Benzazepine fused ring derivative as v2 receptor antagonist

Abstract

Disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Specifically, disclosed is a class of benzazepine fused ring derivatives as V2 receptor antagonists.

Description

Benzazepine derivatives as V2 receptor antagonists

[0001] The present invention claims the following priority:

[0002] Application No. CN2024108654996, Application Date: June 28, 2024;

[0003] Application No. CN2024113289738, Application Date: September 23, 2024;

[0004] Application No. CN2024119424019, Application Date: December 25, 2024;

[0005] Application No. CN2025103628237, Application Date: March 25, 2025. TECHNICAL FIELD

[0006] The present invention relates to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, and in particular, the present invention relates to a class of benzazepine derivatives as V2 receptor antagonists. BACKGROUND

[0007] Hormones play an important role in the regulation of homeostasis in the human body, among which arginine vasopressin (AVP) is closely related to the regulation of water and sodium metabolism in the human body. Metabolic disorders of arginine vasopressin (AVP) can cause hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, cirrhosis, kidney disease, hypertension, and edema, etc. Arginine vasopressin (AVP) receptor antagonists can inhibit the binding of AVP to the receptor, thereby playing a therapeutic role in the above diseases. Arginine vasopressin V2 receptor antagonists represented by tolvaptan can increase free water excretion while not affecting electrolyte metabolism, thereby becoming an ideal drug for treating the above diseases. However, the marketed AVP V2 receptor antagonists, such as tolvaptan, are metabolized by liver metabolic enzymes, which produce a large amount of metabolites in the body and cause severe drug-induced liver toxicity. FDA has given a black box warning on the drug product label, limiting its application. Therefore, it is very important to develop new V2 receptor antagonists with high efficiency and low side effects. SUMMARY

[0008] In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

[0009] wherein,

[0010] X is selected from CR4R5 or NR6;

[0011] Y is selected from O or S;

[0012] Z is selected from O, S or CR4R5;

[0013] T1, T2are each independently selected from N or CR T ;

[0014] Ring B is selected from C 6-20 aryl or 5-20 membered heteroaryl, said C 6-20 aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2, or 3 R B ;

[0015] Ring C is selected from C 6-20 aryl or 5-20 membered heteroaryl, said C 6-20 aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2, or 3 R C ;

[0016] R1, R2, R3, R4, R5, R6, R B , R C are each independently at each occurrence selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 aryl or 5-20 membered heteroaryl, said C 1- 20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2, or 3 R;

[0017] R T are each independently at each occurrence selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-6 alkyl or C 1-6 heteroalkyl, said C 1-6 alkyl and C 1-6 heteroalkyl are optionally substituted with 1, 2, or 3 R;

[0018] R is each occurrence independently selected from H, F, Cl, Br, I, CN, OH, NH2, SF5, CHO, COOH, C 1-20 alkyl or C 1-20 heteroalkyl, said C 1-20 alkyl and C 1-20 heteroalkyl are optionally substituted with 1, 2, or 3 R;

[0019] Each occurrence of R' is independently selected from H, F, Cl, Br, I, CN, OH, NH2, or C. 1-6 alkyl;

[0020] m1, m2, m3, n, and p are each independently selected from 0, 1, or 2;

[0021] The above C 1-6 Heteroalkyl, C 1-20 Heteroalkyl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from O, N and S or heteroatoms of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-.

[0022] In one aspect of the invention, the invention provides a compound of formula (Ⅰ'), an optical isomer thereof, or a pharmacologically acceptable salt thereof.

[0023] in,

[0024] X is selected from CR4R5 or NR6;

[0025] Y is selected from O or S;

[0026] Z is selected from O, S, or CR4R5;

[0027] T1 and T2 are independently selected from N or CR. T ;

[0028] Ring B is selected from C 6-20 Aryl or 5-20 heteroaryl, wherein C 6-20 Aryl groups and 5-20 heteroaryl groups are optionally capped with 1, 2, or 3 R groups. B replace;

[0029] Ring C is selected from C 6-20 Aryl or 5-20 heteroaryl, wherein C 6-20 Aryl groups and 5-20 heteroaryl groups are optionally capped with 1, 2, or 3 R groups. C replace;

[0030] R1, R2, R3, R4, R5, R6, R B R C Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20aryl or 5-20 membered heteroaryl, said C 1- 20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2, or 3 R;

[0031] R T each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-6 alkyl or C 1-6 heteroalkyl, C 1-6 alkyl and C 1-6 heteroalkyl are optionally substituted with 1, 2, or 3 R;

[0032] each occurrence of R is independently selected from H, F, Cl, Br, I, CN, OH, NH2, SF5, CHO, COOH, C 1-20 alkyl or C 1-20 heteroalkyl, C 1-20 alkyl and C 1-20 heteroalkyl are optionally substituted with 1, 2, or 3 R’;

[0033] each occurrence of R’ is independently selected from H, F, Cl, Br, I, CN, OH, NH2, or C 1-6 alkyl;

[0034] m1, m2, m3, n are independently selected from 0, 1, or 2;

[0035] the above C 1-6 heteroalkyl, C 1-20 heteroalkyl, 3-20 membered heterocycloalkyl, and 5-20 membered heteroaryl contain 1, 2, or 3 heteroatoms independently selected from O, N, and S or a heteroatom group of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-.

[0036] In some embodiments of the present application, the compound of formula (I) has a structure as shown in any one of formulae (II-1) to (II-3):

[0037] In some embodiments of the present application, the compound of formula (I) has a structure as shown in any one of formulae (II-1) to (II-3):

[0038] In some embodiments of the present application, the structure of the compound shown in formula (I') is shown in formula (I'-1), formula (I'-2) or formula (I'-3):

[0039] In some embodiments of the present application, R is independently selected from H, F, Cl, Br, I, CN, OH, NH2, SF5, CHO, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-C 1-6 alkylthio, -C 1-6 alkyl-C 1-6 alkylamino, C 1-6 alkyl-OH, C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl, C 1-6 alkyl-C(=O)-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, C 1-6 alkyl-NH-C(=O)-C 1-6 alkyl, -NH-S(=O)2-C 1-6 alkyl or C 1-6 alkyl-NH-S(=O)2-C 1-6 alkyl,

[0040] the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-C 1-6 alkylthio, -C 1-6 alkyl-C 1-6 alkylamino, C 1-6 alkyl-OH, C 1-6 alkyl-NH2, -C(=O)-C 1-6 alkyl, C 1-6 alkyl-C(=O)-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, C 1-6 alkyl-NH-C(=O)-C 1-6 alkyl, -NH-S(=O)2-C 1-6 alkyl and C1-6 alkyl-NH-S(=0)2-C 1-6 alkyl is optionally substituted with 1, 2, or 3 R', and other variables are as defined herein.

[0041] In some embodiments of the application, R is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, C(=0)NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, -C 1-4 alkyl-OH, -C 1-4 alkyl-NH2, -C(=0)-C 1-4 alkyl or -NH-C(=0)-C 1-4 alkyl, said C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, -C 1-4 alkyl-OH, -C 1-4 alkyl-NH2, -C(=0)-C 1-4 alkyl and -NH-C(=0)-C 1-4 alkyl is optionally substituted with 1, 2, or 3 R'; and other variables are as defined herein.

[0042] In some embodiments of the application, R is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, C(=0)NH2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 alkylamino, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio and C 1-3 alkylamino is optionally substituted with 1, 2, or 3 R'; and other variables are as defined herein.

[0043] In some embodiments of the application, R is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH2, SF5, CHO, COOH, CH3, C2H5, CF3, CHF2, CH2F, CF2Cl, CF2Br, CF2I,

[0044] In some embodiments of the application, R B each occurrence is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH2, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group may be optionally substituted with 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0045] In some embodiments of the present invention, R B Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylthio or C 1-4 Alkylamino, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylthio and C 1-4 The alkylamino group may be optionally substituted with 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0046] In some embodiments of the present invention, R B Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio and C 1-3 The alkylamino group may be optionally substituted with 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0047] In some embodiments of the present invention, ring B is selected from C. 6-12 Aryl or 5-12 heteroaryl, wherein C 6-12 Aryl and 5-12 heteroaryl groups are optionally surrounded by 1, 2 or 3 R groups. B Replacement; other variables are as defined in this invention.

[0048] In some embodiments of the application, ring B is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, or indolyl, optionally substituted with 1, 2, or 3 R B substituents; other variables are as defined in the application.

[0049] In some embodiments of the application, ring B is selected from

[0050] Y1, Y2are each independently selected from N and CR Y ;

[0051] R Y is, at each occurrence, independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-6 alkyl or C 1-6 heteroalkyl, said C 1-6 alkyl and C 1-6 heteroalkyl is optionally substituted with 1, 2, or 3 R;

[0052] m4is selected from 0, 1, or 2, and other variables are as defined in the application.

[0053] In some embodiments of the application, R Y is, at each occurrence, independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, or C 1-4 alkylamino, said C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, and C 1-4 alkylamino is optionally substituted with 1, 2, or 3 R, and other variables are as defined in the application.

[0054] In some embodiments of the application, R Y is, at each occurrence, independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or C 1-3 alkylamino, said C 1-3 alkyl, C 1-3 alkoxy, C 1-3alkylthio and C 1-3 alkylamino optionally substituted with 1, 2, or 3 R, the other variables being as defined herein.

[0055] In some embodiments of the application, Ring B is selected from

[0056] In some embodiments of the application, R C each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F, 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 aryl and 5-12 membered heteroaryl optionally substituted with 1, 2, or 3 R, the other variables being as defined herein.

[0057] In some embodiments of the application, R C each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F, 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, said C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 R, the other variables being as defined herein.

[0058] In some embodiments of the application, R C each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F, cyclopentyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, or thienyl, said cyclopentyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, and thienyl are optionally substituted with 1, 2, or 3 R, and other variables are as defined herein.

[0059] In some embodiments of the application, R C each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F, cyclopentyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, and thienyl are optionally substituted with 1, 2, or 3 R, and other variables are as defined herein.

[0060] In some embodiments of the application, ring C is selected from C 6-12 aryl or 5-12 membered heteroaryl, said C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with 1, 2, or 3 R C ; and other variables are as defined herein.

[0061] In some embodiments of the application, ring C is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, and indolyl, said phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, thiopyranyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, and indolyl are optionally substituted with 1, 2, or 3 R C ; and other variables are as defined herein.

[0062] In some embodiments of the application, ring C is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or thienyl, said phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and thienyl are optionally substituted with 1, 2, or 3 R C ; and other variables are as defined herein.

[0063] In some embodiments of the application, ring C is selected from

[0064] In some embodiments of the application, ring C is selected from

[0065] In some embodiments of the application, R3, R4, R5, R6, each occurrence, is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and C 1- 6alkylamino optionally substituted with 1, 2 or 3 R, the other variables being as defined in the application.

[0066] In some embodiments of the application, each occurrence of R3, R4, R5, R6is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F, 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or C 1-4 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio and C 1- 4alkylamino optionally substituted with 1, 2 or 3 R, the other variables being as defined in the application.

[0067] In some embodiments of the application, each occurrence of R3, R4, R5, R6is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F, 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 alkylamino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio and C 1- 3alkylamino optionally substituted with 1, 2 or 3 R, the other variables being as defined in the application.

[0068] In some embodiments of the application, each occurrence of R3, R4, R5, R6is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F,

[0069] In some embodiments of the application, the structural unit is selected from

[0070] In some embodiments of the application, the structural unit is selected from

[0071] In some embodiments of the application, the structural unit is selected from

[0072] In some embodiments of the application, the compound of formula (I) has a structure according to any one of formulae (III-1) to (III-4):

[0073] In some embodiments of the application, each occurrence of R1is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino optionally substituted with 1, 2, or 3 R, and the other variables are as defined in the application.

[0074] In some embodiments of the application, each occurrence of R1is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, or C 1-4 alkylamino, said C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, and C 1-4 alkylamino optionally substituted with 1, 2, or 3 R, and the other variables are as defined in the application.

[0075] In some embodiments of the application, each occurrence of R2is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or C 1-6 alkylamino, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino optionally substituted with 1, 2, or 3 R, and the other variables are as defined in the application.

[0076] In some embodiments of the application, each occurrence of R2is independently selected from H, F, Cl, Br, I, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, or C 1-4 alkylamino, said C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, and C1-4 Alkylamino is optionally substituted with 1, 2, or 3 R, and other variables are as defined herein.

[0077] The present application also provides a compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from

[0078] In some embodiments of the present application, the above-mentioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is selected from

[0079] In another aspect of the present application, the present application also provides a pharmaceutical composition. In some embodiments of the present application, the above-mentioned pharmaceutical composition protects the above-mentioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments of the present application, the above-mentioned pharmaceutical composition further comprises a pharmaceutical excipient.

[0081] In another aspect of the present application, the present application also provides use of the above-mentioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating a disease associated with arginine vasopressin V2 receptor.

[0082] In some embodiments of the present application, the disease associated with arginine vasopressin V2 receptor comprises one or more of hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, fluid retention, cardiac edema, hepatic edema, ascites in cirrhosis, renal disease, hypertension, and edema.

[0083] In another aspect of the present application, the present application also provides use of the above-mentioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating autosomal dominant polycystic kidney disease.

[0084] The present application has at least one of the following technical effects:

[0085] 1) Compared with the prior art, the compound of the present application has lower hepatotoxicity, which is specifically manifested by, but not limited to: the compound of the present application can reduce the inhibition of bile excretion into the bile duct, does not capture GSH (glutathione), and / or does not produce DM4103-like metabolites;

[0086] 2) Compared with the prior art, the proportional dose-effect of the compound of the present application has no hook effect in AVP-induced LLC-PK1 cell proliferation, so that the compound of the present application has better efficacy;

[0087] 3) The compounds of the present application do not inhibit CYP compared to the conventional art;

[0088] 4) The compounds of the present application have a longer half-life compared to the conventional art, thus, prolonging the drug effect;

[0089] 5) The compounds of the present application have high selectivity for V2 receptor compared to the conventional art.

[0090] Definitions and Descriptions

[0091] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as indefinite or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. Where a trade name appears herein, it is intended to designate the corresponding product or active ingredient thereof.

[0092] The term "pharmaceutically acceptable" as used herein, pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0093] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application that is found to possess the specific substituents of the compounds of the present application and is prepared from relatively non-toxic, inoffensive materials. When the compounds of the present application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the base in either a neat or inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or like salts. When the compounds of the present application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid in either a neat or inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, hydro sulfuric, hydriodic, phosphorous, and the like; and organic acids such as acetic, propionic, isobutyric, trifluoroacetic, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, ethanesulfonic, and the like; also salts of amino acids such as arginine and the like, and salts of organic acids like glucuronic, and the like. Certain specific compounds of the present application contain both basic and acidic functionalities as a result of which two salt forms can exist. In one salt form, the compound is rendered sufficiently basic or acidic by the presence of the counterion thereby rendering the compound a sufficiently acidic or basic salt form to form a salt with the counterion.

[0094] Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.

[0095] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures thereof, such as, for example, partial racemate and scalemic mixtures, and all such isomeric forms are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included in the present application.

[0096] Unless otherwise stated, a solid line wedge bond and a dashed line wedge bond indicate the absolute configuration about a stereocenter.

[0097] Unless otherwise stated, the term "tautomer" or "tautomer forms" refers to different functional group isomers that are in dynamic equilibrium at room temperature and rapidly interconvert. If tautomers are possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0098] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, increased efficacy, increased biological half-life, etc. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0099] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0100] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0101] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by one, two, or three Rs, the group can optionally be substituted by up to three Rs, and each case has an independent option for R. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound. For example, Can be selected wait.

[0102] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When L2 represents a single bond, it means that the structure is actually A hyphen ("-") not between two letters or symbols indicates the connection site of a substituent. For example, C 1-6 Alkyl carbonyl group - refers to a carbonyl group connected to the rest of the molecule via a carbonyl group. 1-6 Alkyl groups. However, when the linking site of the substituent is obvious to those skilled in the art, such as halogen substituents, the "-" may be omitted.

[0103] Unless otherwise specified, when the valence bonds of groups in the structural unit are marked with dashed lines... In this context, dashed lines represent the connection points between the structural unit and other parts of the molecule. For example, in the "structural unit" section... In the text, the dashed line represents... The connection points between a group and other parts of a molecule. For example, in a "structural unit". In the text, the dashed line represents... and The fusion junctions thus form

[0104] When a substituent is recited without indicating that it is attached to a substituted group by a particular atom, then the substituent can be attached by any atom in the substituent that results in a stable compound, for example, a pyridyl group as a substituent can be attached at any of the carbon atoms of the pyridyl ring to the group being substituted.

[0105] When a linking group is recited without indicating its direction of attachment, its direction of attachment is arbitrary, for example, wherein the linking group L is wherein the linking group L is wherein the phenyl group and the cyclopentyl group are attached in the same direction as the reading order from left to right wherein the phenyl group and the cyclopentyl group are attached in the opposite direction as the reading order from left to right Combinations of the linking groups, substituents, and / or variations thereof are only permitted if such combinations result in stable compounds.

[0106] Unless otherwise specified, the number of atoms in a ring refers to the number of atoms that are bonded together to form the ring itself (e.g., monocyclic compounds, fused ring compounds, spirocyclic compounds, bridged ring compounds, crosslinked compounds, carbocyclic compounds, heterocyclic compounds). The number of atoms in a ring is often defined as the ring size, for example, a "4-6 membered ring" refers to a "ring" that is arranged around 4-6 atoms. When a ring is substituted, the atoms included in the substituent are not included in the number of atoms in the ring. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

[0107] Unless otherwise specified, the term "alkyl" refers to saturated hydrocarbon radicals for example, straight-chain alkyl groups, branched-chain alkyl groups, and cyclic alkyl groups that can be attached to the rest of the molecule by a single bond, by a carbon-carbon bond, by a carbon-heteroatom bond, or by a heteroatom-heteroatom bond. Unless otherwise specified, alkyl groups can be optionally substituted. Unless otherwise specified, the term "alkyl" includes "C

[0108] Unless otherwise specified, the term "C 1-20 alkyl" is used to denote straight chain or branched chain saturated carbon hydride groups consisting of from 1 to 20 carbon atoms. The C 1-20 alkyl groups include C 1-19 , C 1-15 , C 1-10 , C 1-5 , C 1-4 , C 2-20 , C 2-12 , C 2-6 alkyl groups and the like; which can be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). The C 1-20Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, sec-butyl, n-pentyl, n-hexyl, 1-methylhexyl, n-nonyl, n-decyl, adamantyl, n-undecyl, n-dodecyl, 2- ethyldodecyl, 2-butyldodecyl, n-icosyl, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4- butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,12-dodecanediyl, 1,14-tetradecanediyl, 1,16-hexadecanediyl, 1,18- octadecanediyl, 1,20-icosanediyl, and the like.

[0109] Unless otherwise specified, the term "C 1-6 "alkyl" is used to denote a saturated carbon hydride group, either straight or branched, consisting of from 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 2-6 alkyl groups; which can be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). The C 1-6 Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu") or t-butyl ("t-Bu"), pentyl, hexyl, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, and the like.

[0110] Unless otherwise specified, the term "heteroalkyl," by itself or in combination with another term, represents a stable straight or branched chain, or combination thereof, having a certain number of carbon atoms and at least one heteroatom or heteroatom group, wherein the "alkyl" is as defined herein. In some embodiments, the heteroatom is selected from O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-20 heteroalkyl; in some embodiments, the heteroalkyl is C 1-6Heteroalkyl. The heteroatom or heteroatom group can be located at any internal position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule. Examples of heteroalkyl include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and the like; up to two of the heteroatoms thereof can be consecutive, such as -CH2-NH-OCH3. Unless otherwise expressly noted in the specification, heteroalkyl is optionally substituted.

[0111] Unless otherwise specified, the term "alkoxy" means an alkyl group as defined above in the present application attached to the remainder of the molecule through an oxygen atom. Unless otherwise specified, an alkoxy group is optionally substituted.

[0112] Unless otherwise specified, the term "C 1-6 "alkyl" in the present application is defined above. Unless otherwise specified, an alkoxy group is optionally substituted. 1-6 C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, and C3 alkoxy, and the like. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propyloxy (including n- propyloxy and isopropyloxy), butyloxy (including n-butyloxy, isobutyloxy, s-butyloxy, and t-butyloxy), pentyloxy (including n-pentyloxy, isopentyloxy, and neopentyloxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, and the like.

[0113] Unless otherwise specified, the term "amino" can be a monovalent divalent or polyvalent

[0114] Unless otherwise specified, the term "alkylamino" means an alkyl group, as defined above in the present invention, attached to the remainder of the molecule through an amino group, as defined above. Unless otherwise specified, an alkylamino group can be optionally substituted.

[0115] Unless otherwise specified, the term "C 1-6 alkylamino" means those alkyl groups, comprising 1 to 6 carbon atoms, attached to the remainder of the molecule through an amino group. The C 1-6 alkylamino groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3, and C2 alkylamino groups, and the like. Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like. 1-6

[0116] Unless otherwise specified, the term "alkylthio" means an alkyl group, as defined above in the present invention, attached to the remainder of the molecule through a sulfur atom. Unless otherwise specified, an alkylthio group can be optionally substituted.

[0117] Unless otherwise specified, the term "C 1-6 alkylthio" means those alkyl groups, comprising 1 to 6 carbon atoms, attached to the remainder of the molecule through a sulfur atom. The C 1-6 alkylthio groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3, and C2 alkylthio groups, and the like. Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like. 1-6

[0118] Unless otherwise specified, the term "cycloalkyl" refers to a stable non-aromatic, monocyclic or polycyclic, saturated hydrocarbon radical composed of carbon and hydrogen atoms, which can include fused, spiro, and / or bridged ring ring systems. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. "C 4-6 ​​"Cycloalkyl" means a cyclic alkyl group having 3-6 ring carbon atoms. Unless otherwise specified, the cycloalkyl group can be optionally substituted. 3-4 "Cycloalkyl" means a cyclic alkyl group having 3-4 ring carbon atoms. Unless otherwise specified, the cycloalkyl group can be optionally substituted.

[0119] Unless otherwise specified, "C 3-20 "Cycloalkyl" means a saturated monocyclic or polycyclic hydrocarbon group having 3-20 ring carbon atoms, for example, having 3-15 ring carbon atoms, for example, 3-6 ring carbon atoms; which can be monovalent, divalent or multivalent. C 3-20 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the like.

[0120] Unless otherwise specified, "C 3-12 "Cycloalkyl" means a saturated monocyclic or polycyclic hydrocarbon group having 3-12 ring carbon atoms, for example, having 3-10 ring carbon atoms, for example, 3-6 ring carbon atoms; which can be monovalent, divalent or multivalent. C 3-12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the like.

[0121] Unless otherwise specified, the term "heterocycloalkyl" means a non-aromatic, saturated cyclic group that exists as a monocyclic, fused ring, spiro, and / or bridged ring, having at least one ring atom that is a heteroatom or heteroatom group, the remainder of which are carbon atoms; in some embodiments, the heteroatom is independently selected at each occurrence from O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2), the nitrogen atom is optionally quaternized, in other embodiments, the heteroatom group is independently selected for each occurrence from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. The heteroatom or heteroatom group can be located at any interior position of the heterocycloalkyl group, including the position of attachment of the heterocycloalkyl group to the remainder of the molecule. In some embodiments, the heterocycloalkyl group is a 3-20 membered heterocycloalkyl group; in some embodiments, the heterocycloalkyl group is a 3-12 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 3-6 membered heterocycloalkyl group. Unless otherwise specified, a heterocycloalkyl group can be optionally substituted. Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, or a heteroatom group as described above, and the remainder carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring systems include spiro, fused, and bridged rings. Further, with respect to the "3-6 membered heterocycloalkyl" group, the heteroatom or heteroatom group can be located at any interior position of the heterocycloalkyl group, including the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 3-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl groups, and the like. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, and the like.

[0122] Unless otherwise specified, when a substituent attached to ring A can be connected to ring A to form a ring, it means that the substituent can be connected to any position of ring A to form a new ring, including a fused, spiro, or bridged ring; where ring A can be selected from the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl groups, and the like as described above. For example, when R in may be connected to to form a 6-membered ring, examples of which include, but are not limited to, etc.

[0123] Unless otherwise specified, C n-n+m or C n -C n+m including any one specific instance of n to n+m carbons, for example C 1-12 including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 including any one range of n to n+m, for example C 1- 12 including C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; by analogy, n-membered to n+m-membered means the number of atoms in a ring is n to n+m, for example 3-12 membered ring includes 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered, 11 membered, and 12 membered rings, as well as any one range of n to n+m, for example 3-12 membered ring includes 3-6 membered, 3-9 membered, 5-6 membered, 5-7 membered, 6-7 membered, 6-8 membered, and 6-10 membered rings, etc.

[0124] Unless otherwise specified, the term "aryl" refers to a hydrocarbon ring system group comprising at least one aromatic ring. In the present invention, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused, spiro, and / or bridged ring systems. Aryl groups include, but are not limited to, benzene, naphthalene, anthracene, fluoranthene, phenanthrene, chrysene, pyrene, tetracene, naphthacene, benzpyrene, acenaphthene, fluorene, and derivatives thereof groups. Unless otherwise specified in the specification, aryl groups can be optionally substituted.

[0125] Unless otherwise specified, the term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 12 membered, containing 1 to 3 heteroatoms; more preferably 5 membered or 6 membered, containing 1 to 3 heteroatoms; non-limiting examples are pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. Heteroaryl groups can be attached to the rest of the molecule through a heteroatom or a carbon atom. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include: pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, fu rofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, quinoline, isoquinoline, perylene, quinoxaline, phenanthridine, berberine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole, and derivatives thereof. Unless otherwise specifically indicated herein, a heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0126] The term "substituted" as used herein means that at least one hydrogen atom in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) is replaced with a bond to a non-hydrogen atom including, but not limited to, halogen atoms (e.g., F, Cl, Br, I), oxygen-containing groups (e.g., hydroxyl, alkoxy, ester), sulfur-containing groups (e.g., thiol, thioalkyl, sulfone, sulfonyl, sulfoxide), nitrogen-containing groups (e.g., amine, amide, dialkylamine, arylamine, aryl-alkyl-amine, diarylamine, N-oxide, imide, enamine), silicon-containing groups (e.g., trialkylsilyl, dialkylarylsilyl, alkylbisarylsilyl, triarylsilyl), and other heteroatoms in various other groups.

[0127] The term "substituted" as used herein also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) is replaced with a higher order bond (e.g., a double or triple bond) to a heteroatom, such as the oxygen in carbonyl, carboxyl, and ester groups, and the nitrogen in imine, oxime, hydrazone, and nitrile groups. For example, "substituted" means that one or more hydrogen atoms in any of the above groups is replaced with -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g Rh , -OR g , -SR g , -SOR g , SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h substituted. "Substituted" can also mean that one or more hydrogen atoms on any of the above groups are replaced with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h . The R g and R h are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. "Substituted" can also mean that one or more hydrogen atoms on any of the above groups are replaced with amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. Additionally, each of the above substituents can be optionally substituted with one or more of the above substituents.

[0128] It will be understood by those skilled in the art that some of the compounds of Formula (I) can comprise one or more chiral centers and, therefore, exist as two or more stereoisomers. Accordingly, the compounds of the present application can exist as individual stereoisomers (e.g., enantiomers, diastereomers) and mixtures of stereoisomers, for example, racemates, in any ratio, and, where appropriate, as tautomers and geometric isomers.

[0129] The term "stereoisomers" as used herein refers to compounds which have identical chemical constitution, but differ in the arrangement of atoms or groups in space.

[0130] The term "enantiomers" as used herein refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0131] The term "diastereomer" as used herein refers to a stereoisomer that has two or more chiral centers and whose molecules are not a mirror image of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated by high resolution analytical methods, such as electrophoresis and chromatography, e.g., HPLC.

[0132] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound, which is dextrorotatory, has the (+) or d designation. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer when there are two stereoisomers and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical process or method. The terms "racemic mixture" and "racemate" mean an equimolar mixture of two enantiomeric forms lacking any optical activity.

[0133] A racemic mixture can be used as is or resolved into its individual isomers. A stereochemically pure compound or a mixture enriched in one or more isomers can be obtained by resolution of the racemic mixture. Methods for separating isomers are well known, including physical methods such as chromatography using a chiral adsorbent. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, individual isomers can be obtained chemically from mixtures by forming diastereomeric salts with a chiral acid (such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, a-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidine-5-carboxylic acid, and the like), fractional crystallization of the salts, and the like, and the isolated salt of the desired isomer is liberated by treatment with an alkali or an acid, optionally repeating the procedure to obtain a second isomer, to yield one or both isomers substantially free of the other, i.e., optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight of the desired stereoisomer. Alternatively, the racemate can be covalently bonded to a chiral compound (auxiliary) to give a diastereomeric mixture, as is well known in the art.

[0134] As used herein, the terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can be interconverted via low-energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0135] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0136] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Attached Figure Description

[0137] Figure 1 is a comparison of the results of LLC-PK1 cell proliferation assay according to an embodiment of the present invention;

[0138] Figure 2 is a comparison of the results of LLC-PK1 cell proliferation assay according to an embodiment of the present invention. Detailed Implementation

[0139] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0140] Unless otherwise specified, all raw materials used in this invention are commercially available.

[0141] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The measurements are given in units of ppm. NMR determinations were performed using Bruker Ascend. TM The NMR spectrometer was set to -400, and the solvents used for determination were deuterium sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0142] MS measurements were performed using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometry systems.

[0143] The HPLC determination used Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1x50mm, 3.5μm column)

[0144] The chiral HPLC analysis determination used THARSFC X5.

[0145] The thin layer chromatography silica gel plate used Yantai Qingdao GF254 silica gel plate, the specification of the silica gel plate used in thin layer chromatography (TLC) was 0.15mm-0.2mm, the specification of the thin layer chromatography separation and purification product was 0.4mm-0.5mm.

[0146] The column chromatography generally used Qingdao marine silica gel 200-300 mesh silica gel as the carrier.

[0147] The high performance liquid preparation used Waters 2767, Waters 2545, and Innovative Hengtong LC3000 preparative chromatograph.

[0148] The chiral preparative column chromatography used Shimadzu LC20-AP, THARSFC PREP80.

[0149] The pressurized hydrogenation reaction used Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0150] The microwave reaction used Biotage initiator+microwave reactor.

[0151] In the experimental examples, unless otherwise specified, the reactions were carried out under argon atmosphere or nitrogen atmosphere.

[0152] The argon atmosphere or nitrogen atmosphere refers to that the reaction bottle is connected with an about 1 liter volume argon or nitrogen balloon.

[0153] The hydrogen atmosphere refers to that the reaction bottle is connected with an about 1 liter volume hydrogen balloon.

[0154] In the experimental examples, unless otherwise specified, the reaction temperature was room temperature, and the temperature range was 20℃-30℃.

[0155] Example 1: Synthesis of compound 1

[0156] Step 1: Synthesis of compound 1-2

[0157] Compound 1-1 (25.0 g) was dissolved in tetrahydrofuran (300 mL) at room temperature, saturated aqueous sodium bicarbonate solution (150 mL) was added, and di-tert-butyl dicarbonate (13.77 g) in tetrahydrofuran (50 mL) was added dropwise. The reaction was stirred at room temperature for 16 hours. Water (300 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (300 mL). The organic phase was collected, washed with water (100 mL), saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 1-2 (26.1 g).

[0158] LCMS (ESI) [M+H] + 615.0.

[0159] Step 2: Synthesis of compound 1-3

[0160] Compound 1-2 (25.3 g) was dissolved in ethyl acetate (400 mL), and sodium periodate (35.2 g) in water (400 mL) was added dropwise. After the addition was completed, ruthenium trichloride trihydrate (100 mg) was added, and the reaction was stirred mechanically for 24 hours. The mixture was filtered through celite, and the filtrate was allowed to stand to separate into layers. Isopropanol (15 mL) was added to the organic phase, and the mixture was stirred at room temperature for 1 hour. The mixture was washed with water (200 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated to 20-40 mL, and n-heptane (100 mL) was added to precipitate the solid. The solid was collected and dried to give compound 1-3 (8.0 g).

[0161] LCMS (ESI) [M+H] + 629.1.

[0162] Step 3: Synthesis of compound 1

[0163] Compound 1-3 (35.0 mg) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature overnight. Dichloromethane (20 mL) was added, and saturated aqueous sodium bicarbonate solution (15 mL) was added to separate into layers. The organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give compound 1 (25.0 mg).

[0164] LCMS (ESI) [M+H] + 529.1.

[0165] 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.16 (s, 1H), 8.11 - 8.04 (m, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.71 (m, 4H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.04 - 4.85 (m, 2H), 2.71 - 2.68 (m, 1H), 2.42 - 2.30 (m, 1H), 2.28 - 2.17 (m, 1H), 2.14 - 1.93 (m, 3H).

[0166] Example 2: Synthesis of compound 2 and compound 3

[0167] Step 1: Synthesis of compound 2 and compound 3

[0168] Compound 1-3 (7.0 g) was added into a three-neck flask, replaced by nitrogen for three times, added tetrahydrofuran (170 mL) and stirred to dissolve. Cooled to -70 °C with ethyl acetate / dry ice bath, slowly added potassium bis(trimethylsilyl)amide (1 M, 27.82 mL) into the reaction flask (about 25 minutes for dropping), stirred for 25 minutes. Slowly added (1R)-(-)-10-camphorsulfonazide (3.83 g) dissolved in tetrahydrofuran into the reaction flask (about 25 minutes for dropping), stirred for 3 hours at low temperature. The reaction solution was directly concentrated to obtain a yellow solid, diluted with dichloromethane (150 mL), added trifluoroacetic acid (30 mL), stirred overnight at room temperature. The reaction solution was directly concentrated to obtain a yellow solid, diluted with ethyl acetate (120 mL), adjusted to pH = 8 with saturated sodium bicarbonate solution under ice bath, separated the organic phase after standing, the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phase was washed with saturated sodium chloride, dried and concentrated, then purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a mixture of two diastereoisomers. The product was further purified by preparative HPLC to obtain compound 2 (1.2 g) and compound 3 (500.0 mg).

[0169] Compound 2:

[0170] LCMS (ESI) [M+H] + 545.0.

[0171] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.33 (s, 1H), 8.11 - 8.04 (m, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.79 - 7.64 (m, 4H), 7.40 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.4, 1H), 7.02 (d, J = 8.3 Hz, 1H), 5.67 (d, J = 6.4 Hz, 1H), 4.97 (d, J = 13.6 Hz, 1H), 4.87 (d, J = 9.3 Hz, 1H), 3.93 (dd, J = 10.1, 6.4 Hz, 1H), 2.71 (t, J = 13.0 Hz, 1H), 2.23 - 1.95 (m, 2H), 1.84 - 1.68 (m, 1H).

[0172] Compound 3:

[0173] LCMS (ESI) [M+H] + 545.0.

[0174] 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.44 (s, 1H), 8.07 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.79 - 7.63 (m, 4H), 7.40 (d, J = 2.3 Hz, 1H), 7.26 - 7.14 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.77 (d, J = 6.2 Hz, 1H), 5.08 - 4.91 (m, 2H), 3.91 (t, J = 6.0 Hz, 1H), 2.73 (t, J = 13.1 Hz, 1H), 2.26 - 2.10 (m, 1H), 2.03 - 1.92 (m, 1H), 1.91 - 1.76 (m, 1H).

[0175] Example 3: Synthesis of compound 4

[0176] Step 1: Synthesis of compound 4-2

[0177] Compound 4-1 (300 mg) was dissolved in dichloromethane (10 mL) at room temperature, triethylamine (166 mg) and methylsulfonyl chloride (125 mg) were added and stirred at room temperature for 2 hours. The reaction was identified to be completed by LCMS, the reaction solution was added with water (20 mL), dichloromethane (10 mL x 3) was used for extraction, the combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (methanol / dichloromethane = 1 / 30) to obtain compound 4-2 (320 mg).

[0178] LCMS (ESI) [M+H] + 623.6.

[0179] Step 2: Synthesis of compound 4-3 and compound 4-4

[0180] Compound 4-2 (230 mg) and sodium azide (150 mg) were dissolved in super dry N,N-dimethylformamide (4 mL) at room temperature, and the reaction was carried out at 50°C overnight. The reaction was identified to be completed by LCMS, the reaction solution was added with water (10 mL), and ethyl acetate (10 mL x 3) was used for extraction, the combined organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain compound 4-3 (80 mg) and compound 4-4 (100 mg).

[0181] LCMS (ESI) [M+H] + 569.8.

[0182] Step 3: Synthesis of compound 4

[0183] Compound 4-3 (15 mg) was placed in a three-necked flask, and then tetrahydrofuran / glacial acetic acid (0.6 mL, V / V = 5 / 1) and zinc powder (26 mg) were added under argon replacement. Then the reaction was carried out at room temperature for 2 hours. The reaction was identified to be completed by LCMS. The reaction solution was quenched by adding saturated sodium bicarbonate (15 mL), filtered, and extracted with ethyl acetate (15 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to obtain compound 4 (1.13 mg).

[0184] LCMS (ESI) [M+H] + 544.3.

[0185] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 8.03 - 7.96 (m, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.75 - 7.67 (m, 4H), 7.40 (d, J = 2.2 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 5.32 (t, J = 4.6 Hz, 2H), 4.98 (d, J = 13.6 Hz, 1H), 4.87 (d, J = 9.5 Hz, 1H), 3.14 (d, J = 10.7 Hz, 1H), 2.71 (s, 1H), 2.19 (d, J = 13.1 Hz, 1H), 2.02 (d, J = 7.4 Hz, 1H), 1.98 (d, J = 6.2 Hz, 1H).

[0186] Example 4: Synthesis of compound 5

[0187] Step 1: Synthesis of compound 5

[0188] Compound 4-4 (30 mg) was placed in a three-necked flask, and then tetrahydrofuran / glacial acetic acid (0.6 mL, V / V = 5 / 1) and zinc powder (68 mg) were added, and argon was replaced. Then the reaction was carried out at room temperature for 3 hours. The reaction was identified by LCMS. The reaction solution was quenched by saturated sodium bicarbonate (20 mL), filtered, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC to obtain compound 5 (6.22 mg).

[0189] LCMS (ESI) [M+H]+ + 544.3.

[0190] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.75 - 7.67 (m, 4H), 7.38 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 5.32 (t, J = 4.6 Hz, 2H), 5.09 (d, J = 9.0 Hz, 1H), 4.96 (d, J = 13.2 Hz, 1H), 3.22 (d, J = 7.1 Hz, 1H), 2.72 (d, J = 13.2 Hz, 1H), 2.18 (d, J = 12.2 Hz, 1H), 2.02 - 1.97 (m, 1H), 1.83 (d, J = 13.9 Hz, 1H).

[0191] Example 5: Synthesis of compound 6, compound 7

[0192] Compound 4-1 (1.0 g) was dissolved in super dry tetrahydrofuran (30 mL), silver oxide (0.85 g) and iodomethane (2.61 g) were added, and stirred at room temperature for 16 hours. LCMS identified that the product was generated, the reaction solution was added water (100 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with water (100 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse phase C18 column chromatography (acetonitrile / water = 2 / 3) to obtain the crude product. The crude product was further purified by two times of climbing plate (methanol / dichloromethane = 1 / 10) to obtain the target product compound 6 (7.21 mg) and compound 7 (1.04 mg).

[0193] Compound 6:

[0194] LCMS (ESI) [M+H] + 559.2.

[0195] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.45 (s, 1H), 8.05 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.71 (dt, J = 16.2, 7.7 Hz, 4H), 7.38 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.92 (dd, J = 19.9, 11.4 Hz, 2H), 3.84 (t, J = 9.3 Hz, 1H), 3.51 (s, 3H), 2.70 (d, J = 26.9 Hz, 1H), 2.09 (d, J = 16.3 Hz, 2H), 2.00 - 1.89 (m, 1H).

[0196] Compound 7:

[0197] LCMS (ESI) [M+H] + 559.2.

[0198] 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.57 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.71 (dt, J = 14.4, 6.4 Hz, 4H), 7.41 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 6.9 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.04 - 4.87 (m, 2H), 3.64 (d, J = 5.1 Hz, 1H), 3.49 (s, 3H), 2.77 - 2.69 (m, 1H), 2.16 - 2.07 (m, 2H), 1.97 - 1.90 (m, 1H).

[0199] Example 6: Synthesis of compound 8

[0200] Step 1: Synthesis of compound 8-1

[0201] Compound 3 (250 mg) was dissolved in dichloromethane (10 mL) at room temperature, triethylamine (135 mg) and methylsulfonyl chloride (100 mg) were added, and stirring was performed at room temperature for 2 hours. The reaction was identified to be completed by LCMS, the reaction solution was added with water (20 mL), extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (methanol / dichloromethane = 1 / 30) to obtain compound 8-1 (100 mg).

[0202] LCMS (ESI) [M+H] 623.3. + 623.3.

[0203] Step 2: Synthesis of compound 8

[0204] Compound 8-1 (100 mg) was dissolved in 1,4-dioxane (5 mL) at room temperature, and tetrabutylammonium fluoride (0.32 mL, 1 M) was added dropwise. The reaction was carried out at 100 °C for 16 h. Water (10 mL) was added for dilution, and ethyl acetate (10 mL x 2) was used for extraction. The organic phase was combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative liquid phase to obtain compound 8 (3.70 mg).

[0205] LCMS (ESI) [M+H] 623.3. + 623.3.

[0206] 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.79 (s, 1H), 8.10-7.95 (m, 2H), 7.81 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 16.2, 7.6 Hz, 4H), 7.41 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 7.1 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.15-5.00 (m, 1H), 4.99-4.88 (m, 2H), 2.84-2.70 (m, 1H), 2.28-2.14 (m, 3H).

[0207] Example 7: Synthesis of compound 9

[0208] Step 1: Synthesis of compound 9-1

[0209] Compound 2 (250 mg) was dissolved in dichloromethane (10 mL) at room temperature, and triethylamine (135 mg) and methyl sulfonyl chloride (100 mg) were added. The reaction was stirred at room temperature for 2 h. The reaction was identified as complete by LCMS. Water (20 mL) was added to the reaction, and dichloromethane (10 mL x 3) was used for extraction. The organic phase was combined and washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 30) to obtain compound 9-1 (87 mg).

[0210] LCMS (ESI) [M+H] 623.3. + 623.3.

[0211] Step 2: Synthesis of compound 9

[0212] Compound 9-1 (40 mg) was dissolved in 1,4-dioxane (5 mL) at room temperature, and tetrabutylammonium fluoride (0.12 mL, 1 M) was added dropwise. The reaction was carried out at 100 °C for 16 hours. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative HPLC to obtain compound 9 (7.56 mg).

[0213] LCMS (ESI) [M+H] + 547.2.

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.00 (s, 1H), 8.10 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.72 (dt, J = 16.4, 7.5 Hz, 4H), 7.40 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.17 (d, J = 8.2 Hz, 1H), 5.03 (d, J = 13.8 Hz, 1H), 4.91 (dd, J = 53.2, 4.9 Hz, 1H), 2.75 (t, J = 11.6 Hz, 1H), 2.28 - 2.15 (m, 1H), 2.11 - 2.04 (m, 1H), 2.03 - 1.95 (m, 1H).

[0215] Example 8: Synthesis of compound 10

[0216] Step 1: Synthesis of compound 10-1

[0217] Compound 1-1 (200 mg) was dissolved in methanol (15 mL) at room temperature, and formaldehyde aqueous solution (0.2 mL) and sodium cyanoborohydride (74 mg) were added successively. The reaction was stirred at room temperature overnight. LCMS detection showed that the reaction was completed. The reaction liquid was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated. Purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) obtained compound 10-1 (80 mg).

[0218] LCMS (ESI) [M+H] + 529.2.

[0219] Step 2: Synthesis of compound 10

[0220] Compound 10-1 (40 mg) was dissolved in ethyl acetate (3 mL) at room temperature, sodium periodate (64.8 mg) in water (3 mL) was added, and ruthenium trichloride hydrate (1.7 mg) was added, and the reaction was allowed to proceed at room temperature overnight. The reaction was identified as complete by LCMS. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3), and the organic phases were combined and concentrated, and purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain a crude product, which was further purified by preparative HPLC to obtain compound 10 (3.09 mg).

[0221] LCMS (ESI) [M+H] + = 543.2.

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.20 (s, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.77-7.72 (m, 1H), 7.69 (d, J = 7.6 Hz, 3H), 7.22 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 5.02-4.88 (m, 2H), 2.83 (s, 3H), 2.70-2.65 (m, 1H), 2.57-2.54 (m, 1H), 2.23-2.12 (m, 1H), 2.10-1.93 (m, 3H).

[0223] Example 9: Synthesis of compound 11

[0224] Step 1: Synthesis of compound 11-2

[0225] Compound 11-1 (300 mg), super dry acetonitrile (5 mL), 6-(2-methylbenzamide)nicotinic acid (253 mg), N-methylimidazole (270 mg), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (520 mg) were added in sequence in a flask at room temperature, and the reaction was allowed to proceed at 30°C overnight. The reaction was identified as complete by LCMS. The reaction solution was concentrated, and purified by C18 reverse phase column chromatography (acetonitrile / water = 4 / 1, formic acid system) to obtain compound 11-2 (400 mg). LCMS (ESI) [M+H] + = 561.3.

[0226] Step 2: Synthesis of compound 11-3

[0227] Compound 11-2 (400 mg) was dissolved in ethyl acetate (6 mL), and a solution of sodium periodate (610 mg) in water (6 mL) was added, followed by the addition of ruthenium trichloride hydrate (16 mg) at room temperature. The reaction was carried out at 30 °C for 3 hours. LCMS detection showed that the raw material / product = 1 / 1. The reaction solution was filtered with diatomite, and the filtrate was added with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 11-3 (400 mg).

[0228] LCMS (ESI) [M+H] + = 575.3.

[0229] Step 3: Synthesis of compound 11

[0230] Compound 11-3 (200 mg) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added at room temperature. The reaction was stirred at room temperature for 30 minutes. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and purified by C18 reverse phase column chromatography (acetonitrile / water = 3 / 2, formic acid system) to obtain compound 11 (19.16 mg, yield 11.60%).

[0231] LCMS (ESI) [M+H] + = 475.2.

[0232] 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 6.9 Hz, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.38 (dd, J = 9.5, 4.7 Hz, 2H), 7.26 (dd, J = 13.6, 7.2 Hz, 2H), 7.18 (d, J = 7.9 Hz, 1H), 7.04 - 6.95 (m, 1H), 4.95 (t, J = 12.7 Hz, 2H), 2.74 - 2.63 (m, 1H), 2.40 - 2.33 (m, 4H), 2.26 - 2.16 (m, 1H), 2.14 - 2.06 (m, 1H), 2.05 - 1.96 (m, 2H).

[0233] Example 10: Synthesis of compound 12

[0234] Step 1: Synthesis of compound 12-2

[0235] Compound 12-1 (2.8 g) was dissolved in dichloromethane (30 mL) in a flask at room temperature, and triethylamine (2.26 g), di-tert-butyl dicarbonate (2.43 g) were added successively. The reaction was stirred at room temperature overnight. LCMS detection showed that the reaction was completed. The reaction solution was poured into water (30 mL), and extracted with dichloromethane (30 mL x 3). The combined organic phase was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 12-2 (3.09 g).

[0236] LCMS (ESI) [M-56+H] + = 421.1.

[0237] Step 2: Synthesis of compound 12-3

[0238] Compound 12-2 (3.09 g) was dissolved in ethyl acetate (30 mL) at room temperature, and a solution of sodium periodate (5.56 g) in water (30 mL) was added, followed by the addition of ruthenium trichloride hydrate (146.54 mg). The reaction was carried out at 25°C for 16 hours. LCMS detection showed that the reaction was completed. The filtrate was added with water (15 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 12-3 (1.9 g).

[0239] LCMS (ESI) [M-100+H] + = 391.1.

[0240] Step 3: Synthesis of compound 12-4

[0241] Compound 12-3 (1.0 g) was dissolved in super-dry tetrahydrofuran (15 mL) at room temperature, and cooled to -60°C. Nitrogen was replaced, and lithium diisopropylamide (2.04 mL, 2.0 M) was slowly added. The reaction was carried out at -60°C for 30 minutes, and iodomethane (0.87 g) was slowly added. The temperature was allowed to rise to room temperature, and the reaction was carried out at room temperature for 1 hour. LCMS detection showed that the reaction was completed. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (5 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 12-4 (0.86 g).

[0242] LCMS (ESI) [M-100+H] + = 405.1.

[0243] Step 4: Synthesis of compound 12-5

[0244] Compound 12-4 (1.29 g) was dissolved in dichloromethane (10 mL) at room temperature, and trifluoroacetic acid (2.5 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction was identified to be completed by LCMS. The excess trifluoroacetic acid was removed by concentration, and the residue was dissolved in dichloromethane (10 mL), and the solution was adjusted to alkaline with saturated sodium bicarbonate (40 mL), and extracted with dichloromethane (30 mL x 3). The combined organic phase was concentrated and purified by C18 reverse phase column chromatography (acetonitrile / water = 3 / 2, formic acid system) to give compound 12-5 (528 mg).

[0245] LCMS (ESI) [M+H] + = 405.1.

[0246] Step 5: Synthesis of compound 12-6

[0247] Compound 12-5 (528 mg) was dissolved in concentrated sulfuric acid (5 mL) at room temperature, and the mixture was reacted at 40°C for 16 hours. The reaction was identified to be completed by LCMS. The reaction solution was added dropwise into ice water (50 mL), and the solution was adjusted to alkaline with 10% sodium hydroxide. The solution was extracted with ethyl acetate (40 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The target product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 1) to give compound 12-6 (145 mg).

[0248] LCMS (ESI) [M+H] + = 251.2.

[0249] Step 6: Synthesis of compound 12

[0250] Compound 6-(2-trifluoromethylbenzamide)nicotinic acid (270 mg) was placed in a three-necked flask, and the flask was replaced with nitrogen. N,N-dimethylacetamide (5 mL) was added, and dichlorosulfoxide (400 mg) was added. The mixture was reacted at room temperature for 1 hour. A solution of compound 12-6 (130 mg) in N,N-dimethylacetamide (3 mL) was added, and the mixture was reacted at room temperature for 1 hour. The reaction was identified to be completed by LCMS. The reaction solution was added with water (20 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The target product was obtained by preparative HPLC to give compound 12 (83.31 mg).

[0251] LCMS (ESI) [M+H] + = 543.1.

[0252] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.70 (dd, J = 17.0, 8.3 Hz, 4H), 7.41 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 6.3 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 5.05 (d, J = 9.2 Hz, 1H), 4.97 (d, J = 13.9 Hz, 1H), 2.73 - 2.66 (m, 1H), 2.46 - 2.41 (m, 1H), 2.21 - 2.10 (m, 1H), 2.09 - 1.94 (m, 1H), 1.92 - 1.81 (m, 1H), 1.12 (d, J = 7.4 Hz, 3H).

[0253] Example 11: Synthesis of compound 13

[0254] Step 1: Synthesis of compound 13-1

[0255] Into a jar flask were added 2-methyl-4-(2-methylbenzamido)benzoic acid (280 mg), super dry acetonitrile (5 mL), compound 11-1 (335 mg), N-methylimidazole (250 mg), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (490 mg) sequentially at room temperature. Stirring at 30 °C overnight. LCMS detection, the reaction was completed. The reaction solution was concentrated, and purified by C18 reverse phase column chromatography (acetonitrile / water = 4 / 1, formic acid system) to give compound 13-1 (70 mg).

[0256] LCMS (ESI) [M+H] + = 574.3.

[0257] Step 2: Synthesis of compound 13-2

[0258] Compound 13-1 (70 mg) was dissolved in ethyl acetate (2 mL) at room temperature, and a solution of sodium periodate (100 mg) in water (2 mL) and ruthenium trichloride hydrate (14 mg) were added, and the reaction was carried out at 30 °C for 16 hours. LCMS detection, raw material / product = 1 / 1. The reaction solution was filtered with diatomite, the filtrate was added with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 13-2 (15 mg).

[0259] LCMS (ESI) [M+H] + = 588.2.

[0260] Step 3: Synthesis of compound 13

[0261] Compound 13-2 (15 mg) was dissolved in dichloromethane (4 mL) at room temperature, and trifluoroacetic acid solution (0.5 mL) was added. The reaction was stirred at room temperature for 30 min. The reaction was identified by LCMS as being complete. The reaction was concentrated under reduced pressure, and purified by C18 reverse column chromatography (acetonitrile / water = 1 / 1, formic acid system) to give compound 13 (6.03 mg).

[0262] LCMS (ESI) [M+H] + = 488.2.

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 7.36 (d, J = 6.4 Hz, 1H), 7.32 - 7.22 (m, 4H), 7.15 - 7.09 (m, 1H), 6.89 - 6.79 (m, 2H), 4.94 - 4.84 (m, 2H), 2.73 - 2.68 (m, 1H), 2.38 (d, J = 9.6 Hz, 2H), 2.35 (s, 3H), 2.34 - 2.33 (m, 3H), 2.26 - 2.18 (m, 1H), 2.06 - 1.98 (m, 2H).

[0264] Example 12: Synthesis of compound 14

[0265] Step 1: Synthesis of compound 14-2

[0266] Compound 14-1 (5.0 g) was dissolved in pyridine (60 mL) in a flask at room temperature, and 2-trifluoromethylbenzoyl chloride (6.31 g) was added. The reaction was stirred at room temperature overnight. The reaction was detected by LCMS as being complete. The reaction was poured into water (100 mL) and stirred, and the solid was filtered after it was precipitated. The filter cake was dried and then slurried with petroleum ether (15 mL), filtered, and dried to give compound 14-2 (9.32 g).

[0267] LCMS (ESI) [M+H] + 338.2.

[0268] Step 2: Synthesis of compound 14-3

[0269] In a flask, compound 14-2 (9.32 g), tetrahydrofuran (80 mL), water (20 mL), sodium hydroxide (5.53 g) were added successively, stirred at 70 °C for 30 min. LCMS detection, the reaction was completed. The reaction solution was cooled, poured into water (200 mL), 2M hydrochloric acid was added to adjust pH = 4, the solid was precipitated and filtered, the filter cake was washed with water (100 mL). The filter cake was collected and dried to give compound 14-3 (8.7 g).

[0270] LCMS (ESI) [M+H] + = 324.2.

[0271] Step 3: synthesis of compound 14-4

[0272] In a flask, compound 11-1 (574 mg), super dry acetonitrile (20 mL), compound 14-3 (580 mg), N-methylimidazole (510 mg), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1000 mg) were added successively, stirred at 30 °C overnight. LCMS detection, the reaction was completed. The reaction solution was concentrated, and purified by C18 reverse phase column chromatography (acetonitrile / water = 4 / 1, formic acid system) to give compound 14-4 (437 mg).

[0273] LCMS (ESI) [M-56+H] + = 572.2.

[0274] Step 4: synthesis of compound 14-5

[0275] Compound 14-4 (437 mg) was dissolved in ethyl acetate (10 mL) at room temperature, and a solution of sodium periodate (600 mg) in water (10 mL) and ruthenium trichloride hydrate (16 mg) was added, and the reaction was carried out at 30 °C for 16 h. The reaction solution was filtered with diatomite, the filtrate was added with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 1) to give compound 14-5 (160 mg).

[0276] LCMS (ESI) [M+H] + = 642.3.

[0277] Step 5: synthesis of compound 14

[0278] Compound 14-5 (160 mg) was dissolved in dichloromethane (10 mL) at room temperature, and trifluoroacetic acid (2 mL) was added, and the reaction was carried out overnight, and LCMS detection showed that the reaction was completed. After concentration, compound 14 (54 mg) was obtained by C18 reverse phase purification (acetonitrile / water = 3 / 2, formic acid system).

[0279] LC-MS (ESI) [M+H] + 542.2.

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.68 (t, J = 7.2 Hz, 2H), 7.53 (d, J = 13.5 Hz, 1H), 7.30 (s, 1H), 7.19 (d, J = 7.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.85 (dd, J = 8.4, 3.9 Hz, 2H), 4.93 - 4.85 (m, 2H), 2.74 - 2.65 (m, 1H), 2.39 - 2.32 (m, 5H), 2.27 - 2.19 (m, 1H), 2.04 - 1.97 (m, 2H).

[0281] Example 13: Synthesis of compound 15

[0282] Step 1: Synthesis of compound 15-2

[0283] Compound 15-1 (100 g) was dissolved in tetrahydrofuran (1000 mL) in an Erlenmeyer flask at room temperature, (R)-(+)-tert-butylsulfinamide (51.97 g), tetraethyl titanate (130.41 g) were added successively, replaced with nitrogen, and stirred at 80 °C overnight. LCMS detection showed that the reaction was completed. The reaction solution was concentrated, and compound 15-2 (75 g) was obtained by column chromatography (A / B = 1 / 3, A: ethyl acetate / dichloromethane = 1 / 1, B: petroleum ether).

[0284] LCMS (ESI) [M-56] + = 453.1.

[0285] Step 2: Synthesis of compound 15-3

[0286] Compound 15-2 (71 g) was dissolved in tetrahydrofuran (700 mL) at room temperature, allyl methyl carbonate (27.30 g), N,N-diisopropylethylamine (40.51 g), and tetraphenylphosphonium palladium (9.06 g) were added, and the reaction was carried out at 65 °C for 16 hours under argon protection. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and compound 15-3 (40.8 g) was obtained by column chromatography (A / B = 1 / 5, A: ethyl acetate / dichloromethane = 1 / 1, B: petroleum ether).

[0287] LCMS (ESI) [M-100] += 493.2.

[0288] Step 3: Synthesis of compound 15-4

[0289] Compound 15-3 (20 g) was dissolved in super dry tetrahydrofuran (500 mL) at room temperature, cooled to minus 50 ℃, replaced with nitrogen, sodium borohydride (6.11 g) was added in batches, naturally warmed up, reacted for 16 hours. LCMS detected that the reaction was completed. The reaction solution was quenched with saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (300 mL x 3), the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (A / B = 1 / 3, A: ethyl acetate / dichloromethane = 1 / 1, B: petroleum ether) to obtain compound 15-4 (10 g).

[0290] LCMS (ESI) [M-100] + = 495.3.

[0291] Step 4: Synthesis of compound 15-5

[0292] Compound 15-4 (10 g) was dissolved in super dry tetrahydrofuran (100 mL) at room temperature, and then borane tetrahydrofuran (3.47 g) was added, and stirred at room temperature for 16 hours. LCMS identified that there was no raw material left, and the reaction was completed. The reaction solution was slowly added with methanol (50 mL) in an ice bath, followed by the addition of hydrogen peroxide (3.44 g) and 30 mL of 2M aqueous sodium hydroxide solution, and reacted at room temperature for 30 minutes. LCMS detected that the reaction was completed. The reaction solution was diluted with water (300 mL), extracted with ethyl acetate (300 mL x 3), the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (A / B = 80%, A-ethyl acetate / dichloromethane = 1 / 1, B-petroleum ether) to obtain compound 15-5 (6.16 g).

[0293] LCMS (ESI) [M+H] + = 513.2.

[0294] Step 5: Synthesis of compound 15-6

[0295] Oxalyl chloride (1.49 g) was dissolved in super dry dichloromethane (30 mL) at room temperature, and cooled to -60 °C under nitrogen. Dimethyl sulfoxide (1.37 g) in dichloromethane was added, and the reaction was allowed to proceed for 1 h. Compound 15-5 (3 g) in dichloromethane was added, and the reaction was allowed to proceed for another 1 h. N,N-diisopropylethylamine (4.54 g) was added, and the reaction was allowed to proceed for 30 min at low temperature, and then at room temperature for 16 h. LCMS detection showed that the reaction was completed. The reaction solution was added dropwise into ice water (50 mL), and extracted with ethyl acetate (40 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (A / B = 18%, A-ethyl acetate / dichloromethane = 1 / 1, B-petroleum ether) gave compound 15-6 (1.86 g).

[0296] LCMS (ESI) [M+H] + = 511.3.

[0297] Step 6: Synthesis of compound 15-7

[0298] Sodium hydroxide (0.84 g) was dissolved in water (35 mL) at room temperature, and cooled to 0 °C. Silver nitrate (1.79 g) was added slowly. Compound 15-6 (1.8 g) in acetonitrile (70 mL) was added dropwise at 0 °C. The reaction was allowed to proceed at room temperature overnight. LCMS detection showed that the reaction was completed. The reaction solution was adjusted to pH 5-6 with 1M hydrochloric acid solution under ice water bath, extracted with ethyl acetate (100 mL x 3), saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (methanol / dichloromethane = 1 / 10) to give compound 15-7 (1.5 g).

[0299] LCMS (ESI) [M+H] + = 527.2.

[0300] Step 7: Synthesis of compound 15-8

[0301] Compound 15-7 (1.5 g) was dissolved in 1,4-dioxane (20 mL) under argon protection, and 4 mol / L hydrogen chloride 1,4-dioxane solution (3.6 mL) was added. The reaction was stirred at room temperature for 5 h. LCMS detection showed that the reaction was completed. The reaction solution was directly dried under reduced pressure to give compound 15-8 (1.1 g).

[0302] LCMS (ESI) [M+H] + = 423.1.

[0303] Step 8: Synthesis of compound 15-9

[0304] Compound 15-8 (1.1 g) was dissolved in N,N-dimethylformamide (20 mL) under argon protection, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0) and N,N-diisopropylethylamine (2.02 g) were added. The reaction was stirred at room temperature overnight. LCMS detection showed that the reaction was completed. The reaction was quenched by adding saturated ammonium chloride (20 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with water (100 mL x 2), saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (methanol / dichloromethane = 1 / 20) gave compound 15-9 (0.95 g).

[0305] LCMS (ESI) [M+H] + = 405.2.

[0306] Step 9: Synthesis of compound 15-10

[0307] Compound 15-9 (0.95 g) was added to polyphosphoric acid (20 mL) under argon protection, and the reaction was reacted at 90°C for 5 hours. LCMS detection showed that the reaction was completed. The reaction was quenched by adding saturated sodium bicarbonate, extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with water (100 mL x 2) and saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (methanol / dichloromethane = 1 / 15) gave compound 15-10 (0.48 g).

[0308] LCMS (ESI) [M+H] + = 251.1.

[0309] Step 10: Synthesis of compound 15

[0310] 6-(2-trifluoromethylbenzamide)nicotinic acid (111.68 mg) was dissolved in N,N-dimethylacetamide (3 mL) under argon protection, and sulfurous chloride (114.21 mg) was added. After stirring at room temperature for 1 hour, compound 15-10 (60 mg) was added. The reaction was stirred at room temperature overnight. LCMS detection showed that the reaction was completed. The reaction was quenched by adding water (15 mL), filtered, and extracted with ethyl acetate (15 mL x 2). The combined organic phases were purified by preparative HPLC to give compound 15 (35.8 mg).

[0311] LCMS (ESI) [M+H] + = 543.2.

[0312] 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.19 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.78 - 7.60 (m, 4H), 7.37 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.99 - 6.86 (m, 1H), 4.85 (dd, J = 41.9, 10.9 Hz, 2H), 2.75 - 2.62 (m, 1H), 2.37 - 2.16 (m, 2H), 1.98 - 1.84 (m, 2H), 1.82 - 1.57 (m, 3H).

[0313] Example 14: Synthesis of compound 16

[0314] Step 1: Synthesis of compound 16

[0315] Compound 15-10 (40 mg) was dissolved in N,N-dimethylacetamide (3 mL) and added to the above reaction solution. The reaction was stirred at room temperature for 16 hours. LCMS detection showed that the reaction was completed. The reaction solution was added with water (20 mL), extracted with ethyl acetate (15 mL x 3), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and the target product was prepared by HPLC to obtain compound 16 (11.51 mg).

[0316] LCMS (ESI) [M+H] + = 502.3.

[0317] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (d, J = 65.3 Hz, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.38 (dd, J = 16.4, 7.6 Hz, 2H), 7.34 - 7.25 (m, 4H), 7.12 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (dd, J = 12.5, 8.4 Hz, 2H), 4.84 (d, J = 13.7 Hz, 1H), 4.72 (d, J = 9.5 Hz, 1H), 2.72 - 2.63 (m, 1H), 2.40 - 2.33 (m, 6H), 2.29 - 2.17 (m, 2H), 1.95 - 1.86 (m, 2H), 1.73 - 1.58 (m, 3H).

[0318] Example 15: Synthesis of compound 17

[0319] Step 1: Synthesis of compound 17

[0320] Compound 14-3 (116 mg) was dissolved in N,N-dimethylacetamide (3 mL) under argon protection, and sulfurous chloride (114 mg) was added. After stirring at room temperature for 1 hour, compound 15-10 (60 mg) was added. The reaction was stirred at room temperature overnight. The reaction was identified as complete by LCMS. The reaction solution was quenched with water (15 mL), filtered, extracted with ethyl acetate (15 mL x 2), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 17 (36.5 mg) was obtained by reverse phase preparative purification.

[0321] LCMS (ESI) [M+H] + = 556.2.

[0322] 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (d, J = 68.8 Hz, 1H), 7.93 (s, 1H), 7.89 - 7.82 (m, 1H), 7.80 - 7.75 (m, 1H), 7.69 (dd, J = 13.8, 7.5 Hz, 2H), 7.51 (d, J = 15.0 Hz, 1H), 7.27 (dd, J = 9.7, 5.3 Hz, 2H), 7.13 (dd, J = 8.3, 2.2 Hz, 1H), 6.83 (dd, J = 17.2, 8.3 Hz, 2H), 4.95 - 4.50 (m, 2H), 2.77 - 2.63 (m, 1H), 2.39 - 2.34 (m, 3H), 2.29 - 2.16 (m, 2H), 1.98 - 1.84 (m, 2H), 1.79 - 1.59 (m, 3H).

[0323] Example 16: Synthesis of compound 18

[0324] Step 1: Synthesis of compound 18

[0325] Compound 18 (19.84 mg) was obtained by the following procedure. 6-(2- methylbenzamido)nicotinic acid (40 mg) was placed in a three-necked flask at room temperature, replaced with nitrogen, N,N-dimethylacetamide (5 mL) was added, and thionyl chloride (68 mg) was added, and the reaction was allowed to proceed at room temperature for 1 hour. LCMS detection showed that the reaction was complete (a signal of methyl ester was sent with methanol). The reaction was not treated, and was directly subjected to the next reaction. Compound 15-10 (40 mg) was dissolved in N,N-dimethylacetamide (3 mL) and added to the above reaction solution, and the reaction was allowed to proceed at room temperature for 16 hours. LCMS detection showed that the reaction was complete. The reaction solution was added with water (20 mL), extracted with ethyl acetate (15 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the target product was obtained by preparation to obtain compound 18 (19.84 mg).

[0326] LCMS (ESI) [M+H] + = 489.2.

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.17 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 5.9 Hz, 2H), 7.26 (dd, J = 12.4, 7.4 Hz, 2H), 7.18 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 4.85 (dd, J = 45.1, 11.6 Hz, 2H), 2.67 (s, 1H), 2.35 (s, 3H), 2.31 - 2.16 (m, 2H), 1.96 - 1.84 (m, 2H), 1.82 - 1.56 (m, 3H).

[0328] Example 17: Synthesis of compound 19

[0329] Step 1: Synthesis of compound 19-2

[0330] Compound 19-1 (7.8 g) was dissolved in dichloromethane (200 mL), p-toluenesulfonyl chloride (24.57 g), pyridine (13.59 g) were added, and the mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction solution was washed with water (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (ethyl acetate / petroleum ether = 1 / 3) to give compound 19-2 (12 g).

[0331] LCMS (ESI) [M+H] + = 336.2.

[0332] Step 2: Synthesis of compound 19-3

[0333] Compound 19-2 (14 g) was dissolved in tetrahydrofuran (200 mL), (R)-(+)-tert- butylsulfinamide (6.06 g), tetraethyl titanate (19.02 g) were added, and the mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction solution was directly applied to a silica gel column (ethyl acetate / petroleum ether = 1 / 3) to give compound 19-3 (17 g).

[0334] LCMS (ESI) [M+H] + = 439.2.

[0335] Step 3: Synthesis of compound 19-4

[0336] Compound 19-3 (15 g) was dissolved in tetrahydrofuran (200 mL), allyl methyl carbonate (11.90 g), N,N-diisopropylethylamine (17.66 g), and tris(triphenylphosphine)palladium (3.95 g) were added, and the mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction solution was directly applied to a silica gel column (ethyl acetate / petroleum ether = 1 / 3) to give compound 19-4 (7.7 g).

[0337] LCMS (ESI) [M+H] + = 479.2.

[0338] Step 4: Synthesis of compound 19-5

[0339] Compound 19-4 (3.7 g) was dissolved in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 3 h after the addition of sodium borohydride (0.73 g) at -50 °C. LCMS showed the reaction was completed. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 19-5 (3.7 g).

[0340] LCMS (ESI) [M+H] = 481.2. + = 377.0.

[0341] Step 5: Synthesis of compound 19-6

[0342] Compound 19-5 (4 g) was dissolved in methanol (10 mL) at room temperature, 4M hydrochloric acid / methanol (10 mL) was added, and the reaction was allowed to proceed at room temperature for 1 hour. After drying, the crude compound 19-6 (4 g) was obtained.

[0343] LCMS (ESI) [M+H] = 377.0. + = 377.0.

[0344] Step 6: Synthesis of compound 19-7

[0345] Compound 19-6 (3.5 g) was dissolved in dichloromethane (50 mL) at room temperature, triethylamine (4.70 g), di-tert-butyl dicarbonate (2.43 g) were added, and the reaction was allowed to proceed at room temperature for 16 hours. Water (50 mL) was added, and the layers were separated. The organic phase was collected and dried by rotary evaporation. Purification by silica gel column (ethyl acetate / petroleum ether = 1 / 3) gave compound 19-7 (1.8 g).

[0346] LCMS (ESI) [M+H] = 477.0. + = 477.0.

[0347] Step 7: Synthesis of compound 19-8

[0348] Compound 19-7 (1.8 g) was dissolved in carbon tetrachloride (1 mL), acetonitrile (1 mL), water (1.5 mL) at room temperature, sodium periodate (5.81 g), ruthenium trichloride (39.14 mg) were added, and the reaction was allowed to proceed at room temperature for 16 hours. Water (10 mL), ethyl acetate (10 mL) were added, and the layers were separated. The organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. Purification by silica gel column (ethyl acetate / petroleum ether = 2 / 1) gave compound 19-8 (1.15 g).

[0349] LCMS (ESI) [M+H] = 494.8. + = 494.8.

[0350] Step 8: Synthesis of compound 19-9

[0351] Compound 19-8 (0.3 g) was dissolved in dichloromethane (3 mL) at room temperature, trifluoroacetic acid (3 mL) was added, and the reaction was allowed to proceed at room temperature for 1 hour. After direct drying, the crude compound 19-9 (0.3 g) was obtained.

[0352] LCMS (ESI) [M+H] = 395.0. + = 395.0.

[0353] Step 9: Synthesis of compound 19-10A and compound 19-10B

[0354] Compound 19-9 (0.4 g) was dissolved in dichloromethane (5 mL) at room temperature. N, N-diisopropylethylamine (654.61 mg), O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (1.15 g) were added. The reaction was stirred at room temperature for 1 hour. Water (10 mL), dichloromethane (10 mL) were added, the layers were separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column (ethyl acetate / petroleum ether = 1 / 1) to give compound 19-10A (0.28 g) and 19-10B (0.12 g).

[0355] LCMS (ESI) [M+H] + = 377.2 (19-10A); LCMS (ESI) [M+H] + = 377.2 (19-10B).

[0356] Step 10: Synthesis of compound 19-11

[0357] Compound 19-10A (278 mg) and polyphosphoric acid (5 mL) were added to a flask at room temperature, and the reaction was stirred at 95 °C for 5 hours. The reaction was cooled to room temperature, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate (20 mL), and the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether = 2 / 3) to give compound 19-11 (60 mg).

[0358] LCMS (ESI) [M+H] + = 222.8.

[0359] Step 11: Synthesis of compound 19

[0360] 6-(2-trifluoromethylbenzamido)nicotinic acid (70 mg) was dissolved in anhydrous dichloromethane (4 mL) at room temperature, and dichlorosulfoxide (107 mg) was added. The reaction was stirred at room temperature for 1 hour, and methanol was used for LC-MS monitoring. The crude acyl chloride was dissolved in anhydrous dichloromethane (4 mL), and methanol was used for monitoring again. No methyl ester signal was detected, and anhydrous pyridine (107 mg) and compound 19-11 (20 mg) were added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL). The organic phase was concentrated to give a crude product. The crude product was purified by HPLC to give compound 19 (16 mg).

[0361] LCMS (ESI) [M+H] = 515.2. + = 515.2.

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.69 (s, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.73 - 7.63 (m, 2H), 7.39 (s, 1H), 7.14 - 6.99 (m, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.48 (d, J = 10.4 Hz, 1H), 3.93 - 3.82 (m, 1H), 3.82 - 3.71 (m, 1H), 2.45 - 2.30 (m, 2H), 2.05 - 1.91 (m, 1H).

[0363] Example 18: Synthesis of compound 20

[0364] Step 1: Synthesis of compound 20

[0365] Compound 6-(2-methylbenzamide)nicotinic acid (72 mg) was dissolved in dry dichloromethane (4 mL) at room temperature, dichlorosulfoxide (134 mg) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by LCMS using methanol as the mobile phase, and a methyl ester signal was observed. The crude acyl chloride was concentrated. The crude product was dissolved in dry dichloromethane (4 mL), and again monitored by LCMS using methanol as the mobile phase. Compound 19-11 (25 mg) and dry pyridine (133 mg) were added, and the reaction was allowed to proceed at room temperature overnight. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL). The organic phase was concentrated to give the crude product. The crude product was purified by HPLC to give compound 20 (20 mg).

[0366] LCMS (ESI) [M+H] = 515.2. + = 515.2.

[0367] 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.69 (s, 1H), 8.19 (s, 1H), 8.13 (dd, J = 8.8, 2.0 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.31 - 7.23 (m, 2H), 7.12 - 7.03 (m, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.48 (d, J = 10.5 Hz, 1H), 3.93 - 3.82 (m, 1H), 3.82 - 3.70 (m, 1H), 2.47 - 2.39 (m, 2H), 2.38 (s, 3H), 2.04 - 1.94 (m, 1H).

[0368] Example 19: Synthesis of compound 21

[0369] Step 1: Synthesis of compound 21-1

[0370] Compound 19-10B (280 mg) was dissolved in polyphosphoric acid (5 mL) at room temperature, and after nitrogen replacement for 3 times, it was reacted at 95 °C for 3 hours. The reaction solution was cooled to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, extracted with ethyl acetate (10 mL), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether = 2 / 3) to give compound 21-1 (100 mg).

[0371] LCMS (ESI) [M+H] + = 222.8.

[0372] Step 2: Synthesis of compound 21

[0373] 6-(2-methylbenzamide)nicotinic acid (92 mg) was dissolved in anhydrous dichloromethane (5 mL) at room temperature, and dichlorosulfoxide (267 mg) was added, and it was reacted at room temperature for 1 hour. Methanol was used for LCMS monitoring, and the methyl ester signal was monitored, and the crude acyl chloride was concentrated. The crude product was dissolved in anhydrous dichloromethane (5 mL), and methanol was used for monitoring again, and the methyl ester signal was confirmed, and anhydrous pyridine (266 mg) and compound 21-1 (50 mg) were added, and it was reacted at room temperature overnight. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL), and the organic phase was concentrated to give a crude product. The crude product was purified by HPLC preparation to give compound 21 (60 mg).

[0374] LCMS (ESI) [M+H] + = 461.4.

[0375] LCMS (ESI) [M+H]1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.32 - 7.25 (m, 2H), 7.19 (d, J = 8.7 Hz, 1H), 6.93 (s, 1H), 4.86 (d, J = 8.2 Hz, 1H), 3.95 (d, J = 12.2 Hz, 1H), 3.59 (s, 1H), 3.10 (s, 1H), 2.61 - 2.54 (m, 1H), 2.38 (s, 3H), 2.01 (dd, J = 17.3, 4.6 Hz, 1H).

[0376] Example 20: Synthesis of compound 22

[0377] Step 1: Synthesis of compound 22

[0378] Dichlorosulfoxide (267 mg) was added to a solution of 6-(2-trifluoromethylbenzamido)nicotinic acid (111 mg) in anhydrous dichloromethane (5 mL) and the reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by LCMS using methanol as the solvent. The crude acyl chloride was obtained by concentration. The crude acyl chloride was dissolved in anhydrous dichloromethane (5 mL) and again monitored by LCMS using methanol as the solvent. Compound 21-1 (50 mg) and anhydrous pyridine (266 mg, 271.34 μL) were added to the reaction mixture and the reaction was allowed to proceed at room temperature overnight. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL). The organic phase was concentrated to give the crude product. The crude product was purified by HPLC to give compound 22 (45 mg).

[0379] LCMS (ESI) [M+H] = 515.4. +

[0380] 1 ​H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.33 (d, J = 9.6 Hz, 2H), 8.15 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.74 - 7.66 (m, 2H), 7.55 (s, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 4.85 (d, J = 8.1 Hz, 1H), 3.96 (d, J = 9.7 Hz, 1H), 3.57 (s, 1H), 3.10 (s, 1H), 2.57 (dd, J = 17.4, 9.7 Hz, 1H), 2.01 (dd, J = 17.2, 4.6 Hz, 1H).

[0381] Example 21: Synthesis of compound 23

[0382] Step 1: Synthesis of compound 23-2

[0383] Compound 23-1 (130 mg) was dissolved in acetonitrile (10 mL) at room temperature. Compound 11-1 (208 mg), N-methylimidazole (88 mg), N,N,N',N'-tetramethyluronium hexafluorophosphate (226 mg) were added. The reaction was stirred at room temperature for 3 hours. Water (30 mL), ethyl acetate (30 mL) were added. The organic phase was collected. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether = 3 / 1) to give compound 23-2 (60 mg).

[0384] LCMS (ESI) [M+H] + = 547.2.

[0385] Step 2: Synthesis of compound 23-3

[0386] Compound 23-2 (60 mg) was dissolved in ethyl acetate (5 mL) and water (5 mL) at room temperature. Ruthenium trichloride (3 mg), sodium periodate (94 mg) were added. The reaction was stirred at room temperature for 16 hours. The mixture was filtered. The filter cake was washed with ethyl acetate (30 mL). The filtrate was collected. The filtrate was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether = 1 / 1) to give compound 23-3 (15 mg).

[0387] LCMS (ESI) [M+H] + = 561.2.

[0388] Step 3: Synthesis of compound 23

[0389] Compound 23-3 (15 mg) was dissolved in hydrochloric acid / dioxane (5 mL) at room temperature, and the reaction was carried out at room temperature for 3 hours. The crude product was obtained by rotary evaporation. Compound 23 (4.5 mg) was obtained by HPLC preparation purification of the crude product.

[0390] LCMS (ESI) [M+H] + = 461.2.

[0391] 1 H NMR (400 MHz, Methanol-d4) δ 8.11 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.88 - 7.76 (m, 2H), 7.58 - 7.47 (m, 2H), 7.41 (dd, J = 8.4, 6.9 Hz, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.5, 2.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.99 (dd, J = 18.5, 11.4 Hz, 2H), 2.72 (dt, J = 14.0, 7.0 Hz, 1H), 2.47 (dd, J = 16.2, 7.8 Hz, 1H), 2.30 (dd, J = 16.2, 11.4 Hz, 1H), 2.17 (d, J = 8.3 Hz, 1H), 2.05 (d, J = 7.2 Hz, 2H).

[0392] Example 22: Synthesis of compound 24

[0393] Step 1: Synthesis of compound 24-2

[0394] Compound 24-1 (180 mg) was dissolved in acetonitrile (20 mL) at room temperature. Compound 11-1 (223 mg), N-methylimidazole (170 mg), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (291 mg) were added, and the reaction was carried out at 50 °C for 16 hours. Water (50 mL), ethyl acetate (50 mL) were added, the organic phase was collected by separation. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether = 3 / 1) to obtain compound 24-2 (240 mg).

[0395] LCMS (ESI) [M+H] + = 565.2.

[0396] Step 2: Synthesis of compound 24-3

[0397] Compound 24-2 (240 mg) was dissolved in ethyl acetate (10 mL) and water (10 mL) at room temperature. Ruthenium trichloride (9 mg), sodium periodate (363 mg) were added and the reaction was carried out at 50 °C for 16 hours. The mixture was filtered, the filter cake was washed with ethyl acetate (50 mL), and the filtrate was collected. The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether = 1 / 1) to give compound 24-3 (200 mg).

[0398] LCMS (ESI) [M+H] + = 579.2.

[0399] Step 3: Synthesis of compound 24

[0400] Compound 24-3 (200 mg) was dissolved in hydrochloric acid / dioxane (5 mL) at room temperature and the reaction was carried out at room temperature for 3 hours. The mixture was concentrated to give a crude product. The crude product was purified by HPLC to give compound 24 (54.6 mg).

[0401] LCMS (ESI) [M+H] + = 479.2.

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.17 (s, 1H), 8.08 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.63 - 7.54 (m, 1H), 7.39 (dd, J = 2.5, 0.8 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.96 (dd, J = 19.8, 11.1 Hz, 2H), 2.79 - 2.64 (m, 1H), 2.43 - 2.30 (m, 1H), 2.28 - 2.17 (m, 1H), 2.16 - 1.93 (m, 3H).

[0403] Example 23: Synthesis of compound 25

[0404] Step 1: Synthesis of compound 25-2

[0405] Compound 25-1 (250 mg) was dissolved in acetonitrile (30 mL) at room temperature. Compound 11-1 (350 mg), N-methylimidazole (222 mg), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (380 mg) were added, and the mixture was reacted at 50 °C for 3 hours. Water (50 mL) and ethyl acetate (50 mL) were added, and the organic phase was collected. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 1) to give compound 25-2 (400 mg).

[0406] LCMS (ESI) [M+H] + = 581.2.

[0407] Step 2: Synthesis of compound 25-3

[0408] Compound 25-2 (400 mg) was dissolved in ethyl acetate (10 mL) and water (10 mL) at room temperature. Ruthenium trichloride (14 mg) and sodium metaperiodate (588 mg) were added, and the mixture was reacted at 50 °C for 16 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was collected. The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 25-3 (60 mg).

[0409] LCMS (ESI) [M+H] + = 595.2.

[0410] Step 3: Synthesis of compound 25

[0411] Compound 25-3 (60 mg) was dissolved in hydrochloric acid / dioxane (5 mL) at room temperature, and the mixture was reacted at room temperature for 3 hours. The mixture was concentrated to give a crude product. The crude product was purified by HPLC preparative purification to give compound 25 (17 mg).

[0412] LCMS (ESI) [M+H] + = 495.2.

[0413] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.60 - 7.45 (m, 3H), 7.42 (dd, J = 7.4, 1.5 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.03 - 4.87 (m, 2H), 2.77 - 2.64 (m, 1H), 2.41 - 2.34 (m, 1H), 2.21 (dd, J = 15.8, 10.9 Hz, 1H), 2.15 - 1.94 (m, 3H).

[0414] Experimental Example 1: IC of compound on inhibition of vasopressin-induced activation of vasopressin receptor V2R 50 Test

[0415] (1) Cell

[0416] HeLa cell line stably expressing human vasopressin receptor V2R (HeLa-V2R): constructed by Shanghai Jikai Gene Chemical Technology Co., Ltd. using lentivirus infection method, and verified by qPCR to stably express human V2R.

[0417] (2) Reagent

[0418] DMEM cell culture medium: brand: Gibco, item number: 11995065; fetal bovine serum: brand: Gibco, item number: 10099-141C; 0.25% trypsin: brand: Gibco, item number: 25200072; Puromycin Dihydrochloride: brand: Gibco, item number: A1113803; cAMP-GS HIRANGE KIT: brand: Cisbio, item number: 62AM6PEB; IBMX: brand: Sigma, item number: i5879; vasopressin AVP: custom-made by Genview Biochemical (Shanghai) Co., Ltd.

[0419] (3) Test method

[0420] HeLa-V2R cells were incubated and cultured in DMEM medium added with 10% fetal bovine serum at 37°C, 5% CO2, and 2 μg / mL puromycin was added to the medium to continuously screen V2R-expressing cells. On the experimental day, the cells were trypsinized, washed twice with the stimulation buffer in the cAMP-GS HIRANGE kit, resuspended and counted, and then prepared into 1.6 x 105cells / mL for use. 6Cells were diluted to 1.5 x 105cells / ml, and IBMX was added to a final concentration of 0.5 mM. 5 μL of cell suspension was transferred to each well of a 384-well plate, and 2.5 μL of the test compound at different concentrations (10 μM with 3-fold dilution, 10 concentration points) or DMSO (minimum value Min, maximum value Max control) was added to the corresponding wells. After incubation at room temperature for 30 minutes, 2.5 μL of vasopressin AVP solution was added to the test compound wells and the maximum value wells to a final concentration of 2.25 nM, and 2.5 μL of stimulation buffer was added to the minimum value wells, and incubation was performed at 25°C for 60 minutes. At the same time, cAMP standard samples were prepared (3-fold dilution from 5.6 μM, 10 concentration points), and 10 μL of cAMP standard was transferred to the corresponding wells of a 384-well plate. The cAMP-d2 fluorescence and anti-cAMP antibody probes provided in the cAMP-GS HIRANGE kit were diluted 5-fold with lysis buffer in the kit, and 5 μL of each was sequentially added to each well of the 384-well plate. After mixing and simple centrifugation, incubation was performed at 25°C for 2 hours, and detection was performed. Sample detection was performed using the HTRF method in the Envision enzyme label instrument, and the fluorescence intensities at 615 nm and 665 nm were detected. Two replicate wells were prepared for each test sample, and 16 replicate wells were prepared for Min and Max.

[0421] (4) Data processing

[0422] The fluorescence intensity ratio FI of each well sample at 665 nm and 615 nm was calculated. 665 / 615 The standard curve was obtained by fitting the log of the standard sample concentration as X and FI 665 / 615 X1000 as Y in the Prism 8.0 software using the “log(inhibitor) vs response – variable slope (four parameters)” model. The FI 665 / 615 X1000 of the test well was taken as Y, and the cAMP concentration corresponding to each sample was calculated according to the above standard curve in the Prism 8.0 software.

[0423] The inhibition percentage was calculated according to the following formula:

[0424] wherein, is the average calculated value of the cAMP concentration in all maximum value wells; is the average calculated value of the cAMP concentration in all minimum value wells; and Ccmpd is the calculated value of the cAMP concentration of the test compound.

[0425] The IC50values were calculated by non-linear regression in Prism 8.0 software with the model of "log(inhibitor) vs response - variable slope (four parameters)", taking % Inhibition as Y value and the logarithm of compound concentration as X. 50 where Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 X) * Hill Slope)).

[0426] The experimental results are shown in Table 1, in which the IC 50 Classification is as follows: "+++++" represents IC 50 < 0.5 nM, "++++" represents 0.5 nM < IC 50 < 5 nM, "+++" represents 5 nM < IC 50 < 50 nM, "++" represents 50 nM < IC 50 < 500 nM, "+" represents 500 nM < IC 50 < 5 μM.

[0427] Table 1: Evaluation of compounds on the inhibition of cAMP increase in human cervical cancer cells (Human V2R Hela-Stable cell line OE2)

[0428] Experimental Example 2: Evaluation of the effect of compounds on the proliferation of porcine kidney epithelial cells LLC-PK1 using Alamarblue method

[0429] (1) Purpose of the experiment: The main purpose of this experiment is to test the effect of compounds on the proliferation of porcine kidney epithelial cells LLC-PK1, and to evaluate the potential of compounds to inhibit the proliferation of kidney epithelial cells in vitro.

[0430] (2) Reagents and consumables

[0431] The reagents and consumables used in this experiment are shown in Tables 2 and 3.

[0432] Table 2 Reagent and consumable information

[0433] Table 3 Cell line information

[0434] (3) Methods and procedures

[0435] Day 1 - Cell sample preparation

[0436] Cell plating: Coat 96-well plates with 0.01% Poly-D-lysine, adding 50 μL to each well. Incubate at room temperature for 10 min, then remove the coating and air-dry at room temperature for 2 h. When cells reach 80-90% confluence, digest with 0.25% Trypsin-EDTA for 5 min, terminate digestion with M199 complete cell culture medium, centrifuge at 1000 rpm for 5 min, and collect the cells. Resuspend the cells in fresh serum-free M199 medium, then count them using a cell counter, and prepare cell lines of 1×10⁶ cells / well. 5 A suspension of cells with a concentration of 1% (v / v) serum was prepared. 200 μL of this cell suspension was spread onto a 96-well plate, sealed with 200 μL of PBS, centrifuged at 1000 rpm for 1 min, and incubated overnight in a CO2 incubator to allow the cells to adhere.

[0437] Day 2 - Cell starvation and Verapamil treatment

[0438] After overnight cell culture, the supernatant was aspirated, and each well was washed once with 200 μL of PBS. After aspirating the supernatant, each well was then filled with 160 μL of M199 medium containing 0.05% FBS and 20 μL of M199 medium containing 50 μM Verapamil (0.05% FBS). Cells were centrifuged at 1000 rpm for 1 min and then incubated in a CO2 incubator for 24 h.

[0439] Day 3 - Compound and AVP1 Treatment

[0440] The test compound powder was dissolved in DMSO to prepare a 10 mM stock solution. The compound was then diluted from 10 mM to 1 mM with DMSO, followed by further dilution to 60 μM (20-fold concentration) with 0.05% FBS M199 medium. A three-fold serial dilution was performed using 0.05% FBS M199 medium containing 6% DMSO, for a total of eight dilutions. 10 μL of the solution was added to each well according to the layout. 10 μL of 0.05% FBS M199 medium containing 6% DMSO was added to each Min and Max well. A 20-fold concentration of AVP1 (0.2 μM) was prepared using 0.05% FBS M199 medium. Following the layout, 10 μL was added to the corresponding cell wells to achieve a final AVP1 concentration of 10 nM. Control wells without AVP1 were treated with 0.05% FBS M199 medium using the same procedure. The cell culture plates were then incubated in a CO2 incubator for 48 h.

[0441] Day 5 - Add Alamarblue to read fluorescence

[0442] Remove the 96-well plate from the incubator, aspirate the supernatant, add 90 μL of serum-free M199 medium and 10 μL of Alamarblue reagent to each well, centrifuge at 1000 rpm for 1 min, incubate in a CO2 incubator for 2 h, and then read the values ​​using SpectraMax i3x.

[0443] (4) Reading

[0444] SpectraMax i3x protocol settings

[0445] Fluorescence Lm1 560,595

[0446] Pattern:Fill

[0447] Density: 5

[0448] Spacing: 1.12mm

[0449] Total points: 21

[0450] Bandwidth:Excitation 9nm,Emission 15nm

[0451] 6Flashed / read

[0452] Read height: 3mm

[0453] (5) Data Analysis

[0454] Measured values: Fluorescence intensity readings of the compound wells

[0455] Maximum value (Min): Fluorescence intensity reading in wells without compound control (Max).

[0456] Minimum (Max): Fluorescence intensity readings from the control wells without AVP treatment (Min).

[0457] Background value: Fluorescence intensity readings from the control wells in the culture medium.

[0458] Normalized measured value: Measured value - Background value

[0459] Normalized maximum value: maximum value - background value

[0460] Normalized minimum: minimum value - background value

[0461] Inhibition rate % = [(Normalized maximum mean - Normalized measured value) / (Normalized maximum mean - Normalized minimum mean)] × 100

[0462] Half-maximal inhibitory concentration (IC50)50 )Nonlinear regression analysis was performed by GraphPad Prism with the following procedure:

[0463] log(inhibitor) vs. response - Variable slope: Y = Bottom + (Top-Bottom) / (1+10^((logIC 50 -X)*HillSlope)),

[0464] Where X: log value of inhibitor concentration; Y: % inhibition at corresponding concentration.

[0465] Table 4 IC of compounds 50

[0466] IC of compounds of the present application 50 The results are shown in Table 4. With compound 10A in PCT / CN2022 / 079350 as a control compound, the experimental results are shown in Figures 1 and 2. After treating LLC-PK1 cells with the compounds of the present application, the cell viability showed a dose-dependent trend of decrease, and the compounds of the present application had no hook effect, and the inhibition of AVP1-induced LLC-PK1 cell proliferation was stronger than that of the control compound, and the activity was more superior.

[0467] Experimental Example 3: Mouse pharmacokinetic test of compound 1 and compound 11

[0468] 1. Experimental purpose

[0469] Male ICR mice were used as test animals, and compound 1 and compound 11 were administered intravenously and orally, respectively. The drug concentration in the plasma at different times was determined by LC-MS / MS method to study the pharmacokinetic characteristics of the compounds of the present application and the comparative compound in mice.

[0470] 2. Experimental scheme

[0471] 2.1 Experimental drugs and animals

[0472] Experimental drugs: compound 1 and compound 11;

[0473] Animals: male SPF level ICR mice, 26-28g, purchased from Shanghai Shengkang Experimental Animal Co., Ltd.

[0474] 2.2 Drug preparation

[0475] Compound 1 and Compound 11 were weighed into a beaker, dissolved in DMSO, and made into a stock solution with a concentration of 4.0 mg / mL. Then, solutol was added, and the mixture was ultrasonicated for 2 min and vortexed for 2 min. Subsequently, saline was added, and the mixture was vortexed for 2 min and ultrasonicated for 2 min to obtain a colorless and clear intravenous administration solution with pH = 7 at a concentration of 0.2 mg / mL, which was used for the intravenous administration of animals in the 1 mpk intravenous administration group.

[0476] Compound 1 and Compound 11 were weighed into a beaker, dissolved in DMSO, and made into a stock solution with a concentration of 20.0 mg / mL. Then, solutol was added, and the mixture was ultrasonicated for 2 min and vortexed for 2 min. Subsequently, saline was added, and the mixture was vortexed for 2 min and ultrasonicated for 2 min to obtain a colorless and clear oral administration solution with pH = 7 at a concentration of 1.0 mg / mL, which was used for the oral administration of animals in the 10 mpk oral administration group.

[0477] 2.3 Administration

[0478] The mice in the intravenous administration group (n = 3) of the test compound were fasted overnight and then administered intravenously (dose 1.0 mg / kg, administration volume 5 mL / kg). The mice were fed 4 hours after administration.

[0479] The mice in the oral administration group (n = 3) of the test compound were fasted overnight and then administered orally (dose 10.0 mg / kg, administration volume 10 mL / kg). The mice were fed 4 hours after administration.

[0480] 3. Operation

[0481] Before administration and at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, 0.05 mL of blood was collected into a 1.5 mL EP tube containing sodium heparin. The collected whole blood was mixed by vortexing twice and placed on wet ice. Within 1 hour, the blood was centrifuged at 8000 rpm for 5 min at 4°C. The supernatant plasma was stored in a -80°C refrigerator until processing and analysis.

[0482] The content of the test compound in the plasma of the mice after oral administration was determined by LC-MS / MS.

[0483] 4. Pharmacokinetic parameter results

[0484] According to the calculated concentrations of the compound in the plasma at different time points, the pharmacokinetic parameters of Compound 1 and Compound 11 in mice were calculated using winnonlin software. The pharmacokinetic parameters of Compound 1 and Compound 11 of the present application are shown in Table 5.

[0485] Table 5: Pharmacokinetic parameters in mice

[0486] Formulation: 5% DMSO + 10% solutol + 85% saline

[0487] The above tests show that the compound of the present application has good exposure and pharmacokinetic characteristics in mice in vivo.

[0488] Experimental Example 4: Rat pharmacokinetic test of compound 1 and compound 11

[0489] 1. Experimental purpose

[0490] Male SD rats were used as test animals, and compound 1 and compound 11 were administered intravenously and orally, respectively. The drug concentration in the plasma at different times was determined by LC-MS / MS method to study the pharmacokinetic characteristics of the compound of the present application and the compound of the comparative example in mice in vivo.

[0491] 2. Experimental scheme

[0492] 2.1 Experimental drugs and animals

[0493] Experimental drugs: compound 1 and compound 11;

[0494] Animals: male SPF SD rats, 170-180 g, purchased from Shanghai Jihui Experimental Animal Co., Ltd.

[0495] 2.2 Drug preparation

[0496] An appropriate amount of compound 1 and compound 11 was weighed, dissolved with an appropriate amount of DMSO, and prepared into a stock solution with a concentration of 4.0 mg / mL. An appropriate amount of solutol was then added, ultrasonicated for 2 min, vortexed for 2 min, an appropriate amount of saline was then added, vortexed for 2 min, and ultrasonicated for 2 min to obtain a colorless and clear intravenous administration solution with pH = 7 at a concentration of 0.2 mg / mL, which was used for animal administration in the 1 mpk intravenous administration group.

[0497] An appropriate amount of compound 1 and compound 11 was weighed, dissolved with an appropriate amount of DMSO, and prepared into a stock solution with a concentration of 20.0 mg / mL. An appropriate amount of solutol was then added, ultrasonicated for 2 min, vortexed for 2 min, an appropriate amount of saline was then added, vortexed for 2 min, and ultrasonicated for 2 min to obtain a colorless and clear oral administration solution with pH = 7 at a concentration of 1.0 mg / mL, which was used for animal administration in the 10 mpk oral administration group.

[0498] 2.3 Drug administration

[0499] The mice in the intravenous administration group of the test compound (n = 3) were fasted overnight and then administered intravenously (dose 1.0 mg / kg, administration volume 5 mL / kg), and fed 4 hours after administration.

[0500] The mice in the test compound oral administration group (n=3) were orally administered (dose 10.0 mg / kg, administration volume 10 mL / kg) after overnight fasting, and were fed 4 hours after administration.

[0501] 3. Operation

[0502] 0.05 mL of blood was collected into a 1.5 mL EP tube containing sodium heparin before administration and at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. The collected whole blood was mixed by vortexing twice, placed on wet ice, and centrifuged at 8000 rpm for 5 min at 4°C within 1 h. The supernatant plasma was stored in a -80°C refrigerator until processing and analysis.

[0503] LC-MS / MS was used to determine the content of the test compound in the plasma of the mice after oral administration.

[0504] 4. Pharmacokinetic parameter results

[0505] According to the calculated concentrations of the compounds in the plasma at different time points, the pharmacokinetic parameters of compound 1 and compound 11 in mice were calculated using winnonlin software. The pharmacokinetic parameters of compound 1 and compound 11 of the present application are shown in Table 6.

[0506] Table 6: Rat pharmacokinetic parameters

[0507] Formulation: 5% DMSO + 10% solutol + 85% saline

[0508] The above tests show that the compounds of the present application have good exposure and pharmacokinetic characteristics in rats.

[0509] The above describes exemplary embodiments of the present application. It should be understood that the scope of protection of the present application is not limited to the above exemplary embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. The compound represented by formula (Ⅰ), its optical isomer, or its pharmacologically acceptable salt, in, X is selected from CR4R5 or NR6; Y is selected from O or S; Z is selected from O, S, or CR4R5; T1 and T2 are independently selected from N or CR. T ; Ring B is selected from C 6-20 Aryl or 5-20 heteroaryl, wherein C 6-20 Aryl groups and 5-20 heteroaryl groups are optionally capped with 1, 2, or 3 R groups. B replace; Ring C is selected from C 6-20 Aryl or 5-20 heteroaryl, wherein C 6-20 Aryl groups and 5-20 heteroaryl groups are optionally capped with 1, 2, or 3 R groups. C replace; R1, R2, R3, R4, R5, R6, R B R C Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 heteroaryl, wherein C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 heteroaryl groups may be substituted by 1, 2 or 3 Rs; R T Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl and C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs; Each time R appears, it is independently selected from H, F, Cl, Br, I, CN, OH, NH2, SF5, CHO, COOH, C 1-20 Alkyl or C 1-20 Heteroalkyl, the C 1-20 Alkyl and C 1-20 The heteroalkyl group may be optionally substituted with 1, 2 or 3 R's; Each occurrence of R' is independently selected from H, F, Cl, Br, I, CN, OH, NH2, or C. 1-6 alkyl; m1, m2, m3, n, and p are each independently selected from 0, 1, or 2; The above C 1-6 Heteroalkyl, C 1-20 Heteroalkyl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl contain 1, 2 or 3 heteroatoms independently selected from O, N and S or heteroatoms of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, S(=O)(=NH)-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-.

2. The compound according to claim 1, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, The structure of the compound shown in formula (Ⅰ) is shown in any one of formulas (Ⅱ-1) to (Ⅱ-3):

3. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R is independently selected from H, F, Cl, Br, I, CN, OH, NH2, SF5, CHO, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkylthio, -C 1-6 Alkyl-C 1-6 Alkylamino, C 1-6 Alkyl-OH, C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl or C 1-6 Alkyl-NH-S(=O)2-C 1-6 alkyl, The C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkylthio, -C 1-6 Alkyl-C 1-6 Alkylamino, C 1-6 Alkyl-OH, C 1-6 Alkyl group -NH2, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl and C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl groups may be optionally substituted with 1, 2 or 3 R's.

4. The compound according to claim 3, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R is independently selected from H, F, Cl, Br, I, CN, OH, NH2, SF5, CHO, COOH, CH3, C2H5, CF3, CHF2, CH2F, CF2Cl, CF2Br, CF2I, 5. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R B Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2 or 3 Rs.

6. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Ring B is selected from Y1 and Y2 are independently selected from N and CR, respectively. Y ; R Y Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl and C 1-6 The heteroalkyl group may be optionally substituted with 1, 2 or 3 Rs; m4 is selected from 0, 1, or 2.

7. The compound according to claim 6, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Ring B is selected from 8. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R C Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 The aryl and 5-12 heteroaryl groups may be optionally substituted with 1, 2 or 3 Rs.

9. The compound according to claim 8, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R C Each occurrence is independently selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, CH2F, Cyclopentyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, or thiopheneyl.

10. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, The ring C is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or thiophene, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, and thiophene groups are optionally surrounded by 1, 2, or 3 R groups. C replace.

11. The compound of claim 10, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Ring C is selected from 12. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Each occurrence of R3, R4, R5, and R6 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2 or 3 Rs.

13. The compound according to claim 12, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, R3, R4, R5, and R6 each appear independently selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, C2H5, CF3, CHF2, and CH2F, respectively.

14. The compound according to claim 1, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Structural unit Selected from 15. The compound according to claim 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Structural unit Selected from 16. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Each occurrence of R1 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2 or 3 Rs.

17. The compound according to any one of claims 1 to 2, its optical isomer, or a pharmacologically acceptable salt thereof, wherein, Each occurrence of R2 is independently selected from H, F, Cl, Br, I, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 The alkylamino group can be optionally substituted with 1, 2 or 3 Rs.

18. A compound of the following formula, its optical isomer, or a pharmacologically acceptable salt thereof, selected from...

19. The compound of claim 18, its optical isomer, or a pharmacologically acceptable salt thereof, wherein the compound is selected from...

20. A pharmaceutical composition, wherein, It includes the compound of any one of claims 1 to 19, its optical isomer, or a pharmaceutically acceptable salt thereof.

21. The use of the compound of any one of claims 1 to 19, its optical isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20 in the preparation of a medicament for the prevention or treatment of diseases related to the arginine vasopressin V2 receptor.

22. The application according to claim 21, wherein, The diseases associated with the arginine vasopressin V2 receptor include one or more of the following: hyponatremia, syndrome of abnormal antidiuretic hormone secretion, congestive heart failure, fluid retention, cardiac edema, hepatic edema, cirrhotic ascites, kidney disease, hypertension, and edema.

23. The use of the compound of any one of claims 1 to 19, its optical isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20 in the preparation of a medicament for the prevention or treatment of autosomal dominant polycystic kidney disease.

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