Substituted pyridazine derivatives and use thereof

Abstract

Provided in the present invention are a series of substituted pyridazine derivatives and the use thereof. Specifically provided are a compound as represented by formula (II) and a pharmaceutically acceptable salt thereof.

Description

Substituted pyridazine derivatives and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to the prior patent application filed with the China National Intellectual Property Office on September 30, 2024 (application number CN2024113812665) and the prior patent application filed with the China National Intellectual Property Office on June 13, 2025 (application number CN2025107987084), the contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present application relates to a series of substituted pyridazine derivatives and their applications, and specifically relates to a compound shown in formula (II), stereoisomers thereof and pharmaceutically acceptable salts thereof. BACKGROUND

[0004] Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) belongs to the NOD-like receptor (NLR) family, also known as NACHT, LRR and PYD domain-containing protein 3 (NLRP3), which is a pattern recognition receptor. It can recognize exogenous pathogens or endogenous tissue damage, so NLRP3 is an important molecule for regulating innate immunity. When pathogens such as bacteria and viruses infect or autologous tissue is damaged, NLRP3 recognizes the damage factor and forms a multi-protein complex, i.e. NLRP3 inflammasome, with linker protein ASC and protease caspase-1, etc. Then Caspase1 is activated. Activated Caspase1 promotes the maturation and release of IL-1β and IL-18, promotes inflammation, and degrades gasdermin D (GSDMD) to induce pyroptosis.

[0005] NLRP3 inflammasome can be activated by a variety of factors, in addition to exogenous bacterial virus infection, can also be activated by mitochondrial reactive oxygen, oxidized mitochondrial DNA, beta-amyloid or alpha-synuclein, hyperglycemia, saturated fatty acids, cholesterol crystals, uric acid crystals, etc. Therefore, NLRP3 inflammasome plays an important role in the occurrence and development of various diseases, such as obesity, type 2 diabetes, atherosclerosis, gout and other metabolic diseases, Alzheimer's disease, Parkinson's syndrome, multiple sclerosis and other neurodegenerative diseases, and various tumors. NLRP3 inflammasome is also involved in various autoimmune diseases, such as arthritis, colitis, schnitzler syndrome, cold porphyrin-related periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold syndrome (FCAS), chronic infantile neurocutaneous articular disease (CINCA) syndrome, neonatal multiple system inflammation (NOMID) and hereditary keratitis and other diseases. Therefore, inhibiting NLRP3 has the potential to treat a variety of diseases.

[0006] At present, there are various NLRP3 inhibitors in the clinical or preclinical research stage, such as MCC-950, DFV890, ZYIL1, OLT117, VTX3232, NT-0796, VENT01, VENT-02, etc., but there is no NLRP3 inhibitor approved for marketing. Therefore, it is of important clinical value and wide application prospect to develop a class of specific NLRP3 inhibitors with good brain entry for treating central nervous system inflammation-related diseases, obesity, etc. SUMMARY

[0007] The present application provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0008] wherein,

[0009] T1 and T2 are independently selected from C and N;

[0010] R 12 is selected from H, -CHO, -CO-R 1b , -SO-R 1b , -SO2-R 1b and the following groups optionally substituted by 1 or more R 1a : C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-4 alkyl-CN;

[0011] R 32 and R 42are each independently selected from the group consisting of H, D, F, CI, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R 3b substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein, when T1is N, R 42 is absent, when T2is N, R 32 is absent;

[0012] or, R 32 and R 42 together with the atom to which they are attached form a group selected from C 3c substituted C 5-12 cycloalkyl, 5-12 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0013] R5is selected from H and the following groups optionally substituted with 1 or more R 5a substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0014] Ring A2is selected from the following groups optionally substituted with 1 or more R a2 substituted C 3-10 cycloalkenyl and 3-10 membered heterocycloalkenyl;

[0015] each R 1a are each independently selected from the group consisting of H, D, F, CI, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and -COC 1-4 alkyl;

[0016] R 1b is selected from the following groups optionally substituted with 1 or more R 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4alkyl, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0017] each R 3b , each R 3c , each R 5a , each R a2 and each R b is independently selected from H, D, F, Cl, Br, I, =0, OH, NH2, CN, SF5 and an optionally R 1-4 substituted group selected from alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1- alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0018] or 2 R 3b , together with the atom to which they are attached, or 2 R 3c , together with the atom to which they are attached, or 2 R a2 , together with the atom to which they are attached, or 2 R b , together with the atom to which they are attached, are independently formed from an optionally R 3-6 substituted group selected from cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0019] each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN and an optionally F 1-4 substituted group selected from alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy.

[0020] The present application also provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0021] wherein,

[0022] T1and T2are independently selected from C and N;

[0023] R 12 is selected from -CO-R 1b , -SO-R 1b , -SO2-R 1b and an optionally R 1a substituted group selected from C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C2-4 alkenyl, C 2-4 alkynyl group, -C 1-4 Alkyl-CN;

[0024] R 32 and R 42 Each is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and optionally labeled with one or more R. 3b The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein, when T1 is N, R 42 It does not exist when T2 is N, R 32 It does not exist;

[0025] Or, R 32 and R 42 The atoms connected to them together form an array optionally bounded by one or more R atoms. 3c The following groups are substituted: C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0026] R5 is selected from H and is arbitrarily chosen by one or more Rs. 5a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0027] Ring A2 is selected from one or more R. a2 The following groups are substituted: C 3-10 Cycloalkenyl and 3-10 membered heterocyclic alkenyl groups;

[0028] Each R 1a The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -COC 1-4 alkyl;

[0029] R1b is selected from the group consisting of optionally substituted by 1 or more R: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0030] each R 3b , each R 3c , each R 5a , each R a2 and each R b is independently selected from the group consisting of H, D, F, Cl, Br, I, =0, OH, NH2, CN, SF5, and the following groups optionally substituted by 1 or more R: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1- 4alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0031] or 2 R 3b together with the atom to which they are attached, or 2 R 3c together with the atom to which they are attached, or 2 R a2 together with the atom to which they are attached, or 2 R b together with the atom to which they are attached, independently form the following groups optionally substituted by 1 or more R: C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0032] each R is independently selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted by 1 or more F: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy.

[0033] In some embodiments of the application, in the above formula (II), each R is independently selected from the group consisting of H, D, F, Cl, OH, NH2, CN, and the following groups optionally substituted by 1 or more F: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, and OC(CH3)2, and the other variables are as defined in the application.

[0034] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CI, OH, NH2, CN, CH3, and CF3, and the other variables are as defined in the application.

[0035] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CI, CN, and the following groups optionally substituted with 1, 2, or 3 F or D: C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl, and the other variables are as defined in the application.

[0036] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CI, OH, NH2, CN, and the following groups optionally substituted with 1 or more F or D: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, and OC(CH3)2, and the other variables are as defined in the application.

[0037] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CI, OH, NH2, CN, CH3, CD3, and CF3, and the other variables are as defined in the application.

[0038] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CI, CN, and the following groups optionally substituted with 1, 2, or 3 F or D: methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the other variables are as defined in the application.

[0039] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CI, CN, and the following groups optionally substituted with 1, 2, or 3 F or D: methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the other variables are as defined in the application.

[0040] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CH3, CD3, and CF3, and the other variables are as defined in the application.

[0041] In some embodiments of the application, each R in the above formula (II) is independently selected from H, D, F, CH3, CD3, and CF3, and the other variables are as defined in the application. 3b , each R 3c , each R 5a , each R a2 , and each R bare each independently selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3, and cyclopropyl, and the other variables are as defined herein.

[0042] In some embodiments of the application, in the above formula (II), each R 3b is independently selected from the group consisting of H, D, F, Cl, CH3, CD3, CF3, CN, 3c is independently selected from the group consisting of H, D, F, Cl, CH3, CD3, CF3, CN, 5a is independently selected from the group consisting of H, D, F, Cl, CH3, CD3, CF3, CN, a2 is independently selected from the group consisting of H, D, F, Cl, CH3, CD3, CF3, CN, b and each R is independently selected from the group consisting of H, D, F, Cl, CH3, CD3, CF3, CN, and the other variables are as defined herein.

[0043] In some embodiments of the application, in the above formula (II), each R b is independently selected from the group consisting of H, D, F, Cl, Br, I, CN, and the following groups optionally substituted with 1 or more R: C 1-3 alkyl, C 1-3 alkoxy, and C 3-6 cycloalkyl, and the other variables are as defined herein.

[0044] In some embodiments of the application, in the above formula (II), each R b is independently selected from the group consisting of H, D, F, Cl, Br, I, CN, and the following groups optionally substituted with 1 or more R: methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the other variables are as defined herein.

[0045] In some embodiments of the application, in the above formula (II), each R b is independently selected from the group consisting of H, D, F, Cl, CN, CH3, CD3, and CF3, and the other variables are as defined herein.

[0046] In some embodiments of the application, in the above formula (II), each R b is independently selected from the group consisting of H, D, F, Cl, CH3, and CF3, and the other variables are as defined herein.

[0047] In some embodiments of the application, in the above formula (II), 2 R 3c together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with 1 or more R, and the other variables are as defined herein.

[0048] In some embodiments of the application, in the above formula (II), 2 R a2 together with the atom to which they are attached form a C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, and the other variables are as defined in the application.

[0049] In some embodiments of the application, in the above formula (II), each R b together with the atom to which they are attached form a cyclopropyl group, and the other variables are as defined in the application. 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, and the other variables are as defined in the application.

[0050] In some embodiments of the application, in the above formula (II), each R b together with the atom to which they are attached form a cyclopropyl group, and the other variables are as defined in the application.

[0051] In some embodiments of the application, in the above formula (II), each R 1a are each independently selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted with one or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3, cyclopropyl, -COCH3, and -COCH2CH3, and the other variables are as defined in the application.

[0052] In some embodiments of the application, in the above formula (II), each R 1a are each independently selected from the group consisting of H, D, F, Cl, CN, CH3, CD3, CFH2, CF2H, CF3, CH2CH3, CH2CF3, OCH3, OCF3, OCD3, and OCH2CH3, and the other variables are as defined in the application.

[0053] In some embodiments of the application, in the above formula (II), each R 1a are each independently selected from the group consisting of H, D, F, Cl, CN, CH3, CD3, and CF3, and the other variables are as defined in the application.

[0054] In some embodiments of the application, in the above formula (II), R 1b is selected from the group consisting of CH3, CH2CH3, OCH3, OCH2CH3, and the other variables are as defined in the application.

[0055] In some embodiments of the application, in the above formula (II), R 1b is selected from the group consisting of CH3, CD3, CF3, OCH3, and OCH2CH3, and the other variables are as defined in the application.

[0056] In some embodiments of the application, in the above formula (II), R5is selected from H, and the other variables are as defined in the application.

[0057] In some embodiments of the application, in the above formula (II), R 12 is selected from H and -CHO, and the other variables are as defined in the application.

[0058] In some embodiments of the application, in the above formula (II), R 12 is H, and the other variables are as defined in the application.

[0059] In some embodiments of the application, in the above formula (II), R 12 is selected from H, -CHO and the following groups optionally substituted with 1 or more R 1a cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, oxetanyl, -CH2CN, -CH2CH2CN, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, COCH3, COCH2CH3, COOCH3, and COOCH2CH3, and the other variables are as defined in the application.

[0060] In some embodiments of the application, in the above formula (II), R 12 is selected from the following groups optionally substituted with 1 or more R 1a cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, oxetanyl, -CH2CN, -CH2CH2CN, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, COCH3, COCH2CH3, COOCH3, and COOCH2CH3, and the other variables are as defined in the application.

[0061] In some embodiments of the application, in the above formula (II), R 12 is selected from the following groups optionally substituted with 1 or more R 1a cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, oxetanyl, -CH2CN, -CH2CH2CN, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, COCH3, COCH2CH3, COOCH3, and COOCH2CH3, and the other variables are as defined in the application. -CH2CN, -CF2CN, COOCH3, COOCH2CH3, COCH3, COCF3, and the other variables are as defined in the application.

[0062] In some embodiments of the application, in the above formula (II), R 12 is selected from -CH2CN, -CF2CN, COOCH3, COOCH2CH3, COCH3and COCF3, and the other variables are as defined in the application.

[0063] In some embodiments of the application, in the above formula (II), R 12 is selected from the group consisting of C 1a substituted with 1 or more R 3-8 cycloalkyl, 3-8 membered heterocycloalkyl and -C 1-4 alkyl-CN, and the other variables are as defined in the application.

[0064] In some embodiments of the application, in the above formula (II), R 12 is selected from the group consisting of C 1a substituted with 1 or more R 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and -C 1-4 alkyl-CN, and the other variables are as defined in the application.

[0065] In some embodiments of the application, in the above formula (II), R 12 is selected from the group consisting of -CH2CN, -CF2CN, and the other variables are as defined in the application.

[0066] In some embodiments of the application, in the above formula (II), R 12 is selected from the group consisting of C 1a substituted with 1 or more R 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, and the other variables are as defined in the application.

[0067] In some embodiments of the application, in the above formula (II), R 12 is selected from the group consisting of C 1a substituted with 1 or more R 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, and the other variables are as defined in the application.

[0068] In some embodiments of the application, in the above formula (II), R 12 is selected from the group consisting of C 1a substituted with 1 or more R 3-6 cycloalkyl, and the other variables are as defined in the application.

[0069] In some embodiments of the application, in the above formula (II), R 12 is selected from the group consisting of C 1asubstituted 3-6 membered heterocycloalkyl, other variables being as defined in the present invention.

[0070] In some embodiments of the present invention, in the above formula (II), R 12 is selected from -CH2CN, -CF2CN, 1a substituted -C 1-4 alkyl-CN, other variables being as defined in the present invention.

[0071] In some embodiments of the present invention, in the above formula (II), R 12 is selected from -CH2CN, -CF2CN, 1a substituted -C 1-2 alkyl-CN, other variables being as defined in the present invention.

[0072] In some embodiments of the present invention, in the above formula (II), R 12 is selected from -CH2CN, other variables being as defined in the present invention. 1-2 alkyl-CN, other variables being as defined in the present invention.

[0073] In some embodiments of the present invention, in the above formula (II), R 12 is selected from other variables being as defined in the present invention.

[0074] In some embodiments of the present invention, in the above formula (II), R 12 is selected from -CH2CN, -CF2CN, other variables being as defined in the present invention.

[0075] In some embodiments of the present invention, in the above formula (II), R 12 is selected from -CH2CN, -CF2CN, other variables being as defined in the present invention.

[0076] In some embodiments of the present invention, in the above formula (II), R 12 is selected from -CH2CN, other variables being as defined in the present invention.

[0077] In some embodiments of the present invention, in the above formula (II), R 32 and R 42 are each independently selected from H, D, F, Cl, Br, I, OH, NH2, CN and optionally substituted alkyl, other variables being as defined in the present invention. 3bThe following groups may be substituted: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, and aziridine, with other variables as defined in this invention.

[0078] In some technical solutions of the present invention, in formula (II) above, R 32 For H or D, R 42 For H, D, or any of 1, 2, or 3 Rs 3b Replacement C 1-4 Alkyl groups, and other variables as defined in this invention.

[0079] In some technical solutions of the present invention, in formula (II) above, R 32 For H or D, R 42 It can be H, D, CH3, CD3 or CF3, and other variables are as defined in this invention.

[0080] In some technical solutions of the present invention, in formula (II) above, R 32 and R 42 The atoms connected to them together form an array optionally bounded by one or more R atoms. 3c The following groups may be substituted: cyclopentyl, cyclopentenyl, phenyl, and pyridyl, with other variables as defined in this invention.

[0081] In some technical solutions of the present invention, in formula (II) above, R 32 and R 42 The atoms attached to them together form cyclopentyl, cyclopentenyl, or pyridyl groups, with other variables as defined in this invention.

[0082] In some technical solutions of the present invention, in formula (II) above, R 32 and R 42 The atoms bonded to them together form cyclopentyl groups, and other variables are as defined in this invention.

[0083] In some technical solutions of the present invention, in the above formula (II), the structural unit Selected from R 42 Selected from H, D, and C, which may be replaced by one or more F or D. 1-3 Alkyl groups, and other variables as defined in this invention.

[0084] In some technical solutions of the present invention, in the above formula (II), the structural unit Selected from The other variables are as defined in the application.

[0085] In some embodiments of the application in the above formula (II), the structural unit is selected from The other variables are as defined in the application.

[0086] In some embodiments of the application in the above formula (II), the structural unit is selected from The other variables are as defined in the application.

[0087] In some embodiments of the application in the above formula (II), ring A2 is selected from 3-10 membered bridged heterocycloalkenyl, and the other variables are as defined in the application. a2 substituted 3-10 membered heterocycloalkenyl, and the other variables are as defined in the application.

[0088] In some embodiments of the application in the above formula (II), ring A2 is selected from 3-10 membered bridged heterocycloalkenyl, and the other variables are as defined in the application.

[0089] In some embodiments of the application in the above formula (II), ring A2 is selected from 6-10 membered bridged heterocycloalkenyl, and the other variables are as defined in the application. a2 substituted 6-10 membered heterocycloalkenyl, and the other variables are as defined in the application.

[0090] In some embodiments of the application in the above formula (II), ring A2 is selected from 6-10 membered bridged heterocycloalkenyl, and the other variables are as defined in the application.

[0091] In some embodiments of the application in the above formula (II), the structural unit is selected from The other variables are as defined in the application.

[0092] In some embodiments of the application in the above formula (II), the structural unit is selected from The other variables are as defined in the application.

[0093] In some embodiments of the application in the above formula (II), the structural unit is selected from The other variables are as defined in the application.

[0094] In some embodiments of the application in the above formula (II), the structural unit Selected from Other variables are as defined in this invention.

[0095] In some technical solutions of this invention, the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from:

[0096] Among them, rings A2 and R b R 42 R 32 R 12 As defined in this invention.

[0097] In some technical solutions of this invention, the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from:

[0098] in,

[0099] Ring A2 is selected from one or more R. a2 Substituted 6-10 membered heterocyclic alkenyl groups;

[0100] R b Selected from H, D, F, Cl, Br, I, CN and the following groups optionally substituted with one or more R: C 1-3 Alkyl, C 1-4 Alkoxy and C 3-6 cycloalkyl;

[0101] R 42 Selected from H, D, F, Cl and optionally by one or more R 3b Replacement C 1-4 alkyl;

[0102] R 32 Selected from H and D;

[0103] R 12 Selected from one or more R 1a The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl and -C 1-4 Alkyl-CN;

[0104] Each R a2 Each R 3b Each R 1a Each R is as defined in this invention.

[0105] In some technical solutions of this invention, the compound of formula (II-1), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0106] in,

[0107] Ring A2 is selected from one or more R. a2 Substituted 3-10-membered heterocyclic alkenyl groups; further, cyclic A2 is selected from 6-10-membered heterocyclic alkenyl groups; even further, cyclic A2 is selected from 6-10-membered bridged heterocyclic alkenyl groups;

[0108] Each R b The following groups are selected independently from H, D, F, Cl, Br, I, CN, and optionally substituted with one or more R groups: C 1-3 Alkyl, C 1- 3-alkoxy and C 3-6 Cycloalkyl; furthermore, each R b They were independently selected from H, D, F, Cl, CN, CH3, CD3, and CF3, respectively;

[0109] R 12 Selected from H and arbitrarily selected by one or more R 1a The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl and -C 1-4 Alkyl-CN;

[0110] R 32 Selected from H and D;

[0111] R 42 Selected from H, D, F, Cl and optionally by one or more R 3b Replacement C 1-4 Alkyl; further, R 42 Selected from H, D, CH3, CD3 or CF3;

[0112] Each R a2 Each R 3b Each of the following is independently selected from H, D, F, Cl, Br, I, and CH3;

[0113] Each R 1a They were independently selected from H, D, F, Cl, CN, CH3, CD3, and CF3, respectively;

[0114] Each R is independently selected from H, D, F, Cl, CN and methyl groups optionally substituted by one, two or three F or D; furthermore, each R is independently selected from H, D, F, CH3, CD3 and CF3.

[0115] In some technical solutions of this invention, the compound of formula (II-1), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0116] Among them, rings A2 and R b R 42 R32 , R 12 as defined in the present application.

[0117] In some embodiments of the present application, the compound of formula (II), (II-1), (II-1-1) or (II-1-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is as defined above, wherein ring A2 is selected from a 3-10 membered bridged cycloalkenyl optionally substituted with 1 or more R a2 substituted 3-10 membered bridged cycloalkenyl, and other variables are as defined in the present application.

[0118] In some embodiments of the present application, the compound of formula (II), (II-1), (II-1-1) or (II-1-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is as defined above, wherein ring A2 is selected from a 3-10 membered bridged cycloalkenyl optionally substituted with 1 or more R a2 substituted 3-10 membered bridged cycloalkenyl, and other variables are as defined in the present application.

[0119] In some embodiments of the present application, the compound of formula (II), (II-1), (II-1-1) or (II-1-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is as defined above, wherein ring A2 is selected from

[0120] In some embodiments of the present application, the compound of formula (II), (II-1), (II-1-1) or (II-1-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is as defined above, wherein ring A2 is selected from 1 is linked to R 12 , and other variables are as defined in the present application.

[0121] In some embodiments of the present application, the compound of formula (II), (II-1), (II-1-1) or (II-1-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0122] wherein R b , R 42 , R 32 and R 12 are as defined in the present application.

[0123] The present application also provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0124] wherein,

[0125] T1 and T2 are each independently selected from C and N;

[0126] L1 is selected from -C 0-4 ​​Alkyl-NR5-, -C 0-4 Alkyl-O-, -C 0-4 Alkyl-S-, -C 0-4 Alkyl-CONR5- and -C 0-4 Alkyl-NR5CO-;

[0127] R1 is selected from H and R 12 ;

[0128] R 12 Selected from one or more R 1a Substituted groups include: 4-10 membered heterocyclic alkyl groups, C 2-4 alkenyl, C 2-4 alkynyl group and -C 1-4 Alkyl-CN and -C 3-6 cycloalkyl-CN;

[0129] R2 is selected from H, D, OH, NH2, CN, and optionally one or more R 2a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0130] R3 is R 31 R4 is R 41 ;

[0131] R 31 and R 41 The atoms connected to them together form an array optionally bounded by one or more R atoms. 3a The following groups are substituted: C 6-12 Bicyclic spirocycloalkyl or 6-12 membered bicyclic spiroheterocycloalkyl;

[0132] Or, R3 is R 32 R4 is R 42 ;

[0133] R 32 and R 42 Each is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and optionally labeled with one or more R. 3b The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0134] Or, R 32 and R 42 The atoms connected to them together form an array optionally bounded by one or more R atoms. 3c The following groups are substituted: C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0135] R5 is selected from H and is arbitrarily chosen by one or more Rs. 5a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0136] Ring A is selected from ring A1 and ring A2;

[0137] Ring A1 is selected from one or more Rs. a1 The following groups are substituted: phenyl, naphthyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic alkyl groups;

[0138] Ring A2 is selected from one or more R. a2 The following groups are substituted: C 3-10 Cycloalkenyl and 3-10 membered heterocyclic alkenyl groups;

[0139] Ring B is selected from one or more R. b The following groups are substituted: phenyl, naphthyl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic alkyl groups;

[0140] Each R 1a Each R 2a Each R 3a Each R 3b Each R 3c Each R 5a Each R a1 Each R a2 and each R b The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1- 4-alkoxy group, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0141] or 2 R 3a together with the atom to which they are attached, or 2 R 3b together with the atom to which they are attached, or 2 R 3c together with the atom to which they are attached, or 2 R a1 together with the atom to which they are attached, or 2 R a2 together with the atom to which they are attached, or 2 R b together with the atom to which they are attached, each independently form an optionally substituted group selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0142] each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN and an optionally F-substituted group selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3and OC(CH3)2; 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy;

[0143] provided that,

[0144] (1) when R3is R 31 , R4is R 41 , ring A is ring A1;

[0145] (2) when R3is R 32 , R4is R 42 , ring A is ring A2, and R1is R 12 .

[0146] In some embodiments of the application, in the above formula (I) or (II), each R is independently selected from H, D, F, Cl, OH, NH2, CN, CH3and CF3, and the other variables are as defined in the application.

[0147] In some embodiments of the application, in the above formula (I) or (II), each R is independently selected from H, D, F, Cl, OH, NH2, CN, CH3and CF3, and the other variables are as defined in the application.

[0148] In some embodiments of the application, in the above formula (I), each R 1a , each R 2a , each R 3a , each R 3b , each R 3c , each R5a each R a1 each R a2 and each R b is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3, and cyclopropyl, with the other variables as defined herein.

[0149] In some embodiments of the application, in the above formula (I), each R 1a each R 2a each R 3a each R 3b each R 3c each R 5a each R a1 each R a2 each R b is independently selected from H, D, F, Cl, CH3, CF3, and cyclopropyl, with the other variables as defined herein.

[0150] In some embodiments of the application, in the above formula (I) or (II), each R 1a is independently selected from H, D, F, Cl, CH3, and CF3, with the other variables as defined herein.

[0151] In some embodiments of the application, in the above formula (I), each R 2a is independently selected from H, D, F, Cl, CH3, and CF3, with the other variables as defined herein.

[0152] In some embodiments of the application, in the above formula (I), each R 3a is independently selected from H, D, F, Cl, CH3, and CF3, with the other variables as defined herein.

[0153] In some embodiments of the application, in the above formula (I), 2 R 3a together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with 1 or more R, with the other variables as defined herein.

[0154] In some embodiments of the application, in the above formula (I) or (II), each R 3b is independently selected from H, D, F, Cl, CH3, and CF3, with the other variables as defined herein.

[0155] In some embodiments of the application, in the above formula (I) or (II), each R 3care each independently selected from H, D, F, CI, CH3, and CF3, and the other variables are as defined in the application.

[0156] In some embodiments of the application, in the above formula (I) or (II), 2 R 3c together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, and the other variables are as defined in the application.

[0157] In some embodiments of the application, in the above formula (I) or (II), each R 5a are each independently selected from H, D, F, CI, CH3, and CF3, and the other variables are as defined in the application.

[0158] In some embodiments of the application, in the above formula (I), each R a1 are each independently selected from H, D, F, CI, CH3, and CF3, and the other variables are as defined in the application.

[0159] In some embodiments of the application, in the above formula (I) or (II), each R a2 are each independently selected from H, D, F, CI, CH3, and CF3, and the other variables are as defined in the application.

[0160] In some embodiments of the application, in the above formula (I) or (II), each R b are each independently selected from H, D, F, CI, CH3, and CF3, and the other variables are as defined in the application.

[0161] In some embodiments of the application, in the above formula (I) or (II), 2 R b together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, and the other variables are as defined in the application.

[0162] In some embodiments of the application, in the above formula (I) or (II), 2 R b together with the atom to which they are attached form a cyclopropyl group, and the other variables are as defined in the application.

[0163] In some embodiments of the application, in the above formula (I), L1is selected from NH, and the other variables are as defined in the application.

[0164] In some embodiments of the application, in the above formula (I) or (II), R 12 is selected from optionally substituted by 1 or more R 1asubstituted azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, -CH2CN, -CH2CH2CN, and -cyclopropyl-CN, and the other variables are as defined in the application.

[0165] In some embodiments of the application, in the above formula (I) or (II), R 12 is selected from -CH2CN, -CF2CN, and the other variables are as defined in the application.

[0166] In some embodiments of the application, in the above formula (I), R2is selected from H, D, OH, NH2, CN, and optionally substituted 2a CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl, and the other variables are as defined in the application.

[0167] In some embodiments of the application, in the above formula (I), R2is selected from OH and NH2, and the other variables are as defined in the application.

[0168] In some embodiments of the application, in the above formula (I), R2is selected from OH, and the other variables are as defined in the application.

[0169] In some embodiments of the application, in the above formula (I), R2is selected from NH2, and the other variables are as defined in the application.

[0170] In some embodiments of the application, in the above formula (I), R3is R 31 , R4is R 41 , R 31 and R 41 together with the atom to which they are attached form an optionally substituted 3a group: and the other variables are as defined in the application.

[0171] In some embodiments of the application, in the above formula (I), R3is R 31 , R4is R 41 , and R 31 and R 41 together with the atom to which they are attached form and the other variables are as defined in the application.

[0172] In some embodiments of the application, in the above formula (I), R3is R 32 , R4is R 42 , R 32 and R 42 are each independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R 3b : CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl, and the other variables are as defined in the application.

[0173] In some embodiments of the application, in the above formula (I), R3is R 32 , R4is R 42 , R 32 is H or D, and R 42 is C 3b alkyl optionally substituted with 1, 2, or 3 R 1-4 , and the other variables are as defined in the application.

[0174] In some embodiments of the application, in the above formula (I), R3is R 32 , R4is R 42 , R 32 is H or D, and R 42 is CH3, CD3, or CF3, and the other variables are as defined in the application.

[0175] In some embodiments of the application, in the above formula (I), R3is R 32 , R4is R 42 , and R 32 and R 42 , together with the atom to which they are attached, form a group selected from cyclopentyl, cyclopentenyl, phenyl, and pyridyl optionally substituted with 1 or more R 3c , and the other variables are as defined in the application.

[0176] In some embodiments of the application, in the above formula (I), R3is R 32 , R4is R 42 , and R 32 and R 42 , together with the atom to which they are attached, form a group selected from cyclopentyl, cyclopentenyl, and pyridyl, and the other variables are as defined in the application.

[0177] In some embodiments of the application, in the above formula (I), R3is R 32R4is R 42 R4is R 32 R4is R 42 and R

[0178] In some embodiments of the application, in the above formula (I), the structural unit is selected from and the other variables are as defined in the application.

[0179] In some embodiments of the application, in the above formula (I), the structural unit is selected from and the other variables are as defined in the application.

[0180] In some embodiments of the application, in the above formula (I), the structural unit is selected from and the other variables are as defined in the application.

[0181] In some embodiments of the application, in the above formula (I), ring A is selected from ring A1, and ring A1 is selected from C a cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with 1 or more R 3-10 and the other variables are as defined in the application.

[0182] In some embodiments of the application, in the above formula (I), ring A1 is selected from 3-10 membered heterocycloalkyl optionally substituted with 1 or more R a and the other variables are as defined in the application.

[0183] In some embodiments of the application, in the above formula (I), the structural unit is selected from and the other variables are as defined in the application. is selected from and the other variables are as defined in the application.

[0184] In some embodiments of the application, in the above formula (I), ring A is selected from ring A2, and ring A2 is selected from 3-10 membered heterocycloalkenyl optionally substituted with 1 or more R a2 and the other variables are as defined in the application.

[0185] In some embodiments of the application, in the above formula (I), ring A is selected from ring A2, and ring A2 is selected from 6-10 membered heterocycloalkenyl optionally substituted with 1 or more R a2 and the other variables are as defined in the application.

[0186] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from The Selected from Other variables are as defined in this invention.

[0187] In some technical solutions of the present invention, in the above formula (I), ring B is selected from one or more R. b The following groups may be substituted: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzimidazolyl, pyridinium-imidazolyl, and pyridinium-pyridazolyl, with other variables as defined in this invention.

[0188] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0189] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0190] In some technical solutions of the present invention, the compound shown in formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0191] in,

[0192] T1 and T2 are independently selected from C and N, respectively;

[0193] L1 is selected from -C 0-4 Alkyl-NR5-, -C 0-4 Alkyl-O-, -C 0-4 Alkyl-S-, -C 0-4 Alkyl-CONR5- and -C 0-4 Alkyl-NR5CO-;

[0194] R1 is H;

[0195] R2 is selected from H, D, OH, NH2, CN, and optionally one or more R 2a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0196] R 31 and R 41 together with the atom to which they are attached form a group selected from C 3a alkyl, C 6-12 alkenyl, C 5a alkynyl, C 1-4 cycloalkyl and 3-6 membered heterocycloalkyl;

[0197] R5is selected from H and a group selected from C 2-4 alkyl, C 2-4 alkenyl, C 3-6 alkynyl, C a1 cycloalkyl and 3-6 membered heterocycloalkyl;

[0198] Ring A1is selected from phenyl, naphthyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 3-10 membered heterocycloalkyl;

[0199] Ring B is selected from phenyl, naphthyl, 5-10 membered heteroaryl, C b cycloalkyl and 3-10 membered heterocycloalkyl;

[0200] each R 3-10 , each R 2a , each R 3a , each R 5a , each R a1 and each R b is independently selected from H, D, F, Cl, Br, I, =0, OH, NH2, CN and a group selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0201] or 2 R 3a together with the atom to which they are attached, or 2 R a1 together with the atom to which they are attached, or 2 R b together with the atom to which they are attached, are independently a group selected from C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0202] each R is independently selected from H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more F: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkoxy.

[0203] In some embodiments of the present application, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0204] wherein,

[0205] T1and T2are each independently selected from C and N;

[0206] L1is selected from -C 0-4 alkyl-NR5-, -C 0-4 alkyl-O-, -C 0-4 alkyl-S-, -C 0-4 alkyl-CONR5-, and -C 0-4 alkyl-NR5CO-;

[0207] R 12 is selected from the following groups optionally substituted with 1 or more R 1a substituents: 4-10 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-4 alkyl-CN, and -C 3-6 cycloalkyl-CN;

[0208] R2is selected from H, D, OH, NH2, CN, and the following groups optionally substituted with 1 or more R 2a substituents: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;

[0209] R 32 and R 42 are each independently selected from H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R 3b substituents: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0210] or, R 32 and R 42 together with the atom to which they are attached form an optionally substituted 5-10 membered heteroaryl; 3c C 5-12 cycloalkyl, 5-12 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0211] R5is selected from H and an optionally substituted group selected from C 5a C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0212] Ring A2is selected from an optionally substituted group selected from C a2 C 3-10 cycloalkenyl and 3-10 membered heterocycloalkenyl;

[0213] Ring B is selected from an optionally substituted group selected from phenyl, naphthyl, 5-10 membered heteroaryl, C b C 3-10 cycloalkyl and 3-10 membered heterocycloalkyl;

[0214] each R 1a , each R 2a , each R 3b , each R 3c , each R 5a , each R a2 and each R b is independently selected from H, D, F, Cl, Br, I, =0, OH, NH2, CN and an optionally substituted group selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1- 4alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl;

[0215] or 2 R 3b together with the atom to which they are attached, or 2 R 3c together with the atom to which they are attached, or 2 R a2 together with the atom to which they are attached, or 2 R b together with the atom to which they are attached, independently form an optionally substituted group selected from C 3-6cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0216] each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN and the following groups optionally substituted with 1 or more F: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy.

[0217] In some embodiments of the present application, the compound of formula (I), (I-1) or (I-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from,

[0218] wherein, T1, T2, R2, ring B, R1, R 31 , R 41 , ring A1, R 12 , R 32 , R 42 and ring A2 are as defined in the application.

[0219] The present application also provides a compound represented by formula (I-3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0220] wherein,

[0221] T1and T2are each independently selected from C and N;

[0222] L1is selected from -C 0-4 alkyl-NR5-, -C 0-4 alkyl-O-, -C 0-4 alkyl-S-, -C 0-4 alkyl-CONR5-, and -C 0-4 alkyl-NR5CO-;

[0223] R 13 is selected from the following groups optionally substituted with 1 or more R 1a -C 1-4 alkyl-CN, -C 3-6 cycloalkyl-CN and -3-6 membered heterocycloalkyl-CN;

[0224] R2is selected from H, D, OH, NH2and the following groups optionally substituted with 1 or more R 2a -CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0225] R 33 and R 43 The atoms connected to them together form an array optionally bounded by one or more R atoms. 3d Substituted groups include: phenyl, 5-6 membered heteroaryl C 4- 8-membered monocyclic cycloalkyl or 4-8-membered monocyclic heterocyclic alkyl;

[0226] R5 is selected from H and is arbitrarily chosen by one or more Rs. 5a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0227] Ring A3 is selected from one or more Rs. a The following groups are substituted: phenyl, naphthyl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic alkyl groups;

[0228] Ring B is selected from one or more R. b The following groups are substituted: benzo5-6 heteroaryl and 5-6 heteroaryl-benzo5-6 heteroaryl;

[0229] Each R 1a Each R 2a Each R 3d Each R 5a Each R a and each R b The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1- 4-alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups;

[0230] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 1-4 Alkyl group.

[0231] In some technical solutions of the present invention, the structural unit in the above formula (I-3) selected from other variables are as defined in the present application.

[0232] In some embodiments of the present application, the structural unit in the above formula (I-3) selected from other variables are as defined in the present application.

[0233] In some embodiments of the present application, the compound of the above formula (I), (I-2) or (I-2-1), stereoisomer thereof or pharmaceutically acceptable salt thereof is selected from

[0234] wherein, ring A2, T1, T2, R5, R 32 , R 42 , R 12 , R b are as defined in the present application.

[0235] In some embodiments of the present application, the compound of the above formula (II), stereoisomer thereof or pharmaceutically acceptable salt thereof is selected from

[0236] wherein, ring A2, R b , R 42 , R 32 , R 12 are as defined in the present application.

[0237] The present application also has some technical solutions with any combination of the above variables.

[0238] The present application also provides the compounds shown in Table A and Table B, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0239] In some embodiments of the present application, the compound of the above Table A, stereoisomer thereof or pharmaceutically acceptable salt thereof is selected from the compounds of Table A1.

[0240] In some embodiments of the present application, the compound of the above Table B, stereoisomer thereof or pharmaceutically acceptable salt thereof is selected from the compounds of Table B1.

[0241] In some embodiments of the present application, the compound of the above Table B1, stereoisomer thereof or pharmaceutically acceptable salt thereof is selected from the compounds of Table B2.

[0242] The compounds of Table A

[0243] The compounds of Table B

[0244] Compounds of Table A1

[0245] Compounds of Table B1

[0246] Compounds of Table B2

[0247] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present application, stereoisomer thereof or pharmaceutically acceptable salt thereof. Further, a pharmaceutically acceptable carrier is also included.

[0248] The present application also provides the use of the above-mentioned compound, stereoisomer thereof or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to NLRP3 inhibitors.

[0249] In some technical solutions of the present application, the above-mentioned diseases related to NLRP3 inhibitors are neuroinflammatory related diseases, immune diseases, Parkinson and / or obesity accompanied by cardiovascular diseases, weight loss and fat reduction, etc.

[0250] The present application also provides the following synthesis methods:

[0251] Technical effects

[0252] The compound of the present application has significant inhibitory activity on THP-1 null cell secretion of IL-1beta; the plasma protein free ratio of the compound of the present application in different species plasma is moderate, and the compound of the present application shows strong or moderate ability of binding with plasma protein; the compound of the present application is moderately or slowly metabolized in mouse and human liver microsomes, and has good stability; the compound of the present application is a high permeability and low efflux compound, has good membrane permeability, and is beneficial to distribution to the brain through the blood-brain barrier; the compound of the present application has no obvious inhibitory effect on human liver microsomal cytochrome P450 enzyme, and has low risk of "drug-drug interaction"; the compound of the present application shows good pharmacokinetic properties in mouse PK experiments, and shows certain brain permeability after intragastrical administration in mice. In the efficacy experiment in the diet-induced obesity (DIO) model of mice, the compound of the present application shows significant single-drug weight loss and body composition improvement efficacy results, and the efficacy can be further improved after combination with semaglutide; and after stopping semaglutide after semaglutide monotherapy or combination therapy for weight loss, oral administration of the compound of the present application alone can significantly delay weight rebound.

[0253] Definitions and Descriptions

[0254] 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 being indefinite or unclear in the absence of a specific definition, but should be understood according to the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0255] The term "pharmaceutically acceptable" as used herein, with respect to compounds, materials, compositions, and / or dosage forms, means those that 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.

[0256] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, which is prepared from a compound of the present application having the specific substituents discovered herein with a relatively nontoxic acid or base. Alkali addition salts are prepared from compounds of the present application having relatively acidic functionalities by contacting such compounds in pure solution or in a suitable inert solvent with a sufficient amount of a base to produce the desired salt. Acid addition salts are prepared from compounds of the present application having relatively basic functionalities by contacting such compounds in pure solution or in a suitable inert solvent with a sufficient amount of an acid to produce the desired salt. The 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 a water-immiscible organic solvent, or in a mixture of the two.

[0257] 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 those that are enantiomeric or diastereomeric pure, or substantially free of a particular isomer. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application. The optical purity of a single configuration compound can be expressed in terms of optical rotation, chiral purity, and / or ee. Among them, chiral purity refers to the content determined by testing means (such as GC, HPLC, SFC, NMR, etc.); ee refers to the percentage of isomer excess or enantiomer excess, which is the difference between the percentage contents of two isomers or two enantiomers. For example, by SFC detection, if the content of one isomer a is 90% and the content of the other isomer b is 10%, the chiral purity of isomer a is 90%, and the ee value is 80%.

[0258] The compounds of the present application can exist in particular tautomeric forms. Unless otherwise specified, the term "tautomer" or "tautomeric forms" refers to isomers that differ in the position or nature of a proton or other donor atom. Tautomers are a special class of functional group isomers. A pair of tautomers can interconvert rapidly, but usually exist in a relatively stable isomer as the predominant form. Different functional group isomers are in dynamic equilibrium and can rapidly interconvert. If tautomers are possible (e.g., in solution), a chemical equilibrium of 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 bonding electrons. For example, 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.

[0259] Unless otherwise specified, the term "enantiomer" or "rotamer" refers to stereoisomers that are mirror images of each other.

[0260] Unless otherwise specified, the term "cis-trans isomer" or "geometric isomer" is caused by the double bond or ring-forming carbon atom single bond cannot rotate freely.

[0261] The term "diastereomer" means a stereoisomer of a molecule that has at least two chiral centers and exists as nonmirror-image relationships between molecules unless otherwise indicated.

[0262] "(+)" means dextrorotary, "(-)" means levorotary, and "(±)" means racemic unless otherwise indicated.

[0263] Unless otherwise indicated, a wedge and a wedge indicates the absolute configuration of a stereocenter, a straight and a straight indicates the relative configuration of a stereocenter, a wavy line indicates a wedge and / or a wedge or a wavy line indicates a straight and / or a straight

[0264] Unless otherwise indicated, a carbon atom bearing an "*" is a chiral carbon atom, and exists in the form of a single enantiomer as either (R) or (S), or is enriched in one enantiomeric form. For example, indicates or or is enriched in one enantiomeric form.

[0265] Unless otherwise indicated, the terms "enriched in one isomer," "isomerically enriched," "enriched in one enantiomer," or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0266] Optically active (R)- and (S)-isomers and the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to yield the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the compound with an appropriate optically active acid or base can be formed, and the desired enantiomer recovered by conventional means known in the art, such as elution from a column or fractional crystallization. Additionally, the separation of enantiomers and diastereomers is typically accomplished by the use of chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of a carbamate from an amine).

[0267] The compounds of the application can contain unnatural proportions of atomic isotopes at one or more of the atoms in a compound. 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 application, whether radioactive or not, are encompassed within the scope of the present application.

[0268] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, which can include variations of deuterium and hydrogen, provided that the valency of the particular atom is not exceeded and that the substituted compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced.

[0269] The term "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0270] The term "optionally substituted" means that the group can or can not be substituted and that the types and number of substituents are any that are chemically possible.

[0271] When any variable (e.g., R) occurs more than one time in a compound, each definition is independent. Thus, if a group is substituted with 0-2 R, then the group is optionally substituted with up to two R's, and at each occurrence R is selected independently. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0272] When the number of linking groups is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0273] When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, such as L representing a single bond in A-L-Z means that the structure is actually A-Z.

[0274] When a substituent is null, it means that the substituent is absent, such as X being null in A-X means that the structure is actually A.

[0275] When a recited substituent does not specify through which atom of the substituent it is connected to the rest of the molecule, the substituent can be bonded through any of its atoms, for example, a pyridyl group as a substituent can be bonded to the rest of the molecule through any of the carbon atoms of the pyridine ring. When a recited linking group does not specify its direction of attachment, its direction of attachment is arbitrary, for example, where the linking group L is -M-W-, then -M-W- can be attached to ring A and ring B to form either in the same direction as the reading order from left to right, or combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0276] Unless otherwise specified, when a group has one or more attachable sites, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the attachment of the chemical bond is not defined in position, and there is an H atom at the attachable site, then upon attachment of the chemical bond, the number of H atoms at the site is reduced by the number of chemical bonds attached, to the corresponding valency group. The attachment of the chemical bond of the site to other groups can be represented by a straight solid line bond a straight dashed line bond or a wavy line . Where the attachment of the chemical bond of the site to other groups is represented by a straight dashed line bond or a wavy line When indicating a point of attachment, it can be a single, double, or triple bond, etc. For example, the straight, solid line bond in -OCH3 indicates attachment to other groups through the oxygen atom in the group; the straight, dashed line bond in -NH2 indicates attachment to other groups through both ends of the nitrogen atom in the group; the wavy line in -C6H4- indicates attachment to other groups through the 1 and 2 carbon atoms in the phenyl group; indicates that any point of attachment on the piperidinyl group can be through one chemical bond, including at least These four modes of attachment, even though H atoms are drawn on the -N-, still include This mode of attachment, the group only has one less H at the point of attachment when attached by one chemical bond to become the corresponding monovalent piperidinyl group.

[0277] Unless otherwise specified, C n-n+m or C n -C n+m Any specific instance of n to n+m carbons also includes any range of n to n+m. For example, C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , etc. Also included are 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. Similarly, n to n+m membered rings means that the number of atoms in the ring is n to n+m, for example, 3-12 membered rings include 3 membered rings, 4 membered rings, 5 membered rings, 6 membered rings, 7 membered rings, 8 membered rings, 9 membered rings, 10 membered rings, 11 membered rings, and 12 membered rings, etc. Also included are 3-6 membered rings, 3-9 membered rings, 5-6 membered rings, 5-7 membered rings, 6-7 membered rings, 6-8 membered rings, and 6-10 membered rings, etc.

[0278] Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent group represents a fluorine, chlorine, bromine, or iodine atom.

[0279] Unless otherwise specified, the term "alkyl" by itself or in combination with other terms represents a straight or branched chain, saturated carbon hydride group consisting of 1 to 20 carbon atoms. It can be monovalent (such as methyl), divalent (such as methylene), or multivalent (such as methine). The alkyl group includes C 1-10 ​alkyl, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, and examples of alkyl include, but are not limited to, methyl (Me), methylene (CH2), methine (CH), ethyl (Et), propyl (including n-propyl and isopropyl), n-butyl, t-butyl, n-pentyl, and the like. In some embodiments of the application, the alkyl is C 1-6 alkyl, including C 1-2 , C 1-3 , C 1-4 , C 2-3 , C 2-4 , C 2-5 , C1, C2, C3, C4, C5, C6alkyl, and the like; in other embodiments of the application, the alkyl is C 1-4 alkyl, including C 1-2 , C 1-3 , C 2-3 , C 2-4 , C1, C2, C3, C4alkyl, and the like; in other embodiments of the application, the alkyl is C 1-3 alkyl, including C 1-2 , C 2-3 , C1, C2, C3alkyl, and the like.

[0280] The term "alkenyl," by itself or in combination with another term, means, unless otherwise specified, a straight-chain or branched-chain hydrocarbon group consisting of 2 to 20 carbon atoms, containing at least one carbon-carbon double bond. It can be monovalent, divalent, or multivalent. The alkenyl group includes C 2-10 alkenyl, C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 alkenyl, and examples of alkenyl include, but are not limited to, ethenyl, propenyl, 1-butenyl, cis-butadienyl, and the like. In some embodiments of the application, the alkenyl is C 2-6 alkenyl, including C 2-3 , C 2-4 , C 2-5 , C2, C3, C4, C5, C6alkenyl, and the like; in other embodiments of the application, the alkenyl is C 2-4 alkenyl, including C 2-3 , C2, C3, C4alkenyl, and the like; in other embodiments of the application, the alkenyl is C 2-3 alkenyl, including C2and C3alkenyl, and the like.

[0281] Unless otherwise specified, the term "alkynyl," by itself or in combination with other terms, refers to straight-chain or branched hydrocarbon groups comprising at least one carbon-carbon triple bond and having from two to twenty carbon atoms. It can be monovalent, divalent or multivalent. The alkynyl groups include C 2-10 alkynyl, C 2-6 alkynyl, C 2-5 alkynyl, C 2-4 alkynyl, C 2-3 alkynyl, and the like. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1 -butynyl, and the like. In some embodiments of the application, the alkynyl group is C 2-6 alkynyl, including C 2-3 , C2, C3, C4, C5, C6alkynyl, and the like; in other embodiments of the application, the alkynyl group is C 2-4 , C2, C3, C4, C5, C6alkynyl, and the like; in other embodiments of the application, the alkynyl group is C 2-5 , C2, C3, C4, C5, C6alkynyl, and the like; in other embodiments of the application, the alkynyl group is C 2-4 alkynyl, including C 2-3 , C2, C3, C4, C5, C6alkynyl, and the like; in other embodiments of the application, the alkynyl group is C 2-3 alkynyl, including C2and C3alkynyl, and the like.

[0282] Unless otherwise specified, the term "alkoxy," by itself or in combination with other terms, refers to those alkyl groups described above attached to the remainder of the molecule through an oxygen atom. It can be monovalent, divalent or multivalent. The alkoxy groups include C 1-10 alkoxy, C 1-6 alkoxy, C 1-5 alkoxy, C 1-4 alkoxy, C 1-3 alkoxy, and the like. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy (including n- propyloxy and isopropyloxy), and the like. In some embodiments of the application, the alkoxy group is C 1-6 alkoxy, including C 1-2 , C 1- 3, C 1-4 , C 2-3 , C 2-4 , C 2-5 , C1, C2, C3, C4, C5, C6alkoxy, and the like; in other embodiments of the application, the alkoxy group is C 1-4 alkoxy, including C 1-2 , C 1-3 , C 2-3 , C 2-4 , C1, C2, C3, C4alkoxy, and the like; in other embodiments of the application, the alkoxy group is C 1-3 alkoxy, including C 1-2 , C 2-3, C1, C2, C3alkoxy, and the like.

[0283] Unless otherwise specified, the term "alkylthio" by itself or in combination with other terms, refers to those alkyl groups attached to the rest of the molecule by a sulfur atom, containing from one to twenty carbon atoms. It can be monovalent, divalent or multivalent. The alkylthio groups include C 1-10 alkylthio, C 1-6 alkylthio, C 1-5 alkylthio, C 1-4 alkylthio, C 1-3 alkylthio, and the like, examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n- and isopropylthio), and the like. In some embodiments of the application, the alkylthio is C 1-6 alkylthio, including C 1-2 , C 1- 3, C 1-4 , C 2-3 , C 2-4 , C 2-5 , C1, C2, C3, C4, C5, C6alkylthio, and the like; in other embodiments of the application, the alkylthio is C 1-4 alkylthio, including C 1-2 , C 1-3 , C 2-3 , C 2-4 , C1, C2, C3, C4alkylthio, and the like; in other embodiments of the application, the alkylthio is C 1-3 alkylthio, including C 1-2 , C 2-3 , C1, C2, C3alkylthio, and the like.

[0284] Unless otherwise specified, the term "alkylamino" by itself or in combination with other terms, refers to those alkyl groups attached to the rest of the molecule by a nitrogen atom, containing from one to twenty carbon atoms. It can be monovalent, divalent or multivalent, including monoalkylamino and dialkylamino groups. The alkylamino groups include C 1-10 alkylamino, C 1-6 alkylamino, C 1-5 alkylamino, C 1-4 alkylamino, C 1-3 alkylamino, and the like, examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, and the like. In some embodiments of the application, the alkylamino is C 1-6 alkylamino, including C 1-2 , C 1-3 , C 1-4 , C 2-3, C 2-4 , C 2-5 , C1, C2, C3, C4, C5, C6alkylamino, etc.; in some embodiments of the application, the alkylamino is C 1-4 alkylamino, including C 1-2 , C 1-3 , C 2- 3, C 2-4 , C1, C2, C3, C4alkylamino, etc.; in some embodiments of the application, the alkylamino is C 1-3 alkylamino, including C 1- 2, C 2-3 , C1, C2, C3alkylamino, etc.

[0285] The term "cycloalkyl" by itself or in combination with other terms, means a saturated or partially unsaturated cyclic hydrocarbon group consisting of 3 to 20 carbon atoms. It can be monovalent, divalent, or multivalent. The cycloalkyl group can optionally contain one or more carbon-carbon double bonds or triple bonds, but none of the rings is aromatic. The cycloalkyl group can be a saturated cycloalkyl group (meaning all rings are saturated), a cycloalkenyl group (meaning at least one carbon-carbon double bond in a monocyclic or polycyclic ring system), etc. The cycloalkyl group can be monocyclic, polycyclic (e.g., spiro, fused, bridged), etc. The cycloalkyl group includes C 5-12 cycloalkyl, C 5-10 cycloalkyl, C 3-10 cycloalkyl, C 3-8 cycloalkyl, C 3- 7cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, C 4-6 cycloalkyl, etc. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc. In some embodiments of the application, the cycloalkyl is C 3-6 cycloalkyl, including C 3-5 , C 4-5 , C 4-6 , C3, C4, C5, C6cycloalkyl, etc. In some embodiments of the application, the cycloalkyl is C 6-12 bicyclic spirocycloalkyl means a 2 cyclic hydrocarbon groups share 1 atom to form a spiro ring, which can be fully saturated or contain 1 or more carbon-carbon double bonds, including 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered bicyclic spirocycloalkyl, etc. In some embodiments of the application, the cycloalkyl is C 3-10Cycloalkenyl groups, which contain at least one carbon-carbon double bond, include 3-5 membered, 4-5 membered, 4-6 membered, 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered cycloalkenyl groups, and the like.

[0286] Unless otherwise specified, the term "heterocycloalkyl," by itself or in combination with another term, means a saturated or partially unsaturated cyclic group consisting of 3 to 20 ring atoms, 1, 2, 3, 4, 5, 6, 7, or 8 of which are heteroatoms independently selected from the group consisting of O, S, and N, with the remainder being carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)2, p is 1 or 2), and wherein the heteroatoms can occupy any available position of the heterocycloalkyl group and the remainder of the positions are carbon atoms, provided that the heterocycloalkyl group is not aromatic. It can be monovalent, divalent, or multivalent. The heterocycloalkyl group can optionally contain one or more carbon-carbon double or triple bonds, but none of the rings is aromatic. The heterocycloalkyl group can be a saturated heterocycloalkyl group (meaning all rings are saturated) or a heterocycloalkenyl group (meaning at least one carbon-carbon double bond is contained in a single or multiple ring system), and the like. The heterocycloalkyl group can be monocyclic or polycyclic (e.g., spiro, fused, bridged), and the like. The heterocycloalkyl group includes 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-5 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, and the like. Examples of 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, etc. In some embodiments of the present application, the heterocycloalkyl is a 3-6 membered heterocycloalkyl, which includes 3-5 membered, 4-5 membered, 4-6 membered, 3 membered, 4 membered, 5 membered, 6 membered heterocycloalkyl, etc. In some embodiments of the present application, the heterocycloalkyl is a 3-10 membered heterocycloalkenyl, which contains at least one double bond, which includes 3-5 membered, 4-5 membered, 4-6 membered, 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-8 membered, 6-9 membered, 6-10 membered, 7-8 membered, 7-9 membered, 7-10 membered, 8-10 membered heterocycloalkenyl, etc. In some embodiments of the present application, the heterocycloalkyl is a 3-10 membered heterocycloalkenyl is a bridged ring. In some embodiments of the present application, the heterocycloalkyl is a 3-10 membered heterocycloalkenyl is selected from 6-10 membered heterocycloalkenyl. In some embodiments of the present application, the heterocycloalkyl is a 3-10 membered heterocycloalkenyl is selected from 6-10 membered bridged heterocycloalkenyl.

[0287] Unless otherwise specified, the term fused (also known as annelated) refers to a structure formed by two rings sharing two adjacent atoms, which can be a bicyclic or polycyclic system, for example The term bridged refers to a structure formed by two rings sharing two non-adjacent atoms, which can be a bicyclic or polycyclic system, for example The term spiro refers to a structure formed by two rings sharing one atom, which can be a bicyclic or polycyclic system, for example

[0288] Unless otherwise specified, the terms "heteroaromatic ring" and "heteroaryl" are used interchangeably, and the term "heteroaryl" by itself or in combination with other terms refers to a monocyclic group or a polycyclic ring system having a conjugated pi-electron system consisting of 5 to 20 ring atoms, 1, 2, 3, 4, 5, 6, 7, or 8 of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms. Where the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)2, p is 1 or 2). The heteroaryl group can be attached to the remainder of the molecule through a heteroatom or carbon atom, and can be monovalent, divalent, or multivalent. The heteroaryl group includes 5-6 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-8 membered, 6-9 membered, 6-10 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heteroaryl. Examples of the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophenyl (including 2-thiophenyl and 3-thiophenyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyridazinyl, pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), indolyl, indazolyl, pyrimidoimidazolyl, etc. In some embodiments of the present application, the heteroaryl group is a 5-10 membered heteroaryl group, which includes 5-6 membered, 5-8 membered, 5-9 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heteroaryl; in other embodiments of the present application, the heteroaryl group is a 5-6 membered heteroaryl group, which includes 5 membered and 6 membered heteroaryl.

[0289] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0290] The compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the single crystal grown is collected by a Bruker D8 venture diffractometer, light source is Cu Kα radiation, scanning method: φ / ω scanning, after collecting relevant data, further using the direct method (Shelxs97) to analyze the crystal structure, the absolute configuration can be confirmed.

[0291] The solvents used in the present application can be commercially available. The compounds are named according to the conventional naming principles in the art or using the software naming, and the commercially available compounds are named according to the supplier's catalog name. BRIEF DESCRIPTION OF DRAWINGS

[0292] Figure 1: The body weight change graph of mice in the DIO efficacy model (I).

[0293] Figure 2: The body weight change graph of mice in the DIO efficacy model (II).

[0294] Figure 3: The body weight change graph of mice in the DIO efficacy model (II). DETAILED DESCRIPTION

[0295] The present application will be described in detail below by way of examples, but it does not mean any unfavorable limitation to the present application. The present application has been described in detail herein, and the specific embodiment manner thereof has also been disclosed, and it will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiment of the present application without departing from the spirit and scope of the present application.

[0296] Intermediate M1

[0297] Step 1: Under nitrogen atmosphere, slowly add trimethylsilyl trifluoromethanesulfonate (48.4 g, 219 mmol) to a solution of compound M1-1 (10 g, 90.8 mmol) and N, N-diisopropyl ethylamine (46.93 g, 363 mmol) in dichloromethane (150 mL) at 0°C, and stir the reaction solution at 0°C for 2 hours. Add 50 mL of water to the reaction solution at 0°C, extract with DCM (50 mL x 3), dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound M1-2. 1H NMR (400 MHz, CDC13) δ = 4.59 (t, J = 2.4 Hz, 1H), 3.02 (td, J = 6.4, 13.2 Hz, 2H), 2.47 (q, J = 7.2 Hz, 2H), 2.39-2.32 (m, 2H), 1.96-1.89 (m, 2H), 0.17 (s, 9H).

[0298] Step 2: To a solution of compound M1-2 (16.52 g, 90.6 mmol) in toluene (200 mL) was added compound M1-3 (11.4 g, 75.5 mmol) portionwise slowly at 25 °C under nitrogen atmosphere. After the addition was completed, the reaction system was warmed to 120 °C and stirred for 2 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1-10: 1) to give compound M1. LCMS (m / z): 214.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 3.08 (t, J = 7.6 Hz, 2H), 2.18 (t, J = 8.0 Hz, 2H), 1.74-1.63 (m, 2H), 1.11-1.04 (m, 2H).

[0299] Intermediate M2

[0300] To a solution of compound M2-1 (4.5 g, 16.4 mmol) and bis(pinacolato)diboron (8.33 g, 32.8 mmol) in dioxane (90 mL) was added potassium acetate (5.47 g, 55.7 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (1.20 g, 1.64 mmol) at room temperature under nitrogen atmosphere. The reaction was warmed to 100 °C and stirred for 2 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-100:1) to give compound M2. 1 H NMR (400 MHz, CDC13) δ = 7.66 (s, 1H), 6.89 (s, 1H), 1.36 (s, 12H).

[0301] Intermediate M3 and M4

[0302] To a solution of compound M1 (0.5 g, 2.32 mmol), (3R)-1-methylpiperidin-3-amine (345 mg, 3.02 mmol) in toluene (10 mL) was added 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (289 mg, 465 μmol), tris(dibenzylideneacetone)dipalladium (213 mg, 232 μmol) and cesium carbonate (1.51 g, 4.65 mmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 100 °C for 5 h. To the reaction was added 3 mL of water and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was separated by preparative reverse phase column (column: Phenomenex luna C18 (250 x 70 mm, 10 μm); mobile phase: [water (0.1% ammonia)-acetonitrile]; gradient (acetonitrile %): 35% - 45%) to give compound M3 and compound M4.

[0303] Compound M3 characterization: LCMS (m / z): 293.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 6.15 (br d, J = 8.0 Hz, 1H), 4.22 - 4.11 (m, 1H), 2.97 - 2.89 (m, 1H), 2.82 (t, J = 7.6 Hz, 2H), 2.67 (br d, J = 10.8 Hz, 1H), 2.21 (s, 3H), 2.17 - 2.09 (m, 2H), 1.97 - 1.83 (m, 3H), 1.72 (td, J = 4.0, 13.2 Hz, 1H), 1.62 - 1.51 (m, 3H), 1.42 - 1.31 (m, 1H), 0.98 - 0.91 (m, 2H).

[0304] Compound M4 characterization: LCMS (m / z): 293.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 4.70 (br d, J = 8.0 Hz, 1H), 4.21 (br s, 1H), 3.01 - 2.90 (m, 2H), 2.54 - 2.25 (m, 4H), 2.22 (s, 3H), 2.18 - 2.10 (m, 2H), 1.70 - 1.57 (m, 4H), 1.55 - 1.47 (m, 2H), 1.04 - 0.94 (m, 2H).

[0305] Intermediate M5 and M6

[0306] Step 1: To a solution of compound M5-1 (5 g, 25.0 mmol) in N,N- dimethylformamide (50 mL) was added iodine acetonitrile (5.00 g, 30.0 mmol) and N,N- diisopropylethylamine (8.07 g, 62.4 mmol) at room temperature under nitrogen atmosphere. The reaction was heated to 60 °C for 2 h. To the reaction was added 150 mL of water, extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 1) to give compound M5-2. 1 H NMR (400 MHz, CDC13) δ = 4.92-4.74 (m, 1H), 3.86-3.74 (m, 1H), 3.52 (d, J = 1.6 Hz, 2H), 2.77 (br d, J = 8.8 Hz, 1H), 2.51 (br t, J = 5.2 Hz, 2H), 2.34 (br dd, J = 6.8, 10.0 Hz, 1H), 1.82-1.59 (m, 4H), 1.45 (s, 9H).

[0307] Step 2: To a solution of compound M5-2 (2 g, 8.36 mmol) in acetonitrile (15 mL) was added dropwise hydrochloric acid dioxane solution (2 M, 62.7 mL) at room temperature under nitrogen atmosphere. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure, the residue was dissolved in 20 mL of methanol, neutralized to pH = 7-8 by slowly adding sodium carbonate under ice water bath, filtered, and the filtrate was concentrated under reduced pressure to give compound M5-3. 1 H NMR (400 MHz, CDC13) δ = 4.92-4.74 (m, 1H), 3.86-3.74 (m, 1H), 3.52 (d, J = 1.6 Hz, 2H), 2.77 (br d, J = 8.8 Hz, 1H), 2.51 (br t, J = 5.2 Hz, 2H), 2.34 (br dd, J = 6.8, 10.0 Hz, 1H), 1.82-1.59 (m, 4H), 1.45 (s, 9H).

[0308] Step 3: To a solution of compound M1 (500 mg, 2.32 mmol), compound M5-3 (324 mg, 2.32 mmol) in toluene (10 mL) was added 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (289 mg, 465 μmol), tris(dibenzylideneacetone)dipalladium (213 mg, 232 μmol) and cesium carbonate (1.51 g, 4.65 mmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 100 °C for 5 h. To the reaction was added 3 mL water and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase column (column: Phenomenex luna C18 (250 x 70 mm, 10 μm); mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 32% - 40%) to give compound M5 (first peak), compound M6 (second peak).

[0309] Characterization of compound M5: 1 H NMR (400 MHz, DMSO-d6) δ = 6.33 - 6.25 (m, 1H), 4.26 - 4.15 (m, 1H), 3.80 (s, 2H), 3.01 (br dd, J = 3.2, 10.0 Hz, 1H), 2.87 - 2.80 (m, 2H), 2.77 - 2.72 (m, 1H), 2.26 - 2.13 (m, 4H), 1.99 - 1.90 (m, 1H), 1.85 - 1.75 (m, 1H), 1.66 - 1.58 (m, 1H), 1.57 - 1.51 (m, 2H), 1.45 - 1.31 (m, 1H), 0.98 - 0.92 (m, 2H); 2D NMR NOE showed that the H1 of NH of compound M5 has a correlation signal with H2 on the five-membered ring.

[0310] Characterization of compound M6: 1 H NMR (400 MHz, DMSO-d6) δ = 4.65 (d, J = 8.4 Hz, 1H), 4.26 - 4.16 (m, 1H), 3.75 (s, 2H), 3.12 - 3.06 (m, 1H), 2.94 - 2.87 (m, 2H), 2.78 - 2.72 (m, 1H), 2.43 - 2.38 (m, 1H), 2.22 - 2.14 (m, 1H), 2.12 - 2.05 (m, 2H), 1.72 - 1.64 (m, 2H), 1.60 - 1.47 (m, 4H), 0.97 - 0.87 (m, 2H); 2D NMR NOE showed that the H1 of NH of compound M6 has a correlation signal with H3 on the three-membered ring;

[0311] Intermediate M7

[0312] Step 1: To a solution of compound M7-1 (12.3 g, 52.34 mmol) in acetonitrile (150 mL) was added cuprous iodide (19.94 g, 104.68 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 55 °C for 0.1 h, then tert-butyl nitrite (8.10 g, 78.51 mmol) was added slowly. The reaction mixture was continued to react for 2 h. The reaction mixture was cooled to room temperature, diluted with 1.5 L water and 40 mL of ammonia water, extracted with ethyl acetate (100 mL x 4), the combined organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: dichloromethane = 1:0-50:1) to give compound M7-2. 1 H NMR (400 MHz, DMSO-d6) d = 7.86-7.81 (m, 1H), 7.80-7.73 (m, 1H).

[0313] Step 2: To a solution of compound M7-2 (9.9 g, 28.62 mmol) in ethanol (110 mL) was added ammonia water (41 mL) at room temperature under nitrogen atmosphere. The reaction mixture was reacted at 80 °C for 12 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with 50 mL of water, extracted with ethyl acetate (50 mL x 4), the combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound M7-3. 1 H NMR (400 MHz, DMSO-d6) d = 7.34 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.05 (s, 2H).

[0314] Step 3: To a solution of compound M7-3 (11.9 g, 34.5 mmol) in ethanol (120 mL) was added tin dichloride dihydrate (39.16 g, 173.5 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was reacted at 70 °C for 2 h. After the reaction was completed, the reaction mixture was poured into 300 mL of ice water, the pH value was adjusted to 8 with 2 M aqueous sodium hydroxide solution, 200 mL of ethyl acetate was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was added with 100 mL of water, extracted with ethyl acetate (100 mL x 4), the combined organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-5:1) to give compound M7-4. LCMS (m / z): 312.9 [M+H] + .

[0315] Step 4: To a solution of compound M7-4 (7.6 g, 24.29 mmol) and trimethyl orthoformate (7.2 g, 48.57 mmol) in tetrahydrofuran (90 mL) was added anhydrous p-toluenesulfonic acid (442 mg, 2.43 mmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 40 °C for 6 h. To the reaction was added 300 mL of water and 20 mL of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL x 4), the combined organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. To the crude product was added petroleum ether / ethyl acetate mixture (3:1, 80 mL), stirred at room temperature for 10 min, filtered and the filter cake was dried to give compound M7-5. LCMS (m / z): 322.9 [M+H] + .

[0316] Step 5: To a solution of compound M7-5 (2.5 g, 7.74 mmol) in N,N-dimethylacetamide (25 mL) was added sodium hydride (495.47 mg, 12.39 mmol, 60% purity) under nitrogen atmosphere at 0 °C. The reaction was stirred at 10 °C for 15 min. The reaction was cooled to 0 °C, and bromomethyl methyl ether (1.74 g, 13.93 mmol) was added dropwise. The reaction was continued to stir at 0-10 °C for 15 min. The reaction was cooled to 0 °C, and 15 mL of saturated ammonium chloride solution was added to quench, and diluted with 200 mL of water. The reaction was extracted with ethyl acetate (30 mL x 4), the combined organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-2:1) to give compound M7-6. LCMS (m / z): 366.9 [M+H] + .

[0317] Step 6: To a solution of compound M7-6 (1.69 g, 4.61 mmol) and methyl fluorosulfonyl difluoroacetate (2.65 g, 13.82 mmol) in N,N-dimethylacetamide (25 mL) was added cuprous iodide (3.07 g, 16.12 mmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 90 °C for 14 h. The reaction was cooled to room temperature, and 150 mL of water and 40 mL of ethyl acetate were added, followed by the addition of 20 mL of ammonia water. The reaction was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 4), the combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-2:1) to give compound M7-7. LCMS (m / z): 309.0 [M+H] + .

[0318] Step 7: To a solution of compound M7-7 (0.95 g, 3.07 mmol) and bis(pinacolato)diboron (1.56 g, 6.15 mmol) in dioxane (20 mL) was added potassium acetate (904.96 mg, 9.22 mmol) and methanesulfonic acid (tricyclohexylphosphine) palladium (II) (225.94 mg, 307.36 μmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 2: 1-1: 1) and then by preparative reverse phase column (column: Spherical C18, 40-60 μm, 250*4.6mm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 75%> to 95%> in 3 min, 95%> for 2 min, 95%> to 75%> in 1 min, 75%> for 1 min, 1 mL / min) to give compound M7-8. LCMS (m / z): 357.2 [M+H] Mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 75%> to 95%> in 3 min, 95%> for 2 min, 95%> to 75%> in 1 min, 75%> for 1 min, 1 mL / min + .

[0319] Step 8: To a solution of compound M7-8 (125 mg, 350.98 μmol) in trifluoromethanesulfonic acid (1 mL) and water (0.5 mL) was added at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 55 °C for 1 h. The reaction mixture was cooled to 0 °C and then slowly added to 30 mL of saturated sodium bicarbonate solution. The combined organic phase was extracted with ethyl acetate (10 mL x 4), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound M7. LCMS (m / z): 275.1 [M+H] + .

[0320] Intermediate M8

[0321] Step 1: To a solution of compound M8-1 (50.0 g, 271.46 mmol) in tetrahydrofuran (300 mL) was added 1 M tetrahydroaluminate lithium in tetrahydrofuran (542.92 mL, 542.92 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by the addition of sodium sulfate decahydrate (16 g) portionwise. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound M8-2. 1 H NMR (400 MHz, CDC13) δ = 5.63 (s, 2H), 3.69 (s, 4H), 2.51 (br s, 2H), 2.21 (s, 4H).

[0322] Step 2: To a solution of compound M8-2 (38 g, 296.48 mmol) and triphenylphosphine (194.41 g, 741.21 mmol) in tetrahydrofuran (500 mL) was added iodine (188.13 g, 741.21 mmol) and imidazole (60.55 g, 889.45 mmol) portionwise under nitrogen atmosphere. The reaction mixture was heated to 80 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0) to give compound M8-3. 1 H NMR (400 MHz, CDC13) δ = 5.70 (s, 2H), 3.51 (s, 4H), 2.45 (s, 4H).

[0323] Step 3: To a solution of compound M8-3 (80 g, 229.91 mmol) in dioxane (900 mL) and water (9 mL) was added indium (105.59 g, 919.64 mmol) portionwise under nitrogen atmosphere. The reaction mixture was heated to 100 °C for 12 h. The reaction mixture was cooled to room temperature and filtered to give compound M8-4. 1 H NMR (400 MHz, CDC13) δ = 5.69 (s, 2H), 2.27 (s, 4H), 0.47 (s, 4H).

[0324] Step 4: To a solution of compound M8-4 (21 g) in dioxane (900 mL) and water (9 mL) was added compound M8-5 (33.67 g, 223.04 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 1-5 / 1) to give compound M8-6. LCMS (m / z): 214.9. [M+H] + ; 1 H NMR (400 MHz, CDC13) δ = 3.11 (s, 4H), 0.82 (s, 4H).

[0325] Step 5: Under a nitrogen atmosphere at room temperature, palladium acetate (20.88 mg, 92.99 μmol) and 2,2-bis(diphenylphosphino)-1,1-binaphthyl (115.80 mg, 186 μmol) were added to anhydrous toluene (3 mL) containing compound M8-6 (200 mg, 930 μmol), (3R)-1-methylpiperidin-3-amine (212.37 mg, 1.86 mmol), and cesium carbonate (908.93 mg, 2.79 mmol). The reaction solution was reacted at 100 °C for 4 hours. The reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 250 × 70 mm × 10 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 30%-50%) to obtain compound M8. LCMS (m / z): 293.1 [M+H] + .

[0326] intermediate M9

[0327] Under a nitrogen atmosphere at 25°C, cesium carbonate (424 mg, 1.30 mmol), 2,2-bis(diphenylphosphino)-1,1-naphthyl (81.1 mg, 130 μmol), and palladium acetate (14.6 mg, 65.1 μmol) were added to a toluene (2 mL) solution of compound M8-6 (140 mg, 650.92 μmol) and compound M5-3 (109 mg, 781 μmol). The nitrogen atmosphere was purged three times, and the reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with 3 mL of water, and extracted with ethyl acetate (3 mL × 3). The combined organic phases were washed with 8 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (column: Spherical C18, 40-60 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 55%-60% to give compound M9. LCMS (m / z): 318.0. [M+H] + .

[0328] Intermediate M10

[0329] Step 1: Under nitrogen protection at 0°C, copper powder (339 g, 5.34 mol) and stannous chloride (1.01 kg, 5.34 mol) were added sequentially to a 2 L aqueous solution containing compound M10-1 (420 g, 3.47 mol) and acetone (155 g, 2.67 mol). The mixture was heated to 25°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was extracted with dichloromethane (1 L × 2). The organic phase was washed with saturated sodium chloride aqueous solution (1 L × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at room temperature to obtain compound M10-2. 1 H NMR (400MHz, CDCl3) δ = 5.94-5.80 (m, 1H), 5.18-5.06 (m, 2H), 2.22 (d, J = 7.6Hz, 2H), 1.21 (s, 6H).

[0330] Step 2: Under a nitrogen atmosphere, silver tetrafluoroborate (10.6 g, 54.4 mmol) was added to a solution of compound M10-2 (43.6 g, 436 mmol), phthalimide (40.0 g, 272 mmol), and iodobenzene acetate (263 g, 815 mmol) in acetonitrile (600 mL), followed by palladium acetate (6.10 g, 27.2 mmol). After purging with nitrogen three times, the reaction was carried out at 60 °C for 12 hours. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated. Acetonitrile (100 mL) was added, followed by filtration again. The filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1-6:1) to obtain compound M10-3. LCMS (m / z): 246.0. [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.88-7.79 (m, 2H), 7.76-7.66 (m, 2H), 5.06-4.92 (m, 1H), 4.21 (t, J = 8.4Hz ,1H),4.05(t,J=8.4Hz,1H),2.46(dd,J=9.6,12.0Hz,1H),2.08-2.05(m,1H),1.48(s,3H),1.31(s,3H).

[0331] Step 3: Under nitrogen protection, 98% hydrazine hydrate (9.37 g, 183 mmol) was slowly added to an ethanol (300 mL) solution of compound M10-3 (15 g, 61.2 mmol), and the reaction was carried out at 70 °C for 2 hours. The reaction solution was diluted with ethanol (300 mL), filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 1:0-25:1) to obtain compound M10. 1H NMR (400 MHz, CDC13) δ (ppm) = 3.97-3.87 (m, 1H), 3.62-3.55 (m, 1H), 3.49-3.42 (m, 1H), 2.04 (dd, J = 7.6, 12.8 Hz, 1H), 1.45 (dd, J = 6.0, 12.4 Hz, 1H), 1.29 (s, 3H), 1.15 (s, 3H).

[0332] Intermediate M11 and M12

[0333] Step 1: Compound M11-1 (30 g, 275 mmol) was dissolved in tetrahydrofuran (500 mL) under nitrogen protection at -70 °C, and vinylmagnesium bromide (1 M tetrahydrofuran solution, 330 mL) was slowly added dropwise. After the addition was completed, the reaction was stirred at -70 °C for 2 hours. Then benzyl chloroformate (58.9 mL, 412 mmol) in tetrahydrofuran (50 mL) was added dropwise under nitrogen protection, and the mixture was stirred at -20 °C for 0.5 hours. Then saturated aqueous ammonium chloride solution (400 mL) was slowly added dropwise to the reaction system under nitrogen flow at 0 °C, and then extracted with ethyl acetate (500 mL x 3). The organic phase was washed with saturated aqueous sodium chloride solution (1 L x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-5: 1) to obtain compound M11-2. LCMS (m / z): 258.0. [M+H] + ; 1 H NMR (400 MHz, CDC13) δ = 7.81 (d, J = 8.4 Hz, 1H), 7.45-7.31 (m, 5H), 5.86-5.74 (m, 1H), 5.36-5.30 (m, 1H), 5.29-5.26 (m, 2H), 5.25-5.20 (m, 1H), 5.19-5.10 (m, 2H), 2.90 (dd, J = 6.8, 16.4 Hz, 1H), 2.56 (d, J = 16.4 Hz, 1H).

[0334] Step 2: To a solution of compound M11-2 (20 g, 77.7 mmol) in tetrahydrofuran (50 mL) was added methylmagnesium bromide (1 M in tetrahydrofuran, 117 mL) dropwise at -70 °C under nitrogen atmosphere. The reaction mixture was stirred at -70 °C for 0.5 h. To the reaction mixture was added copper cyanide (9.75 g, 109 mmol) in tetrahydrofuran (200 mL) dropwise at -70 °C. The reaction mixture was stirred at -70 °C for 4 h. The reaction was quenched by the addition of saturated ammonium chloride solution (500 mL) at 0 °C. The reaction mixture was extracted with ethyl acetate (500 mL x 3). The organic phase was combined and washed with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1-8:1) to give compound M11-3. 1 H NMR (400 MHz, CDC13) δ = 7.40-7.33 (m, 5H), 5.97-5.86 (m, 2H), 5.23-5.10 (m, 8H), 2.67 (d, J = 5.6 Hz, 4H).

[0335] Step 3: To a solution of compound M11-3 (14.0 g, 49.1 mmol) in toluene (1.5 L) was added Grubb’s II catalyst (4.17 g, 4.91 mmol) at 80 °C under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated. To the reaction mixture was added water (50 mL) and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1-7:1) to give compound M11-4. 1 H NMR (400 MHz, CDC13) δ = 7.44-7.34 (m, 5H), 6.23 (d, J = 10.8 Hz, 2H), 5.21 (s, 2H), 4.90-4.85 (m, 2H), 2.85-2.75 (m, 1H), 2.70-2.58 (m, 1H), 2.46-2.31 (m, 2H).

[0336] Step 4: To a solution of compound M11-4 (8.3 g, 32.3 mmol) in ammonium acetate (49.7 g, 645 mmol) in methanol (250 mL) was added at 0 °C under nitrogen atmosphere and stirred for 15 min. To the reaction mixture was added sodium cyanoborohydride (20.3 g, 323 mmol) in 3 portions at 0 °C. The reaction mixture was warmed to 70 °C and stirred for 1 h. The reaction was quenched by the addition of water (30 mL) and concentrated. The residue was directly separated by reverse phase column (column: Phenomenex luna C18 20-45 μm, 250*50mm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 40% to 60%) to give compound M11-5. LCMS (m / z): 259.3 [M+H] Mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 40% to 60%) to give compound M11-5. LCMS (m / z): 259.3 [M+H] + ; 1 H NMR (400 MHz, CDC13) δ = 7.40-7.30 (m, 5H), 6.39-5.96 (m, 2H), 5.19-5.14 (m, 2H), 4.65 (d, J = 10.0 Hz, 2H), 3.14-2.92 (m, 1H), 2.38-1.77 (m, 2H), 1.59-1.49 (m, 2H).

[0337] Step 5: To a solution of compound M11-5 (269 mg, 1.04 mmol) and compound M11-6 (170 mg, 1.04 mmol) in tert-amyl alcohol (4 mL) was added cesium carbonate (1.02 g, 3.13 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1- biphenyl) (2-methylamino-1,1-biphenyl-2-yl) palladium(II) (88.7 mg, 104 μmol) sequentially at room temperature under nitrogen atmosphere. The reaction mixture was purged with nitrogen for 3 times and stirred at 100 °C for 6 h. The reaction mixture was poured into 5 mL of water and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column (column: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 40% to 60%) and (column: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [water (0.1% trifluoroacetic acid) - acetonitrile]; gradient (acetonitrile %): 20% to 45%) to give compound M11-7 and compound M12-7. LCMS detection (Instrument: SHIMADZU LCMS-2020, Column: HALO C 183.0 X 30 mm, 5 μm; mobile phase: phase A water / 0.0375% trifluoroacetic acid, phase B acetonitrile / 0.01875% trifluoroacetic acid]; gradient: B% raised from 5% to 95% in 0-0.5 min, B% maintained at 95% in 0.5-0.8 min, B% 5% in 0.81-1.05 min, flow rate 1.5 mL / min, column temperature 50 °C, detector: PDA, 220 nm & 254 nm), the retention time of compound M11-7 was 0.519 min, and the retention time of compound M12-7 was 0.483 min.

[0338] Compound M11-7 characterization: LCMS: 385.0 [M+H] + ; 1 H NMR (400 MHz, CDC13) δ = 7.41-7.32 (m, 5H), 6.99 (s, 1H), 6.16 (br d, J = 6.8 Hz, 2H), 5.23-5.14 (m, 2H), 4.78-4.63 (m, 3H), 3.97 (br d, J = 8.4 Hz, 1H), 2.29-2.09 (m, 2H), 2.05 (s, 3H), 1.65-1.53 (m, 1H), 1.46-1.35 (m, 1H); 2D NMR NOE showed that the H1 of the methyl group was correlated with the H2 of NH, and the specific structure was as follows:

[0339] Compound M12-7 characterization: LCMS: 385.0 [M+H] + .

[0340] Step 6: Under a nitrogen atmosphere at room temperature, a 33% hydrobromic acid / acetic acid solution (1.0 mL, 6.08 mmol) was added to a solution of compound M11-7 (100 mg, 260 μmol) in dichloromethane (1 mL), and the reaction was allowed to proceed at 25 °C for 1 hour. The reaction solution was poured into 5 mL of an aqueous solution, washed with ethyl acetate (5 mL x 3), and the aqueous phase was collected and adjusted to pH = 11 with 2M aqueous sodium hydroxide solution, then extracted with ethyl acetate / methanol (volume ratio 10 / 1, 7 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M11-8.

[0341] Step 7: To a solution of compound M11-8 (65.0 mg, 259 pmol) and N,N- diisopropylethylamine (135 pL, 778 pmol) in dimethyl sulfoxide (1 mL) was added iodine acetonitrile (43.3 mg, 259 pmol) at room temperature under nitrogen atmosphere, and the reaction was stirred at 60 °C for 1 h. The reaction was poured into 3 mL of water solution, extracted with ethyl acetate (3 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound M11.

[0342] Step 8: Compound M12 was prepared according to Steps 6-7 using compound M12-7 as the starting material.

[0343] Intermediate M13

[0344] Step 1: Solution 1 was a solution of compound M13-1 (500 g) in anhydrous tetrahydrofuran (5000 mL); Solution 2 was vinylmagnesium bromide (2.5 M in tetrahydrofuran, 4582 mL); Solution 3 was benzyl chloroformate (1563.27 g) in anhydrous tetrahydrofuran (5000 mL). The fluidic chemistry steps were as follows:

[0345] Solution 1 was pumped into flow reactor 1 (-20.0 °C) by pump 1 (30.007 mL / min) while solution 2 was pumped into flow reactor 1 (-20.0 °C) by pump 2 (49.993 mL / min), and flow reactor 1 was held for 3.0 min before being pumped into flow reactor 2 (-20.0 °C).

[0346] Solution 3 was pumped into flow reactor 2 (-20.0 °C) by pump 3 (35.66 mL / min) and held for 2.075 min.

[0347] The contents of flow reactor 2 were pumped into reactor 3 (-20.0 °C) and held for 2.075 min.

[0348] The reaction mixture was collected and the reaction mixture was added dropwise into 1000 mL of saturated aqueous ammonium chloride solution to quench. The mixture was extracted with ethyl acetate (1500 mL x 3), and the organic phase was washed with saturated aqueous sodium chloride solution (1 L x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-5: 1) to give compound M13-2. LCMS (m / z): 258.2 [M+H] + .

[0349] Step 2: To a solution of cuprous cyanide (68.23 g, 761.80 mmol) in tetrahydrofuran (1200 mL) was added methyl lithium (1.6 M in ether, 544.15 mL) dropwise at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 1.5 h, the mixture was cooled to -70 °C, and vinylmagnesium bromide (1 M in tetrahydrofuran, 816.22 mL) was added dropwise. After the addition was completed, the mixture was stirred at -70 °C for 0.5 h. Then a solution of compound M13-2 (140 g, 544.15 mmol) in tetrahydrofuran (120 mL) was added dropwise. After the addition was completed, the mixture was stirred at -70 °C to -20 °C for 1 h. The reaction mixture was cooled to 0 °C and saturated ammonium chloride solution (1000 mL) was added dropwise. The mixture was extracted with ethyl acetate (1000 mL x 3). The organic phase was combined and washed with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100:1 to 10:1) to give compound M13-4. LCMS (m / z): 358.1 [M+H] + ; 1 H NMR (400 MHz, CDC13) d (ppm) = 12.42 (s, 1H), 7.45-7.35 (m, 5H), 6.03-5.82 (m, 2H), 5.50 (s, 1H), 5.23-5.10 (m, 6H), 4.30-4.21 (m, 2H), 2.79-2.68 (m, 1H), 2.50 (dd, J = 3.1, 17.8 Hz, 1H), 1.32-1.28 (m, 3H).

[0350] Step 3: To a solution of compound M13-4 (150 g, 419.70 mmol) in dichloromethane (3 L) was added GRUBB’S second generation catalyst (4.17 g, 4.91 mmol, CAS: 246047-72-3) at 25 °C under nitrogen atmosphere. After heating to 35 °C for 16 h, the reaction mixture was concentrated to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 4:1) to give compound M13-5.

[0351] Step 4: To a mixture of compound M13-5 (106 g, 321.85 mmol) in ethanol (1000 mL) and tetrahydrofuran (1000 mL) was added sodium borohydride (30.44 g, 804.62 mmol) slowly at -10 °C under nitrogen atmosphere. The reaction was stirred at -10 °C for 0.5 h. The reaction was quenched by dropwise addition to hydrochloric acid (1 M, 500 mL) and extracted with ethyl acetate (800 mL x 3). The combined organic phase was washed with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1-3: 1) to give compound M13-6.

[0352] Step 5: To a solution of compound M13-6 (250 g, 754.46 mmol) and triethylamine (419.88 g, 4.14 mol) in 1,2-dichloroethane (2500 mL) was added trifluoroacetic anhydride (316.92 g, 1.51 mol) dropwise at 25 °C under nitrogen atmosphere. The reaction was stirred at 70 °C for 24 h after the addition was completed. The reaction was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1-20: 1) to give compound M13-7.

[0353] Step 6: To a solution of compound M13-7 (176 g, 561.68 mmol) in ethanol (1760 mL) was added lithium hydroxide aqueous solution (2 M, 1404 mL) slowly at 25 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 16 h. The reaction was adjusted to pH 3 with dilute hydrochloric acid (6 M) and concentrated under reduced pressure to remove most of the organic solvent. The reaction was extracted with ethyl acetate (1 L x 3) and the combined organic phase was washed with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound M13-8.

[0354] Step 7: To a solution of compound M13-8 (120 g, 420.62 mmol) in tetrahydrofuran (1200 mL) was added diphenyl phosphorazide (127.33 g, 462.68 mmol) and triethylamine (63.84 g, 630.93 mmol) slowly at 25 °C under nitrogen atmosphere. The reaction was stirred at 70 °C for 1 h. The reaction was concentrated under reduced pressure and the residue was added with dioxane (600 mL) and 10% citric acid aqueous solution (600 mL) and stirred at 60 °C for 12 h. The reaction was diluted with 600 mL of water and extracted with ethyl acetate (1000 mL x 3). The combined organic phase was washed with 800 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1-10: 1) to give compound M13-9.

[0355] Step 8: To a solution of compound M13-9 (64 g, 248.76 mmol) in methanol (3200 mL) was added slowly ammonium acetate (383.48 g, 4.98 mol) under nitrogen atmosphere at 25 °C, after stirring for 20 minutes, sodium cyanoborohydride (156.32 g, 2.48 mol) was added, the reaction was stirred at 70 °C for 1 hour. To the reaction mixture was added slowly 300 mL water, then the organic solvent was removed by reduced pressure concentration, the residue was adjusted to pH 11 with 10% sodium hydroxide aqueous solution, extracted with ethyl acetate (500 mL x 3), the combined organic phase was washed with 400 mL saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 10 pm; 100 A; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 35% - 40%) to give an eluent containing the target product, after removing the organic solvent by reduced pressure concentration, the pH was adjusted to 11 with 10% sodium hydroxide aqueous solution, extracted with ethyl acetate (1000 mL x 3), the combined organic phase was washed with 800 mL saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give compound M13. LCMS (m / z): 259.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 7.42 - 7.28 (m, 5H), 6.35 - 6.06 (m, 2H), 5.19 - 5.00 (m, 2H), 4.69 - 4.26 (m, 2H), 2.95 - 2.81 (m, 1H), 1.68 - 1.43 (m, 2H), 1.35 - 1.17 (m, 2H). Chiral test (column: Chiralpak IE-3 150 x 4.6 mm I.D., 3 pm; mobile phase: A phase is n-hexane, B phase is ethanol (0.05% diethylamine); gradient (B%): 40%) showed that compound M13 contained 4 isomers with retention times of 5.164 min, 5.677 min, 6.361 min and 6.885 min, respectively, in a ratio of about 4:4:1:1.

[0356] Step 9: Compound M13 was separated by chiral column preparation to obtain compounds M13A, M13B, M13C and M13D. The chiral detection (chromatographic column: Chiralpak IE-3 150 x 4.6 mm I.D., 3 pm; mobile phase: A phase is n-hexane, B phase is ethanol (0.05% diethylamine); gradient (B%): 40%) results showed that the retention time of compound M13A was 5.172 min (chiral purity was 98.77%), the retention time of compound M13B was 5.679 min (chiral purity was 93.08%), the retention time of compound M13C was 6.327 min (chiral purity was 100%), and the retention time of compound M13D was 6.851 min (chiral purity was 90.91%), respectively. Two-dimensional nuclear magnetic analysis showed that the NH and the bridge olefin bond (-CH=CH-) in the structures of compounds M13A and M13B were on the same side.

[0357] Intermediate M14

[0358] Step 1: To a solution of compound M14-1 (53.8 g, 779.01 mmol) and pyridine (75.45 mL, 934.81 mmol) in dichloromethane (500 mL) was added acetyl chloride (73.38 g, 934.81 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 5-10 °C for 12 h. The reaction was filtered, and the filter cake was rinsed with dichloromethane (200 mL). The filtrate was washed with water (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 1 / 0 to 10 / 1) to give compound M14-2. 1 H NMR (400 MHz, CDCl3) d = 5.76 (d, J = 2.8 Hz, 1H), 5.69 (d, J = 2.8 Hz, 1H), 2.24 (s, 3H).

[0359] Step 2: To a solution of compound M14-3 (25 g, 316.06 mmol) and sodium borohydride (12.94 g, 342.06 mmol) in ethanol (500 mL) was added ethyl chloroformate (36.105 g, 332.69 mmol) dropwise at -70 °C under nitrogen atmosphere. The reaction was stirred at -70 °C for 2 h. To the reaction was added water (1000 mL) and hydrochloric acid (500 mL, 1 M) slowly at 0 °C, and the combined organic phase was extracted with ethyl acetate (500 mL*2), washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound M14-4. LCMS (m / z): 154.2 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 6.65 (br d, J = 7.8 Hz, 1H), 5.93-5.80 (m, 1H), 5.55 (br s, 1H), 5.18 (br s, 1H), 4.26 (br d, J = 11.8 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.23-1.16 (m, 3H).

[0360] Step 3: A mixture of compound M14-4 (18 g, 117.5 mmol) and compound M14-2 (18 g, 162 mmol) was heated to 105 °C under nitrogen atmosphere for 60 h. The reaction mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate 8 / 1 to 3 / 1) to give compound M14-5. 1 H NMR (400 MHz, CDCl3) δ = 6.73-6.55 (m, 1H), 6.55-6.21 (m, 1H), 5.45-5.29 (m, 1H), 4.26-4.13 (m, 2H), 3.45-3.36 (m, 1H), 3.10-2.87 (m, 2H), 2.60-2.34 (m, 1H), 2.13-2.05 (m, 3H), 1.92-1.81 (m, 1H), 1.33-1.23 (m, 3H).

[0361] Step 4: To a solution of compound M14-5 (4.4 g, 16.65 mmol) in methanol (16 mL) was added sodium methoxide (5.4 M in methanol, 6.17 mL) dropwise at 5-10 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h. To the reaction was added water (20 mL) dropwise at 0 °C, and extracted with ethyl acetate (200 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 7 / 1 to 2 / 1) to give compound M14-6. 1 H NMR (400 MHz, CDCl3) δ = 6.74-6.53 (m, 1H), 6.52-6.29 (m, 1H), 5.08-4.81 (m, 1H), 4.22-4.11 (m, 2H), 3.56-3.30 (m, 1H), 3.25-2.81 (m, 2H), 2.44-2.15 (m, 2H), 1.27 (q, J = 7.2 Hz, 3H).

[0362] Step 5: To a solution of compound M14-6 (2 g, 10.25 mmol) in methanol (40 mL) was added ammonium acetate (15.8 g, 205 mmol) at 5-10 °C under nitrogen atmosphere. After 15 min, the reaction was cooled to 0 °C in an ice-water bath, and sodium cyanoborohydride (6.44 g, 102 mmol) was added portionwise. After the addition was complete, the reaction was slowly warmed to 70 °C and stirred for 1 h. The reaction was cooled to 0 °C, and 50 mL of water and 300 mL of ethyl acetate were added. The aqueous phase was extracted with ethyl acetate / methanol (10 / 1, 80 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse-phase column chromatography (column: Phenomenex luna C18, mobile phase: H20-acetonitrile, gradient (acetonitrile %): 13%-17%) to give compound M14. 1 H NMR (400 MHz, CDC13) δ = 6.59-6.31 (m, 2H), 4.76-4.46 (m, 1H), 4.19-4.06 (m, 2H), 3.48-3.31 (m, 1H), 3.23-3.10 (m, 1H), 3.09-2.84 (m, 1H), 2.78 (br s, 1H), 2.26-1.90 (m, 2H), 1.33-1.18 (m, 3H).

[0363] Example 1

[0364] To a solution of compound M3 (120 mg, 410 μmol), compound M2 (198 mg, 615 μmol) in ethylene glycol dimethyl ether (3 mL) and water (0.3 mL) was added potassium carbonate (113 mg, 820 μmol) and tetrakis(triphenylphosphine)palladium (47.4 mg, 41.0 μmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 90 °C for 4 h. After the reaction was completed, 3 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by neutral alumina column chromatography (petroleum ether: ethyl acetate = 3: 1, then ethyl acetate:methanol = 10: 1), and then by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: [water (ammonia water)-acetonitrile]; gradient (acetonitrile %): 42%-72%) to give compound 1. LCMS (m / z): 452.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 7.13 (s, 1H), 7.09 (s, 1H), 6.00 (br d, J = 8.0 Hz, 1H), 5.26 (s, 2H), 4.31-4.19 (m, 1H), 2.95 (br d, J = 7.6 Hz, 1H), 2.76 (br t, J = 7.6 Hz, 2H), 2.69-2.58 (m, 1H), 2.18 (s, 3H), 2.02 (br t, J = 7.6 Hz, 2H), 1.96-1.81 (m, 3H), 1.74-1.65 (m, 1H), 1.62-1.48 (m, 1H), 1.43-1.30 (m, 1H), 0.69 (br s, 2H), 0.63 (br s, 2H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.228; SFC detection (Chromolith Speed ROD® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%) : 5% - 40%) Retention time of compound 1 was 1.549 min with 100% chiral purity.

[0365] Example 2

[0366] Compound 2 was prepared from compound M4 and compound M2 following the synthetic procedure described in the above examples. Compound 2 was obtained after purification by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: [water (ammonia) - acetonitrile]; gradient (acetonitrile%): 55% - 85%). LCMS (m / z): 452.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.13 (s, 1H), 7.09 (s, 1H), 6.00 (br d, J = 8.0 Hz, 1H), 5.26 (s, 2H), 4.31-4.19 (m, 1H), 2.95 (br d, J = 7.6 Hz, 1H), 2.76 (br t, J = 7.6 Hz, 2H), 2.69-2.58 (m, 1H), 2.18 (s, 3H), 2.02 (br t, J = 7.6 Hz, 2H), 1.96-1.81 (m, 3H), 1.74-1.65 (m, 1H), 1.62-1.48 (m, 1H), 1.43-1.30 (m, 1H), 0.69 (br s, 2H), 0.63 (br s, 2H); 19F NMR (376 MHz, DMSO-d6) d = -61.273; SFC detection (Chromolith® SpeedRay® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%) : 5% - 40%) Retention time of compound 2: 1.733 min, chiral purity: 100%.

[0367] Example 3

[0368] Compound 3 was prepared from compound M5 and compound M2 following the synthetic procedure of the above examples. Compound 3 was obtained after purification by prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 pm; mobile phase: [water (ammonia) - acetonitrile]; gradient (acetonitrile%): 38% - 68%). LCMS (m / z): 477.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 7.14 (s, 1H), 7.09 (s, 1H), 6.13 (d, J = 8.0 Hz, 1H), 5.27 (s, 2H), 4.35 - 4.22 (m, 1H), 3.78 (s, 2H), 3.04 (br dd, J = 3.6, 10.0 Hz, 1H), 2.81 - 2.69 (m, 3H), 2.23 - 2.09 (m, 2H), 2.03 (br t, J = 7.6 Hz, 2H), 1.93 (br dd, J = 4.0, 7.6 Hz, 1H), 1.82 - 1.70 (m, 1H), 1.68 - 1.52 (m, 1H), 1.45 - 1.32 (m, 1H), 0.70 (br s, 2H), 0.63 (br s, 2H); 19 F NMR (376 MHz, DMSO-d6) d = -61.228; SFC detection (Chromolith® SpeedRay® column: Chiralpak IC-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%) : 20% - 60%) Retention time of compound 3: 1.434 min, chiral purity: 98.81%.

[0369] Example 4

[0370] The crude product of compound 4 was prepared from compound M6 and compound M2 by referring to the synthesis method of the above examples, and purified by preparative separation on a reversed-phase column (chromatographic column: Phenomenex luna C18 (250 x 70 mm, 10 pm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 28% - 32%), and then purified by prep-HPLC (chromatographic column: Waters Xbridge 150 x 25 mm x 5 pm; mobile phase: [water (0.5% ammonia water) - acetonitrile]; gradient (acetonitrile %): 62% - 82%) to obtain compound 4. LCMS (m / z): 477.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 7.47 (s, 1H), 7.24 (s, 1H), 5.95 (s, 2H), 4.68 (d, J = 8.4 Hz, 1H), 4.42 - 4.30 (m, 1H), 3.82 - 3.72 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.81 (br d, J = 7.6 Hz, 1H), 2.60 - 2.53 (m, 1H), 2.46 - 2.34 (m, 2H), 2.03 (t, J = 7.6 Hz, 2H), 1.76 - 1.65 (m, 2H), 1.64 - 1.50 (m, 4H), 0.97 - 0.87 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) d = -61.277; SFC detection (chromatographic column: Chiralpak OD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase is supercritical CO2, B phase is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20% - 60%) the retention time of compound 4 is 1.067 min, and the chiral purity is 100%.

[0371] Example 5

[0372] Step 1: The crude product of compound 5 was prepared from compound M1, compound M2 and compound M10 by referring to the synthesis method of the above examples, and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 - 2: 1), and then purified by preparative separation on a reversed-phase column (chromatographic column: Phenomenex luna C18 20-45 pm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 55%) to obtain compound 5. LCMS (m / z): 453.1. [M+H] + .

[0373] Step 2: Compound 5 was prepared by SFC preparative separation (Chromatographic column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); Mobile phase: A phase was supercritical CO2, B phase was acetonitrile / isopropanol (0.1% ammonia); Gradient (B%): 25%) to give compounds 5A and 5B. Compound 5A characterization: LCMS (m / z): 453.2 [M+H] + ; 1 H NMR (400 MHz, CDC13) δ = 7.33 (s, 1H), 7.10 (s, 1H), 4.95-4.84 (m, 1H), 4.19 (dd, J = 5.6, 9.6 Hz, 1H), 4.09 (d, J = 6.8 Hz, 1H), 3.76 (dd, J = 2.8, 9.6 Hz, 1H), 3.04 (t, J = 7.6 Hz, 2H), 2.31 (dd, J = 7.6, 13.2 Hz, 1H), 2.12 (t, J = 7.6 Hz, 2H), 1.71 (dd, J = 4.0, 13.2 Hz, 1H), 1.52-1.48 (m, 1H), 1.38 (s, 3H), 1.29 (s, 3H), 1.26 (s, 2H), 1.04-0.96 (m, 2H); 19 F NMR (376 MHz, CDC13) δ (ppm) = -62.725; SFC detection (Chromatographic column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; Mobile phase: A phase was supercritical CO2, B phase was isopropanol / acetonitrile (0.05% diethylamine); Gradient (B%): 20%-60%) Compound 5A retention time was 0.960 min with 100% chiral purity. Compound 5B characterization: LCMS (m / z): 453.2 [M+H] + ; 1 H NMR (400 MHz, CDC13) δ = 7.33 (s, 1H), 7.10 (s, 1H), 4.95-4.84 (m, 1H), 4.19 (dd, J = 5.6, 9.6 Hz, 1H), 4.09 (d, J = 6.8 Hz, 1H), 3.76 (dd, J = 2.8, 9.6 Hz, 1H), 3.04 (t, J = 7.6 Hz, 2H), 2.31 (dd, J = 7.6, 13.2 Hz, 1H), 2.12 (t, J = 7.6 Hz, 2H), 1.71 (dd, J = 4.0, 13.2 Hz, 1H), 1.52-1.48 (m, 1H), 1.38 (s, 3H), 1.29 (s, 3H), 1.26 (s, 2H), 1.04-0.96 (m, 2H); 19F NMR (376 MHz, CDC13) δ = -62.725; SFC detection (Chromatographic column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 μm; Mobile phase: A phase: Supercritical CO2, B phase: isopropanol / acetonitrile (0.05% diethylamine); Gradient (B%): 20% - 60%) Retention time of compound 5B was 1.065 min with 100% chiral purity.

[0374] Example 6

[0375] Step 1 : To a solution of compound 6-1 (300 mg, 1.59 mmol) in N-methylpyrrolidine (3 mL) was added compound M5-3 (287 mg, 2.06 mmol) and N,N-diisopropylethylamine (820 mg, 6.35 mmol) under nitrogen atmosphere at room temperature. The reaction was heated to 140 °C for 12 h. After the reaction was cooled to room temperature, iodacetonitrile (132 mg, 793 μmol) was added and the reaction was heated to 60 °C for 1 h. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filtrate was purified by prep-HPLC (Chromatographic column: Spherical C18, 40-60 μm, 30 x 100 mm; Mobile phase: [water (0.1% formic acid) - acetonitrile]; Gradient (acetonitrile%): 30-35%) to give compound 6-2. Mobile phase: [water (0.1% formic acid) - acetonitrile]; Gradient (acetonitrile%): 30-35%) to give compound 6-2. 1 H NMR (400 MHz, DMSO-d6) δ = 3.99 - 3.89 (m, 1H), 3.82 - 3.73 (m, 1H), 3.67 (d, J = 1.6 Hz, 2H), 3.11 - 2.91 (m, 3H), 2.87 (br t, J = 7.2 Hz, 2H), 2.83 - 2.65 (m, 3H), 2.14 - 2.01 (m, 2H), 1.98 - 1.86 (m, 1H), 1.8 - 1.71 (m, 1H), 1.64 - 1.45 (m, 1H), 1.36 - 1.21 (m, 1H).

[0376] Step 2: To a solution of compound M7 (40 mg, 137.09 μmol) and compound 6-2 (55.09 mg, 150.80 μmol) in dioxane (1.5 mL) was added 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (8.93 mg, 13.71 μmol) and potassium phosphate (1.5 M in water, 274.18 μL) under nitrogen atmosphere at room temperature. The reaction was heated at 100 °C for 1 h. The reaction was diluted with 4 mL water and extracted with ethyl acetate (2 mL x 6). The combined organic phase was washed with 5 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated by prep-HPLC (column: Spherical C18, 40-60 μm, 4.6*250mm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 50%). Step 2: To a solution of compound M7 (40 mg, 137.09 μmol) and compound 6-2 (55.09 mg, 150.80 μmol) in dioxane (1.5 mL) was added 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (8.93 mg, 13.71 μmol) and potassium phosphate (1.5 M in water, 274.18 μL) under nitrogen atmosphere at room temperature. The reaction was heated at 100 °C for 1 h. The reaction was diluted with 4 mL water and extracted with ethyl acetate (2 mL x 6). The combined organic phase was washed with 5 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated by prep-HPLC (column: Spherical C18, 40-60 μm, 4.6*250mm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 50%). Step 2: To a solution of compound M7 (40 mg, 137.09 μmol) and compound 6-2 (55.09 mg, 150.80 μmol) in dioxane (1.5 mL) was added 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (8.93 mg, 13.71 μmol) and potassium phosphate (1.5 M in water, 274.18 μL) under nitrogen atmosphere at room temperature. The reaction was heated at 100 °C for 1 h. The reaction was diluted with 4 mL water and extracted with ethyl acetate (2 mL x 6). The combined organic phase was washed with 5 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated by prep-HPLC (column: Spherical C18, 40-60 μm, 4.6*250mm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 50%). + .

[0377] Step 3: To a solution of compound 6-3 (12 mg, 24.72 μmol) in hydrochloric acid (6 M, 1 mL) was added under nitrogen atmosphere at room temperature. The reaction was heated at 70 °C for 0.5 h. The reaction was diluted with 20 mL saturated sodium bicarbonate and extracted with ethyl acetate (10 mL x 4). The combined organic phase was washed with 10 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia) - acetonitrile]; gradient (acetonitrile %): 30-60%) to give compound 6. LCMS (m / z): 442.2 [M+H] + ; 1 H NMR (400 MHz, CD3OD) d = 8.36 (s, 1H), 7.73-7.69 (m, 1H), 7.64 (br d, J = 7.2 Hz, 1H), 4.16 (br d, J = 8.8 Hz, 1H), 3.96 (br d, J = 12.4 Hz, 1H), 3.76 (s, 2H), 3.21-2.85 (m, 7H), 2.22-2.05 (m, 3H), 1.99-1.87 (m, 1H), 1.83-1.68 (m, 1H), 1.55-1.40 (m, 1H); 19F NMR (376 MHz, CD3OD) d = -62.314; SFC detection (Chromatographic column: OJ-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase: supercritical CO2, B phase: isopropyl alcohol (0.05% diethylamine); Gradient (B%): 5-40%) Retention time of compound 6 was 2.349 min with 100% chiral purity.

[0378] Example 7

[0379] Step 1: To a solution of compound M6 (80 mg, 251.72 pmol) and compound M7 (101 mg, 276 pmol, 75% purity) in dioxane (1.2 mL) was added 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (16.40 mg, 25.18 pmol) and potassium phosphate (1.5 M in water, 503.44 pL) under nitrogen atmosphere at room temperature. The reaction was heated at 100 °C for 1 h. The reaction was cooled to room temperature, diluted with 10 mL of water and extracted with ethyl acetate (3 mL x 4). The combined organic phase was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to get the crude product which was purified by preparative reverse phase column (Chromatographic column: Spherical C18, 40-60 pm, 150*25mm; Mobile phase: [water (0.1% formic acid) - acetonitrile]; Gradient (acetonitrile %): 50-90%) to get compound 7-1. LCMS (m / z): 512.3 [M+H] Mobile phase: [water (0.1% formic acid) - acetonitrile]; Gradient (acetonitrile %): 50-90%) to get compound 7-1. LCMS (m / z): 512.3 [M+H] + .

[0380] Step 2: To a solution of compound 7-1 (80 mg, 111 pmol, 71% purity) in hydrochloric acid (6 M, 2 mL) was added under nitrogen atmosphere at room temperature. The reaction was heated at 70 °C for 0.5 h. The reaction was cooled to 0 °C and slowly added to 30 mL of saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate (10 mL x 4). The combined organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to get the crude product which was purified by preparative reverse phase column (Chromatographic column: Phenomenex luna C18 150*25mm*10pm; Mobile phase: [water (0.1% formic acid) - acetonitrile]; Gradient (acetonitrile %): 36-46%) and then by prep-HPLC (Chromatographic column: Waters Xbridge 150*25mm*5pm; Mobile phase: [water (0.5% ammonia) - acetonitrile]; Gradient (acetonitrile %): 33-63%) to get compound 7. LCMS (m / z): 468.2 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ = 8.34 (s, 1H), 7.72-7.67 (m, 1H), 7.64-7.58 (m, 1H), 4.52-4.45 (m, 1H), 3.71 (s, 2H), 3.07 (br t, J = 7.6 Hz, 2H), 2.85 (br d, J = 8.8 Hz, 1H), 2.75-2.61 (m, 2H), 2.59-2.47 (m, 1H), 2.17 (t, J = 7.6 Hz, 2H), 1.91-1.57 (m, 6H), 1.09-0.95 (m, 2H); 19 F NMR (376 MHz, CD3OD) δ = -62.360; SFC detection (Chromolpack AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: isopropanol / acetonitrile (0.05% diethylamine); gradient (B%) : 5-40%) Retention time of compound 7 was 0.992 min with 100% chiral purity.

[0381] Example 8

[0382] To a solution of compound M8 (80 mg, 273.22 pmol), compound M2 (131.77 mg, 409.83 pmol) and potassium carbonate (113.28 mg, 819.65 pmol) in dioxane (1.5 mL) and water (0.5 mL) was added 1,1-bis(diphenylphosphino)ferrocene palladium chloride (19.99 mg, 27.32 pmol) under nitrogen atmosphere at room temperature. The reaction was heated at 90 °C for 2 h. The reaction was cooled to room temperature, diluted with 5 mL water, extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with 10 mL saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was separated by thin layer chromatography (dichloromethane:methanol = 10:1, Rf = 0.39) and then purified by reverse phase column (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 20%-50%) to give compound 8. LCMS (m / z): 452.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) d = 7.35 (s, 1H), 7.23 (s, 1H), 6.20-6.01 (m, 3H), 4.35-4.20 (m, 1H), 2.96 (br d, J = 9.6 Hz, 1H), 2.88 (s, 2H), 2.75 (s, 2H), 2.65 (br d, J = 11.6 Hz, 1H), 2.20 (s, 3H), 1.99-1.81 (m, 3H), 1.76-1.65 (m, 1H), 1.63-1.48 (m, 1H), 1.43-1.28 (m, 1H), 0.71-0.52 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) d = -61.288; SFC detection (Chromatographic column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; Mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); Gradient (B%): 10% - 60%), the retention time of compound 8 was 1.247 min, and the chiral purity was 100%.

[0383] Example 9

[0384] To a mixture solution of compound M9 (50 mg, 157 pmol) and compound M2 (65.8 mg, 205 pmol) in ethylene glycol dimethyl ether (1 mL) and water (0.1 mL) was added potassium carbonate (43.5 mg, 315 pmol) and tetrakis(triphenylphosphine)palladium (18.2 mg, 15.7 pmol) under nitrogen atmosphere at 25 °C, and the reaction solution was stirred at 90 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with 3 mL of water, extracted with ethyl acetate (3 mL x 3), and the combined organic phase was washed with 8 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by preparative reverse phase column (Chromatographic column: Phenomenex luna C18 250 x 70 mm x 10 pm; Mobile phase: water (0.1% formic acid) - acetonitrile; Gradient (acetonitrile%): 30% - 60%) to give compound 9. LCMS (m / z): 477.1. [M+H] + ; 1H NMR (400 MHz, DMSO-d6) d = 7.35 (s, 1H), 7.23 (s, 1H), 6.24 (d, J = 8.0 Hz, 1H), 6.13 (s, 2H), 4.39-4.22 (m, 1H), 3.77 (s, 2H), 3.03 (br dd, J = 3.6, 10.4 Hz, 1H), 2.88 (s, 2H), 2.80-2.70 (m, 3H), 2.22-2.09 (m, 2H), 1.98-1.89 (m, 1H), 1.85-1.71 (m, 1H), 1.67-1.52 (m, 1H), 1.36 (dq, J = 4.0, 12.0 Hz, 1H), 0.71-0.55 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) d = -61.295; SFC detection (Chromolith Speed ROD column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%): 10% to 60%), the retention time of compound 9 was 1.479 min with a chiral purity of 100.0%.

[0385] Example 10

[0386] Step 1: To a solution of compound M8-6 (500 mg, 2.32 mmol) and compound M10 (764.99 mg, 6.65 mmol) in N-methylpyrrolidine (5 mL) was added N,N- diisopropylethylamine (901.36 mg, 6.97 mmol) under nitrogen atmosphere. The reaction was heated at 140 °C for 12 h. The reaction was cooled to room temperature, filtered, and the filtrate was purified by reverse phase column chromatography: Phenomenex luna C18 20-45 pm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile%): 40% - 70%) to give compound 10-1. LCMS (m / z): 294.1. [M+H] Step 1: To a solution of compound M8-6 (500 mg, 2.32 mmol) and compound M10 (764.99 mg, 6.65 mmol) in N-methylpyrrolidine (5 mL) was added N,N- diisopropylethylamine (901.36 mg, 6.97 mmol) under nitrogen atmosphere. The reaction was heated at 140 °C for 12 h. The reaction was cooled to room temperature, filtered, and the filtrate was purified by reverse phase column chromatography: Phenomenex luna C18 20-45 pm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile%): 40% - 70%) to give compound 10-1. LCMS (m / z): 294.1. [M+H] + .

[0387] Step 2: Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (137.66 mg, 119 μmol) was added to a solution of compound 10-1 (350 mg, 1.19 mmol), compound M2 (574.57 mg, 1.79 mmol), and potassium carbonate (329.29 mg, 2.38 mmol) in ethylene glycol dimethyl ether (3.5 mL) and water (0.35 mL). The mixture was purged with nitrogen three times, and the reaction was carried out at 90 °C for 3 hours. The reaction solution was cooled to room temperature, 15 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (Phenomenex luna C18 20-45 μm). Mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 40%-70% to give compound 10. LCMS (m / z): 453.1. [M+H] + .

[0388] Step 3: Compound 10 (400 mg, 883.2 μmol) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm; mobile phase: A phase is supercritical CO2, B phase is isopropanol (0.1% ammonia); gradient (B%): 32%) to obtain two products, which were then preparatively separated by reversed-phase column (column: Phenomenex luna C18 20-45 μm). Mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 40%-70%) to obtain compounds 10A and 10B.

[0389] Characterization of compound 10A: LCMS (m / z): 453.2. [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.36 (s, 1H), 7.23 (s, 1H), 6.53 (d, J = 6.0Hz, 1H), 6. 12(s,2H),4.76(qd,J=6.8,14.0Hz,1H),4.13(dd,J=6.8,8.8Hz,1H),3.64(d d,J=6.4,8.8Hz,1H),2.88(s,2H),2.78(s,2H),2.20(dd,J=8.0,12.4Hz,1H) ,1.83(dd,J=7.2,12.4Hz,1H),1.30(s,3H),1.21(s,3H),0.73-0.50(m,4H); 19F NMR (376 MHz, DMSO-d6) d = -61.302; SFC detection (Chiralpak IC 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: isopropanol (0.05% diethylamine); gradient (B%): 20-60%) retention time of compound 10A was 0.932 min with 99.45% chiral purity.

[0390] Compound 10B was characterized by LCMS (m / z): 453.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 7.36 (s, 1H), 7.23 (s, 1H), 6.53 (d, J = 6.0 Hz, 1H), 6.12 (s, 2H), 4.76 (qd, J = 6.8, 14.0 Hz, 1H), 4.13 (dd, J = 6.8, 8.8 Hz, 1H), 3.64 (dd, J = 6.0, 8.8 Hz, 1H), 2.88 (s, 2H), 2.78 (s, 2H), 2.20 (dd, J = 8.0, 12.4 Hz, 1H), 1.83 (dd, J = 7.2, 12.4 Hz, 1H), 1.30 (s, 3H), 1.21 (s, 3H), 0.74-0.55 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) d = -61.295; SFC detection (Chiralpak IC 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: isopropanol (0.05% diethylamine); gradient (B%): 20-60%) retention time of compound 10B was 1.123 min with 98.86% chiral purity.

[0391] Example 11

[0392] Step 1: To a solution of compound M5-3 (388 mg, 2.79 mmol) in toluene (10 mL) was added compound M8-6 (500 mg, 2.32 mmol), cesium carbonate (2.27 g, 6.97 mmol), (±)-2,2-bis(diphenylphosphino)-1,1'-binaphthalene (144.75 mg, 232.47 pmol) and tris(dibenzylideneacetone)dipalladium (212.88 mg, 232.47 pmol) under nitrogen atmosphere at room temperature. The reaction was heated to 100 °C for 4 h. After the reaction was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The residue was separated by preparative reverse phase column [column: Spherical C18, 40-60 pm, 150*4.6 mm I.D., 5 pm; mobile phase: A phase: acetonitrile, B phase: water (0.05% formic acid); gradient (B%): 20-60%] to give compound M8-7 (100 mg, 20.0% yield). Mobile phase: Water (0.1% formic acid) - acetonitrile; Gradient (acetonitrile %): 75%] to get compound 11-1. LCMS (m / z): 318.1 [M+H] + .

[0393] Step 10: To a solution of compound M7 (124 mg, 453 pmol) and compound 11-1 (120 mg, 377 pmol) in dioxane (6 mL) was added 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (24.61 mg, 37.76 pmol) and aqueous potassium phosphate (1.5 M, 755.15 pL) under nitrogen atmosphere at room temperature. The reaction was heated at 100 °C for 1 h. The reaction was cooled to room temperature, diluted with 6 mL of water, extracted with ethyl acetate (6 mL x 3), the combined organic phase was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to get the crude product which was purified by preparative reverse phase HPLC [Column: Spherical C18, 40-60 pm, 150 x 4.6 mm; Mobile phase: Water (0.1% formic acid) - acetonitrile; Gradient (acetonitrile %): 20-50%] to get compound 11-2. LCMS (m / z): 512.3 [M+H] Mobile phase: Water (0.1% formic acid) - acetonitrile; Gradient (acetonitrile %): 75%] to get compound 11-1. LCMS (m / z): 318.1 [M+H] + .

[0394] Step 11: To a solution of compound 10 (25 mg, 48.87 pmol) in hydrochloric acid (6 M, 1 mL) was added under nitrogen atmosphere at room temperature. The reaction was heated at 70 °C for 1 h. The reaction was cooled to 0 °C, slowly added to 20 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to get the crude product which was purified by preparative HPLC [Column: Phenomenex luna C18 150*25mm*10pm; Mobile phase: Water (formic acid) - acetonitrile; Gradient (acetonitrile %): 20-50%] to get compound 11. LCMS (m / z): 468.2 [M+H] + ; 1 H NMR (400 MHz, CD3OD) d = 8.36 (s, 1H), 7.71-7.65 (m, 1H), 7.64-7.58 (m, 1H), 4.49-4.39 (m, 1H), 3.71 (s, 2H), 3.16 (br s, 1H), 3.13 (d, J = 1.6 Hz, 2H), 2.88 (s, 2H), 2.82-2.74 (m, 1H), 2.47-2.33 (m, 2H), 2.11-2.00 (m, 1H), 1.94-1.84 (m, 1H), 1.82-1.70 (m, 1H), 1.61-1.49 (m, 1H), 0.73 (d, J = 6.4 Hz, 4H);19 F NMR (376 MHz, CD3OD) d = -62.349.

[0395] Example 12

[0396] To a mixture solution of compound M11 (50.0 mg, 172 pmol) and compound 12-1 (74.3 mg, 259 pmol) in dioxane (1 mL) and water (0.2 mL) was added potassium carbonate (71.5 mg, 518 pmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (12.6 mg, 17.3 pmol) under nitrogen atmosphere at room temperature, and the reaction was carried out at 100 °C for 1 h after replacing nitrogen three times. The reaction solution was poured into 3 mL of water solution, extracted with ethyl acetate (4 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-2:1), and then by reverse phase column chromatography preparation separation (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient (acetonitrile%): 10%-40%) to give compound 12. LCMS (m / z): 415.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) d = 7.47 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 0.8 Hz, 1H), 7.01-6.96 (m, 2H), 6.09 (s, 2H), 4.64-4.52 (m, 1H), 4.14 (br d, J = 8.4 Hz, 1H), 3.83-3.77 (m, 2H), 3.33 (s, 2H), 2.31 (ddd, J = 2.8, 6.4, 13.2 Hz, 2H), 2.19 (d, J = 0.8 Hz, 3H), 1.71-1.66 (m, 2H); 19 F NMR (376 MHz, CDCl3) d = -63.053.

[0397] Example 13

[0398] To a mixture solution of compound M11 (110 mg, 380 pmol) and compound 13-1 (117 mg, 569 pmol) in dioxane (1 mL) and water (0.2 mL) was added potassium carbonate (157 mg, 1.14 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (27.8 mg, 38.0 pmol) under nitrogen atmosphere at room temperature. The reaction was replaced by nitrogen for three times and reacted at 100 °C for 1 h. After the reaction was cooled to room temperature, it was poured into 5 mL of water and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-2:1), reversed phase column preparation separation (column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient (acetonitrile%): 30%-60%) and reversed phase column preparation separation (column: Phenomenex luna C18 (250*70mm, 10pm); mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 20%-45%) to give compound 13. LCMS (m / z): 416.0 [M+H] + . 1 H NMR (400 MHz, CDC13) d = 7.68 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.30 (d, J = 1.2 Hz, 1H), 7.15-7.10 (m, 1H), 6.12 (s, 2H), 4.59-4.42 (m, 1H), 4.29-4.22 (m, 1H), 3.83-3.76 (m, 2H), 3.32 (s, 2H), 2.28 (ddd, J = 2.8, 6.4, 13.2 Hz, 2H), 2.22 (s, 3H), 1.70-1.65 (m, 2H); 19 F NMR (376 MHz, CDC13) d = -63.051.

[0399] Example 14

[0400] To a mixture solution of compound M12 (30 mg, 102 pmol) and compound 13-1 (30.2 mg, 155 pmol) in dioxane (0.5 mL) and water (0.1 mL) was added potassium carbonate (42.9 mg, 310 pmol) and 2-(dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (8.66 mg, 10.3 pmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 100 °C for 1 h. After the reaction was cooled to room temperature, it was poured into 5 mL of water and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) and high performance liquid chromatography (preparative column: Waters Xbridge C18 150 x 25 mm x 5 pm; mobile phase: [water (10 mM NH4HCO3) - acetonitrile]; gradient (acetonitrile %): 25%-55%) to give compound 14. LCMS (m / z): 416.1 [M+H] + . 1 H NMR (400 MHz, CDC13) d = 12.34-11.54 (m, 1H), 7.54-7.48 (m, 1H), 7.35 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.09 (s, 2H), 4.47-4.38 (m, 1H), 4.32-4.18 (m, 1H), 3.81-3.81 (m, 2H), 3.31 (s, 2H), 2.45 (s, 3H), 2.19 (ddd, J = 2.8, 6.4, 13.2 Hz, 2H), 1.69-1.62 (m, 2H); 19 F NMR (376 MHz, CDC13) d = -63.053.

[0401] Example 15

[0402] Step 1: To a solution of compound 15-1 (90.0 g, 373 mmol) in N,N- dimethylformamide (1000 mL) was added potassium carbonate (67.1 g, 485 mmol), potassium iodide (3.10 g, 18.7 mmol) and benzyl bromide (57.5 g, 336 mmol) portionwise slowly under nitrogen atmosphere at room temperature. The reaction was stirred at 120 °C for 3 h. The reaction was diluted with 3000 mL of water solution, extracted with ethyl acetate (1000 mL x 3), the combined organic phase was washed with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-10:1) to give compound 15-2. 1 H NMR (400 MHz, CDC13) d = 7.69 (d, J = 8.0 Hz, 1H), 7.54-7.48 (m, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.39-7.33 (m, 1H), 7.19-7.10 (m, 2H), 5.20 (s, 2H).

[0403] Step 2: To a solution of compound 15-2 (34 g, 102.68 mmol) and bis(neopentyl glycolato)diboron (34.8 g, 154 mmol) in dioxane (1000 mL) was added bis(diphenylphosphino phenyl ether) palladium(II) chloride (7.35 g, 10.27 mmol) and potassium acetate (40.31 g, 410.72 mmol) under nitrogen atmosphere at room temperature. After three times of nitrogen replacement, the reaction was stirred at 100 °C for 3 h. The reaction was filtered, the filtrate was concentrated under reduced pressure to give a crude product which was separated by reverse phase column chromatography preparation (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 55%-65%) to give compound 15-3. 1 H NMR (400 MHz, DMSO-d6) d = 8.07 (s, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.45-7.38 (m, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.33-7.26 (m, 2H), 5.23 (s, 2H).

[0404] Step 3: To a solution of compound M1-6 (32.5 g, 199.38 mmol) and compound 15-3 (59.03 g, 199.38 mmol) in N,N-dimethylacetamide (600 mL) was added [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2-amino-1,1-biphenyl-2-yl)palladium(II) (6.33 g, 9.97 mmol) and potassium phosphate (3 M aqueous solution, 199.38 mL) portionwise slowly under nitrogen atmosphere at 25 °C. After the addition was complete, the reaction was purged with nitrogen three times and stirred at 60 °C for 2 h. The reaction was diluted with 2000 mL of water and extracted with ethyl acetate (1000 mL x 3). The combined organic phase was washed with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40% - 60%) to give compound 15-4. LCMS (m / z): 379.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 7.93 (s, 1H), 7.63 - 7.54 (m, 2H), 7.53 - 7.47 (m, 1H), 7.37 - 7.28 (m, 3H), 7.24 (d, J = 6.8 Hz, 2H), 5.26 (s, 2H), 2.13 (s, 3H).

[0405] Step 4: To a solution of compound 15-4 (9.00 g, 23.7 mmol) and compound M13 (12.9 g, 47.5 mmol) in toluene (90 mL) was added (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl) (2-methylamino-1,1-biphenyl-2-yl)palladium(II) (2.02 g, 2.38 mmol) and sodium tert-butoxide (6.85 g, 71.3 mmol) under nitrogen atmosphere at 25 °C. The reaction was stirred at 70 °C for 2 h. The reaction was diluted with 500 mL of water and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 60% - 70%) to give compound 15-5. LCMS (m / z): 601.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 7.56-7.42 (m, 5H), 7.41-7.17 (m, 10H), 6.33-6.16 (m, 2H), 5.23 (s, 2H), 5.18-5.08 (m, 2H), 4.85-4.65 (m, 1H), 4.60-4.45 (m, 1H), 4.11 (br s, 1H), 1.97 (br s, 1H), 1.93-1.77 (m, 3H), 1.70-1.56 (m, 2H), 1.46-1.34 (m, 1H). In the structure of compound 15-5, NH and the stereochemistry of the bridging alkene (-CH=CH-) are on the same side. The specific structure of compound 15-5 is as follows:

[0406] Step 5: To a solution of compound 15-5 (4.9 g, 8.16 mmol) in dichloromethane (30 mL) was added hydrobromic acid in acetic acid (20 mL, 33% purity) slowly under nitrogen atmosphere at 25 °C. The reaction was stirred at 25 °C for 1 h. The reaction was diluted with 40 mL water and washed with ethyl acetate (50 mL x 3). The aqueous phase was filtered and prepared by reverse phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 50% - 60%) to give the formate salt of compound 15-6. LCMS (m / z): 377.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.38 (d, J = 7.6 Hz, 1H), 7.29-7.15 (m, 2H), 6.82-6.65 (m, 2H), 6.30 (dd, J = 1.7, 6.0 Hz, 1H), 6.19 (br d, J = 6.0 Hz, 1H), 4.34 (br s, 2H), 4.18 (br s, 1H), 2.03 (s, 3H), 1.92-1.69 (m, 2H), 1.64-1.42 (m, 2H). In the structure of compound 15-6, NH and the stereochemistry of the bridging alkene (-CH=CH-) are on the same side. The specific structure of compound 15-6 is as follows:

[0407] Step 6: To a solution of compound 15-6 (3.2 g, formate salt) and N,N- diisopropylethylamine (3.1 g, 12.02 mmol) in dimethyl sulfoxide (40 mL) was added iodine ethyl cyanide (1.34 g, 8.02 mmol) slowly under nitrogen atmosphere at 25 °C and stirred for 1 h at 25 °C. The reaction was filtered and the filtrate was separated by reverse phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 20% - 30%) to give compound 15. LCMS (m / z): 416.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 11.24 - 9.89 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.26 - 7.12 (m, 2H), 6.65 (d, J = 0.6 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 6.11 (dd, J = 1.8, 5.4 Hz, 1H), 5.99 (dd, J = 1.6, 5.6 Hz, 1H), 4.24 - 4.04 (m, 1H), 3.94 - 3.85 (m, 1H), 3.60 (br d, J = 1.6 Hz, 1H), 3.50 - 3.38 (m, 2H), 2.02 (s, 3H), 1.77 - 1.52 (m, 2H), 1.45 - 1.28 (m, 2H). In the structure of compound 15, NH is syn to the bridge olefinic bond (-CH=CH-), and the specific structure is as follows:

[0408] Step 7: Compound 15 was separated by SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 pm); mobile phase: A phase: supercritical carbon dioxide, B phase: isopropyl alcohol (0.1% ammonia water); gradient (B%): 30%) to give compound 15A and compound 15B. Compound 15A was characterized: LCMS (m / z): 416.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.96 - 10.00 (m, 1H), 7.39 (br d, J = 7.6 Hz, 1H), 7.26 - 7.16 (m, 2H), 6.66 (s, 1H), 6.48 (br d, J = 7.6 Hz, 1H), 6.11 (dd, J = 1.6, 5.6 Hz, 1H), 5.99 (dd, J = 1.6, 5.6 Hz, 1H), 4.12 (br d, J = 2.8 Hz, 1H), 3.86 (br s, 1H), 3.60 (br s, 1H), 3.43 (br d, J = 3.4 Hz, 2H), 2.01 (s, 3H), 1.77 - 1.67 (m, 1H), 1.65 - 1.55 (m, 1H), 1.44 - 1.30 (m, 2H); SFC detection (Chiralpak® IC 50*4.6 mm I.D., 3 μm; mobile phase: A phase: Supercritical carbon dioxide, B phase: Ethanol (0.05% diethylamine); gradient (B%): 10% - 60%), Compound 15A retention time: 1.317 min, chiral purity: 98.2%.

[0409] Compound 15B characterization: LCMS (m / z): 416.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.42 - 7.33 (m, 1H), 7.24 - 7.12 (m, 2H), 6.65 (s, 1H), 6.46 (br d, J = 7.6 Hz, 1H), 6.11 (dd, J = 1.6, 5.6 Hz, 1H), 5.99 (dd, J = 1.6, 5.6 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.86 (br s, 1H), 3.60 (br s, 3H), 2.02 (s, 3H), 1.71 (br dd, J = 6.0, 11.2 Hz, 1H), 1.64 - 1.52 (m, 1H), 1.42 - 1.29 (m, 2H); SFC detection (Chiralpak® IC 50*4.6 mm I.D., 3 μm; mobile phase: A phase: Supercritical carbon dioxide, B phase: Ethanol (0.05% diethylamine); gradient (B%): 10% - 60%), Compound 15B retention time: 1.444 min, chiral purity: 99.0%.

[0410] In the structures of compounds 15A and 15B, the NH and the bridge ene bond are in the same side, and the specific structures are as follows:

[0411] Example 16

[0412] Step 1: To a solution of compound 15-6 (160 mg, 425 pmol) and compound 16-1 (2.18 g, 12.7 mmol) in methanol (5 mL) was added sodium cyanoborohydride (133 mg, 2.13 mmol) slowly at 25 °C under nitrogen atmosphere. The reaction was stirred at 70 °C for 1 h. Water (50 mL) was added to the reaction mixture, which was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 30% - 40%) and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 - 1:1) to give compound 16-2. LCMS (m / z): 532.4 [M+1] + The NH and the bridge ene bond in the structure of compound 16-2 are on the same side.

[0413] Step 2: Compound 16-2 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 pm); mobile phase: A phase: supercritical carbon dioxide, B phase: isopropyl alcohol / acetonitrile (4:1) (0.1% NH3H2O); gradient (B%): 40%) to give compound 16-2A and compound 16-2B. SFC detection (column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: isopropyl alcohol / acetonitrile (0.05% diethylamine); gradient (B%): 20% - 60%), the retention time of compound 16-2A was 1.220 min, and the chiral purity was 100%; the retention time of compound 16-2B was 1.481 min, and the chiral purity was 100%. The NH and the bridge ene bond in the structure of compound 16-2A and 16-2B are on the same side.

[0414] Step 3: To a solution of compound 16-2A (25 mg, 47.03 pmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.3 mL) at 25 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 35% - 45%) to give compound 16A. LCMS (m / z): 432.3 [M+1] + 1 ​H NMR (400 MHz, DMSO-d6) δ = 8.41 (br s, 1H), 7.36 (br d, J = 7.6 Hz, 1H), 7.26 (br d, J = 4.0 Hz, 1H), 7.17 (br d, J = 7.6 Hz, 1H), 6.64 (br s, 1H), 6.51-6.43 (m, 1H), 6.07 (br s, 1H), 5.96 (br s, 1H), 4.12 (br d, J = 3.6 Hz, 1H), 3.85-3.72 (m, 3H), 3.65-3.28 (m, 5H), 2.01 (br d, J = 2.4 Hz, 3H), 1.73 (br d, J = 6.4 Hz, 1H), 1.69-1.56 (m, 1H), 1.48-1.31 (m, 2H); SFC detection (Chromolith® SpeedRay® column: Chiralpak IG-3 50*4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical carbon dioxide, B phase: methanol (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound 16A was 1.702 min, and the chiral purity was 100%. In the structure of compound 16A, the NH and the bridge olefin bond have the same side stereoconfiguration, and the specific structure is as follows:

[0415] Step 4: Compound 16B was prepared from compound 16-2B according to the procedure of Step 3. LCMS (m / z): 432.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 7.36 (d, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.17 (br d, J = 7.6 Hz, 1H), 6.64 (s, 1H), 6.46 (br d, J = 7.6 Hz, 1H), 6.10-6.03 (m, 1H), 5.99-5.92 (m, 1H), 4.15-4.11 (m, 1H), 3.76 (br s, 3H), 3.58 (br d, J = 4.4 Hz, 3H), 3.50 (br s, 1H), 3.37-3.31 (m, 1H), 2.01 (s, 3H), 1.79-1.70 (m, 1H), 1.66-1.57 (m, 1H), 1.47-1.32 (m, 2H); SFC detection (Chromolith® SpeedRay® column: Chiralpak IG-3 50*4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical carbon dioxide, B phase: methanol (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound 16B was 1.422 min, and the chiral purity was 100%. In the structure of compound 16B, the NH and the bridge olefin bond are on the same side, and the specific structure is as follows:

[0416] Example 17

[0417] Referring to the synthesis method of the above examples, compound 17, compound 17A and compound 17B were prepared. LCMS (m / z): 419.1 [M+H] + .

[0418] Example 18

[0419] Step 1: To a solution of compound 15-4 (780 mg, 2.06 mmol) and compound M14 (958.41 mg) in toluene (15 mL) was added 2-(dicyclohexylphosphino)-3,6-dimethoxy-2-4-6-triisopropyl-1,1- biphenyl (110.54 mg, 205.93 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2-4-6- triisopropyl-1,1-biphenyl (110.54 mg, 205.93 μmol), sodium tert-butoxide (791.61 mg, 8.24 mmol) and methyl 2-(2-aminophenyl)acetate (1.01 g, 5.12 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10% ethyl acetate in hexane) to give compound 17 (700 mg, 2.06 mmol, 100% yield). LCMS (m / z): 419.1 [M+H] Molecular sieve (100 mg), the reaction solution was reacted at 80 °C for 2.5 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to give compound 18-1. LCMS (m / z): 539.2 [M+H] + .

[0420] Step 2: To a solution of compound 18-1 (150 mg, 278.52 μmol) in dichloromethane (2 mL) was added hydrobromic acid (46.42 μL, 30% acetic acid solution) and acetic acid (79.72 μL) under nitrogen atmosphere at room temperature, the reaction solution was reacted at 20 °C for 4 h. To the reaction solution was added sodium bicarbonate to adjust pH to 7-8, extracted with dichloromethane (10 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was purified by preparative separation, the method as follows (chromatography column: Waters Xbridge C18 150*25mm*5μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; gradient (acetonitrile %): 25%-55%) to give compound 18-2. LCMS (m / z): 449.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.37 (br d, J = 7.6 Hz, 1H), 7.17 (br d, J = 7.6 Hz, 1H), 7.14 (s, 1H), 6.77 (d, J = 14.0 Hz, 1H), 6.65 (t, J = 6.8 Hz, 1H), 6.43-6.31 (m, 1H), 5.03-4.95 (m, 1H), 4.52-4.43 (m, 1H), 4.20-4.08 (m, 2H), 3.30-3.22 (m, 1H), 2.99-2.85 (m, 2H), 2.37-2.28 (m, 1H), 2.14 (s, 3H), 1.33-1.22 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) δ = -64.274.

[0421] Step 3: To a solution of compound 18-2 (80 mg, 178.40 μmol) in ethanol (2 mL) and water (0.2 mL) was added potassium hydroxide (500.45 mg, 8.92 mmol) under nitrogen atmosphere at room temperature, the reaction solution was reacted at 85 °C for 12 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase column chromatography to give compound 18-3. LCMS (m / z): 377.2 [M+H] + .

[0422] Step 4: To a solution of compound 18-3 (50 mg, 132.85 pmol) and iodoacetonitrile (22.18 mg, 132.85 pmol) in dimethyl sulfoxide (1 mL) was added N, N- diisopropylethylamine (69.42 pL, 398.54 pmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 25 °C for 1 h. Water (10 mL) was added to the reaction mixture, which was extracted with dichloromethane (10 mL x 2). The combined organic phase was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound 18. LCMS (m / z): 416.2 [M+H] + .

[0423] Step 5: Compound 18 was separated by SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 pm); mobile phase: A phase: supercritical carbon dioxide, B phase: EtOH (0.1% ammonia water); gradient (B%): 40%) to give compound 18A and compound 18B. Compound 18A characterization: LCMS (m / z): 416.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.71-10.18 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.23 (br d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.65 (s, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.33 (d, J = 7.2 Hz, 1H), 6.22-6.14 (m, 1H), 4.45-4.26 (m, 1H), 3.88-3.78 (m, 1H), 3.72-3.53 (m, 2H), 3.00 (dd, J = 2.0, 9.2 Hz, 1H), 2.68 (br d, J = 2.0 Hz, 1H), 2.12-2.03 (m, 1H), 2.01 (s, 3H), 1.96 (br d, J = 9.2 Hz, 1H), 1.13-1.04 (m, 1H); F NMR (400 MHz, DMSO-d6) d = -61.179; SFC detection (column: Chiralcel OX-3 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%): 5%-40%) Compound 18A retention time: 1.651 min, chiral purity: 99.61%.

[0424] Compound 18B characterization: LCMS (m / z): 416.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.65 - 10.15 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.23 (br d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 6.65 (d, J = 0.8 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.33 (d, J = 7.2 Hz, 1H), 6.17 (dd, J = 5.6, 7.6 Hz, 1H), 4.47 - 4.31 (m, 1H), 3.83 (t, J = 3.6 Hz, 1H), 3.76 - 3.51 (m, 2H), 3.00 (dd, J = 2.0, 9.2 Hz, 1H), 2.68 (br dd, J = 2.4, 4.4 Hz, 1H), 2.15 - 2.05 (m, 1H), 2.01 (s, 3H), 1.96 (br d, J = 9.2 Hz, 1H), 1.16 - 1.01 (m, 1H); F NMR (400 MHz, DMSO-d6) δ = -61.179; SFC detection (Chiralpak IC 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%): 5% - 40%) Retention time of compound 18B was 2.023 min with 99.59% chiral purity.

[0425] Example 19

[0426] Step 1: To a solution of compound 15-6 (150 mg, 398 pmol) in methanol (4 mL) was added 3-oxetanone (574 mg, 7.97 mmol) and sodium cyanoborohydride (125 mg, 1.99 mmol) sequentially under nitrogen atmosphere at room temperature. The reaction was stirred at 60 °C for 1 h. To the reaction was added 10 mL of water and 40 mL of ethyl acetate, the mixture was partitioned, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / methanol = 1 / 0 - 20 / 1) to give compound 19. LCMS (m / z): 433.1 [M+l] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.55-10.32 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.24-7.17 (m, 2H), 6.65 (s, 1H), 6.45 (d, J = 7.6 Hz, 1H), 6.05 (dd, J = 1.6, 5.6 Hz, 1H), 5.94 (dd, J = 1.6, 5.6 Hz, 1H), 4.51 (dt, J = 3.6, 6.4 Hz, 2H), 4.35-4.29 (m, 2H), 4.18-4.07 (m, 1H), 3.68 (br s, 1H), 3.56-3.49 (m, 1H), 3.41-3.38 (m, 1H), 2.07 (s, 3H), 1.80-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.47-1.30 (m, 2H). Note: in the structure of compound 19, the NH and the bridge ene bond stereo configuration are on the same side.

[0427] Step 2: Compound 19 was prepared by SFC preparation separation (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: A phase is supercritical CO2, B phase is ethanol (0.1% ammonia water); gradient (B%): 55%) to give compound 19A and compound 19B. Compound 19A was characterized: LCMS (m / z): 433.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.42 (br s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.27-7.16 (m, 2H), 6.66 (s, 1H), 6.57-6.38 (m, 1H), 6.11-6.01 (m, 1H), 6.00-5.91 (m, 1H), 4.59-4.45 (m, 2H), 4.41-4.26 (m, 2H), 4.25-4.03 (m, 1H), 3.75-3.61 (m, 1H), 3.60-3.46 (m, 1H), 3.45-3.36 (m, 1H), 2.01 (s, 3H), 1.82-1.70 (m, 1H), 1.69-1.57 (m, 1H), 1.49-1.32 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.181; SFC detection (column: Chiralpak AD-3 50x4.6mm I.D., 3um; mobile phase: A phase is supercritical CO2, B phase is ethanol (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound 19A was 1.344 min, and the chiral purity was 100%.

[0428] Compound 19B Spectrum: LCMS (m / z): 433.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.35 (br d, J = 7.6 Hz, 1H), 7.19-7.07 (m, 2H), 6.64 (s, 1H), 6.40 (br d, J = 7.6 Hz, 1H), 6.05 (d, J = 5.6 Hz, 1H), 5.94 (br d, J = 5.6 Hz, 1H), 4.59-4.42 (m, 2H), 4.32 (br t, J = 5.2 Hz, 2H), 4.20-4.05 (m, 1H), 3.69 (br s, 1H), 3.52 (td, J = 6.0, 12.0 Hz, 1H), 3.39 (br s, 1H), 2.03 (s, 3H), 1.79-1.70 (m, 1H), 1.69-1.59 (m, 1H), 1.47-1.29 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.140; SFC detection (Chromatographic column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; Mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); Gradient (B%): 10%-60%), the retention time of compound 19B was 2.003 min, and the chiral purity was 99.79%.

[0429] In the structures of compounds 19A and 19B, the NH and the bridge olefin bond are on the same side, and the specific structure is as follows:

[0430] Example 20

[0431] Step 1: To a solution of compound 20-1 (200 mg, 1.85 mmol) and pyridine (293 mg, 3.70 mmol) in dichloromethane (4 mL) was added triflic anhydride (678 mg, 2.41 mmol) dropwise under nitrogen atmosphere at -40 °C. The reaction solution was reacted at 0 °C for 0.5 h. 10 mL of saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (5 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-2. 1 H NMR (400 MHz, CDCl3) δ = 5.28-5.17 (m, 1H), 3.27-3.13 (m, 2H), 3.10-2.95 (m, 2H).

[0432] Step 2: To a solution of compound 15-5 (500 mg, 832 μmol) in ethanol (5 mL) and water (5 mL) was added potassium hydroxide (1.40 g, 25.0 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 85 °C for 12 h. The reaction was cooled to 0 °C, adjusted to pH 9 with 4 M hydrochloric acid, and concentrated under reduced pressure to give a crude product. The crude product was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 20-45 μm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 45% - 50%) to give compound 20-3. Mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 45% - 50%) to give compound 20-3. 1 H NMR (400 MHz, DMSO-d6) δ = 7.51 (s, 1H), 7.45 (q, J = 8.0 Hz, 2H), 7.36 - 7.29 (m, 5H), 6.64 (s, 1H), 6.56 (br d, J = 7.6 Hz, 1H), 6.26 (dd, J = 2.0, 6.0 Hz, 1H), 6.16 (dd, J = 1.6, 6.0 Hz, 1H), 5.22 (s, 2H), 4.26 - 4.17 (m, 1H), 4.13 (br s, 1H), 3.95 (br s, 1H), 1.96 (s, 3H), 1.84 - 1.75 (m, 1H), 1.72 - 1.62 (m, 1H), 1.59 - 1.48 (m, 1H), 1.42 - 1.34 (m, 1H). In the structure of compound 20-3, the NH and the bridge ene bond are in the same side.

[0433] Step 3: To a solution of compound 20-3 (160 mg, 343 μmol) in N,N-dimethylacetamide (3 mL) was added compound 20-2 (123 mg, 514 μmol) and sodium carbonate (145 mg, 1.37 mmol) at room temperature under nitrogen atmosphere. After the reaction was stirred at room temperature for 1 h, compound 20-2 (41.1 mg, 171 μmol) was added. The reaction was stirred at room temperature for another 1 h. To the reaction was added 10 mL of water, and the mixture was extracted with ethyl acetate (4 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by TLC preparative chromatography (ethyl acetate / methanol = 8 / 1) to give compound 20-4. LCMS (m / z): 557.2 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 7.51 (s, 1H), 7.49-7.40 (m, 2H), 7.33-7.28 (m, 5H), 6.63 (s, 1H), 6.46 (br d, J = 7.6 Hz, 1H), 6.06 (dd, J = 1.6, 5.6 Hz, 1H), 5.95 (dd, J = 1.2, 5.2 Hz, 1H), 5.22 (s, 2H), 4.40-4.29 (m 1H), 4.12-4.01 (m, 1H), 3.76-3.68 (m, 1H), 3.44-3.42 (m, 1H), 2.85-2.76 (m, 1H), 2.65-2.60 (m, 1H), 2.32-2.21 (m, 2H), 1.96 (s, 3H), 1.74-1.65 (m, 1H), 1.61-1.53 (m, 1H), 1.42-1.30 (m, 2H). In the structure of compound 20-4, the NH and the bridge bond are on the same side of the stereo configuration.

[0434] Step 4: To a solution of compound 20-4 (70 mg, 126 pmol) in dichloromethane (170 pL) was added hydrobromic acid (1.89 mmol, 341 pL, 30% in acetic acid) dropwise at room temperature under nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give the crude product, which was separated by reverse phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40-45%) to give compound 20. LCMS (m / z): 467.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.51 (s, 1H), 7.49-7.40 (m, 2H), 7.33-7.28 (m, 5H), 6.63 (s, 1H), 6.46 (br d, J = 7.6 Hz, 1H), 6.06 (dd, J = 1.6, 5.6 Hz, 1H), 5.95 (dd, J = 1.2, 5.2 Hz, 1H), 5.22 (s, 2H), 4.40-4.29 (m 1H), 4.12-4.01 (m, 1H), 3.76-3.68 (m, 1H), 3.44-3.42 (m, 1H), 2.85-2.76 (m, 1H), 2.65-2.60 (m, 1H), 2.32-2.21 (m, 2H), 1.96 (s, 3H), 1.74-1.65 (m, 1H), 1.61-1.53 (m, 1H), 1.42-1.30 (m, 2H). In the structure of compound 20-4, the NH and the bridge bond are on the same side of the stereo configuration.

[0435] Step 5: Compound 20 was separated and purified by SFC (Chromatographic column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 pm); Mobile phase: A phase was supercritical CO2, B phase was ethanol (0.1% ammonia water); Gradient (B%): 20%) to give Compound 20A and Compound 20B.

[0436] Compound 20A characterization: LCMS (m / z): 467.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.53-10.37 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.22 (br d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 6.65 (s, 1H), 6.46 (d, J = 7.9 Hz, 1H), 6.07 (dd, J = 1.8, 5.6 Hz, 1H), 5.96 (dd, J = 1.8, 5.6 Hz, 1H), 4.12-4.03 (m, 1H), 3.73 (br s, 1H), 3.45 (br s, 1H), 2.86-2.77 (m, 1H), 2.71-2.59 (m, 2H), 2.33-2.23 (m, 2H), 2.01 (s, 3H), 1.78-1.66 (m, 1H), 1.65-1.53 (m, 1H), 1.45-1.31 (m, 2H); SFC detection (Chromatographic column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase was supercritical CO2, B phase was ethanol (0.05% diethylamine); Gradient (B%): 5%-40%), the retention time of Compound 20A was 1.348 min, and the chiral purity was 99.37%.

[0437] Compound 20B characterization: LCMS (m / z): 467.2 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.44 (br s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.22 (br d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 6.68-6.62 (m, 1H), 6.46 (d, J = 7.9 Hz, 1H), 6.07 (dd, J = 1.8, 5.6 Hz, 1H), 5.96 (dd, J = 1.8, 5.6 Hz, 1H), 4.12-4.04 (m, 1H), 3.73 (br s, 1H), 3.48-3.43 (m, 1H), 2.87-2.76 (m, 1H), 2.72-2.62 (m, 2H), 2.34-2.21 (m, 2H), 2.01 (s, 3H), 1.79-1.65 (m, 1H), 1.65-1.53 (m, 1H), 1.45-1.31 (m, 2H); SFC detection (Chromolith® SpeedRay® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%): 5% - 40%), the retention time of compound 20B was 1.541 min, and the chiral purity was 99.79%.

[0438] In the structures of compounds 20A and 20B, the NH and the bridge ene bond are on the same side, and the specific structures are as follows:

[0439] Example 21

[0440] Compound 21, compound 21A and compound 21B were prepared according to the synthetic method of the above examples. LCMS (m / z): 432.2 [M+1] + .

[0441] Example 22

[0442] Step 1: To a solution of compound 22-1 (500 mg, 2.07 mmol) in dioxane (5 mL) and water (1.25 mL) was added trimethyl boroxine (989 mg, 3.94 mmol), cesium carbonate (1.69 g, 5.19 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (75.9 mg, 103 μmol) slowly in batches at room temperature under nitrogen atmosphere. After three times of nitrogen replacement, the reaction was stirred at 100 °C for 1 h. The reaction was diluted with 50 mL of water solution, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-1:1) to give compound 22-2.

[0443] Step 2: To a solution of compound 22-2 (300 mg, 1.70 mmol) in toluene (5 mL) was added sodium hydride (136 mg, 3.41 mmol, 60% purity) slowly at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 0.5 h, and then iodine (432 mg, 1.70 mmol) was added slowly. The reaction was stirred at 0 °C for 1 h. The reaction was diluted with 50 mL of water solution, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-1:1) to give compound 22-3.

[0444] Step 3: To a solution of compound 22-3 (500 mg, 1.66 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (297 mg, 2.15 mmol), potassium iodide (13.7 mg, 82.8 μmol) and benzyl bromide (255 mg, 1.49 mmol) slowly in batches at 25 °C under nitrogen atmosphere. The reaction was stirred at 120 °C for 1 h. The reaction was diluted with 50 mL of water solution, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-1:1) to give compound 22-4. 1 H NMR (400 MHz, CDC13) δ = 7.59-7.52 (m, 2H), 7.48-7.40 (m, 2H), 7.37 (br t, J = 6.4 Hz, 1H), 7.18 (br s, 1H), 6.91 (br s, 1H), 5.25-5.13 (m, 2H), 2.66-2.48 (m, 3H).

[0445] Step 4: To a solution of compound 22-4 (500 mg, 1.28 mmol) and bis(neopentylglycolato)diboron (432 mg, 1.91 mmol) in 5 mL of dioxane was added bis(diphenylphosphino phenyl ether) palladium(II) chloride (91.3 mg, 127 μmol) and potassium acetate (500 mg, 5.10 mmol) under nitrogen atmosphere at room temperature. After three times of nitrogen purging, the mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 55% - 65%) to give compound 22-5.

[0446] Step 5: To a solution of compound 22-5 (300 mg, 967 μmol) and compound 22-6 (288 mg, 1.94 mmol) in methoxycyclopentane (1 mL) was added [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2-amino-1,1-biphenyl-2-yl)palladium(II) (70.5 mg, 96.7 μmol) and potassium phosphate (3 M in water, 967 μL) under nitrogen atmosphere at 25 °C. The mixture was heated at 90 °C for 1 h. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40% - 60%) to give compound 22-7.

[0447] Step 6: To a solution of compound 22-7 (300 mg, 792 μmol) and compound M13 (323 mg, 1.19 mmol) in toluene (4 mL) was added (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl) (2-methylamino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (67.3 mg, 79.2 μmol), sodium tert-butoxide (228 mg, 2.38 mmol) and Molecular sieve (30 mg), 70 °C, 2 h. To the reaction solution, 50 mL water solution was added to dilute, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with 30 mL saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give the crude product, which was separated by reverse phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 60% - 70%) to give compound 22-8. LCMS (m / z): 601.3 [M+H] + In the structure of compound 22-9, the NH and the bridging alkene bond have the same side stereoconfiguration.

[0448] Step 7: To a solution of compound 22-8 (200 mg, 332.98 pmol) in dichloromethane (2 mL) was added 33% hydrobromic acid / acetic acid solution (2 mL) slowly under nitrogen atmosphere at 25 °C, and stirred at 25 °C for 1 h. To the reaction solution, 5 mL water was added to dilute, extracted with ethyl acetate (5 mL x 3), the aqueous phase was separated by reverse phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 50% - 60%) to give compound 22-9. LCMS (m / z): 377.1 [M+1] + In the structure of compound 22-9, the NH and the bridging alkene bond have the same side stereoconfiguration.

[0449] Step 8: To a solution of compound 22-9 (115 mg, 305 pmol) and N,N- diisopropylethylamine (118 mg, 916 pmol) in dimethyl sulfoxide (3 mL) was added iodacetonitrile (51.0 mg, 30 pmol) slowly under nitrogen atmosphere at 25 °C, and stirred at 25 °C for 1 h. The reaction solution was filtered, and the filtrate was separated by reverse phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 55% - 65%) to give compound 22. LCMS (m / z): 416.2 [M+H] + In the structure of compound 22, the NH and the bridging alkene bond have the same side stereoconfiguration.

[0450] Step 9: Compound 22 (80 mg, 186.23 pmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 pm); mobile phase: A phase: supercritical carbon dioxide, B phase: isopropyl alcohol (0.1% NH3H2O); gradient (B%): 40%) to give compound 22A and compound 22B;

[0451] Compound 22A characterization: LCMS (m / z): 416.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.19 - 10.05 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.12 (dd, J = 1.6, 5.6 Hz, 1H), 6.02 (dd, J = 1.6, 5.6 Hz, 1H), 4.22 - 4.09 (m, 1H), 3.88 (br s, 1H), 3.61 (br s, 1H), 3.50 - 3.39 (m, 2H), 2.13 (s, 3H), 1.80 - 1.70 (m, 1H), 1.69 - 1.56 (m, 1H), 1.45 - 1.31 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.342; SFC: Column: Chiralpak IC-3 50 x 4.6 mm I.D., 3 pm; Mobile Phase: A phase is supercritical carbon dioxide, B phase is isopropyl alcohol (0.05% diethylamine); Gradient (B%): 20% - 60%) Retention time for compound 22A was 1.155 min with 100% chiral purity.

[0452] Compound 22B characterization: LCMS (m / z): 416.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.19 - 10.05 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.12 (dd, J = 1.6, 5.6 Hz, 1H), 6.02 (dd, J = 1.6, 5.6 Hz, 1H), 4.22 - 4.09 (m, 1H), 3.88 (br s, 1H), 3.61 (br s, 1H), 3.50 - 3.39 (m, 2H), 2.13 (s, 3H), 1.80 - 1.70 (m, 1H), 1.69 - 1.56 (m, 1H), 1.45 - 1.31 (m, 2H); 19F NMR (376 MHz, DMSO-d6) d = -61.342; SFC: Column: Chiralpak IC-3 50 x 4.6 mm I.D., 3 pm; Mobile phase: A phase: Supercritical carbon dioxide, B phase: Isopropyl alcohol (0.05% diethylamine); Gradient (B%): 20% - 60%) Retention time for compound 22B: 1.500 min, Chiral purity: 100%.

[0453] In the structure of compounds 22A and 22B, the NH and the bridge ene bond are on the same side, and the specific structure is as follows:

[0454] Example 23

[0455] Step 1: Compound 23-1 (1.19 g, 10.63 mmol), sodium cyanoborohydride (167 mg, 2.66 mmol) were added to a solution of compound 15-6 (200 mg, 531 pmol) in methanol (3 mL) under nitrogen atmosphere at room temperature. The reaction was stirred at 60 °C for 1 h. 10 mL of water and 30 mL of ethyl acetate were added to the reaction, and the mixture was partitioned. The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative reverse phase column chromatography (column: Phenomenex luna C18 20-45 pm; mobile phase: water (0.1% ammonia) - acetonitrile; gradient (acetonitrile%): 24%) to give a crude product. The crude product was dissolved in dichloromethane (4 mL) and stirred at room temperature for 10 min. The mixture was filtered and the filter cake was dried to give compound 23. LCMS (m / z): 473.3 [M+H] Step 2: Compound 23 (100 mg, 211 pmol) was dissolved in dichloromethane (2 mL) and stirred at room temperature for 10 min. The mixture was filtered and the filter cake was dried to give compound 24. LCMS (m / z): 473.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.45 (br s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.63 (s, 1H), 6.41 (br d, J = 8.0 Hz, 1H), 6.02 (dd, J = 1.6, 5.6 Hz, 1H), 5.91 (dd, J = 1.6, 5.6 Hz, 1H), 4.52-4.46 (m, 4H), 4.09-3.99 (m, 1H), 3.69 (br s, 1H), 3.41-3.39 (m, 1H), 2.75-2.64 (m, 1H), 2.28-2.16 (m, 2H), 2.01 (s, 3H), 1.91-1.83 (m, 2H), 1.76-1.62 (m, 1H), 1.60-1.46 (m, 1H), 1.43-1.24 (m, 2H). In the structure of compound 23, NH and the bridge olefinic bond are on the same side.

[0456] Step 2: Compound 23 was separated and purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 pm); mobile phase: A phase was supercritical carbon dioxide, B phase was ethanol (0.1% ammonia water); gradient (B%): 35%), to obtain compound 23A and compound 23B. Compound 23A was characterized: LCMS (m / z): 473.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.45 (br s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.63 (s, 1H), 6.41 (br d, J = 8.0 Hz, 1H), 6.02 (dd, J = 1.6, 5.6 Hz, 1H), 5.91 (dd, J = 1.6, 5.6 Hz, 1H), 4.52-4.46 (m, 4H), 4.09-3.99 (m, 1H), 3.69 (br s, 1H), 3.41-3.39 (m, 1H), 2.75-2.64 (m, 1H), 2.28-2.16 (m, 2H), 2.01 (s, 3H), 1.91-1.83 (m, 2H), 1.76-1.62 (m, 1H), 1.60-1.46 (m, 1H), 1.43-1.24 (m, 2H). In the structure of compound 23, NH and the bridge olefinic bond are on the same side. 19F NMR (376 MHz, DMSO) d = -61.128; SFC detection (Chromolith Speed ROD® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 10-60%), retention time of compound 23B was 1.307 min with 99.03% chiral purity.

[0457] Compound 23B characterization: LCMS (m / z): 473.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 7.35 (br d, J = 7.6 Hz, 1H), 7.18-7.08 (m, 2H), 6.62 (s, 1H), 6.37 (br d, J = 7.6 Hz, 1H), 6.01 (dd, J = 1.6, 5.6 Hz, 1H), 5.91 (dd, J = 1.6, 5.6 Hz, 1H), 4.52-4.45 (m, 4H), 4.09-3.98 (m, 1H), 3.70 (br s, 1H), 3.40-3.39 (m, 1H), 2.73-2.64 (m, 1H), 2.28-2.17 (m, 2H), 2.02 (s, 3H), 1.92-1.83 (m, 2H), 1.74-1.64 (m, 1H), 1.58-1.48 (m, 1H), 1.43-1.27 (m, 2H); 19 F NMR (376 MHz, DMSO) d = -61.128; SFC detection (Chromolith Speed ROD® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 10-60%), retention time of compound 23B was 1.307 min with 99.03% chiral purity.

[0458] In the structures of compounds 23A and 23B, the NH is syn to the stereochemistry of the bridged enyne bond, and the specific structures are as follows:

[0459] Example 24

[0460] Step 1: To a solution of compound 24-1 (700 mg, 7.77 mmol) in dichloromethane (6 mL) was added potassium tert-butoxide (1 M in tetrahydrofuran, 11.6 mL) portionwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 0.5 h. To the reaction was added p-toluenesulfonyl chloride (1.78 g, 9.32 mmol) portionwise at 0 °C. The reaction was continued to stir at 25 °C for 1 h. To the reaction was added aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-1:1) to give compound 24-2. 1 H NMR (400 MHz, DMSO-d6) d = 7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.33-5.11 (m, 1H), 5.05-4.95 (m, 1H), 2.49-2.43 (m, 4H), 2.42 (s, 3H).

[0461] Step 2: To a solution of compound 20-3 (500 mg, 1.07 mmol) and compound 24-2 (393 mg, 1.61 mmol) in N,N-dimethylacetamide (5 mL) was added sodium carbonate (341 mg, 3.22 mmol) and potassium iodide (356 mg, 2.14 mmol) at 25 °C under nitrogen atmosphere. The reaction was continued to stir at 85 °C for 12 h. To the reaction was added water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative reversed-phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 50% - 70%) and then by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1-1:1) to give compound 24-3. LCMS (m / z): 539.3 [M+H] + .

[0462] Step 3: To a solution of compound 24-3 (220 mg, 408 pmol) in dichloromethane (3 mL) was added hydrobromic acid (5 mL, 33% in acetic acid) slowly under nitrogen atmosphere at 25 °C. The reaction was stirred at 25 °C for 3 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative reversed-phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% FA) - acetonitrile; gradient (acetonitrile %): 40% - 50%) to give compound 24. LCMS (m / z): 449.2 [M+1] + .

[0463] Step 4: Compound 24 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: A phase: supercritical carbon dioxide, B phase: isopropanol + acetonitrile (0.1% ammonia water); gradient (B%): 40%), then separated by SFC (column: DAICEL CHIRALPAK IG 250 mm x 30 mm x 5 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: isopropanol (0.1% ammonia water); gradient (B%): 25%) to give compound 24A, compound 24B, compound 24C and compound 24D.

[0464] Compound 24A characterization: LCMS (m / z): 449.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.60 - 10.06 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.31 - 7.11 (m, 2H), 6.64 (s, 1H), 6.43 (d, J = 7.6 Hz, 1H), 6.03 (dd, J = 1.6, 5.6 Hz, 1H), 5.92 (dd, J = 1.6, 5.6 Hz, 1H), 5.39 - 5.01 (m, 1H), 4.18 - 4.00 (m, 1H), 3.83 - 3.72 (m, 1H), 3.49 - 3.43 (m, 1H), 3.05 - 2.95 (m, 1H), 2.25 - 2.07 (m, 4H), 2.01 (s, 3H), 1.77 - 1.65 (m, 1H), 1.62 - 1.52 (m, 1H), 1.46 - 1.30 (m, 2H); 19F NMR (376 MHz, DMSO-d6) d = -61.175, -169.529. SFC detection (Chromatographic column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase is supercritical carbon dioxide, B phase is isopropyl alcohol + acetonitrile (0.05% diethylamine); Gradient (B%): 20-60%), the retention time of compound 24A was 0.845 min with 100% chiral purity.

[0465] Compound 24C characterization: LCMS (m / z): 449.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.57-10.27 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.30-7.15 (m, 2H), 6.65 (s, 1H), 6.43 (br d, J = 7.6 Hz, 1H), 6.05 (dd, J = 1.6, 5.6 Hz, 1H), 5.95 (dd, J = 1.6, 5.6 Hz, 1H), 4.90-4.66 (m, 1H), 4.08 (br d, J = 7.2 Hz, 1H), 3.73 (br s, 1H), 3.44 (br s, 1H), 2.49-2.39 (m, 3H), 2.01 (s, 3H), 1.96-1.81 (m, 2H), 1.75-1.66 (m, 1H), 1.65-1.53 (m, 1H), 1.45-1.29 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) d = -61.184, -165.077. SFC detection (Chromatographic column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase is supercritical carbon dioxide, B phase is isopropyl alcohol + acetonitrile (0.05% diethylamine); Gradient (B%): 20-60%), the retention time of compound 24C was 0.888 min with 100% chiral purity.

[0466] Compound 24B characterization: LCMS (m / z): 449.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.64 - 10.28 (m, 1H), 7.40 (br d, J = 7.6 Hz, 1H), 7.26 - 7.16 (m, 2H), 6.64 (s, 1H), 6.44 (br d, J = 8.0 Hz, 1H), 6.08 - 5.87 (m, 2H), 5.34 - 5.09 (m, 1H), 4.13 - 4.00 (m, 1H), 3.75 (br s, 1H), 3.49 - 3.42 (m, 1H), 3.04 - 2.93 (m, 1H), 2.15 (br d, J = 18.2 Hz, 4H), 2.05 - 1.96 (m, 3H), 1.75 - 1.66 (m, 1H), 1.62 - 1.51 (m, 1H), 1.45 - 1.29 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.167, -169.483. SFC detection (Chromathograhic column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase is supercritical carbon dioxide, B phase is isopropanol + acetonitrile (0.05% diethylamine); Gradient (B%): 20% - 60%), the retention time of compound 24B was 1.298 min with 100% chiral purity.

[0467] Compound 24D was characterized by LCMS (m / z): 449.3 [M+H] + ; 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.52 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.15 (br d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.09 (dd, J = 1.6, 5.6 Hz, 1H), 5.93 (dd, J = 1.6, 5.6 Hz, 1H), 4.89 - 4.76 (m, 1H), 4.76 - 4.60 (m, 2H), 4.01 - 3.86 (m, 1H), 3.71 (br s, 1H), 3.53 (br s, 1H), 2.64 - 2.50 (m, 3H), 2.50 - 2.46 (m, 3H), 2.19 - 2.01 (m, 3H), 1.91 (br dd, J = 6.0, 12.4 Hz, 1H), 1.82 - 1.69 (m, 2H), 1.42 (br d, J = 9.2 Hz, 1H); 19F NMR (376MHz, DMSO-d6) δ=-61.174, -165.061. SFC detection (column: Chiralpak IG-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol + acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 24D was 1.604 min, and the chiral purity was 100%.

[0468] Example 25

[0469] Step 1: Under a nitrogen atmosphere at 0°C, add acetic acid (7 mL) to a solution of compound 15-6 (0.3 g, 797 μmol) and compound 25-1 (861 mg, 11.9 mmol). Molecular sieve (50 mg) and trimethylcyanosilane (1.42 g, 14.4 mmol) were stirred at room temperature for 16 hours. The reaction solution was quenched dropwise in saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (10 mL × 3), washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 20-45 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 60%-65% to give compound 25. LCMS (m / z): 458.0 [M+H] + .

[0470] Step 2: Compound 25 was separated by SFC (column: DAICEL CHIRALPAK AD, 250 mm × 30 mm, 10 μm; mobile phase: A phase was supercritical CO2, B phase was EtOH (0.1% NH3H2O); gradient (B%): 45%) to obtain compounds 25A and 25B. Characterization of compound 25A: LCMS (m / z): 458.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) d = 10.49 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.25-7.17 (m, 2H), 6.69 (s, 1H), 6.60 - 6.52 (m, 1H), 6.17 (dd, J = 2.0, 6.0 Hz, 1H), 6.04 (dd, J = 2.0, 6.0 Hz, 1H), 4.76 (dd, J = 6.4, 9.2 Hz, 2H), 4.57 (dd, J = 4.0, 6.4 Hz, 2H), 4.21 - 4.09 (m, 1H), 4.04 - 3.92 (m, 1H), 3.73 (s, 1H), 2.02 (s, 3H), 1.85 - 1.76 (m, 1H), 1.74 - 1.63 (m, 1H), 1.53 - 1.33 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) d (ppm) = -61.193. SFC detection (Chromolith® SpeedRay® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: EtOH (0.05% diethylamine); gradient (B%): 10% - 60%), the retention time of compound 25A was 1.415 min with 100% chiral purity.

[0471] Compound 25B was characterized by LCMS (m / z): 458.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.49 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.25-7.17 (m, 2H), 6.69 (s, 1H), 6.60 - 6.52 (m, 1H), 6.17 (dd, J = 2.0, 6.0 Hz, 1H), 6.04 (dd, J = 2.0, 6.0 Hz, 1H), 4.76 (dd, J = 6.4, 9.2 Hz, 2H), 4.57 (dd, J = 4.0, 6.4 Hz, 2H), 4.21 - 4.09 (m, 1H), 4.04 - 3.92 (m, 1H), 3.73 (s, 1H), 2.02 (s, 3H), 1.85 - 1.76 (m, 1H), 1.74 - 1.63 (m, 1H), 1.53 - 1.33 (m, 2H); 19F NMR (376 MHz, DMSO-d6) d (ppm) = -61.187 (s, IF). SFC detection (Chromolith® SpeedRay® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: EtOH (0.05% diethylamine); gradient (B%): 10% - 60%), the retention time of compound 25B was 1.681 min with a chiral purity of 99.02%.

[0472] Example 26

[0473] Referring to the above synthesis method of examples, compound 26A and compound 26B were prepared. LCMS (m / z): 473.2 [M+H] + .

[0474] Example 27

[0475] Step 1: To a solution of compound 20-3 (500 mg, 1.07 mmol) and compound 27-1 (486 mg, 2.78 mmol) in glacial acetic acid (8 mL) was added trimethylsilyl cyanide (260 mg, 2.62 mmol) dropwise at 5 °C under nitrogen atmosphere. After the addition, the reaction was stirred at 25 °C for 40 h. The reaction was slowly added to saturated aqueous sodium carbonate solution (50 mL) (final pH > 8) and extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase column chromatography (column: Spherical C18, 40-60 pm, 150 x 4.6 mm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 50% - 100%) to give compound 27-2. LCMS (m / z): 532.3 [M+H] mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 50% - 100%) to give compound 27-2. LCMS (m / z): 532.3 [M+H] + .

[0476] Step 2: To a solution of compound 27-2 (200 mg, 376.24 pmol) in dichloromethane (2 mL) was added 33% hydrogen bromide in acetic acid (4 mL) dropwise at room temperature under nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction was cooled to 0 °C and diluted with 5 mL of water. The mixture was allowed to stand and separate. The aqueous phase was adjusted to pH 9 with 2 M aqueous sodium hydroxide solution at 0 °C and extracted with ethyl acetate (15 mL x 4). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase column chromatography (column: Spherical C18, 40-60 pm, 150 x 4.6 mm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 50% - 100%) to give compound 27-3. LCMS (m / z): 532.3 [M+H] Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 20% yielded compound 27. LCMS (m / z): 442.2 [M+H] + .

[0477] Step 3: Compound 27 (120 mg) was prepared and separated by SFC (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: A phase is supercritical CO2, B phase is EtOH (0.1% ammonia); gradient (B%): 30%), to obtain compound 27A and compound 27B.

[0478] Characterization of compound 27A: LCMS (m / z): 442.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ=10.44(br s,1H),7.41(d,J=7.6Hz,1H),7.25-7.18(m,2H),6.66(s,1H),6.49(d,J=7.6Hz,1H),6.23(dd,J=2.0,5.6Hz,1H),6.12(dd,J=2.0,5.6Hz,1H),4. 15-4.07(m,1H),4.02-3.90(m,1H),3.81-3.77(m,1H),2.02(s,3H),1.7 3-1.64(m,1H),1.58-1.45(m,1H),1.43-1.29(m,2H),1.22-1.04(m,4H); 19 F NMR (376MHz, DMSO-d6) δ=-61.167. SFC detection (column: Chiralcel OX-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical CO2, B phase is EtOH (0.05% diethylamine); gradient (B%): 5%-40%), the retention time of compound 27A was 1.483 min, and the chiral purity was 100%.

[0479] Characterization of compound 27B: LCMS (m / z): 442.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) d = 10.44 (br s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.25-7.18 (m, 2H), 6.66 (s, 1H), 6.49 (d, J = 7.6 Hz, 1H), 6.23 (dd, J = 2.0, 5.6 Hz, 1H), 6.12 (dd, J = 2.0, 5.6 Hz, 1H), 4.15-4.07 (m, 1H), 4.02-3.90 (m, 1H), 3.81-3.77 (m, 1H), 2.02 (s, 3H), 1.73-1.64 (m, 1H), 1.58-1.45 (m, 1H), 1.43-1.29 (m, 2H), 1.22-1.04 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) d = -61.174. SFC detection (Chromolith Speed ROD column: Chiralcel OX-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: EtOH (0.05% diethylamine); gradient (B%): 5% - 40%), the retention time of compound 27A was 1.816 min with 100% chiral purity.

[0480] Example 28

[0481] Step 1: To a solution of compound 22-8 (400 mg, 665.97 pmol) in ethanol (6 mL) was added potassium hydroxide (1.12 g, 19.98 mmol) and water (6 mL) under nitrogen atmosphere at room temperature. The reaction was stirred at 85 °C for 48 h after purging nitrogen for three times. The reaction was directly concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile%): 45% - 55%) to give compound 28-1. LCMS (m / z): 467.3 [M-1] + .

[0482] Step 2: To a solution of compound 28-1 (200 mg, 428.73 μmol) in N,N- dimethylacetamide (6 mL) was added sodium carbonate (181.76 mg, 1.71 mmol) and compound 22-2 (154.44 mg, 643.09 μmol) under nitrogen atmosphere at 25 °C. The reaction was stirred at 25 °C for 1 h. To the reaction was added water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative reverse phase column chromatography (column: Phenomenex luna C18 150 x 25mm x 10 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 20% - 30%) to give compound 28-2. LCMS (m / z): 557.3 [M+H] + .

[0483] Step 3: To a solution of compound 28-2 (70 mg, 125.77 μmol) in dichloromethane (1 mL) was added 33% hydrobromic acid in acetic acid (2 mL) slowly under nitrogen atmosphere at 25 °C. The reaction was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure to give a crude product, which was purified by preparative reverse phase column chromatography (column: Phenomenex luna C18 150 x 25mm x 10 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 30% - 40%) to give compound 28; LCMS (m / z): 467.2 [M+1] + .

[0484] Step 4: Compound 28 was separated by SFC (column: DAICEL CHIRALPAK IK (250mm*25mm, 10 μm); mobile phase: A phase: supercritical CO2, B phase: isopropanol (0.1% ammonia); gradient (B%): 18%) to give compound 28A and compound 28B. Compound 28A characterization: LCMS (m / z): 467.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.15 (s, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.15-7.01 (m, 2H), 6.84 (d, J = 9.2 Hz, 1H), 6.59 (br d, J = 6.0 Hz, 1H), 6.16-5.92 (m, 2H), 4.11 (br d, J = 3.6 Hz, 1H), 3.74 (br s, 1H), 3.46 (br s, 1H), 2.92-2.58 (m, 3H), 2.42-2.21 (m, 2H), 2.12 (s, 3H), 1.83-1.70 (m, 1H), 1.61 (br s, 1H), 1.50-1.32 (m, 2H); SFC detection (Chiralpak IK-3 50*4.6 mm I.D., 3 μm; Mobile Phase: A phase is supercritical carbon dioxide, B phase is isopropyl alcohol (0.05% diethylamine); Gradient (B%): 5%-40%), the retention time of compound 28A was 1.638 min, and the chiral purity was 100%.

[0485] Compound 28B was characterized by LCMS (m / z): 467.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.17 (br s, 1H), 7.30-7.18 (m, 1H), 7.14-7.03 (m, 2H), 6.96-6.81 (m, 1H), 6.80-6.46 (m, 1H), 6.36-5.86 (m, 2H), 4.30-4.00 (m, 1H), 3.89-3.65 (m, 1H), 3.55-3.43 (m, 1H), 2.99-2.58 (m, 3H), 2.47-2.18 (m, 2H), 2.13 (s, 3H), 1.85-1.72 (m, 1H), 1.70-1.53 (m, 1H), 1.51-1.30 (m, 2H); SFC detection (Chiralpak IK-3 50*4.6 mm I.D., 3 μm; Mobile Phase: A phase is supercritical carbon dioxide, B phase is isopropyl alcohol (0.05% diethylamine); Gradient (B%): 5%-40%), the retention time of compound 28B was 1.749 min, and the chiral purity was 98.25%.

[0486] Example 29

[0487] Step 1: To a solution of compound 22-8 (500 mg, 832.5 pmol) in dichloromethane (5 mL) was added dropwise 33% hydrogen bromide in acetic acid (15 mL) at 5 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 0.5 h. The reaction was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Spherical C18, 40-60 pm, 150x30mm, 5pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 15% to 95% in 10 min, 95% for 2 min, 95% to 15% in 2 min, 15% for 2 min; flow rate: 20 mL / min) to give compound 22-9. LCMS (m / z): 377.2 [M+H] Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 15% to 95% in 10 min, 95% for 2 min, 95% to 15% in 2 min, 15% for 2 min; flow rate: 20 mL / min) to give compound 29-1. LCMS (m / z): 377.2 [M+H] + .

[0488] Step 2: To a solution of compound 29-1 (150 mg, 398.54 pmol) and compound 27-1 (694.7 mg, 3.99 mmol) in glacial acetic acid (3 mL) was added dropwise trimethylsilyl cyanide (420 mg, 4.23 mmol) at 5 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 13.5 h. The reaction was slowly added to 35 mL saturated aqueous sodium carbonate solution (final pH > 9) and extracted with ethyl acetate (15 mL x 4), and the combined organic phase was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Spherical C18, 40-60 pm, 150x30mm, 5pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 15% to 95% in 10 min, 95% for 2 min, 95% to 15% in 2 min, 15% for 2 min; flow rate: 20 mL / min) to give compound 29. LCMS (m / z): 442.1 [M+H] Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 15% to 95% in 10 min, 95% for 2 min, 95% to 15% in 2 min, 15% for 2 min; flow rate: 20 mL / min) to give compound 29-1. LCMS (m / z): 377.2 [M+H] + .

[0489] Step 3: Compound 29 was separated by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10pm); mobile phase: A phase: supercritical CO2, B phase: EtOH (0.1% NH3*H2O); gradient (B%): 45%) to give compound 29A and compound 29B. Compound 29A was characterized: LCMS (m / z): 442.2 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.14 (br s, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.24 (dd, J = 1.6, 5.6 Hz, 1H), 6.14 (dd, J = 1.6, 5.6 Hz, 1H), 4.13-4.07 (m, 1H), 4.04-3.93 (m, 1H), 3.82-3.77 (m, 1H), 2.13 (s, 3H), 1.76-1.67 (m, 1H), 1.59-1.45 (m, 1H), 1.43-1.30 (m, 2H), 1.24-1.06 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.311. SFC detection (Column: Chiralpak IC-3 50 x 4.6 mm I.D., 3 pm; Mobile phase: A phase: supercritical CO2, B phase: EtOH (0.05% diethylamine); Gradient (B%): 10-60%), the retention time of compound 29A was 0.884 min with 100% chiral purity.

[0490] Compound 29B spectra: LCMS (m / z): 442.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.14 (br s, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.24 (dd, J = 1.6, 5.6 Hz, 1H), 6.14 (dd, J = 1.6, 5.6 Hz, 1H), 4.13-4.07 (m, 1H), 4.04-3.93 (m, 1H), 3.82-3.77 (m, 1H), 2.13 (s, 3H), 1.76-1.67 (m, 1H), 1.59-1.45 (m, 1H), 1.43-1.30 (m, 2H), 1.24-1.06 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.311. SFC detection (Column: Chiralpak IC-3 50 x 4.6 mm I.D., 3 pm; Mobile phase: A phase: supercritical CO2, B phase: EtOH (0.05% diethylamine); Gradient (B%): 10-60%), the retention time of compound 29B was 1.116 min with 99.70% chiral purity.

[0491] Example 30

[0492] Step 1: Refer to the synthesis method of above examples, compound 30 was prepared. LCMS (m / z): 449.2 [M+1] + .

[0493] Step 2: Compound 30 was separated by SFC (column: DAICEL CHIRALPAK IG 250mm*30mm*5μm; mobile phase: A phase: supercritical CO2, B phase: isopropanol (0.1% ammonia water); gradient (B%): 35%), to get a mixture of compound 30A and 30B, compound 30C and compound 30D.

[0494] The mixture of compound 30A and 30B was characterized by LCMS (m / z): 449.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.30-10.00 (m, 1H), 7.33-7.17 (m, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.88-6.80 (m, 1H), 6.70-6.50 (m, 1H), 6.04 (br d, J = 4.8 Hz, 1H), 6.00-5.83 (m, 1H), 5.36-5.08 (m, 1H), 4.10 (br s, 1H), 3.84-3.71 (m, 1H), 3.53-3.44 (m, 1H), 3.00 (br d, J = 3.6 Hz, 1H), 2.49-2.43 (m, 2H), 2.17 (br d, J = 5.6 Hz, 2H), 2.14-2.09 (m, 3H), 1.80-1.68 (m, 1H), 1.65-1.53 (m, 1H), 1.51-1.30 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) d = -61.334, -169.466. SFC detection (column: Chiralpak IG-3 50*4.6mm I.D., 3μm; mobile phase: A phase: supercritical carbon dioxide, B phase: EtOH (0.05% diethylamine); gradient (B%): 5%-40%), showed that the retention time of the mixture of compound 30A and 30B was 1.735 min and 1.816 min, with a ratio of about 1:1.

[0495] Compound 30C was characterized by LCMS (m / z): 449.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 10.29 - 10.01 (m, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.83 (d, J = 9.2 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.06 (dd, J = 1.7, 5.6 Hz, 1H), 5.97 (dd, J = 1.6, 5.5 Hz, 1H), 4.99 - 4.62 (m, 1H), 4.23 - 4.01 (m, 1H), 3.74 (br s, 1H), 3.45 (br s, 1H), 2.47 (br d, J = 6.0 Hz, 3H), 2.13 (s, 3H), 1.97 - 1.81 (m, 2H), 1.79 - 1.69 (m, 1H), 1.65 - 1.55 (m, 1H), 1.44 - 1.29 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.326, -165.091. SFC detection (Chromolith® SpeedRay® column: Chiralpak IG-3 50*4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical carbon dioxide, B phase: EtOH (0.05% diethylamine); gradient (B%): 5% - 40%), showed the retention time of compound 30C was 1.971 min with 96.50% chiral purity.

[0496] Compound 30D was characterized by LCMS (m / z): 449.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.34 - 9.98 (m, 1H), 7.22 (br d, J = 9.2 Hz, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.84 (br d, J = 8.8 Hz, 1H), 6.71 - 6.46 (m, 1H), 6.33 - 5.80 (m, 2H), 4.96 - 4.64 (m, 1H), 4.23 - 4.02 (m, 1H), 3.88 - 3.64 (m, 1H), 3.54 - 3.42 (m, 1H), 2.42 (br s, 3H), 2.13 (s, 3H), 1.98 - 1.82 (m, 2H), 1.78 - 1.71 (m, 1H), 1.65 - 1.54 (m, 1H), 1.46 - 1.30 (m, 2H); 19F NMR (376 MHz, DMSO-d6) d = -61.334, -165.106. SFC detection (Chromathograhic column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase: Supercritical carbon dioxide, B phase: EtOH (0.05% diethylamine); Gradient (B%): 5%-40%), showed the retention time of compound 30D was 2.019 min with chiral purity 99.75%.

[0497] Example 31

[0498] To a solution of compound 15A (100 mg, 241 pmol) in tetrahydrofuran (1 mL) was added sodium hydride (48.1 mg, 1.20 mmol, 60% purity) portionwise at 0 °C under nitrogen atmosphere, stirred at 0 °C for 1 h, then added deuterium oxide (1 mL) to the reaction mixture, continued to react at 25 °C for 12 h. Added aqueous ammonium chloride solution (10 mL) to the reaction mixture, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reversed-phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 pm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile%): 40%-60%) to give compound 31A. LCMS (m / z): 418.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.69-10.23 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.26-7.15 (m, 2H), 6.66 (d, J = 0.8 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.11 (dd, J = 2.0, 5.6 Hz, 1H), 5.99 (dd, J = 2.0, 5.6 Hz, 1H), 4.17-4.05 (m, 1H), 3.90-3.79 (m, 1H), 3.60 (br d, J = 2.0 Hz, 1H), 2.02 (s, 3H), 1.77-1.67 (m, 1H), 1.67-1.56 (m, 1H), 1.44-1.31 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) d = -61.181.

[0499] Example 32

[0500] Compound 32A, compound 32B, compound 32C and compound 32D were prepared according to the synthetic method of the above examples. LCMS: 449.2 [M+H] + .

[0501] Example 33

[0502] Compound 33A and compound 33B were prepared according to the synthetic method of the above examples. LCMS: 467.2 [M+H] + .

[0503] Example 34

[0504] To a solution of compound 15-6 (100 mg, 266 μmol) and formic acid (10.0 μL, 266 μmol) in N,N-dimethylformamide (1 mL) was added EDCI (61.1 mg, 319 μmol), HOBt (43.1 mg, 319 μmol) and triethylamine (111 μL, 797 μmol) successively under nitrogen atmosphere at room temperature. The reaction solution was stirred at 25 °C for 1 hour. Water (30 mL) was added to the reaction solution, which was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reversed-phase column chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40% - 50%) to give compound 34. LCMS: 405.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 10.63 - 10.34 (m, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.40 (dd, J = 3.6, 7.6 Hz, 1H), 7.27 - 7.18 (m, 2H), 6.74 - 6.61 (m, 2H), 6.39 - 6.19 (m, 2H), 4.99 - 4.79 (m, 1H), 4.75 - 4.55 (m, 1H), 4.12 - 3.96 (m, 1H), 2.03 (s, 3H), 1.92 - 1.80 (m, 1H), 1.72 - 1.57 (m, 2H), 1.55 - 1.38 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.187.

[0505] Example 35

[0506] Compound 15-6 (95 mg, 251 μmol) was separated by SFC (Chromatography column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); Mobile phase: A phase: supercritical carbon dioxide, B phase: methanol (0.2% ammonia water); Gradient (B%): 50%) to give compound 35A and compound 35B.

[0507] Compound 35A was characterized by LCMS: 377.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.38 (d, J = 8.0 Hz, 1H), 7.20 (br s, 2H), 6.65 (s, 1H), 6.43 (br d, J = 7.6 Hz, 1H), 6.24 (dd, J = 1.2, 5.6 Hz, 1H), 6.15 (dd, J = 1.6, 5.6 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.97 (br s, 1H), 3.75 (br s, 1H), 3.69 - 3.55 (m, 1H), 2.02 (s, 3H), 1.82 - 1.72 (m, 1H), 1.68 - 1.57 (m, 1H), 1.56 - 1.44 (m, 1H), 1.30 (br dd, J = 5.6, 12.4 Hz, 1H); 19 F NMR (376 MHz, DMSO-d6) δ = -61.179. SFC detection (Chromatography column: Chiralpak IC-3 50*4.6 mm I.D., 3 μm; Mobile phase: A phase: supercritical carbon dioxide, B phase: methanol (0.05% diethylamine); Gradient (B%): 10% - 60%), the retention time of compound 35A was 1.509 min, and the chiral purity was 99.59%.

[0508] Compound 35B was characterized by LCMS: 377.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 7.37 (d, J = 7.6 Hz, 1H), 7.27 - 7.14 (m, 2H), 6.66 (s, 1H), 6.53 (br d, J = 7.6 Hz, 1H), 6.26 (br d, J = 5.2 Hz, 1H), 6.16 (br d, J = 5.2 Hz, 1H), 4.20 (br s, 1H), 4.11 (br s, 1H), 3.91 (br s, 2H), 2.02 (s, 3H), 1.85 - 1.75 (m, 1H), 1.67 (br d, J = 10.8 Hz, 1H), 1.60 - 1.46 (m, 1H), 1.37 (br dd, J = 4.8, 12.0 Hz, 1H).19 F NMR (376 MHz, DMSO-d6) d = -61.169. SFC detection (Chromathographic column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: methanol (0.05% diethylamine); gradient (B%): 10% - 60%), retention time of compound 35B was 1.787 min with a chiral purity of 98.91%.

[0509] Biological test data

[0510] Test Example 1 : THP-1 null cell secretion of IL-1 beta test

[0511] Experimental reagents:

[0512] Human IL-1 b ELISA kit: supplier BD, item number 557953, stored at 4°C;

[0513] LPS (lipopolysaccharide): supplier Sigma, item number L6529, stored at -20°C;

[0514] ATP: supplier Sigma, item number A2383, stored at -20°C.

[0515] Experimental method:

[0516] Day 1 : Dilute the cell suspension using complete medium containing PMA and without the addition of antibiotics, plate THP-1 null cells in a 96-well cell culture plate at a cell number of 100000 per well. Place the cell culture plate in an incubator at 37°C with a carbon dioxide concentration of 5% for 24 hours.

[0517] Day 2: After the end of the incubation of day 1, dilute the compounds using 1640 medium without phenol red and serum and containing 25 mM HEPES so that the final DMSO concentration is 0.5%. Remove the supernatant from the cell culture plate, add 160 pL of compound solution to the cell culture plate, add an equivalent amount of medium containing 0.5% DMSO to the positive control and negative control wells. Subsequently, place the cell culture plate in an incubator at 37°C with a carbon dioxide concentration of 5% for 1 hour.

[0518] Dilute LPS using 1640 medium without phenol red and serum and containing 25 mM HEPES. After the end of the compound treatment, add the LPS solution to the compound wells and the positive control wells of the cell culture plate, add an equivalent volume of medium to the negative control wells. Subsequently, place the cell culture plate in an incubator at 37°C with a carbon dioxide concentration of 5% for 3.5 hours.

[0519] ATP was diluted using 1640 medium without phenol red and serum and with 25 mM HEPES. After LPS treatment, ATP solution was added to the compound wells and positive control wells of the cell culture plate, and an equal volume of medium was added to the negative control wells. The cell culture plate was then placed in an incubator for 0.5 hours at 37°C and a 5% carbon dioxide concentration.

[0520] After ATP treatment, the supernatant was removed for later use.

[0521] Day 3: The collected supernatant was tested for IL-1beta ELISA according to the kit instructions.

[0522] Data processing:

[0523] The absorbance value at 450 nm minus the absorbance value at 570 nm was the raw data. After converting the raw data of each well into the concentration of IL-1beta using the standard curve, the inhibition rate of each well of the compound wells was calculated using the IL-1beta concentration of the positive control and negative control. The IC50 was obtained using a four-parameter equation to fit the curve. 50 The experimental results are shown in Table 1. Among them, AAA represents IC 50 ≤ 20 nM; AA represents 20 nM < IC 50 ≤ 100 nM; A represents 100 nM < IC 50 ≤ 200 nM, B represents 200 nM < IC 50 ≤ 1000 nM, C represents IC 50 > 1000 nM.

[0524] Table 1: Test results of THP-1 null cell secretion of IL-1beta

[0525] Conclusion: The compound of the present application has significant inhibitory activity on the secretion of IL-1beta by THP-1 null cells.

[0526] Test Example 2: Plasma protein binding experiment (equilibrium dialysis method)

[0527] The frozen CD-1 mouse, Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human plasma were thawed in flowing cold tap water. After the plasma was completely thawed, it was centrifuged at 3220 x g for 5 minutes and the suspended and precipitated materials were removed. 597 μL of the above-mentioned blank plasma of each species was taken, 3 μL of the working solution of the test sample or the control sample was added and mixed thoroughly to obtain a plasma sample (n = 1) with a concentration of 2 μM of the test sample and the control sample. The concentration of the organic phase DMSO was 0.5%. The sample was mixed thoroughly before the next step.

[0528] Take 50 μL of the plasma samples of the test and control samples into the sample receiving plate (n = 3), immediately add 50 μL of blank PBS, then add 600 μL of the termination solution to the T0 samples of the test and control samples respectively, and store at 2-8°C, waiting for subsequent processing with other dialyzed samples.

[0529] Add 100 μL of the test and control plasma samples to the dosing end of each dialysis well (n = 3), and add 100 μL of blank PBS to the receiving end corresponding to the dialysis well. Place the dialysis plate in a 5% CO2incubator, incubate at 37°C with about 100 rpm shaking for 4 hours.

[0530] After dialysis, take 50 μL of the dialyzed PBS samples and dialyzed plasma samples (n = 3) into a new 96-well plate (sample receiving plate). Add a corresponding volume of corresponding blank plasma or PBS to the samples so that the final volume of each sample well is 100 μL, and the volume ratio of plasma to PBS is 1:1. All samples are subjected to protein precipitation before LC-MS / MS analysis.

[0531] Conclusion: The plasma protein free ratio of the compound of the present application in different species plasma is moderate, showing strong or moderate ability to bind to plasma proteins.

[0532] Test Example 3: Liver microsomal stability

[0533] The test substance is prepared into a 10 mM DMSO solution with DMSO, and then diluted to 100 μM with 100% acetonitrile to obtain a working solution (organic phase content: 99% acetonitrile, 1% DMSO).

[0534] Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.

[0535] Add 445 μL of the microsomal working solution (liver microsomal protein concentration is 0.56 mg / mL) to the T60 incubation plate and NCF60 incubation plate respectively, and then place the above incubation plates in a 37°C water bath for pre-incubation for about 10 minutes.

[0536] After pre-incubation, add 5 μL of the test or control compound working solution to the T60 incubation plate and NCF60 incubation plate respectively, and mix well.

[0537] The reaction was initiated by adding 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate; 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regenerating system working solution were added to the T0 termination plate, and 54 μL of sample was taken from the T60 incubation plate to the T0 termination plate (T0 sample production). In the blank plate, only 54 μL of microsomal working solution, 6 μL of NADPH regenerating system working solution and 180 μL of stop solution were added. The reaction was initiated by adding 44 μL of NADPH regenerating system working solution to each well of the T60 incubation plate. Thus, in the samples of test compounds or control compounds, the final concentrations of the compounds, testosterone, diclofenac and propafenone were 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0538] After incubation for an appropriate time (e.g., 5, 15, 30, 45 and 60 minutes), 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) was added to each sample well of the termination plate, and then 60 μL of sample was taken from the T60 incubation plate or the NCF60 incubation plate to terminate the reaction.

[0539] All sample plates were shaken and centrifuged at 3220 x g for 20 minutes, and then 80 μL of supernatant was taken from each well and diluted into 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis. The in vitro elimination rate constant ke of the test compounds and control compounds was obtained by converting the ratio of the peak area of the compound to the internal standard in the following formula into the remaining percentage. The in vitro liver microsomal intrinsic clearance (CLint) was calculated by ke int (mic)) was calculated by the following formula: CLint int (mic) = 0.693 / T 1 / 2 / microsomal protein content (microsomal concentration mg / mL at the time of incubation).

[0540] The experimental results showed that compounds 14, 15A, 18A, 19B, 22A, 28B and 31A had low clearance rates in mouse and human liver microsomes, and showed moderate or slow metabolism.

[0541] Conclusion: The compounds of the present application are moderately or slowly metabolized in mouse and human liver microsomes, and have good stability.

[0542] Test Example 4: In vitro MDCKII-MDR1 monolayer cell permeability test

[0543] MDR1-MDCK II cell line authorized by the laboratory of Piet Borst of the Netherlands Cancer Institute was used as an in vitro model for permeability evaluation experiment, which is a Madin-Darby canine kidney cell (MDCK II) transfected with human multidrug resistance gene (MDR1), and the cell can predict the permeability of compounds in barriers with high efflux effect such as duodenum, blood-brain barrier, liver cells and kidney units.

[0544] MDR1-MDCK II cells were inoculated into a Transwell-96 well cell plate, and the transport experiment was carried out after the cells formed a complete monolayer membrane structure. The test concentration of the drug was 2.00 μM, HBSS solution containing 10.0 mM HEPES (pH 7.40±0.05) was used as the transport buffer, and bidirectional permeability research was carried out on the MDR1-MDCK II cell model, and the incubation was carried out at 37°C, 5% CO2 for 150 minutes. The fluorescence yellow detection experiment was used to determine the integrity of the cell monolayer membrane, and low and high passive permeability controls and P-gp transport positive substrates were included in the experiment. After the incubation, part of the samples from the donor chamber and the receiving chamber were transferred and extracted with acetonitrile containing a suitable internal standard (IS). The protein was precipitated under the condition of 3220xg centrifugation for 20 minutes, and the supernatant was diluted with ultrapure water if necessary, and finally determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) technology using the appropriate MRM conversion of the analyte and the internal standard. The apparent permeability coefficient (Papp app , cm / s) and the efflux ratio (ER) were calculated according to the following equation:

[0545] Wherein, V R is the volume of the receiving end solution (0.075 mL for the A side and 0.25 mL for the B side); Area is the relative surface area of the cell monolayer (0.0804 cm 2 ); Time is the incubation time (9000s); C0is the peak area ratio of the compound at the administration end; C R are the peak area ratios of the compounds at the administration end and the receiving end, respectively.

[0546] The experimental results show that the solvent recovery rates of the test compounds of the application are all greater than 75%, and all show the characteristics of high permeability and low efflux.

[0547] Conclusion: The compounds of the application show the characteristics of high permeability and low efflux, have good membrane permeability, and are beneficial to distribution to the brain through the blood-brain barrier.

[0548] Test Example 5: Cytochrome P450 enzyme (CYP) inhibition research

[0549] Test purpose:

[0550] Determination of the inhibitory effect of the test compound on the activity of human liver microsomal cytochrome P450 isozyme (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).

[0551] Experimental method:

[0552] The test compound (10.0 mM) was gradiently diluted to prepare a working solution (100x final concentration), and the working solution concentrations were 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150 and 0.0050 mM, respectively. Meanwhile, a working solution of each positive inhibitor of P450 isozyme (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (with midazolam as a probe substrate)) and its specific substrate mixture was prepared. Human liver microsomes stored in a refrigerator below -60°C were thawed on ice, and then diluted with potassium phosphate buffer (PB) to prepare a working solution with a certain concentration (0.253 mg / mL).

[0553] 20.0 μL of the substrate mixture was added to the reaction plate (20.0 μL of PB was added to the blank well), and then 158 μL of the human liver microsomal working solution was added to the reaction plate, which was placed on ice for use. At this time, 2.00 μL of each concentration of the test compound (N=1) and the specific inhibitor (N=2) was added to the corresponding well, and the non-inhibitor (no test compound or positive inhibitor) group was added to the corresponding organic solvent as a control group sample (the test compound control sample was DMSO:MeOH=1:1, and the positive control sample was DMSO:MeOH=1:9). After pre-incubation at 37°C for 10 min, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate, which was incubated at 37°C for 10 min. The reaction was terminated by adding 400 μL of pre-cooled acetonitrile solution (containing an internal standard). The reaction plate was placed on a shaker and shaken for 10 min to mix. Then, it was centrifuged at 4°C and 4000 rpm for 20 min. 200 μL of supernatant was added to 100 μL of water for sample dilution. Finally, the plate was sealed and shaken for 10 min to mix, and then subjected to LC-MS / MS detection. The experimental results are shown in Table 2 below.

[0554] Table 2 Inhibition results of the compound of the present application on human liver microsomal cytochrome P450 enzyme (CYP)

[0555] The experimental results show that the IC50 of compound 19B and compound 22A for inhibiting human liver microsomal cytochrome P450 isozyme (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) is less than 1.0 μM. 50All are greater than 26 μM.

[0556] Conclusion: The compounds of the present application have no obvious inhibitory effect on the five main cytochrome P450 enzymes of human liver microsomes, and the risk of "drug-drug interaction" is low.

[0557] Test Example 6: Mouse PK study

[0558] Male C57 BL / 6 mice 6, divided into 2 groups, 3 animals in each group. Intravenous (iv) group was administered at a dose of 2 mg / kg, and the solvent was 5% DMSO / 50% PEG400 / 45% (5% glucose); the oral administration (po) group was administered at a dose of 10 mg / kg, and the solvent was 0.5% MC / 0.2% Tween80 / water.

[0559] Whole blood was collected at 5 min (only iv group), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, and the whole blood was placed in an anticoagulant tube containing EDTA-K2, and plasma was prepared by centrifugation. After blood collection at 24 h, the oral administration group was administered again (the dose was kept at 10 mg / kg), and whole blood (plasma) and brain tissue were collected at 2 h after the second administration. The concentration of the test molecule in plasma and brain tissue was quantitatively detected by LC-MS / MS, and the PK parameters were calculated by Phoenix WinNonlin.

[0560] The results of plasma pharmacokinetics after intravenous and oral administration of mice are shown in Table 3, and the results of drug distribution in brain and CSF after oral administration are shown in Table 4. Among them: CL represents clearance, Vdss represents distribution volume, T 1 / 2 is the half-life, AUC 0-last represents the area under the whole blood concentration-time curve from 0 to the last quantifiable time point; F represents the bioavailability.

[0561] Table 3: PK test results of the compounds of the present application in mice

[0562] Table 4: Tissue distribution results of the compounds of the present application after oral administration in mice

[0563] Conclusion: The compounds of the present application all exhibit a long half-life, a low plasma clearance rate and good oral bioavailability in mice, and have good pharmacokinetic properties; and after oral administration in mice, the brain-blood ratio is high, and all exhibit certain brain penetration.

[0564] Test Example 7: In vivo efficacy (I)

[0565] Purpose of the test:

[0566] Pharmacodynamics of test compounds in a diet-induced obesity (DIO) mouse model.

[0567] Experimental Methods:

[0568] Male C57BL / 6J mice at 6 weeks of age were fed with high-fat chow for 16 weeks, and the body weight was greater than 50 grams. After one week of adaptive feeding, the experiment started (recorded as Day 0), and the body weight and food remaining were weighed in the morning of Day 0, and the body fat of the animals was detected by MRI, and then the DIO mice were grouped according to the body weight and body fat results: DIO model control group (Vehicle group) and test group.

[0569] Day 1 started the administration, and the administration time was 15 days. The Vehicle group was the administration vehicle; the specific administration scheme of the test group was shown in Table 5; vehicle 1 was normal saline, and vehicle 2 was 5% DMSO + 10% solutol aqueous solution. The body weight of the mice was weighed and recorded every day, and the food intake was then detected, and then the body fat of the mice was detected (Day 15).

[0570] Table 5: Administration scheme of pharmacodynamics in vivo

[0571] The experimental results were shown in Table 6, and the body weight change of the mice was shown in Figure 1. The experimental results showed that, compared with the Vehicle group, compounds 15A, 19B and 20B could significantly reduce the body weight. Among them, at a single drug dose of 40 mg / kg, the weight loss effect of compound 20B was the strongest, which was better than that of Semaglutide at a single drug dose of 10 nmol / kg; compound 15A combined with Semaglutide could further significantly reduce the body weight, which was significantly better than the weight loss effect of Semaglutide alone.

[0572] At the same time, compounds 15A, 19B and 20B could reduce the fat / weight ratio of the animals and increase the lean body weight / weight ratio. Compound 15A combined with Semaglutide could further reduce the fat / weight ratio of the animals and increase the lean body weight / weight ratio, and the effect was better than that of Semaglutide alone.

[0573] Table 6: Body weight change rate and body composition results of mice at the end of pharmacodynamics experiment in vivo Note: All data are presented as mean ± standard error, *P<0.05, **P<0.01, ****P<0.0001, compared with the Vehicle group, One-Way ANOVA.

[0574] Conclusion: The compound of the present application can significantly reduce the body weight of animals and improve body composition in the diet-induced obesity (DIO) model of mice. After combined with Semaglutide, it can further significantly reduce body weight and improve body composition, showing good in vivo efficacy.

[0575] Test Example 8: In vivo efficacy (II)

[0576] Purpose of the test:

[0577] Efficacy of the test compound in the diet-induced obesity (DIO) model of mice.

[0578] Experimental method:

[0579] After 16 weeks of feeding high-fat granular feed to 6-week-old male C57BL / 6J mice, the body weight is greater than 50 grams, which is used for the test. After one week of adaptive feeding, the experiment starts (recorded as Day 0), the body weight and food remaining are weighed in the morning of Day 0, and the animal body fat is detected by MRI, then the DIO mice are grouped according to the body weight and body fat results: DIO model control group (Vehicle group) and test group, 12 animals in each group.

[0580] This test is divided into two stages, the first stage: Day 1 starts to give medicine, the giving time is 21 days, the Vehicle group is the medicine solvent; the specific giving scheme of the test group is shown in Table 7. The second stage: on Day 21, the animals in test group 1 are re-grouped into test group 1A and test group 1B, and the animals in test group 2 are re-grouped into test group 2A and test group 2B, 6 animals in each group. Day 22 starts to give medicine again, the giving time is 21 days, the Vehicle group is the medicine solvent; the specific giving scheme of the test group is shown in Table 8. Solvent 1 is normal saline, and solvent 2 is 5% DMSO+10% solutol aqueous solution. The body weight and food intake of mice are recorded every day.

[0581] Table 7: In vivo efficacy giving scheme (Day 1-Day 21)

[0582] Table 8: In vivo efficacy giving scheme (Day 22-Day 42)

[0583] The experimental results of the change of animal body weight in test group 1 are shown in Figure 2, and the experimental results of the change of animal body weight in test group 2 are shown in Figure 3. Among them, the animal body weight is calculated as average body weight.

[0584] In test group 1, after 21 days of semaglutide administration, the animal body weight decreased from 51.2 g to 43.7 g. In test group 1A, after 21 days of drug withdrawal, the animal body weight rebounded from 43.7 g to 51.7 g, while in test group 1B, after 21 days of semaglutide withdrawal and administration of compound 15A, the animal body weight rebounded from 43.7 g to 47.9 g. Test group 1B can delay the body weight rebound by about 47.5% compared with test group 1A.

[0585] In test group 2, after 21 days of administration of semaglutide and compound 15A, the animal body weight decreased from 51.2 g to 41.3 g. In test group 2A, after 21 days of drug withdrawal, the animal body weight rebounded from 41.3 g to 50.5 g, while in test group 2B, after 21 days of semaglutide withdrawal and maintenance of administration of compound 15A, the animal body weight rebounded from 41.3 g to 46.1 g. Test group 2B can delay the body weight rebound by about 47.8% compared with test group 2A.

[0586] Conclusion: In the diet-induced obesity (DIO) mouse model, after semaglutide monotherapy or semaglutide combined with the compound of the present application for weight loss, the withdrawal of semaglutide and the oral administration of the compound of the present application alone can significantly delay the rebound of body weight.

Claims

a compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein T1and T2are each independently selected from C and N; R 12 is selected from H, -CHO, -CO-R 1b , -SO-R 1b , -SO2-R 1b and the following groups optionally substituted by 1 or more R 1a : C 3-10 ycloalkyl, 3-10 membered heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-4 alkyl-CN; R 32 and R 42 are each independently selected from the group consisting of H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R 3b C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl, wherein R 42 is absent when T1is N, and R 32 is absent when T2is N; Or, R 32 and R 42 The atoms connected to them together form an array optionally bounded by one or more R atoms. 3c The following groups are substituted: C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; R5is selected from H and optionally substituted with 1 or more R 5a substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl; Ring A2is selected from optionally substituted a2 the following groups: C 3-10 cycloalkenyl and 3-10 membered heterocycloalkenyl; Each R 1a The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -COC 1-4 alkyl; R 1b Selected from the following groups substituted with one or more R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups; each R 3b , each R 3c , each R 5a , each R a2 and each R b is independently selected from H, D, F, Cl, Br, I, =0, OH, NH2, CN, SF5 and an optionally substituted group selected from the following: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1- 4alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl; or 2 R 3b together with the atom to which they are attached, or 2 R 3c together with the atom to which they are attached, or 2 R a2 together with the atom to which they are attached, or 2 R b independently of each other, form, together with the atom to which they are attached, a group C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; each R is independently selected from H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more F: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkoxy. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, each R is independently selected from H, D, F, Cl, OH, NH2, CN, CH3, CD3, and CF3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, each R 3b , each R 3c , each R 5a , each R a2 , and each R b is independently selected from H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3, and cyclopropyl; further, each R 3b , each R 3c , each R 5a , each R a2 , and each R b is independently selected from H, D, F, CI, CH3, CD3, CF3, CN, The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, each R 1a is independently selected from the group consisting of H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3, cyclopropyl, -COCH3, and -COCH2CH3; further, each R 1a is independently selected from the group consisting of H, D, F, CI, CN, CH3, CD3, CFH2, CF2H, CF3, CH2CH3, CH2CF3, OCH3, OCF3, OCD3, and OCH2CH3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R 1b selected from the following groups optionally substituted with 1 or more R: CH3, CH2CH3, OCH3, OCH2CH3; further, R 1b selected from CH3, CD3, CF3, OCH3, and OCH2CH3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R 12 is selected from H and -CHO; or, R 12 is selected from the group consisting of optionally substituted C 1a , C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, and -C 1-4 alkyl-CN. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R 12 is selected from H, -CHO and the following groups optionally substituted with 1 or more R 1a substituted with 1 or more R 12 is selected from H, -CHO and the following groups optionally substituted with 1 or more R -CH2CN, -CF2CN, COOCH3, COOCH2CH3, COCH3, COCF3, The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R 32 and R 42 are each independently selected from H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R 3b CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl; further, R 32 is H or D, and R 42 is H, D, CH3, CD3, or CF3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R 32 and R 42 The atoms connected to them together form an array optionally bounded by one or more R atoms. 3c The following groups are substituted: cyclopentyl, cyclopentenyl, phenyl, and pyridyl; furthermore, R 32 and R 42 Together with the atoms attached to them, they form cyclopentyl, cyclopentenyl, and pyridyl groups. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, Structural unit selected from the group consisting of R 42 selected from H, D and C 1-3 alkyl; further, structural units selected from the group consisting of The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, Ring A2 is selected from one or more R. a2 Substituted 3-10 membered heterocyclic alkenyl groups; furthermore, ring A2 is selected from 3-10 membered bridged heterocyclic alkenyl groups. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 11, wherein, Structural unit selected from the group consisting of The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, Structural unit selected from the group consisting of The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, is selected from, wherein, Rings A2, R b , R 42 , R 32 , R 12 as defined in any one of claims 1 to 13. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 14, wherein A2is selected from the group consisting of optionally substituted 3-10 membered a2 substituted 3-10 membered heterocycloalkenyl; further, ring A2is selected from the group consisting of 6-10 membered heterocycloalkenyl; still further, ring A2is selected from the group consisting of 6-10 membered bridged heterocycloalkenyl; each R b are each independently selected from the group consisting of H, D, F, CI, Br, I, CN, and the following groups optionally substituted with 1 or more R: C 1-3 alkyl, C 1- 3alkoxy, and C 3-6 cycloalkyl; further, each R b are each independently selected from the group consisting of H, D, F, CI, CN, CH3, CD3, and CF3; R 12 is selected from H and optionally substituted C 1a substituted C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, and -C 1-4 alkyl-CN; R 32 selected from H and D; R 42 selected from H, D, F, CI, and optionally substituted C 3b alkyl; further, R 1-4 alkyl; further, R 42 selected from H, D, CH3, CD3, or CF3; each R a2 , each R 3b is independently selected from H, D, F, Cl, Br, I, and CH3; Each R 1a They were independently selected from H, D, F, Cl, CN, CH3, CD3, and CF3, respectively; each R is independently selected from H, D, F, Cl, CN, and methyl optionally substituted with 1, 2, or 3 F or D; further, each R is independently selected from H, D, F, CH3, CD3, and CF3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 15, is selected from, wherein R b , R 42 , R 32 and R 12 are as defined in claim 15. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of Tables A and / or B; further, the compound, stereoisomer, or pharmaceutically acceptable salt thereof according to Table A is selected from the compounds of Table A1, and the compound, stereoisomer, or pharmaceutically acceptable salt thereof according to Table B is selected from the compounds of Table B1; further, the compound, stereoisomer, or pharmaceutically acceptable salt thereof according to Table B1 is selected from the compounds of Table B2. Use of the compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-17 in the manufacture of a medicament for treating a disease associated with an NLRP3 inhibitor.

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