-OH.

[2016] B19. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing statements, wherein B has the following formula (B-1a):

[2017] (B-1a).

[2018] B20. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing statements, wherein B has the following formula (B-1b):

[2019] (B-1b).

[2020] B21. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing statements, wherein (C1a) has the formula (C1):

[2021] (C-1)

[2022] Where R N It is H or methyl;

[2023] R C1 and R C2 Together with the carbon atoms they are bonded to, they form fused benzene rings or C6 heteroaromatic rings, which are optionally separated by one or more R atoms. C3 Group substitution;

[2024] Where R C3 Selected from

[2025] (i)CN;

[2026] (ii)P(=O)Me2;

[2027] (iii)C(=O)OH;

[2028] (iv)C 1-6 Hydrocarbons, which are optionally C 1-6 Alkyl substitution;

[2029] (v)C 1-6 Alkoxy;

[2030] (vi)C 1-6 Alkyl amide;

[2031] (vii)C 5-6 Mixed aromatics;

[2032] (viii) Halogenated groups; and

[2033] (ix)C 1-6 Alkyl acyl group.

[2034] B22. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B20, wherein C has the following formula:

[2035] (C-2a)

[2036] Q 1 Q 2 Q3 and Q 4 Both are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is selected from N, C-CN, C-CONMe2 and CP(=O)(Me)2, and the other three are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is N-Me, and the adjacent Q 1 Q 2 Q 3 Or Q 4 One of them is C=O, and the other two are CH.

[2037] B23. The compound or a pharmaceutically acceptable salt thereof as described in statement B22, wherein Q 1 Q 2 Q 3 and Q 4 Both are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is N-Me, and the adjacent Q is... 1 Q 2 Q 3 Or Q 4 One of them is C=O, and the other two are CH.

[2038] B24. The compound or a pharmaceutically acceptable salt thereof as described in statement B23, wherein Q 1 Q 2 Q 3 and Q 4 Both are CH; or Q 1 and Q 2 One of them is N-Me, and the other is C=O, and Q 3 and Q 4 For CH.

[2039] B25. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B20, wherein C is selected from one of the following formulas:

[2040]

[2041] B26. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B20, wherein C is selected from one of the following formulas:

[2042]

[2043] B27. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B20, wherein C is selected from:

[2044]

[2045] B28. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein A is selected from:

[2046]

[2047] And C is selected from:

[2048] .

[2049] B29. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein ABC has the formula (I-Ax), (I-Bx), (I-By), (I-Bax), (I-Bay), (I-Bbx), and (I-Bcx), wherein all definitions are based on statement B1:

[2050] (I-Ax);

[2051] (I-Bx);

[2052] (I-By);

[2053] (I-Bax),

[2054] (I-Bay);

[2055] (I-Bbx); and

[2056] (I-Bcx).

[2057] B30. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein ABC has the formula (I-Cx), (I-Cax), (I-Cbx), (I-Ccx), (I-Cdx), (I-Cex), (I-Cfx), and (I-Cgx), wherein all definitions are based on statement B1 or formula (C-2a);

[2058] (I-Cx);

[2059] (I-Cax);

[2060] (I-Cbx);

[2061] (I-Ccx);

[2062] (I-Cdx),

[2063] (I-Cex),

[2064] (I-Cfx),

[2065] (I-Cgx).

[2066] B31. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein ABC has formula (IV-A) or (IV-B), wherein all definitions are based on statement B1 or formula (C-2a):

[2067] (IV-A);

[2068] (IV-B).

[2069] B32. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein ABC has the formula (II-Ax), (II-Aax), (II-Abx), (II-Acx), (II-Adx), (II-Bx), (II-Bax), (II-Bbx), wherein all definitions are based on statement B1:

[2070] (II-Ax);

[2071] (II-Aax);

[2072] (II-Abx);

[2073] (II-Acx);

[2074] (II-Adx);

[2075] (II-Bx);

[2076] (II-Bax);

[2077] (II-Bbx).

[2078] B33. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein ABC has the formula (II-Cx), (II-Cax), (II-Cbx), (II-Ccx), (II-Cfx), and (II-Cgx), wherein all are defined according to statement B1 or formula (C-2a):

[2079] (II-Cx);

[2080] (II-Cax);

[2081] (II-Cbx);

[2082] (II-Ccx);

[2083] (II-Cdx),

[2084] (II-Cex),

[2085] (II-Cfx),

[2086] (II-Cgx).

[2087] B34. The compound or a pharmaceutically acceptable salt thereof as described in statement B1, wherein ABC has the formula (III-Ax), (III-Bx), (III-Cx), (III-Cax), (III-Cbx), (III-Ccx), (III-Cfx), and (III-Cgx), wherein all definitions are based on statement B1 or formula (C-2a):

[2088] (III-Ax);

[2089] (III-Bx);

[2090] (III-Cx);

[2091] (III-Cax);

[2092] (III-Cbx);

[2093] (III-Ccx);

[2094] (III-Cdx),

[2095] (III-Cex),

[2096] (III-Cfx),

[2097] (III-Cgx).

[2098] B35. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B20, B22 to B26 and B28 to B34, wherein X is F.

[2099] B36. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B20, B22 to B26 and B28 to B34, wherein X is H.

[2100] B37. The compound according to statement B1, wherein the compound is selected from one of the compounds listed in Tables 1 and 2 or a pharmaceutically acceptable salt thereof.

[2101] B38. The compound according to statement B1, wherein the compound is selected from one of the compounds listed in Table 1 or a pharmaceutically acceptable salt thereof.

[2102] B39. The compound or a pharmaceutically acceptable salt thereof described in any of the foregoing statements, for use in therapy.

[2103] B40. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B38, and a pharmaceutically acceptable diluent, carrier, or excipient.

[2104] B41. A compound or a pharmaceutically acceptable salt thereof according to any one of statements B1 to B38, or a pharmaceutical composition according to statement B40, for use in the treatment of cardiovascular diseases.

[2105] B42. The compound or a pharmaceutically acceptable salt thereof used according to statement B41, wherein the compound is applied simultaneously, separately, or sequentially in combination with additional active ingredients selected from the group consisting of:

[2106] i) Statins or their pharmaceutically acceptable salts;

[2107] ii) Cholesterol absorption inhibitors or their pharmaceutically acceptable salts;

[2108] iii) SGLT2 inhibitors or pharmaceutically acceptable salts thereof;

[2109] iv) P2Y12 inhibitors or pharmaceutically acceptable salts thereof;

[2110] v) ATP-citrate lyase inhibitors or pharmaceutically acceptable salts thereof; and

[2111] vi) Antihypertensive drugs or their pharmaceutically acceptable salts.

[2112] B43. The compound or a pharmaceutically acceptable salt thereof used as described in statement B41, wherein the treatment comprises administering to a subject in need a first amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a second amount of at least one additional active ingredient, wherein the first amount and the second amount to...

Claims

1. A compound of formula (I) ABC (I) Or its pharmaceutically acceptable salt. Where A has one of the following properties: (A1a), where the wavy line indicates the attachment point with B; X 1 Is it N or CR? A3 ; R A1 Choose from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted; (v)C 1-6 alkoxy groups, optionally surrounded by OH, one or more halogroups, or C 1-6 Alkyl amide substitution; (vi)C 1-6 Alkyl esters; (vii)C 1-6 Alkyl acyl; and (viii)OH; R A2 Choose from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted; (v)C 1-6 Alkyl groups, which are optionally converted by OH, C 1-6 Alkyl amide or one or more halogroups are substituted; (vi)C 1-6 Acylamide (wherein the acyl group is optionally substituted with H or methyl); (vii)C 1-6 Thioalkyl; (viii)C 1-6 Alkyl esters; (ix)C 1-6 Alkyl acyl; (x)C 4-5 Heterocyclic groups; (xi)C5 heteroaryl; (xii)C 1-6 Alkylamide, which is optionally C 1-3 Alkyl amide, CN, OH, C 2-3 alkynyl group, C 4-6 Heterocyclic group or C 1-3 Alkyl substitution, wherein the C 1-3 The alkyl group may optionally be substituted with one or more halogroups or OH groups; (xiii)OH; and (xiv)C 1-6 Alkylamino; R A3 Choose from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, carboxyl group, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Alkyl acylamino, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted; (v)OH; (vi)C 1-6 Alkoxy groups, which may optionally be substituted with OH, NH2, C4 heterocyclic groups or one or more halogroups; (vii)C 1-6 Acyloxy group; (viii) C4 heterocyclic group; (ix)NH2; (x)C 1-6 Alkylamino groups, which may optionally be substituted with CN, OH or C4 heterocyclic groups; (xi)C 1-6 Dialkylamino, which is optionally substituted with -NH2; (xii)C 1-6 Acylamide (where the acyl substituent is H or Me); (xiii) amidoyl or methyl-amidinyl; (xiv) carboxylamino; (xv)C 1-6 Thioalkyl groups, which are optionally substituted with OH or NH2; (xvi)C 1-6 alkylsulfinyl; (xvii)C 1-6 Alkyl sulfonyl group, which is optionally substituted with one or more haloyl groups; (xviii)C 1-6 sulfonylimide group; (xix)C 1-6 Alkyloxyphosphine group; (xx) carboxyl group; (xxi)C(=O)NH2; (xxii)C 1-6 Alkyl esters; (xxiii)C 1-6 An alkyl acyl group, optionally substituted with one or more halogroups; and (xxiv)C 1-6 Alkyl amide; Or R A3 and R A2 Together with the carbon atoms they are bonded to, they form: (i) C can be arbitrarily substituted 5-7 Heterocyclic rings; (ii) C can be arbitrarily substituted 5-7 Mixed aromatic rings; (iii) Optionally substituted C6-carbon aromatic rings; (iv) Optional substitution of C 5-7 carbon ring in, When present, one, two, three, or four optional substituents are independently selected from C. 1-6 Alkyl, Halogenated, C 1-6 Alkoxy, NH2, C 1-6 Alkylamino, OH, and CN; (A2a) The wavy line indicates the attachment point with B; Z 1 Selected from O or S; R A5 Choose from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv) A C1 alkyl group, optionally substituted with one or more OH, CN, or one or more halogroups; and (v)C1 alkoxy group, which is optionally substituted with one or more halogroups; R A6 Choose from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted; (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted; (vi)C 1-6 Alkylamino; (vii)C 1-6 Thioalkyl; (viii)C 1-6 Alkyloxyphosphine; and (ix)C 1-6 Alkylphosphonoyl; R A7 Choose from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted; (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups and one or more halogenated groups; (vi) C4 heterocyclic group; (vii)C 1-6 Alkylamino groups, optionally substituted with CN, OH, or C4 heterocyclic groups; (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2; (A2b) The wavy line indicates the attachment point with B; Z 6 Is it N or CH? Z 7 Is it N or CR? A8 Z 8 and Z 9 Choose independently from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Alkyl acyl, C 1-6 Alkoxy or one or more halogroups are substituted; (v)C 1-6 Alkyl groups, which are optionally C 1-6 Alkyl amide, C 1-6 Alkylphosphonoyl or one or more haloyl groups are substituted; (vi)C 1-6 Alkylamino (vii)C 1-6 Thioalkyl, (viii)C 1-6 Alkyloxyphosphine; and (ix)C 1-6 Alkylphosphonoyl; R A8 Choose from the following groups: (i)H; (ii) Halogenated groups; (iii)CN; (iv)C 1-6 Hydrocarbons, optionally reacted with OH, CN, C 1-6 Thioalkyl, C 1-6 Alkoxy, C 1-6 Alkyl acyl, C 1-6 Acyloxy group, C(=O)OH, C 1-6 Alkyl esters, C 1-6 Alkylamino, -C(=O)NH2, C 1-6 Alkyl amide, C 1-6 Acylamide, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl or one or more haloyl groups are substituted; (v)C 1-6 Alkoxy groups, which are optionally substituted with NH2, C4 heterocyclic groups or one or more halogenated groups; (vi) C4 heterocyclic group; (vii)C 1-6 Alkylamino groups, which may optionally be substituted with CN, OH or C4 heterocyclic groups; (viii)C 1-6 Dialkylamino, optionally substituted with -NH2; and (ix)C 1-6 Thioalkyl groups, which are optionally substituted with OH or -NH2; (A3a) or (A3b) Where R A9 Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 1-methylcyclopropyl, and 2-methylcyclopropyl; (A4) Where R A4 Selected from H, CN, -OCF2H, cyclopropyl, Cl, and methyl; Where B has the following formula (B-1) The wavy line indicates the attachment points to A and C; R B1 It is H, OH, =CHCH2-OH, C 1-4 Alkoxy or C 1-4 Alkyl, the C 1-4 Alkyl groups may optionally be replaced by OH or OMe; Where C has the following formula: (C-1a) Where X is hydrogen or fluorine; Where R N It is H, methyl, or optionally C 1-3 Benzyl groups substituted with alkoxy groups; R C1 and R C2 Together with the carbon atoms they are bonded to, they form fused benzene rings or C6 heteroaromatic rings, which are optionally separated by one or more R atoms. C3 Group substitution; Where R C3 Selected from (i)CN; (ii)P(=O)Me2; (iii)C(=O)OH; (iv)C 1-6 Hydrocarbons, which are optionally C 1-6 Alkyl substitution; (v)C 1-6 Alkoxy; (vi)C 1-6 Alkyl amide; (vii)C 5-6 Mixed aromatics; (viii) Halogenated group; (ix)C 1-6 Alkyl acyl; and (x)Oxide group.

2. The compound according to claim 1, wherein A has the formula (A1a), (A2b), (A3a) and (A3b).

3. The compound according to claim 1 or 2, wherein (A1a) has the formula (A1). 。 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A has the formula (A1), (A2b), (A3a), and (A3b).

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein (A1a) is selected from one of the following formulas: 。 6. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R A2 Selected from H, chlorine, methyl, CF3 and OCF2H.

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R A3 Choose from the following groups: H, methyl, and OH.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein (A2a) is selected from one of the following formulas: 。 9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein (A2b) has the formula (A2b5): (A2b5) 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R A9 It is a methyl group.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from the following formula: 、 、 、 、 、 , , and .

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from the following formula: 。 13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from the following formula: 。 14. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein B has the formula (B-1): (B-1) The wavy line indicates the attachment points to A and C; Where R B1 Choose from the following groups: -H, -OH, -OMe, -O-ethyl, -CH2OH, -CH2CH2OH and =CHCH2-OH.

15. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein B has the following formula (B-1a): (B-1a)。 16. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein B has the following formula (B-1b): (B-1b)。 17. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein C has the following formula: (C-2a) Q 1 Q 2 Q 3 and Q 4 Both are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is selected from N, C-CN, CC(=O)NMe2 and CP(=O)(Me)2, and the other three are CH; or Q 1 Q 2 Q 3 and Q 4 One of them is N-Me, and the adjacent Q 1 Q 2 Q 3 Or Q 4 One of them is C=O, and the other two are CH.

18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein C is selected from one of the following formulas: 。 19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from: And C is selected from: 。 20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein X is F.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein X is H.

22. The compound of claim 1, wherein the compound is selected from one of the compounds listed in Tables 1 and 2 or a pharmaceutically acceptable salt thereof.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, for use in a therapeutic manner.

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

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 24, for use in the treatment of cardiovascular diseases.

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