Aromatic ring-fused thienodiazepine compounds and uses thereof

Abstract

The present disclosure belongs to the technical field of medicine, and relates to an aromatic ring and thiazodiazepine compound and use thereof, and further relates to a preparation method of the aromatic ring and thiazodiazepine compound and a pharmaceutical composition containing the compound. The present disclosure specifically relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and use thereof.

Description

[0001] Cross-references to related applications This disclosure claims priority and benefits to Chinese Patent Application No. 202411721275.4 and Chinese Patent Application No. 202510081834.8, filed with the China National Intellectual Property Administration, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the field of pharmaceutical technology and relates to an aromatic cyclothiazolium compound and its uses. This disclosure also relates to a method for preparing the aromatic cyclothiazolium compound and a pharmaceutical composition containing the compound. Background Technology

[0003] NTCP (sodium taurocholate cotransporting polypeptide) is a sodium ion-taurocholate cotransporter encoded by the SLC10A1 gene. NTCP is a major protein on the hepatocyte membrane that transports sodium ions and bile acids, playing a crucial role in the enterohepatic circulation of bile acids and serving as a potential target for antiviral and cholestasis indications. NTCP is located in the basolateral domain (blood side) of hepatocytes in humans, rats, and other species; it is undetectable in any other tissues.

[0004] The HBV envelope protein consists of three proteins: large envelope proteins (LHBs), medium envelope proteins (MHBs), and small envelope proteins (SHBs), including the preS1, preS2, and S regions. Scientists have discovered that HBV and HDV enter hepatocytes by binding to NTCP, which possesses the HBV preS1 surface protein domain. Furthermore, in vitro knockout of NTCP effectively inhibits HBV / HDV infection of hepatocytes. Therefore, the antiviral mechanism of currently under investigation NTCP inhibitors relies on the specific binding and blocking of the hepatocyte surface protein NTCP. This NTCP inhibition prevents HBV and HDV from entering cells, thereby preventing hepatocyte infection. In addition, regarding bile acid metabolism, inhibiting NTCP reduces bile acid entry into the liver, leading to an increase in the circulating bile acid pool. The increased bile acid pool can act as an FXR agonist. Simultaneously, NTCP inhibition significantly improves hepatic fat accumulation and steatosis, alleviating liver damage. Invention Details On the one hand, this disclosure relates to compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0006] in, X is selected from C(R) a R b) or NR c ; L is selected from bond, O, S, (C(R) a R b )) p 、(NR c ) q or (C(R) a R b )) i -(NR c ) j ; W 1 and W 2 Each is independently selected from CH or N; R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2)nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl or 5-14-membered heteroaryl groups may optionally be further substituted by one or more substituents; Or, R 1 and R 2 Together with the carbon atoms attached to them, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may optionally be further substituted with one or more substituents; Or, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form 3-14 membered heterocyclic groups, which may optionally be further substituted by one or more substituents; R a and R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may optionally be further substituted with one or more substituents; R c Selected from hydrogen, hydroxyl, amino, mercapto, C 1-12 Alkyl or C 1-12 alkoxy, the amino, C 1-12 Alkyl or C 1-12 The alkoxy group may optionally be further substituted by one or more substituents; Or, when L is selected from (C(R) a R b )) p or (C(R) a Rb )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may optionally be further substituted with one or more substituents; Or, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached to them, they form 3-14 membered heterocyclic groups, which may optionally be further substituted by one or more substituents; Or, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, they form a 3-14 membered heterocyclic group, which may optionally be further substituted by one or more substituents; R 3 Selected from hydrogen, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3-(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl or 5-10 membered heteroaryl may optionally be further substituted by one or more substituents; A is selected from , , , , , or ; Ring B is selected from C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 3-14 The cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl or 5-14-membered heteroaryl groups may optionally be further substituted by one or more substituents; R 4 Selected from C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C3-14 The cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl or 5-14-membered heteroaryl groups may optionally be further substituted by one or more substituents; R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-12 Alkyl or C 1-12 Alkoxy; the amino, C 1-12 Alkyl or C 1-12 The alkoxy group may optionally be further substituted by one or more substituents; R a1 R a2 Or R a3 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, or 5-14 membered heteroaryl, wherein the amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl, 3-14 membered heterocyclic, 6-104 membered aryl or 5-14 membered heteroaryl may optionally be further substituted by one or more substituents; p, q, i, or j are each independently selected from 1, 2, or 3; m is selected from 0, 1, or 2; n and n1 are each independently selected from 0, 1, 2, 3 or 4; The conditions are: When A is selected L is the bond, and R 1 and R 2 Each is independently selected from hydrogen or unsubstituted C. 1-12 When alkyl, R 4 The phenyl group is either unsubstituted or non-substituted.

[0007] In some embodiments, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, in, X is selected from C(R) a R b ) or NR c ; L is selected from bond, O, S, (C(R) a R b )) p 、(NR c )q or (C(R) a R b )) i -(NR c ) j ; W 1 and W 2 Each is independently selected from CH or N; R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-12Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl groups may optionally be further subjected to one or more R groups. aa replace; Or, R 1 and R 2 Together with the carbon atoms attached to them, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups may optionally be further substituted with one or more R groups. bb replace; Or, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form 3-14 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. bb replace; R a and R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups may optionally be further substituted with one or more R groups. cc replace; R c Selected from hydrogen, hydroxyl, amino, mercapto, C 1-12 Alkyl or C 1-12 alkoxy, the amino, C 1-12 Alkyl or C 1-12 The alkoxy group may optionally be further reacted with one or more R groups. e replace; Or, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c )j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups may optionally be further substituted with one or more R groups. d1 replace; Or, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached to them, they form 3-14 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. d2 replace; Or, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, they form a 3-14 membered heterocyclic group, which may optionally be further bonded by one or more R atoms. d3 replace; R 3 Selected from hydrogen, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2)n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-10-membered heteroaryl groups may optionally be further subjected to one or more R groups. f replace; A is selected from , , , , , or ; Ring B is selected from C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl groups may optionally be further subjected to one or more R groups. g replace; R 4 Selected from C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl groups may optionally be further subjected to one or more R groups. h replace; R 5 and R 5’Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-12 Alkyl or C 1-12 Alkoxy; the amino, C 1-12 Alkyl or C 1-12 The alkoxy group may optionally be further reacted with one or more R groups. i replace; R a1 R a2 Or R a3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, or 5-14 membered heteroaryl, wherein the amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-104-membered aryl, or 5-14-membered heteroaryl groups may optionally be further subjected to one or more R groups. j replace; R aa R bb R cc R d1 R d2 R d3 R e R f R g R h R i and R j Each is independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, mercapto, =O, C. 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n O(CH2) n S(O)m R al -(CH2) n P(O)R a2 R a3 -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The C 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 The cycloalkyl or 3-14 membered heterocycloalkyl group may optionally be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano; p, q, i, or j are each independently selected from 1, 2, or 3; m is selected from 0, 1, or 2; n and n1 are each independently selected from 0, 1, 2, 3 or 4; The conditions are: When A is selected L is the bond, and R 1 and R 2 Each is independently selected from hydrogen or unsubstituted C. 1-12 When alkyl, R 4 The phenyl group is either unsubstituted or non-substituted.

[0008] In some embodiments, the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts, in, X is selected from C(R) a R b ) or NRc ; L is selected from bond, O, S, (C(R) a R b )) p 、(NR c ) q or (C(R) a R b )) i -(NR c ) j ; W 1 and W 2 Each is independently selected from CH or N; R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2)nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups may optionally be further reacted with one or more R groups. aa replace; Or, R 1 and R 2 Together with the carbon atoms attached to them, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups may optionally be further substituted with one or more R groups. bb replace; Or, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form 3-12 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. bb replace; R a and R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups may optionally be further substituted with one or more R groups. cc replace; R c Selected from hydrogen, hydroxyl, amino, mercapto, C 1-6 Alkyl or C 1-6 alkoxy, the amino, C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups. e replace; Or, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups may optionally be further substituted with one or more R groups. d replace; Or, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached to them, they form 3-12 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. d replace; Or, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, they form a 3-12 membered heterocyclic group, which may optionally be further bonded by one or more R atoms. d replace; R 3 Selected from hydrogen, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)ORal -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups may optionally be further reacted with one or more R groups. f replace; A is selected from , , , , , or ; Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups may optionally be further reacted with one or more R groups. g replace; R 4 Selected from C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups may optionally be further reacted with one or more R groups. h replace; R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl or C 1-6 Alkoxy; the amino, C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups. i replace; R a1 R a2 or R a3 Each group is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups may optionally be further reacted with one or more R groups. j replace; R aa R bb R cc R d R e R f R g R h R i and R j Each is independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, mercapto, =O, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)Ral -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n O(CH2) n S(O) m R al -(CH2) n P(O)R a2 R a3 -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups may optionally be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano; p, q, i, or j are each independently selected from 1, 2, or 3; m is selected from 0, 1, or 2; n and n1 are each independently selected from 0, 1, 2, 3 or 4; The conditions are: When A is selected L is the bond, and R 1 and R 2 Each is independently selected from hydrogen or unsubstituted C. 1-12 When alkyl, R 4The phenyl group is either unsubstituted or non-substituted.

[0009] In some implementations, the R described in this disclosure d Selected from R d1 R d2 Or R d3 .

[0010] In some implementations, the R described in this disclosure d1 R d2 Or R d3 It can be R d .

[0011] In some implementation schemes, R aa R bb R cc R d1 R d2 R d3 R e R f R g R h R i and R j Each is independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, mercapto, =O, C. 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n P(O)R a2 R a3 -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 Ra3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The C 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 The cycloalkyl or 3-14 membered heterocycloalkyl group may optionally be further substituted with one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano.

[0012] In some implementation schemes, R aa R bb R cc R d R e R f R g R h R i and R j Each is independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, mercapto, =O, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n P(O)R a2 R a3 -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2)nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl and 3-6-membered heterocyclic groups may optionally be further substituted with one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano.

[0013] In some implementation schemes, R aa R bb R cc R d R e R f R g R h R i and R j Each is independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, mercapto, =O, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2)n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl and 3-6-membered heterocyclic groups may optionally be further substituted with one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano.

[0014] In some implementations, the phrase "by one or more" is independently selected from 1, 2, 3, 4, 5, or 6.

[0015] In some implementations, the phrase "by one or more" is independently selected from 1, 2, 3, 4, or 5.

[0016] In some implementations, the phrase "by one or more" is independently selected from 1, 2, 3, or 4.

[0017] In some implementations, the term "by one or more" is independently selected from 1, 2, or 3.

[0018] In some embodiments, the term "heterogeneous" is independently selected from heteroatoms of oxygen, sulfur, nitrogen, and phosphorus, wherein nitrogen atoms are optionally quaternized or oxidized to N(O), sulfur atoms are optionally oxidized to S(O) or S(O)2, phosphorus atoms are optionally oxidized to P(O) or P(O)2, and other variables are as defined in this disclosure.

[0019] In some embodiments, the term "heteroatom" is independently selected from heteroatoms of oxygen, sulfur, and nitrogen, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), the sulfur atom is optionally oxidized to S(O) or S(O)2, and other variables are as defined in this disclosure.

[0020] In some implementation schemes, R a and Rb Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups. cc replace.

[0021] In some implementation schemes, R a and R b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further reacted with one or more R groups. cc replace.

[0022] In some implementation schemes, R a and R b Each is independently selected from hydrogen or C. 1-3 Alkyl, the C 1-3 Alkyl groups may optionally be further reacted with one or more R cc replace.

[0023] In some implementation schemes, R a and R b Each is independently selected from hydrogen, methyl, or ethyl.

[0024] In some implementation schemes, R a and R b Each is independently selected from hydrogen or methyl.

[0025] In some implementation schemes, R a Selected from hydrogen, R b Selected from methyl; or R a Selected from methyl, R b Selected from hydrogen.

[0026] In some implementation schemes, R a and R b All are selected from hydrogen.

[0027] In some implementation schemes, R a and R b All are selected from methyl groups.

[0028] In some implementation schemes, R c Selected from hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further reacted with one or more R e replace.

[0029] In some implementation schemes, Rc Selected from hydrogen or C 1-3 Alkyl, the C 1-3 Alkyl groups may optionally be further reacted with one or more R e replace.

[0030] In some implementation schemes, R c Selected from hydrogen, methyl, or ethyl, wherein the methyl or ethyl group is optionally independently reacted with one or more R groups. e replace.

[0031] In some implementation schemes, R c Selected from hydrogen, or optionally substituted methyl or ethyl groups with deuterium.

[0032] In some implementation schemes, R c Selected from hydrogen or methyl groups optionally substituted with deuterium.

[0033] In some implementation schemes, R c Selected from hydrogen, methyl, ethyl or -CD3.

[0034] In some implementation schemes, R c Selected from hydrogen, methyl, or -CD3.

[0035] In some implementation schemes, R c Selected from methyl.

[0036] In some implementation schemes, R c Selected from hydrogen.

[0037] In some implementation schemes, W 1 and W 2 All are CH.

[0038] In some implementation schemes, W 1 For N, W 2 For CH.

[0039] In some implementation schemes, W 2 For N, W 1 For CH.

[0040] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C3-6 cycloalkyl or 3-6 membered heterocyclic groups may optionally be further reacted with one or more R d or R d1 replace.

[0041] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form C 3-6 cycloalkyl, the C 3-6 The cycloalkyl group may optionally be further reacted with one or more R d or R d1 replace.

[0042] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiohexyl, azacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrothiophene, tetrahydrofuranyl, tetrahydropyranyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiohexyl, azacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrothiophene, tetrahydrofuranyl, tetrahydropyranyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, or morpholinyl groups may optionally be further atomized by one or more R groups. d or R d1 replace.

[0043] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) jAt the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, which may optionally be further reacted with one or more R groups. d or R d1 replace.

[0044] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form cyclopropyl, cyclobutyl, or aziridine, which may optionally be further reacted with one or more R... d or R d1 replace.

[0045] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form cyclopropyl or cyclobutyl groups, which may optionally be further reacted with one or more R groups. d or R d1 replace.

[0046] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At that time, R on the same carbon atom a and R b Together with the carbon atoms attached to them, they form a cyclopropyl group, which may optionally be further reacted with one or more R... d or R d1 replace.

[0047] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At that time, R on different carbon atoms a and R b Together with the carbon atoms attached to them, they form a cyclobutyl group, which may optionally be further reacted with one or more R... d Or R d1 replace.

[0048] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j In this case, "same or different carbon atoms" means "two same or two different carbon atoms"; or, "same carbon atoms" means "two same carbon atoms"; or, "different carbon atoms" means "two different carbon atoms".

[0049] In some implementations, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j In this case, "same or different carbon atoms" means "two same or two different carbon atoms at both ends"; or, "same carbon atoms" means "two same carbon atoms at both ends"; or, "different carbon atoms" means "two different carbon atoms at both ends".

[0050] In some implementations, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached to them, they form 3-6 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. d Or R d2 replace.

[0051] In some implementations, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached thereto, they form 1,3-diazacyclobutane, imidazoalkyl, or piperazine groups, which may optionally be further atomized by one or more R... d or R d2 replace.

[0052] In some implementations, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached thereto, they form 1,3-diazacyclobutane, which may optionally be further reacted with one or more R... d or R d2 replace.

[0053] In some implementations, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j In this context, "different nitrogen atoms" refers to "two different nitrogen atoms".

[0054] In some implementations, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j In this context, "different nitrogen atoms" refers to "two different nitrogen atoms at both ends".

[0055] In some implementations, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atoma And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, they form a 3-6 membered heterocyclic group, which may optionally be further bonded by one or more R atoms. d or R d3 replace.

[0056] In some implementations, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, it forms an azahexacyclobutyl, pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, piperidinyl, or piperazine group, wherein the azahexacyclobutyl, pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, piperidinyl, or piperazine group may optionally be further atomized by one or more R... d or R d3 replace.

[0057] In some implementations, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, it forms a nitrogen-containing heterocyclic butyl group, which may optionally be further reacted with one or more R... d or R d3 replace.

[0058] In some implementations, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the "R on the carbon atom" a And the R atoms on the carbon and nitrogen atoms connected to it. c "and the nitrogen atom attached to it" is "R on a carbon atom" a And the R atom on the carbon atom and a nitrogen atom attached to it. c "And the nitrogen atom attached to it."

[0059] In some implementations, when L is selected from (C(R) a R b )) i -(NRc ) j At that time, the "R on the carbon atom" a And the R atoms on the carbon and nitrogen atoms connected to it. c And the nitrogen atom attached to it is the R on a carbon atom at one end. a And the R atom on the carbon atom attached to it, and on the nitrogen atom at the other end. c "And the nitrogen atom attached to it."

[0060] In some implementations, X is selected from NR c .

[0061] In some embodiments, X is selected from CH2, CH(CH3), C(CH3)2 or N(CH3), and X is optionally substituted with one or more deuterium.

[0062] In some implementations, X is selected from CH2, CH(CH3), C(CH3)2 or N(CH3).

[0063] In some implementations, X is selected from .

[0064] In some implementations, X is selected from N(CH2CH3).

[0065] In some implementations, X is selected from NH, N(CH2D), N(CHD2), or N(CD3).

[0066] In some implementations, X is selected from NH or N(CD3).

[0067] In some implementations, X is selected from CH2, N(CH3), NH, N(CD3), or... .

[0068] In some implementations, X is selected from CH2 or N(CH3).

[0069] In some implementations, X is selected from N(CD3) or N(CH3).

[0070] In some implementations, X is selected from N(CH3).

[0071] In some implementations, L is selected from key, (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j .

[0072] In some implementations, p, q, i, or j are each independently selected from 1 or 2.

[0073] In some implementations, i and j are each selected from 1.

[0074] In some implementations, q is 2.

[0075] In some implementations, L is selected from key, -C(R) a R b )-、-C(R a R b )-C(R a R b )-、-C(R a R b )-NR c -、-C(R a R b )-C(R a R b )-C(R a R b )- or C(R a R b )-C(R a R b )-NR c .

[0076] In some implementations, L is selected from C(R) a R b ), -C(R a R b )-C(R a R b - or -C(R) a R b )-NR c -

[0077] In some implementations, L is selected from key.

[0078] In some implementations, L is selected from bonds, CH2, CH(CH3), C(CH3)2, , , , or Each r is independently selected from 1, 2, 3, or 4. In some implementations, each r is independently selected from 1 or 2.

[0079] In some implementations, L is selected from bonds, CH2, CH(CH3), C(CH3)2, , , , , or .

[0080] In some implementations, L is selected from bonds, CH2, C(CH3)2, , or .

[0081] In some implementations, structural fragment LR 4 Selected from -R 4 -OR 4 -SR 4 、-(C(R a R b )) p -R 4 、-(NR c ) q -R 4 、-(C(R a R b )) i -(NR c ) j -R 4 or -(NR) c ) j -(C(R a R b )) i -R 4 .

[0082] In some implementations, structural fragment LR 4 Selected from -R 4 、-(C(R a R b )) p -R 4 or -(C(R) a R b )) i -(NR c ) j -R 4 .

[0083] In some implementations, structural fragment LR 4 Selected from -R 4 -CH2R 4 -C(CH3)2R 4 , , or .

[0084] In some implementation schemes, R cc R d1 R d2 Rd3 and R e Each is independently selected from deuterium, halogen, hydroxyl, amino, cyano, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.

[0085] In some implementation schemes, R cc R d1 R d2 R d3 and R e Each is independently selected from deuterium, halogen, or hydroxyl.

[0086] In some implementation schemes, R cc R d1 R d2 R d3 and R e Each is independently selected from F.

[0087] In some implementation schemes, R cc R d and R e Each is independently selected from deuterium, halogen, hydroxyl, amino, cyano, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.

[0088] In some implementation schemes, R cc R d and R e Each is independently selected from deuterium, halogen, or hydroxyl.

[0089] In some implementation schemes, R cc R d and R e Each is independently selected from F.

[0090] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, NH2, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkyl group or -(CH2) n OR al The C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups.aa Replacement. In some implementations, R 1 and R 2 Each is independently selected from -(CH2) n R al Or C 3-6 Cycloalkyl.

[0091] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkyl group or -(CH2) n OR al The C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups. aa replace.

[0092] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen and C. 1-6 Alkyl group, -(CH2) n R al C 3-6 Cycloalkyl or -(CH2) n OR al The C 1-6 Alkyl groups can be further reacted with one or more R aa replace.

[0093] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen and C. 1-6 Alkyl group, -(CH2) n R al Or -(CH2) n OR al The C 1-6 Alkyl groups can be further reacted with one or more R aa replace.

[0094] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen and C. 1-6 Alkyl or -(CH2) n OR al The C 1-6 Alkyl groups can be further reacted with one or more R aa replace.

[0095] In some implementations, n and n1 are each independently selected from 0, 1, or 2.

[0096] In some implementations, n is selected from 1 or 2.

[0097] In some implementations, n is selected from 0.

[0098] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OR al -CH2CH2OR al The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups may optionally be further reacted with one or more R groups. aa Replacement. In some implementations, R 1 and R 2 Each is independently selected from -CH2R al In some implementations, R 1 and R 2 Each is independently selected from cyclopropyl or cyclobutyl.

[0099] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, isopropyl, n-butyl, cyclopropyl, -CH2R al -CH2OR al -CH2CH2OR al The n-butyl group may optionally be further reacted with one or more R aa replace.

[0100] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, n-butyl, and -CH2R. al -CH2OR al -CH2CH2OR al The n-butyl group may optionally be further reacted with one or more R aa replace.

[0101] In some implementation schemes, R 1 and R 2 Together with the carbon atoms attached to them, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 cycloalkyl or 3-6 membered heterocyclic groups may optionally be further reacted with one or more R bb replace.

[0102] In some implementation schemes, R 1 and R 2Together with the carbon atoms attached to them, they form cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiohexacyclobutyl, azacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrothiophene, tetrahydrofuranyl, tetrahydropyranyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, or morpholinyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, thiohexacyclobutyl, azacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrothiophene, tetrahydrofuranyl, tetrahydropyranyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, or morpholinyl groups may optionally be further atomized by one or more R groups. bb replace.

[0103] In some implementation schemes, R 1 and R 2 Together with the carbon atoms attached to them, they form a cyclopentyl group, which may optionally be further reacted with one or more R... bb replace.

[0104] In other implementations, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form 3-6 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. bb replace.

[0105] In other implementations, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached thereto, they form a nitrogen-containing heterocyclic butyl, pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, piperidinyl, or piperazine group, wherein the nitrogen-containing heterocyclic butyl, pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, piperidinyl, or piperazine group may optionally be further atomized by one or more R... bb replace.

[0106] In other implementations, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form a pyrrolidinyl or piperidinyl group, which may optionally be further reacted with one or more R groups. bb replace.

[0107] In some implementation schemes, R a1 R a2 Or Ra3 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups may optionally be further reacted with one or more R j Replacement. In some implementations, R a1 R a2 Or R a3 Each is independently selected from phenyl or 5-6-membered heteroaryl groups, wherein the phenyl or 5-6-membered heteroaryl group may optionally be further converted by one or more R groups. j replace.

[0108] In some implementation schemes, R a1 R a2 Or R a3 Each is independently selected from hydrogen and C. 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group may optionally be further reacted with one or more R j Replacement. In some implementations, R a1 R a2 Or R a3 Each is independently selected from phenyl, and the phenyl may optionally be further reacted with one or more R j Replacement. In some implementations, R a1 R a2 Or R a3 Each is independently selected from a 5-membered heteroaryl group, which may optionally be further selected by one or more R groups. j replace.

[0109] In some implementation schemes, R a1 R a2 Or R a3 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl or phenyl, wherein C 1-6 Alkyl, C 3-6 cycloalkyl or phenyl may optionally be further oxidized by one or more R j replace.

[0110] In some implementation schemes, R a1 R a2 Or R a3Each of the following is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or phenyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or phenyl may optionally be further reacted with one or more R j replace.

[0111] In some implementation schemes, R a1 R a2 Or R a3 Each is independently selected from methyl, ethyl, cyclopropyl, or phenyl, and the methyl, ethyl, cyclopropyl, or phenyl group may optionally be further reacted with one or more R... j Replacement. In some implementations, R a1 R a2 Or R a3 Each group is independently selected from thiazolyl groups, which may optionally be further selected by one or more R groups. j replace.

[0112] In some implementation schemes, R a1 R a2 Or R a3 Each of the following is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl groups may optionally be further substituted by one or more R groups. j replace.

[0113] In some implementation schemes, R a1 R a2 Or R a3 Each is independently selected from hydrogen, methyl, ethyl, tert-butyl, or cyclopentyl, wherein the methyl, ethyl, tert-butyl, or cyclopentyl group may optionally be further reacted with one or more R groups. j replace.

[0114] In some implementation schemes, R aa R bb and R j Each is independently selected from deuterium, halogen, hydroxyl, amino, cyano, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.

[0115] In some implementation schemes, R aa R bb and R jEach is independently selected from deuterium, halogen, or hydroxyl. In other embodiments, R bb Selected from C 1-3 Alkyl, the C 1-3 The alkyl group may be further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino, or cyano. In other embodiments, R bb Selected from methyl or ethyl. In other embodiments, R bb Selected from ethyl.

[0116] In some implementation schemes, R aa R bb and R j Each is independently selected from F.

[0117] In some implementation schemes, R a1 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further reacted with one or more R j replace.

[0118] In some implementation schemes, R a1 Selected from C 1-3 alkyl.

[0119] In some implementation schemes, R a1 The molecule is selected from methyl, ethyl, cyclopropyl, or phenyl, and the methyl, ethyl, cyclopropyl, or phenyl molecule may optionally be further substituted with one or more F molecules.

[0120] In some implementation schemes, R a1 It is selected from methyl, ethyl, cyclopropyl or 2-fluorophenyl.

[0121] In some implementation schemes, R a1 Selected from methyl or ethyl.

[0122] In some implementation schemes, R j Selected from F or -(CH2) n S(O) m R al .

[0123] In some implementation schemes, R j Selected from F or -SR al .

[0124] In some implementation schemes, R j Selected from F or -SCH3.

[0125] In some implementation schemes, R 1 and R 2 Together with the carbon atoms attached to them, they form a cyclopentyl group.

[0126] In other implementations, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form a pyrrolidinyl or piperidinyl group, which may optionally be further substituted with one or more methyl or ethyl groups; R 1 Selected from H.

[0127] In other implementations, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form a pyrrolidinyl or piperidinyl group, which may optionally be further substituted with an ethyl group; R 1 Selected from H. In other embodiments, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms bonded to them, they form , or ;R 1 Selected from H. In other embodiments, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms bonded to them, they form or ;R 1 Selected from H.

[0128] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OR al -CH2CH2OR al The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups may optionally be further substituted with one or more F groups, R. a1 Selected from methyl or ethyl.

[0129] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, isopropyl, n-butyl, cyclopropyl, -CH2R al -CH2OR al -CH2CH2OR al The n-butyl group may optionally be further replaced by one or more F groups, Ra1 Selected from methyl, ethyl or cyclopropyl.

[0130] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, n-butyl, and -CH2R. al -CH2OR al -CH2CH2OR al The n-butyl group may optionally be further replaced by one or more F groups, R a1 Selected from methyl, ethyl or cyclopropyl.

[0131] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, isopropyl, n-butyl, cyclopropyl, -CH2OCH2CH3 or -CH2CH2OCH3, wherein the n-butyl group may optionally be further substituted with one or more F groups.

[0132] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3, wherein the n-butyl group may optionally be further substituted with one or more F groups.

[0133] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3, wherein the n-butyl may optionally be further substituted by one or more F.

[0134] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen or n-butyl, and the n-butyl may be further substituted with one or more F.

[0135] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, isopropyl, n-butyl, cyclopropyl, , , , , -CH2OCH2CH3 or -CH2CH2OCH3.

[0136] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, n-butyl, , , , , -CH2OCH2CH3 or -CH2CH2OCH3.

[0137] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, n-butyl, , , , -CH2OCH2CH3 or -CH2CH2OCH3.

[0138] In some implementation schemes, R 1 Selected from H.

[0139] In some implementation schemes, R 1 Selected from H, R 2 Selected from isopropyl, n-butyl, cyclopropyl, , , , , -CH2OCH2CH3 or -CH2CH2OCH3.

[0140] In some implementation schemes, R 1 Selected from H, R 2 Selected from n-butyl, , , , , -CH2OCH2CH3 or -CH2CH2OCH3.

[0141] In some implementation schemes, R 1 Selected from H, R 2 Selected from n-butyl, , , , -CH2OCH2CH3 or -CH2CH2OCH3.

[0142] In some implementation schemes, R 1 Selected from H, R 2 Selected from n-butyl.

[0143] In some implementation schemes, R 1 Selected from H, R 2 Selected from .

[0144] In some implementation schemes, R 1 Selected from H, R 2 Selected from isopropyl.

[0145] In some implementation schemes, R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkyl group or -(CH2) n S(O) m R al The amino group, C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups. f Replacement. In other implementations, R 3 Selected from C 3-6 Cycloalkyl or -(CH2) n NR a2 R a3 The C 3-6 The cycloalkyl group may optionally be further reacted with one or more R f Replacement. In some implementations, R 3 Selected from -(CH2) n OR al In some implementations, R 3 Selected from phenyl, said phenyl may optionally be further reacted with one or more R f replace.

[0146] In some implementation schemes, R 3 Selected from halogens, hydroxyl groups, NH2, cyano groups, and C. 1-3 Alkyl, C 1-3 Alkyl group or -(CH2) n S(O) m R al The C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further reacted with one or more R groups. f replace.

[0147] In some implementation schemes, R 3 Selected from methyl, ethyl, methoxy, ethoxy, or -(CH2). n S(O) m R al The methyl, ethyl, methoxy, and ethoxy groups may optionally be further reacted with one or more R groups. f Replacement. In other implementations, R 3 Selected from cyclopropyl, cyclobutyl, or -(CH2) n NR a2 R a3 The cyclopropyl or cyclobutyl group may optionally be further reacted with one or more R groups. f Replacement. In other implementations, R3 Selected from phenyl, said phenyl may optionally be further reacted with one or more R f replace.

[0148] In some implementation schemes, R 3 Selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, and -(CH2). n OR al -(CH2) n NR a2 R a3 -(CH2) n S(O) m R al The methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl group may optionally be further reacted with one or more R groups. f replace.

[0149] In some implementation schemes, R 3 Selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -OR al -NR a2 R a3 -S(O) m R al The methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl group may optionally be further reacted with one or more R groups. f replace.

[0150] In some implementation schemes, R 3 Selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -OR al -NR a2 R a3 -SR al The methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclobutyl group may optionally be further reacted with one or more R groups. f replace.

[0151] In some implementation schemes, R 3 Selected from H, halogen, cyano, methyl, ethoxy, cyclopropyl, -OR al -NR a2 R a3 -SR al phenyl, wherein the methyl, ethoxy, cyclopropyl or phenyl group may optionally be further reacted with one or more R f replace.

[0152] In some implementation schemes, R 3 Selected from methyl, ethoxy, cyclopropyl, -OR al -NR a2 R a3-SR al The methyl, ethoxy, or cyclopropyl group may optionally be further reacted with one or more R groups. f replace.

[0153] In some implementation schemes, R f Selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.

[0154] In some implementation schemes, R f Selected from deuterium, halogens or hydroxyl groups.

[0155] In some implementation schemes, R f Selected from F.

[0156] In some implementation schemes, R 3 Selected from -(CH2) n S(O) m R al In other implementations, R 3 Selected from cyclopropyl or -(CH2) n NR a2 R a3 .

[0157] In some implementations, m is selected from 0.

[0158] In some implementation schemes, R a1 Selected from methyl.

[0159] In other implementations, R a2 or R a3 Each is independently selected from H or methyl.

[0160] In other implementations, R a2 or R a3 All are selected from methyl groups.

[0161] In some implementation schemes, R 3 The methyl group is selected from H, -SCH3, -SCH2CH3, F, Cl, CN, methyl, ethoxy, cyclopropyl, -N(CH3)2, phenyl, -O-phenyl, wherein the methyl, ethoxy, cyclopropyl, phenyl or -O-phenyl may optionally be further substituted with one or more F.

[0162] In some implementation schemes, R 3 Selected from -SCH3. In some other embodiments, R 3Selected from cyclopropyl or -N(CH3)2. In other embodiments, R 3 The phenyl group is selected from H, -SCH2CH3, Cl, CN, or phenyl, and the phenyl group may optionally be further substituted with one or more F groups.

[0163] In other implementations, R 3 Selected from methyl, CF3CH2O- or .

[0164] In other implementations, R 3 Selected from H, -SCH3, -SCH2CH3, F, Cl, CN, methyl, -CF3, CF3CH2O-, cyclopropyl, -N(CH3)2, or .

[0165] In other implementations, R 3 Selected from H, -SCH3, -SCH2CH3, Cl, CN, methyl, CF3CH2O-, cyclopropyl, -N(CH3)2, or .

[0166] In other implementations, A is selected from... or .

[0167] In some implementation schemes, A is selected from .

[0168] In some implementation schemes, R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl or C 1-3 Alkoxy; the amino, C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further reacted with one or more R groups. i replace.

[0169] In some implementation schemes, R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, or C. 1-3 Alkyl; the C 1-3 Alkyl groups may optionally be further reacted with one or more R i replace.

[0170] In some implementation schemes, R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, NH2, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy group may optionally be further reacted with one or more R groups.i Replacement. In other implementations, R 5 and R 5’ Each element is independently selected from hydrogen, deuterium, halogen, or methyl, and the methyl group may optionally be further reacted with one or more R... i Replacement. In other implementations, R 5 and R 5’ All are selected from methyl groups.

[0171] In some implementation schemes, R 5 Selected from hydrogen, deuterium, or halogens.

[0172] In some implementation schemes, R 5 Selected from hydrogen or F. In other embodiments, R... 5 Selected from methyl, said methyl group optionally further converted to one or more R i replace.

[0173] In some implementation schemes, R 5 Selected from F. In other embodiments, R 5 Selected from CF3.

[0174] In some implementation schemes, R i Selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.

[0175] In some implementation schemes, R i Selected from deuterium, halogens or hydroxyl groups.

[0176] In some implementation schemes, R i Selected from F.

[0177] In some implementation schemes, A is selected from In some implementations, A is selected from... R 4 Not for and .

[0178] In some implementation schemes, A is selected from .

[0179] In some implementation schemes, A is selected from Or, in some other implementations, A is selected from , or Ring B is selected from C. 3-10Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. g replace.

[0180] In some implementation schemes, A is selected from Or, in some other implementations, A is selected from , or Ring B is selected from C. 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups may optionally be further subjected to one or more R groups. g replace.

[0181] In some implementation schemes, A is selected from Or, in some other implementations, A is selected from , or Cycle B is selected from phenyl or 5-6 heteroaryl groups, wherein the phenyl or 5-6 heteroaryl group may optionally be further oxidized by one or more R groups. g replace.

[0182] In some implementation schemes, A is selected from Or, in some other implementations, A is selected from , or Ring B is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thiophene, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, wherein the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thiophene, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl group may optionally be further oxidized by one or more R groups. g Replacement. In other embodiments, ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, thiocyclobutyl, aziridine, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazoalkyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, or morpholinyl, wherein ring B may optionally be further replaced by one or more R g replace.

[0183] In some implementation schemes, A is selected from Or, in some other implementations, A is selected from , or Ring B is selected from phenyl, pyrrole, furanyl, thiophene, or pyridyl, and the phenyl, pyrrole, furanyl, thiophene, or pyridyl group may optionally be further oxidized by one or more R groups. g Replacement. In other embodiments, ring B is selected from cyclopropyl, cyclobutyl, cyclohexyl, aziridine, or thiazolyl, and ring B may optionally be further replaced by one or more R... g replace.

[0184] In some implementation schemes, A is selected from , , , In this case, the two bonds connected to ring B are bonded to different ring atoms. Alternatively, the two bonds connected to ring B are bonded to the same ring atom.

[0185] In some implementation schemes, A is selected from Or, in some other implementations, A is selected from , or Ring B is selected from , , , , , , , , , , or The ring B may optionally be further divided by one or more R g Replacement. In other embodiments, ring B is selected from... , , , , or The ring B may optionally be further divided by one or more R g replace.

[0186] In some implementation schemes, A is selected from Ring B is selected from , , , , , , or The ring B may optionally be further divided by one or more R g Replacement. In other embodiments, A is selected from... Ring B is selected from , or The ring B may optionally be further divided by one or more R g replace.

[0187] In other implementations, A is selected from... , or Ring B is selected from , , or The ring B may optionally be further divided by one or more R g replace.

[0188] In some implementation schemes, A is selected from Ring B is selected from or The ring B may optionally be further divided by one or more R g replace.

[0189] In other implementations, A is selected from... or .

[0190] In other implementations, A is selected from... or .

[0191] In some implementation schemes, R g Selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.

[0192] In some implementation schemes, R g The group is selected from halogen, hydroxyl, NH2, methyl, ethyl, methoxy or ethoxy, wherein the methyl, ethyl, methoxy or ethoxy group may optionally be further substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino or cyano.

[0193] In some implementation schemes, R g The group is selected from halogens, hydroxyl groups, NH2, methyl groups, ethyl groups, methoxy groups, or ethoxy groups, wherein the methyl, ethyl, methoxy, or ethoxy groups may optionally be further substituted by one or more substituents selected from halogens.

[0194] In some implementation schemes, R gThe molecule is selected from halogen, hydroxyl, NH2, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy group may optionally be further substituted with one or more F groups.

[0195] In some implementation schemes, R g Selected from F, methyl, or trifluoromethyl.

[0196] In some implementation schemes, R g Selected from F.

[0197] In some implementation schemes, A is selected from Ring B is selected from , , , , , , , , , , , or .

[0198] In other implementations, A is selected from... Ring B is selected from , or .

[0199] In other implementations, A is selected from... , or Ring B is selected from , , or .

[0200] In some implementation schemes, A is selected from Ring B is selected from , , , or .

[0201] In some implementation schemes, A is selected from Structural unit Selected from , , , , , , , or The ring B may optionally be further divided by one or more Rg Replacement. In other embodiments, A is selected from... Structural unit Selected from , or The ring B may optionally be further divided by one or more R g replace.

[0202] In some implementation schemes, A is selected from Structural unit Selected from , or The ring B may optionally be further divided by one or more R g replace.

[0203] In some implementation schemes, A is selected from Structural unit Selected from , , , , , , , , , , , , , or .

[0204] In other implementations, A is selected from... Structural unit Selected from , or .

[0205] In some implementation schemes, A is selected from Structural unit Selected from , , , , , , or .

[0206] In other implementations, A is selected from... , or Structural unit , or Selected from , , or The ring B may optionally be further divided by one or more R g replace.

[0207] In other implementations, A is selected from... , or Structural unit , or Selected from , , or .

[0208] In other implementations, A is selected from... or Structural unit or Selected from or .

[0209] In some implementation schemes, R 4 Selected from C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 3-14 The cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl groups may optionally be further substituted by one or more substituents.

[0210] In some other implementation schemes, R 4 Selected from C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl groups may optionally be further subjected to one or more R groups. h replace.

[0211] In some implementation schemes, R 4 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-10 heteroaryl, wherein C 3-10Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h replace.

[0212] In some other implementation schemes, R 4 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further reacted with one or more R h replace.

[0213] In some implementation schemes, R 4 Selected from C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-12 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-12 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h Replacement. In some implementations, R 4 Selected from C 8-10 cycloalkyl, the C 8-10 The cycloalkyl group may optionally be further reacted with one or more R h Replacement. In some implementations, R 4 Selected from C 8-10 Polycyclic cycloalkyl, the C 8-10 Polycyclic cycloalkyl groups may optionally be further reacted with one or more R h Replacement. In some implementations, R 4 Selected from C 8-10 Polycyclic cycloalkyl groups, wherein the polycyclic group is a bicyclic, tricyclic, or tetracyclic ring, and the C 8-10 Polycyclic cycloalkyl groups may optionally be further reacted with one or more R h replace.

[0214] In some implementation schemes, R 4 Selected from C 5-8 cycloalkyl, C 6-11 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, C 6-11 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h replace.

[0215] In some implementation schemes, R 4 Selected from C 5-8 cycloalkyl, phenyl, C 9-11 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, phenyl, C 9-11 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups.h replace.

[0216] In some implementation schemes, R 4 Selected from C 5-8 cycloalkyl, C 9-11 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, C 9-11 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h replace.

[0217] In some implementation schemes, R 4 Selected from phenyl, indololinyl, isoindololinyl, benzodioxolane, benzopyrazolidinecycloyl, benzoimidazolidinecycloyl, benzotetrahydrothiophenecycloyl, benzotetrahydrofurancycloyl, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyrancycloyl, benzothiazolylcycloyl, benzoisothiazolylcycloyl, benzooxazolidinecycloyl, benzoisoxazolidinecycloyl, benzopiperidinecycloyl, benzopiperazincycloyl, benzomorpholinylcycloyl, benzothiazincycloyl, pyrroleyl, pyrazolyl, imidazolyl, oxazolyl , isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thiophene, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuran cycloyl, benzothiophene cycloyl, benzothiazole cycloyl, benzoxazolyl, indole, isoyindole, benzimidazole cycloyl, indazole, pyrrolo[2,3-b]pyridine cycloyl, pyrrolo[2,3-c]pyridine cycloyl, pyrrolo[3,2-c]pyridine cycloyl, pyrrolo[3,2-b]pyridine cycloyl, imidazo[4,5-b]pyridine Cyclic groups, imidazo[4,5-c]pyridine cycloyl, imidazo[1,2-a]pyridine cycloyl, imidazo[1,5-a]pyridine cycloyl, pyrazolo[4,3-d]pyridine cycloyl, pyrazolo[4,3-c]pyridine cycloyl, pyrazolo[3,4-c]pyridine cycloyl, pyrazolo[1,5-a]pyridine cycloyl, thieno[3,2-b]pyridine cycloyl, thieno[2,3-b]pyridine cycloyl, purine group, indazinyl, quinolinyl, isoquinolinyl, pyrrolo[1,2-a] The R group comprises: pyrazinylcycloyl group, imidazo[1,2-c]pyrimidinecycloyl group, pyrazo[1,5-a]pyrazinylcycloyl group, pyrrolo[1,2-a]pyrazinylcycloyl group, 2,3-dihydrofurano[2,3-b]pyridinecycloyl group, 2,3-dihydrofurano[3,2-b]pyridinecycloyl group, 2,3-dihydrofurano[3,2-c]pyridinecycloyl group, 2,3-dihydrofurano[2,3-c]pyridinecycloyl group, bicyclo[1.1.1]pentyl or bicyclo[2.2.2]octyl group. 4 Optionally, it can be further modified by one or more R h Replacement. In some implementations, R 4Selected from 2,3-dihydrobenzo[b][1,4]dioxinyl, 6,7-dihydro-4H-pyrazole[5,1-c][1,4]oxazinyl, wherein R 4 Optionally, it can be further modified by one or more R h replace.

[0218] In some other implementation schemes, R 4 The group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl group may optionally be further oxidized by one or more R groups. h replace.

[0219] In some other implementation schemes, R 4 Selected from tert-butyl.

[0220] In other implementations, R 4 Selected from cyclobutyl, cyclopentyl, cyclohexyl, 1,2-dihydropyridyl, adamantyl, benzocyclobutyl, benzocyclopentyl, or benzocyclohexyl, wherein R 4 Optionally, it can be further modified by one or more R h replace.

[0221] In some implementation schemes, R 4 The R is selected from phenyl, indololinyl, isoindololinyl, benzopyrazolidinecycloalkyl, benzotetrahydrofurancycloalkyl, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyrancycloalkyl, benzopiperidinecycloalkyl, furanyl, thienyl, pyridyl, benzothienylcycloalkyl, benzothiazolecycloalkyl, benzooxazolylcycloalkyl, indolyl, benzimidazolecycloalkyl, thieneno[3,2-b]pyridylcycloalkyl, thieneno[2,3-b]pyridylcycloalkyl, quinolinyl, isoquinolinyl, 2,3-dihydrofuraneno[2,3-b]pyridylcycloalkyl, 2,3-dihydrofuraneno[3,2-b]pyridylcycloalkyl, 2,3-dihydrofuraneno[3,2-c]pyridylcycloalkyl or bicyclic[1.1.1]pentyl, wherein the R 4 Optionally, it can be further modified by one or more R h replace.

[0222] In other implementations, R 4 Selected from cyclobutyl, 1,2-dihydropyridyl, adamantyl, or benzocyclobutyl, wherein R 4 Optionally, it can be further modified by one or more R h replace.

[0223] In some implementation schemes, R 4The R is selected from indololinyl, isoindololinyl, benzopyrazolidinecycloyl, benzotetrahydrofurancycloyl, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyrancycloyl, benzopiperidinecycloyl, furanyl, thienyl, pyridyl, benzothienylcycloyl, benzothiazolecycloyl, benzooxazolyl, indolyl, benzimidazolecycloyl, thieno[3,2-b]pyridylcycloyl, thieno[2,3-b]pyridylcycloyl, quinolinyl, isoquinolinyl, 2,3-dihydrofurano[2,3-b]pyridylcycloyl, 2,3-dihydrofurano[3,2-b]pyridylcycloyl, 2,3-dihydrofurano[3,2-c]pyridylcycloyl or bicyclic [1.1.1]pentyl, wherein the R 4 Optionally, it can be further modified by one or more R h replace.

[0224] In some implementation schemes, R 4 Selected from cyclobutyl, 1,2-dihydropyridyl, adamantyl, benzocyclobutyl, phenyl, indololinyl, isoindololinyl, benzopyrazolidinecycloyl, benzotetrahydrofurancycloyl, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyrancycloyl, benzodioxolanecycloyl, benzotetrahydropyrancycloyl, benzopiperidinecycloyl, furanyl, thienyl, pyridyl, benzothienylcycloyl, benzothiazolecycloyl, benzooxazolylcycloyl, indolyl, benzoimidazolylcycloyl, thien[3, 2-b]pyridine cycloyl, thieno[2,3-b]pyridine cycloyl, quinolinyl, isoquinolinyl, 2,3-dihydrofurano[2,3-b]pyridine cycloyl, 2,3-dihydrofurano[3,2-b]pyridine cycloyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 6,7-dihydro-4H-pyrazol[5,1-c][1,4]oxazinyl, 2,3-dihydrofurano[3,2-c]pyridine cycloyl or bicyclic[1.1.1]pentyl, wherein R 4 Optionally, it can be further modified by one or more R h replace.

[0225] In some implementations, when R 4 When containing an aromatic ring structure (e.g., a phenyl ring structure) or a heteroaromatic ring (e.g., a thiophene ring structure), the structural segment LR 4 In the middle, L and R 4 The aromatic ring or heteroaromatic ring is connected.

[0226] In some implementation schemes, R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or The R 4 Optionally, it can be further modified by one or more R h Replacement. In some implementations, R 4 Selected from , , or The R 4 Optionally, it can be further modified by one or more R h Replacement. In other implementations, R 4 Selected from , , , , or The R 4 Optionally, it can be further modified by one or more R h Replacement. In other implementations, R 4 Selected from The R 4 Optionally, it can be further modified by one or more R h replace.

[0227] In some implementation schemes, R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or The R 4 Optionally, it can be further modified by one or more R h replace.

[0228] In some implementation schemes, R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or The R 4 Optionally, it can be further modified by one or more R h replace.

[0229] In some implementation schemes, R 4 Selected from The R 4 Optionally, it can be further modified by one or more R h Replace, and L is selected from C(R) a R b ) or -C(R a R b )-C(R a R b )-.

[0230] In some implementation schemes, R 4 Selected from The R 4 Optionally, it can be further modified by one or more R h Replace, and W 1 and W 2 One of them is N, and the other is CH.

[0231] In some implementation schemes, R h Selected from deuterium, halogens, hydroxyl groups, NH2, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(CH2) n C(O)R al -(CH2) n NR a2 C(O)(CH2) nl R a3 Or -(CH2) n C(O)NR a2 (CH2) nl R a3 The C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl group may optionally be further substituted with one or more substituents selected from deuterium, O, halogen, hydroxyl, amino, or cyano. In other embodiments, R h Selected from -(CH2) n P(O)R a2 R a3 In other implementations, R hSelected from -(CH2) n O(CH2) n S(O) m R al In some implementations, R h Selected from -(CH2) n R al .

[0232] In some implementation schemes, R h Selected from halogens, hydroxyl groups, =O, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic alkyl, -(CH2) n C(O)R al -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -(CH2) n O(CH2) n S(O) m R al Or -(CH2) n P(O)R a2 R a3 The C 1-6 Alkyl, C 1-6 The alkoxy or 3-6 membered heterocyclic alkyl group may optionally be further substituted with one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano.

[0233] In some implementation schemes, R h Selected from halogens, hydroxyl groups, =O, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic alkyl, -C(O)R al -NR a2 C(O)R a3 -OCH2SR al or -P(O)R a2 R a3 The C 1-6 Alkyl, C 1-6 The alkoxy or 3-6 membered heterocyclic alkyl group may optionally be further substituted with one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano.

[0234] In some implementation schemes, R h Selected from halogens, =O, C 1-6 Alkyl, C1-6 Alkoxy, 3-6 membered heterocyclic alkyl, -(CH2) n C(O)R al -(CH2) n NR a2 C(O)(CH2) nl R a3 Or -(CH2) n C(O)NR a2 (CH2) nl R a3 The C 1-6 The alkyl or 3-6 membered heterocyclic alkyl group may optionally be further substituted with one or more substituents selected from deuterium, =O, halogen, hydroxyl, amino or cyano.

[0235] In some implementations, n1 is selected from 0.

[0236] In some implementations, n is selected from 0.

[0237] In some implementation schemes, R h Selected from halogens, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, oxacyclobutyl, thiocyclobutyl, azacyclobutyl, pyrrolidinyl, pyrazolylyl, imidazolidinyl, tetrahydrothiopheneyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolyl, oxazolylyl, isoxazolylyl, piperidinyl, piperazinyl, morpholinyl, -C(O)R al -NR a2 C(O)R a3 or -C(O)NR a2 R a3 The methyl, ethyl, isopropyl, methoxy, ethoxy, oxeherabutyl, thioheterobutyl, azaheterobutyl, pyrrolidinyl, pyrazolylyl, imidazoalkyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazoalkyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, and morpholinyl groups may optionally be further substituted with one or more substituents selected from deuterium, O, halogen, hydroxyl, amino, or cyano. In some embodiments, R h Selected from thiazolyl.

[0238] In some implementation schemes, R h Selected from halogens, hydroxyl groups, =O, methyl groups, methoxy groups, pyrrolidine groups, and -C(O)R groups. al -NR a2 C(O)R a3 -OCH2SR al or -P(O)R a2 R a3The methyl, methoxy, or pyrrolidinyl group may optionally be further substituted with one or more substituents selected from deuterium, O, halogen, hydroxyl, amino, or cyano.

[0239] In some implementation schemes, R a2 Selected from hydrogen.

[0240] In some implementation schemes, R a3 Selected from C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group may optionally be further reacted with one or more R j replace.

[0241] In some implementation schemes, R a3 The methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl groups are selected, and the methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or cyclopentyl groups may optionally be further oxidized by one or more R groups. j replace.

[0242] In some implementation schemes, R a3 Selected from tert-butyl or cyclopentyl.

[0243] In some implementation schemes, R h Selected from F, =O, methyl, pyrrolidine, -C(O)CH3, Or -C(O)NHC(CH3)3, wherein the methyl or pyrrolyl group may optionally be further substituted with one or more substituents selected from =O or halogens. In other embodiments, R h Selected from Or a methoxy group, which may optionally be further substituted with one or more halogens. In other embodiments, R h Selected from hydroxyl or -OCH2SCH3. In some embodiments, R h Selected from Cl or thiazole group.

[0244] In some implementation schemes, R h Selected from F, =O, methyl, pyrrolidine, -C(O)CH3, Or -C(O)NHC(CH3)3, wherein the methyl or pyrrolidinyl group may optionally be further substituted with one or more substituents selected from =O or F. In other embodiments, R h Selected from Or a methoxy group, which may optionally be further substituted with one or more F or Cl. In other embodiments, R h Selected from Or methoxy group, which may optionally be further substituted with one or more F groups.

[0245] In some implementation schemes, R h Selected from F, hydroxyl, =O, methyl, methoxy, pyrrolidine, -C(O)CH3, -OCH2SCH3, -C(O)NHC(CH3)3, The methyl, methoxy, or pyrrolidinyl group may optionally be further substituted with one or more substituents selected from =O, F, or Cl.

[0246] In some implementation schemes, R h Selected from F, =O, methyl, trifluoromethyl, -C(O)CH3, Or -C(O)NHC(CH3)3. In other embodiments, R h Selected from Or methoxy. In other embodiments, R h Selected from hydroxyl, CH3SCH2O- or .

[0247] In some implementation schemes, R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0248] In other implementations, R 4 Selected from , , , , , , , or .

[0249] In some implementation schemes, R 4 Selected from , , or .

[0250] In some implementation schemes, R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0251] In some implementation schemes, R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0252] In some implementation schemes, R 4 Selected from , , , , , , , , , , , or .

[0253] In some implementation schemes, R 4 Selected from And L is selected from C(R) a R b ) or -C(R a R b )- C(R a R b )-.

[0254] In some implementation schemes, R 4 Selected from And L is selected from the key.

[0255] In some implementation schemes, R 4 Selected from L is selected from the key, and W 1 and W 2 One of them is N, and the other is CH.

[0256] In some implementation schemes, R 4 Selected from L is selected from the key, and W 1 and W 2 One of them is N, and the other is CH.

[0257] In some implementation schemes, R 4 Selected from or The R 4 Optionally, it can be further modified by one or more R h replace.

[0258] In some implementation schemes, R 4 Selected from or The R 4Optionally, it can be further modified by one or more R h Replacement, and L is selected from the key.

[0259] In other implementations, R 4 Selected from or .

[0260] In some embodiments, the compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof of this disclosure are selected from compounds of formula (I-1), compounds of formula (I-2), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0261] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of X and ring B are as described in this disclosure.

[0262] In some embodiments, the compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof of this disclosure are selected from compounds of formula (II-1), compounds of formula (II-2), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0263] Among them, R 2 R 3 R 4 R 5 The definitions of X and ring B are as described in this disclosure.

[0264] In some embodiments, the compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof of this disclosure are selected from compounds of formula (III-1), compounds of formula (III-2), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0265] Among them, R 1 R 2 R 3 R 4 R 5 The definition of ring B is as described in this disclosure.

[0266] In some embodiments, the compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof of this disclosure are selected from compounds of formula (IV-1), compounds of formula (IV-2), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0267] Among them, R 1 R 2 R 4 R 5 The definition of ring B is as described in this disclosure.

[0268] In some embodiments, the compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein are selected from compounds of formula (Ia), (I-1a), (I-2a), (II-1a), (II-2a), (III-1a), (III-2a), (IV-1a), (IV-2a), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0269]

[0270] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of X and ring B are as described in this disclosure.

[0271] In some embodiments, the compounds of formula (I) of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (V-1a), (V-1b), (VI-1a), (VI-1b), (VII-1a), (VII-1b), (VIII-1a), (VIII-1b), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0272] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of X and ring B are as described in this disclosure.

[0273] In some embodiments, the compounds of formula (I) of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from compounds of formula (IX-1a), (IX-1b), (X-1a), (X-1b), (XI-1a), (XI-1b), (XII-1a), (XII-1b), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0274] In some implementations, this disclosure includes the variables defined above and their implementations, as well as any combination thereof.

[0275] In some embodiments, the compounds of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 。

[0276] In some embodiments, the compounds of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: .

[0277] On the other hand, this disclosure provides pharmaceutical compositions comprising the compounds described above, their stereoisomers or pharmaceutically acceptable salts thereof, or their crystalline or amorphous forms.

[0278] In another aspect, this disclosure provides pharmaceutical compositions comprising the above-described compounds of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the pharmaceutical composition is administered in single or multiple doses of 0.01 mg to 2000 mg, or 0.1 mg to 2000 mg, or 1 mg to 2000 mg, or 0.01 mg to 1000 mg, or 0.1 mg to 1000 mg, or 1 mg to 1000 mg, or 0.01 mg to 500 mg, or 0.1 mg to 500 mg, or 1 mg to 500 mg.

[0279] In some embodiments, the pharmaceutical compositions of this disclosure further include pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. In some embodiments of this disclosure, the pharmaceutical compositions include, but are not limited to, formulations suitable for oral, parenteral, or topical administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid dosage form suitable for oral administration. In some embodiments, the pharmaceutical composition includes, but is not limited to, tablets and capsules.

[0280] In some embodiments, the pharmaceutically acceptable excipients disclosed herein include one or more of binders, fillers, disintegrants, lubricants, flow aids, sweeteners, or flavoring agents.

[0281] In some embodiments, the pharmaceutical compositions disclosed herein are tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, or dispersants.

[0282] In some embodiments, the pharmaceutical compositions disclosed herein are tablets or capsules.

[0283] In some embodiments, the pharmaceutical compositions disclosed herein are prepared by methods such as mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, and freeze-drying.

[0284] In some embodiments, the pharmaceutical composition is packaged in a kit that also includes instructions for using the above-disclosed compound, its stereoisomers, or pharmaceutically acceptable salts thereof to treat a disease.

[0285] On the other hand, this disclosure provides a method for treating or preventing disease, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the aforementioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0286] In some embodiments, the daily dose range of the method is 0.01 mg to 1000 mg, preferably 0.1 mg to 500 mg.

[0287] In some embodiments, the method uses a daily dose range of 0.002 mg / kg to 200 mg / kg, or 0.009 mg / kg to 9 mg / kg, based on mammalian body weight.

[0288] In some implementations, the method is based on mammalian body weight, and the daily dose range is not 10 mg / kg.

[0289] On the other hand, this disclosure provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating or preventing diseases.

[0290] On the other hand, this disclosure provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the treatment or prevention of diseases.

[0291] On the other hand, this disclosure provides the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the treatment or prevention of diseases.

[0292] In some embodiments, the disease is selected from diseases associated with inhibition of sodium taurocholate cotransporter peptide (NTCP) and / or inhibition of sodium-dependent bile acid transporter protein (ASBT).

[0293] In some implementations, the diseases associated with inhibition of sodium taurocholate cotransporter peptide (NTCP) and / or inhibition of sodium-dependent bile acid transporter protein (ASBT) are selected from conditions, disorders, and diseases that require inhibition of bile acid circulation, such as cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver diseases.

[0294] In some embodiments, inhibition of sodium taurocholate cotransporter (NTCP) and / or inhibition of sodium-dependent bile acid transporter (ASBT) is selected from selective inhibition of sodium taurocholate cotransporter (NTCP) or simultaneous inhibition of sodium taurocholate cotransporter (NTCP) and sodium-dependent bile acid transporter (ASBT).

[0295] Technical effect The disclosed compound exhibits good inhibitory activity against NTCP and / or ASBT, and can selectively inhibit NTCP and / or ASBT. The disclosed compound also has good in vitro and in vivo efficacy and pharmacokinetic properties.

[0296] definition Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0297] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0298] The term "pharmaceutically acceptable salt" refers to the salt of the compounds disclosed herein, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this disclosure, with a specific substituent. When the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this disclosure contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0299] The pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0300] The compounds disclosed herein can exist in specific stereoisomer forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, ( R )- and( S - Enantiomers, diastereomers, ( D )-Isomer, ( L (Isomers, racemic mixtures thereof, and other mixtures thereof, such as mixtures enriched with enantiomers or diastereomers, are all within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.)

[0301] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0302] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0303] The compounds disclosed herein may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), Iodine-125 ( 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.

[0304] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0305] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0306] The term "one or more substitutions" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, and the number of substituents may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, based on what is chemically feasible.

[0307] The term "substituent" as used herein includes, but is not limited to, the terms "alkyl," "alkenyl," "alkynyl," "spirocycloalkyl," "fused cycloalkyl," "bridged cycloalkyl," "heterocyclic," "spiroheterocyclic," "fused heterocyclic," "bridged heterocyclic," "alkoxy," "cycloalkyl," "heterocyclic," "heteroaryl," "alkane," "heteroalkyl," "heteroaryl," etc., and corresponding non-limiting or exemplary groups. Some non-limiting examples of the "substituent" include deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, carboxaldehyde group, imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl Halogenated-alkynyl, cycloalkynyl, halogenated-cycloalkynyl, heteroalkyl, halogenated-heteroalkyl, alkoxy, alkathioyl, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkathioyl, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkathioyl, heterocyclic, heterocyclicoxy, heterocyclicthioyl, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic alkathioyl, acyl, acyloxy, carbamate group, amide group, ureyl, epoxy group and ester group, etc., wherein said groups are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, carboxyl, -C(O)O-alkyl, - OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkyl, heterocyclic alkyloxy, heterocyclic alkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0308] In some embodiments of this document, the "substituent" is selected from deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated - C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 The ester group and oxo group, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)O-C 1-12 Alkyl group, -OC(O)- C 1-12 Alkyl group, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C) 1-12 Alkyl)2、-NHC(O)- C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12 Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0309] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. For example, C 1-3 This means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0310] In this article, "mn" refers to integer elements within a given range. For example, "3-12" means that the group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 elements. Similarly, "5-10" means that the group can have 5, 6, 7, 8, 9, or 10 elements.

[0311] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0312] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0313] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of the linking group, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0314] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds (…). ), straight dashed key ( ), or wavy lines ( () indicates that the oxygen atom in the group is bonded to another group. For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in the group is bonded to another group. The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. or This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... , , , Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0315] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0316] The term "hydroxyl group" refers to the -OH group.

[0317] The term "amino" refers to the -NH2 group.

[0318] The term "thiol" refers to the -SH group.

[0319] The term "cyano" refers to the -CN group.

[0320] The term "nitro" refers to the -NO2 group.

[0321] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1The alkyl group is a hydrocarbon group. This alkyl group can be straight-chain or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0322] The term "alkoxy" refers to -O-alkyl.

[0323] The term "alkylamino" refers to -NH-alkyl.

[0324] The term "dialkylamino" refers to -N(alkyl)2.

[0325] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0326] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), and 1,3-butyrynyl (-C≡CC≡CH).

[0327] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups; preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0328] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include: , , , and .

[0329] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include: and .

[0330] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include: , , , , , , , and .

[0331] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include: , , , and .

[0332] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl ring, and non-limiting examples include indenyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl ring may be optionally substituted or unsubstituted.

[0333] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon; wherein the ring atoms may further be boron or P(O). p (Where p is an integer from 0 to 2). Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably tetrahydrofuranyl, pyrazolyl, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring. Non-limiting examples of heterocyclic groups include:

[0334] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The ring atoms are (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of shared spiroatoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0335] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0336] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0337] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic ring. It should be understood that the fused system formed after fusion falls within the scope of "heterocyclic group" as defined in this disclosure. Non-limiting examples of "heterocyclic group" also include:

[0338] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) aromatic ring having a conjugated π-electron system, preferably 6- to 10-membered. The aromatic ring can be a phenyl ring or a naphthyl ring, more preferably a phenyl ring. The aromatic ring can be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aromatic ring. It should be understood that the fused system formed after fusion falls within the scope of "aryl" as defined in this disclosure. Non-limiting examples of "aryl" include: phenyl, naphthyl, ... ,

[0339] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaromatic ring in the heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, and can be, for example, an imidazole ring, furanyl ring, thiophene ring, thiazolyl ring, pyrazolyl ring, oxazolyl ring, pyrroleyl ring, triazolyl ring, tetrazolyl ring, pyridinyl ring, pyrimidinyl ring, thiadiazole ring, pyrazinyl ring, etc., preferably a triazolyl ring, thiophene ring, imidazole ring, pyrazolyl ring, pyrimidinyl ring, or thiazolyl ring; more preferably a triazolyl ring, pyrroleyl ring, thiophene ring, thiazolyl ring, or pyrimidinyl ring. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. It should be understood that the fused system formed after fusion falls within the scope of "heteroaryl" as defined in this disclosure. Non-limiting examples of "heteroaryl" include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.

[0340]

[0341] The term "treatment" means administering the compounds or preparations described in this disclosure to improve or eliminate a disease or one or more symptoms related to said disease, and includes: (i) Suppress the disease or disease state, i.e., curb its development; (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0342] The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0343] The term “therapeutic effective amount” means (i) treating a particular disease, condition, or disorder, or (ii) alleviating, improving, or eliminating one or more symptoms of a particular disease, condition, or disorder. The amount of the compound of this disclosure constituting a “therapeutic effective amount” varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

[0344] The term "preventive effective amount" refers to the amount of the disclosed compound used to prevent or delay the specific disease, condition, or disorder described herein. The amount of the disclosed compound constituting a "preventive effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0345] The therapeutic or preventative dose of the disclosed compound may be determined based on factors such as the specific intended use for treatment or prevention, the manner of administration of the compound, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the disclosed compound in the pharmaceutical composition may not be fixed and may depend on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compound may be provided, for example, by means of a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 0.001 mg / kg to about 1000 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model testing systems.

[0346] The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning "including but not limited to".

[0347] "Pharmaceutical composition" means containing one or more compounds described herein, their isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertment of its biological activity.

[0348] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of the disclosed invention with suitable pharmaceutically acceptable excipients.

[0349] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art.

[0350] The terms "single dose" or "unit dosage form" refer to the smallest packaged unit of a medicine containing a certain amount of active ingredient. For example, if a box of medicine contains seven capsules, then each capsule is a single dose or unit dosage form; if a box of medicine contains seven tablets, then each tablet is a single dose unit dosage form.

[0351] The term "multiple doses" consists of multiple single doses.

[0352] The term "daily dose" refers to the dose administered to a patient each day.

[0353] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0354] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0355] The raw materials or intermediates used in the embodiments of this disclosure can be obtained commercially or prepared by methods in the prior art.

[0356] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this disclosure), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0357] In some embodiments, certain compounds of this disclosure can be prepared by those skilled in the art of organic synthesis by referring to the following routes: Route 1:

[0358] Route 2:

[0359] Route 3:

[0360] Among them, R 2 R 4 The definition of ring B is as described in this disclosure. Detailed Implementation

[0361] For clarity, the invention is further illustrated by examples, but these examples are not intended to limit the scope of this disclosure. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the invention without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0362] The compounds disclosed herein can be prepared by those skilled in the art of organic synthesis with reference to the routes or methods of the following embodiments. The resulting compounds can be characterized using known instruments or methods, including but not limited to mass spectrometry, nuclear magnetic resonance, etc.

[0363] The following abbreviations are used in this disclosure: Boc stands for tert-butyloxycarbonyl; Example 1: Preparation of Compound 1

[0364] At 0 °C, Boc-leucine (25.00 g), aniline (10.07 g), triethylamine (21.88 g), and 1-propylphosphoric anhydride (41.30 g) were added to N,N-dimethylformamide (90 mL), and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 1A (26.12 g). MS (ESI): m / z 329.41 [M+Na] + .

[0365] Intermediate 1A (26.12 g) was reacted with 1,4-dioxane (250 mL) and a 1,4-dioxane solution of hydrogen chloride (4 M, 106 mL) at room temperature with stirring. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 1B (16.43 g). MS (ESI): m / z 207.37 [M+H] + .

[0366] At 0°C, intermediate 1B (10.00 g) and a tetrahydrofuran solution (2 M, 60.5 mL) of the borane dimethyl sulfide complex were added to 100 mL of tetrahydrofuran. The mixture was stirred at 75°C until complete. After the reaction was complete, methanol (50 mL) was added to quench the reaction mixture, and the mixture was stirred at 60°C for 1 hour. The solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to obtain intermediate 1C (5.67 g). MS (ESI): m / z 193.39 [M+H] + .

[0367] At 0 °C, intermediate 1C (1.00 g), intermediate K (2.27 g), and triethylamine (1.21 g) were added to tetrahydrofuran (50 mL), and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 1D (2.51 g). MS (ESI): m / z 518.94 [M+H] + .

[0368] Intermediate 1D (2.50 g), potassium carbonate (1.24 g), and copper powder (0.31 g) were reacted in N,N-dimethylformamide (25 mL) with stirring at 115 °C. After the reaction was complete, the mixture was filtered, the filtrate was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 1E (1.88 g). MS (ESI): m / z 439.10 [M+H] + .

[0369] Intermediate 1E (1.88 g), cesium carbonate (1.24 g), and methyl iodoform (3.04 g) were reacted in N-methylpyrrolidone (10 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 1F (2.07 g). MS (ESI): m / z 452.98 [M+H] + .

[0370] Intermediate 1F (2.07 g) and sodium methanethiol (1.60 g) were added to N,N-dimethylformamide (25 mL), and the mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 1G (1.71 g). MS (ESI): m / z 407.21 [M+H] + .

[0371] Intermediate 1G (1.71 g) was prepared chirally (CHIRALART Cellulose-SC column (30*250 mm, 5 μm), elution system: ethanol / n-hexane (15% / 85%)) to give intermediate 1H (RT = 1.787 min, 1.42 g), MS (ESI): m / z 407.28 [M+H] + And intermediate 1I (RT = 1.073 min, 0.31 g), MS (ESI): m / z 407.42 [M+H] + .

[0372] Intermediate 1H (0.50 g), triethylamine (0.19 g), and trifluoromethanesulfonic anhydride (0.42 g) were reacted in dichloromethane (15 mL) at 0 °C with stirring. After the reaction was complete, the reaction mixture was poured into water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 1J (0.61 g). MS (ESI): m / z 539.08 [M+H] + .

[0373] Intermediate 1J (0.61 g), (5-(methoxycarbonyl)thiophen-3-yl)boronic acid (0.25 g), tripotassium phosphate (0.48 g), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.09 g) were reacted in 1,4-dioxane (15 mL) and water (1.5 mL) under nitrogen protection with stirring at 100 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and intermediate 1K (0.52 g) was obtained by column chromatography (elution system: dichloromethane / methanol). MS (ESI): m / z 531.25 [M+H] + .

[0374] Intermediate 1K (200 mg) and lithium hydroxide monohydrate (32 mg) were reacted in 1,4-dioxane (6 mL) and water (2 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 3) with 1M dilute hydrochloric acid solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to give compound 1 (160 mg). MS (ESI): m / z 517.1289 [M+H] + .

[0375] 1 H NMR (500 MHz, DMSO- d 6) δ 7.97 (s, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.23-7.20 (m, 2H), 7.15 (s, 1H), 6.81-6.77 (m, 3H), 4.10 (d, J = 16.1 Hz, 1H), 3.82 (d, J= 8.3 Hz, 1H), 3.28-3.10 (m, 1H), 2.54 (s, 3H), 2.35 (s, 3H), 1.68-1.49 (m, 2H), 1.43-1.27 (m, 4H), 0.91 (t, J = 6.7 Hz, 3H). Example 2: Preparation of Compound 2

[0376] Following the preparation method of compound 1 in Example 1, intermediate 1H was replaced with intermediate 1I to obtain compound 2 (80 mg). MS (ESI): m / z 517.1289 [M+H] + .

[0377] 1 H NMR (500 MHz, DMSO- d 6) δ 7.90 (s, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.23-7.20 (m, 2H), 7.14 (s, 1H), 6.81–6.77 (m, 3H), 4.09 (d, J = 16.1 Hz, 1H),3.83 (s, 1H), 3.26-3.08 (m, 1H), 2.53 (s, 3H), 2.35 (s, 3H), 1.69-1.49 (m,2H), 1.44-1.28 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). Example 3: Preparation of Compound 3

[0378] At 0 °C, Boc-D-ortholeucine (3.0 g), 3-aminothiophene hydrochloride (1.8 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (5.9 g), and triethylamine (7.2 mL) were added to N,N-dimethylformamide (80 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water and dried to give intermediate 3A (4.0 g). MS (ESI): m / z 313.09 [M+H] + .

[0379] At 0°C, intermediate 3A (4.0 g) and trifluoroacetic acid (10 mL) were added to dichloromethane (30 mL), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate solution under ice-water bath conditions. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 3B (3.3 g). MS (ESI): m / z 213.11 [M+H] + .

[0380] At 0 °C, intermediate 3B (3.3 g) and a tetrahydrofuran solution (2 M, 22 mL) of a borane dimethyl sulfide complex were added to 60 mL of tetrahydrofuran. The mixture was stirred at 75 °C until complete. After the reaction was complete, methanol (20 mL) was added to quench the reaction mixture, and the mixture was stirred at 60 °C for 1 hour. The solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 3C (1.2 g). MS (ESI): m / z 199.15 [M+H] + .

[0381] At 0 °C, intermediate 3C (1.20 g), intermediate K (2.45 g), and N,N-diisopropylethylamine (2.1 mL) were added to tetrahydrofuran (60 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 3D (2.10 g). MS (ESI): m / z 524.91 [M+H] + .

[0382] Intermediate 3D (2.10 g), potassium carbonate (0.99 g), and copper powder (0.25 g) were reacted in N,N-dimethylformamide (50 mL) with stirring at 115 °C. After the reaction was complete, the mixture was filtered, the filtrate was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 3E (1.30 g). MS (ESI): m / z 445.02 [M+H] + .

[0383] Intermediate 3E (1.30 g), cesium carbonate (1.90 g), and iodomethane (2.00 g) were reacted in N-methylpyrrolidone (40 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 3F (1.30 g). MS (ESI): m / z 459.01 [M+H] + .

[0384] Intermediate 3F (1.30 g) and sodium methanethiol (0.98 g) were added to N,N-dimethylformamide (30 mL), and the mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 3G (0.80 g). MS (ESI): m / z 413.13 [M+H] + .

[0385] At 0°C, intermediate 3G (200 mg) was added to 10 mL of N,N-dimethylformamide, and sodium hydride (97 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (263 mg) in 1 mL of N,N-dimethylformamide was added dropwise. After the addition was complete, the mixture was stirred at 70°C. After the reaction was complete, a saturated ammonium chloride aqueous solution was added sequentially to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 3H (160 mg). MS (ESI): m / z 529.17 [M+H] + .

[0386] Intermediate 3H (160.0 mg) and lithium hydroxide monohydrate (32 mg) were reacted in 1,4-dioxane (8 mL) and water (2 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 3 (70 mg). MS (ESI): m / z 501.0980 [M+H] + .

[0387] 1 H NMR (500 MHz, DMSO-d 6) δ 7.55 (d, J = 18.5 Hz, 1H), 7.46 (s, 1H), 7.36 (dd, J = 3.1, 5.1 Hz, 1H), 7.18 (s, 1H), 6.57 (d, J = 4.5 Hz, 1H), 6.39 (s,1H), 3.86 (d, J = 15.0 Hz, 2H), 3.33-3.31 (m, 1H), 2.51 (s, 3H), 2.41 (s, 3H), 1.66-1.45 (m, 2H), 1.43-1.27 (m, 4H), 0.93-0.89 (m, 3H). Example 4: Preparation of Compound 4

[0388] Following the preparation method of compound 3 in Example 3, compound 4 (60 mg) was obtained by replacing Boc-D-leucine with Boc-L-leucine. MS (ESI): m / z 501.0987 [M+H] + .

[0389] 1 H NMR (500 MHz, DMSO- d 6) δ 7.36-7.35 (m, 2H), 7.21 (d, J = 18.3 Hz,1H), 7.17 (s, 1H), 6.55 (d, J = 4.8 Hz, 1H), 6.35 (s, 1H), 3.86-3.83 (m, 2H), 3.33-3.31 (m, 1H), 2.50 (s, 3H), 2.40 (s, 3H), 1.62-1.47 (m, 2H), 1.41-1.29(m, 4H), 0.92-0.90(m, 3H). Example 5: Preparation of Compound 5

[0390] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 4-methoxybenzylamine to obtain compound 5 (100 mg). MS (ESI): m / z 539.1686 [M+H] + .

[0391] 1 H NMR (500 MHz, DMSO- d 6) δ 7.48 (d, J = 18.7 Hz, 1H), 7.39 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.84 (s, 1H), 4.66 (d, J = 14.4Hz, 1H), 4.43 (d, J = 14.4 Hz, 1H), 3.73 (s, 3H), 3.63-3.55 (m, 1H), 3.24 (m,1H), 3.09-3.06 (m, 1H), 2.56 (s, 3H), 2.39 (s, 3H), 1.52-1.41 (m, 1H), 1.20(m, 3H), 1.11 (m, 2H), 0.80 (t, J = 7.1 Hz, 3H). Example 6: Preparation of Compound 6

[0392] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 2,3-dihydrobenzofuran-5-amine to obtain compound 6 (30 mg). MS (ESI): m / z 537.1530 [M+H] + .

[0393] 1 H NMR (500 MHz, DMSO- d 6) δ 7.33 (s, 1H), 7.20 (d, J = 18.2 Hz, 1H), 6.86 (s, 1H), 6.78 (s, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 9.1 Hz, 1H), 4.46 (t, J = 8.6 Hz, 2H), 3.93 (d, J = 15.8 Hz, 1H), 3.72 (d, J = 9.0 Hz, 1H), 3.21(m, 1H), 3.11 (t, J= 8.6 Hz, 2H), 2.56 (s, 3H), 2.29 (s, 3H), 1.55-1.49 (m,2H), 1.39-1.27 (m, 4H), 0.89 (t, J = 6.6 Hz, 3H). Example 7: Preparation of Compound 7

[0394] Following the preparation method of compound 3 in Example 3, compound 7 (60 mg) was obtained by replacing 3-aminothiophene hydrochloride with bicyclo[1.1.1]pentane-1-amine hydrochloride. MS (ESI): m / z 485.1579 [M+H] + .

[0395] 1 H NMR (500 MHz, DMSO- d 6) δ 7.49 (d, J = 18.6 Hz, 1H), 7.36 (s, 1H), 6.99 (s, 1H), 3.66 (s, 1H), 3.39 (m, 2H), 2.54 (s, 3H), 2.51 (s, 3H), 2.45(s, 1H), 2.11 (d, J = 8.6 Hz, 3H), 1.94 (d, J = 8.5 Hz, 3H), 1.57-1.43 (m, 2H), 1.40-1.31 (m, 4H), 0.92 (t, J = 6.0 Hz, 3H). Example 8: Preparation of Compound 8

[0396] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with bicyclo[1.1.1]pentane-1-amine hydrochloride, and Boc-D-leucine was replaced with Boc-L-ortholeucine to obtain compound 8 (10 mg). MS (ESI): m / z 485.1579 [M+H] + .

[0397] 1 H NMR (500 MHz, DMSO- d6) δ 7.26 (s, 1H), 7.21-7.17 (m, 1H), 6.98 (s,1H), 3.66 (s, 1H), 3.39 (m, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.44 (s, 1H), 2.09 (d, J = 8.6 Hz, 3H), 1.93 (d, J = 8.3 Hz, 3H), 1.57-1.43 (m, 2H), 1.40-1.30(m, 4H), 0.92 (t, J = 6.9 Hz, 3H). Example 9: Preparation of Compound 9

[0398] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 2,3-dihydrobenzofuran-6-amine to obtain compound 9 (40 mg). MS (ESI): m / z 537.1533 [M+H] + .

[0399] 1 H NMR (500 MHz, DMSO- d 6) δ 13.58 (brs, 1H), 7.74 (d, J = 18.6 Hz, 1H),7.53 (s, 1H), 7.12 (s, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.11 (s, 2H), 4.49-4.45(m, 2H), 3.99 (d, J = 16.0 Hz, 1H), 3.83-3.82 (m, 1H), 3.21 (m, 1H), 3.05 (t, J =8.6 Hz, 2H), 2.49 (s, 3H), 2.41 (s, 3H), 1.62-1.56 (m, 1H), 1.53-1.47 (m,1H), 1.39-1.29 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). Example 10: Preparation of Compound 10

[0400] Sodium hydride (2.28 g, 60% w / w) was slowly added to a solution of Boc-D-homoserine (5.00 g) in N,N-dimethylformamide (50 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Iodomethane (9.71 g) was then added, and the mixture was stirred at room temperature after the addition was complete. Once the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 10A (5.60 g). MS (ESI): m / z 248.10 [M+H] + .

[0401] At 0 °C, intermediate 10A (5.60 g) and trifluoroacetic acid (20 mL) were added to dichloromethane (80 mL), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure to give intermediate 10B (5.91 g). MS (ESI): m / z 148.15 [M+H] + .

[0402] At 0 °C, intermediate 10B (3.94 g), intermediate K (5.00 g), and triethylamine (6.94 g) were added to tetrahydrofuran (150 mL), and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 10C (3.11 g). MS (ESI): m / z 472.00 [M+H] - .

[0403] Intermediate 10C (2.50 g) and sodium hydroxide (0.53 g) were reacted in tetrahydrofuran (40 mL) and water (10 mL) at room temperature with stirring. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 3) with 1M dilute hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 10D (2.30 g). MS (ESI): m / z 457.97 [M+H] - .

[0404] Intermediate 10D (2.30 g), aniline (0.47 g), N,N-diisopropylethylamine (1.93 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.28 g) were reacted in N,N-dimethylformamide (45 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 10E (1.08 g). MS (ESI): m / z 534.87 [M+H] + .

[0405] At 0 °C, intermediate 10E (1.08 g) and a tetrahydrofuran solution (2 M, 2.5 mL) of a boronane dimethyl sulfide complex were added to 40 mL of tetrahydrofuran. The mixture was stirred at 75 °C until complete. After the reaction was complete, methanol (20 mL) was added to quench the reaction mixture, and the mixture was stirred at 60 °C for 1 hour. The solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 10F (1.04 g). MS (ESI): m / z 520.94 [M+H] + .

[0406] Following the preparation method of compound 3 in Example 3, intermediate 3D was replaced with intermediate 10F to obtain compound 10 (25 mg). MS (ESI): m / z 497.1213 [M+H] + .

[0407] 1 H NMR (500 MHz, DMSO- d 6) δ 7.43 (s, 1H), 7.37 (d, J = 18.3 Hz, 1H),7.19-7.15 (m, 3H), 6.74 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 8.1 Hz, 2H), 4.12 (d, J =16.2 Hz, 1H), 4.01 (s, 1H), 3.50-3.43 (m, 3H), 3.29 (s, 3H), 2.52 (s, 3H), 2.40 (s, 3H), 1.88-1.82 (m, 1H), 1.80-1.73 (m, 1H).

[0408] Example 11: Preparation of Compound 11

[0409] At room temperature, 4.50 g of 1-benzyl-2-methyl-(R)-azacyclopropane-1,2-dicarboxylic acid ester was added to chloroform (40 ml) with stirring, followed by the addition of 67 ml of ethanol and 2.4 ml of boron trifluoride diethyl ether. After the addition was complete, the reaction mixture was stirred at room temperature. Once the reaction was complete, the reaction solution was poured into ice water, extracted with dichloromethane, and the organic phase was washed successively with water and saturated brine. The phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 11A (5.10 g).

[0410] Intermediate 11A (5.10 g), palladium on carbon (2.00 g, palladium content 10%, water content 50%), was reacted in methanol (40 mL) with hydrogen purging three times, and then stirred at room temperature. After the reaction was complete, the mixture was filtered and concentrated to obtain intermediate 11B (2.89 g).

[0411] Following the preparation method of compound 10 in Example 10, intermediate 10B was replaced with intermediate 11B to obtain compound 11 (100 mg). MS (ESI): m / z 497.1219 [M+H] + .

[0412] 1 H NMR (500 MHz, DMSO- d 6) δ 7.74 (d, J = 18.6 Hz, 1H), 7.56 (s, 1H),7.23-7.15 (m, 3H), 6.76 (t, J = 7.2 Hz, 1H), 6.70 (d, J = 8.00 Hz, 2H), 4.04 (s,2H), 3.66-3.58 (m, 2H), 3.51-3.47 (m, 3H), 2.59 (s, 3H), 2.41 (s, 3H), 1.16(t, J = 6.9 Hz, 3H). Example 12: Preparation of Compound 12

[0413] Intermediate 3E (1.00 g), cesium carbonate (1.10 g), and p-methoxybenzyl bromide (0.80 g) were reacted in N-methylpyrrolidone (20 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 12A (1.00 g). MS (ESI): m / z 565.12 [M+H] + .

[0414] Intermediate 12A (1.00 g) and sodium methanethiol (0.62 g) were added to N,N-dimethylformamide (35 mL). The mixture was stirred at 80 °C until complete. After the reaction was finished, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to obtain intermediate 12B (0.90 g). MS (ESI): m / z 519.20 [M+H] + .

[0415] At 0°C, intermediate 12B (900 mg) was added to 20 mL of N,N-dimethylacetamide, and sodium hydride (347 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (941 mg) in 2 mL of N,N-dimethylformamide was added dropwise. After the addition was complete, the mixture was stirred at 70°C. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 12C (560 mg). MS (ESI): m / z 635.27 [M+H] + .

[0416] Intermediate 12C (560 mg) and lithium hydroxide monohydrate (93 mg) were reacted in 1,4-dioxane (20 mL) and water (5 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 12D (460 mg). MS (ESI): m / z 607.20 [M+H] + .

[0417] Intermediate 12D (460 mg) was reacted in trifluoroacetic acid (40 mL) with stirring at 55 °C. After complete reaction, the reaction mixture was poured into ethyl acetate, adjusted to weakly acidic pH (approximately 5) with sodium bicarbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 12 (140 mg). MS (ESI): m / z 487.0831 [M+H] + .

[0418] 1 H NMR (500 MHz, DMSO- d 6) δ 13.61 (brs, 1H), 7.54-7.51 (m, 2H), 7.40(d, J = 9.3 Hz, 1H), 7.37-7.35 (m, 1H), 7.19 (s, 1H), 6.59-6.56 (m, 1H), 6.37(s, 1H), 4.14 (d, J = 15.2 Hz, 1H), 3.49–3.39 (m, 1H), 3.00-2.92 (m, 1H), 2.41(s, 3H), 1.62-1.51 (m, 1H), 1.51-1.25 (m, 5H), 0.90 (t, J = 7.2 Hz, 3H). Example 13: Preparation of Compound 13

[0419] Following the preparation method of Compound 1 in Example 1, (5-(methoxycarbonyl)thiophene-3-yl)boronic acid was replaced with 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester to obtain Compound 13 (80 mg). MS (ESI): m / z 517.1304 [M+H] + .

[0420] 1 H NMR (500 MHz, DMSO- d 6) δ 12.89 (s, 1H), 8.39 (d, J = 1.5 Hz, 1H),7.73 (s, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.24 (t, J = 7.9 Hz, 2H), 7.13 (s, 1H), 6.84 (dd,J = 8.2, 4.9 Hz, 3H), 4.11 (d, J = 16.0 Hz, 1H), 3.79 (d, J = 11.6 Hz,1H), 3.44 (s, 1H), 2.57 (s, 3H), 2.36 (s, 3H), 1.63-1.54 (m, 2H), 1.41-1.28(m, 4H), 0.91 (t, J = 6.9 Hz, 3H). Example 14: Preparation of Compound 14

[0421] Following the preparation method of Compound 1 in Example 1, (5-(methoxycarbonyl)thiophen-3-yl)boronic acid was replaced with (4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid to obtain Compound 14 (80 mg). MS (ESI): m / z 535.1201 [M+H] + .

[0422] 1 H NMR (500 MHz, DMSO- d 6) δ 7.95 (d, J = 4.2 Hz, 1H), 7.62 (s, 1H), 7.24(dd, J = 8.5, 7.1 Hz, 2H), 7.15 (s, 1H), 6.86-6.78 (m, 3H), 4.11 (d, J = 16.1 Hz, 1H), 3.81 (d, J = 11.4 Hz, 1H), 3.41 (s, 1H), 2.55 (s, 3H), 2.34 (s, 3H), 1.65-1.52 (m, 2H), 1.41-1.30 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). Example 15: Preparation of Compound 15

[0423] Following the preparation method of Compound 1 in Example 1, (5-(methoxycarbonyl)thiophene-3-yl)boronic acid was replaced with 2-methoxycarbonylpyridine-4-boronic acid pinacol ester to obtain Compound 15 (100 mg). MS (ESI): m / z 510.1530 [M+H] - .

[0424] 1 H NMR (500 MHz, DMSO- d 6) δ 8.85 (s, 1H), 8.11 (s, 1H), 7.72-7.68 (m,1H), 7.65 (s, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.18 (s, 1H), 6.86-6.83 (m, 3H), 4.13 (d, J = 16.2 Hz, 1H), 3.81 (s, 1H), 3.45 (s, 1H), 2.58 (s, 3H), 2.34 (s,3H), 1.68-1.48 (m, 2H), 1.47-1.28 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). Example 16: Preparation of Compound 16

[0425] Following the preparation method of compound 10 in Example 10, intermediate 10B was replaced with D-oroleucine methyl ester hydrochloride, and aniline was replaced with 1-methyl-5-aminoindole to obtain compound 16 (40 mg). MS (ESI): m / z 548.1699 [M+H] + .

[0426] 1 H NMR (500 MHz, Methanol-) d 4) δ 7.45 (s, 1H), 7.37-7.31 (m, 3H), 7.18-7.14 (m, 1H), 6.97 (dd, J = 8.7, 2.2 Hz, 1H), 6.60 (s, 1H), 6.38 (d, J = 3.0 Hz,1H), 4.03-3.93 (m, 2H), 3.79 (s, 3H), 3.72 (s, 1H), 2.84 (s, 3H), 2.06 (s,3H), 1.50-1.43 (m, 2H), 1.36-1.29 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). Example 17: Preparation of Compound 17

[0427] Following the preparation method of compound 16 in Example 16, 1-methyl-5-aminoindole was replaced with 6-amino-1-methylbenzimidazole to obtain compound 17 (18 mg). MS (ESI): m / z 549.1651 [M+H] + .

[0428] 1 H NMR (500 MHz, Methanol-) d 4) δ 8.49 (s, 1H), 7.59 (s, 1H), 7.56 (d, J =9.0 Hz, 1H), 7.38 (d, J = 17.5 Hz, 1H), 7.10 (s, 1H), 7.02-6.98 (m, 1H), 6.91(dd, J = 9.0, 2.3 Hz, 1H), 4.20 (d, J = 16.0 Hz, 1H), 4.02-3.99 (m, 1H), 3.89 (s,3H), 3.49 (s, 1H), 2.62 (s, 3H), 2.33 (s, 3H), 1.67-1.61 (m, 2H), 1.51-1.36(m, 4H), 0.95 (t, J = 7.0 Hz, 3H). Example 18: Preparation of Compound 18

[0429] Intermediate 1H (100 mg), methyl trans-3-hydroxycyclobutanecarboxylate (35 mg), diethyl azodicarbonate (129 mg), and triphenylphosphine (194 mg) were reacted in tetrahydrofuran (5 mL) by microwave at 60 °C. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to give intermediate 18A (140 mg). MS (ESI): m / z 519.19 [M+H] + .

[0430] Following the preparation method of compound 3 in Example 3, intermediate 3H was replaced with intermediate 18A to obtain compound 18 (78 mg). MS (ESI): m / z 505.1832 [M+H] + .

[0431] 1 H NMR (500 MHz, Methanol- d4) δ 7.24 (s, 1H), 7.17-7.14 (m, 2H), 7.02(s, 1H), 6.75-6.72 (m,1H), 6.65-6.63 (m, 2H), 4.80-4.74 (m, 1H), 4.06-3.97(m, 2H), 3.27 (m, 1H), 2.93-2.86 (m, 1H), 2.83-2.75 (m, 2H), 2.53 (s, 3H), 2.42-2.37 (m, 2H), 2.31 (s, 3H), 1.61-1.54 (m, 2H), 1.48-1.33 (m, 4H), 0.96(t, J = 7.10 Hz, 3H). Example 19: Preparation of Compound 19

[0432] Following the preparation method of compound 18 in Example 18, methyl trans-3-hydroxycyclobutanecarboxylate was replaced with methyl cis-3-hydroxycyclobutanecarboxylate to obtain compound 19 (56 mg). MS (ESI): m / z 505.1836 [M+H] + .

[0433] 1 H NMR (500 MHz, Methanol- d 4) δ 7.17-7.14 (m, 3H), 7.03 (s, 1H), 6.75-6.72 (m,1H), 6.65-6.63 (m, 2H), 5.03-4.98 (m, 1H), 4.06-3.97 (m, 2H), 3.27(m, 1H), 3.22-3.16 (m, 1H), 2.82-2.74 (m, 2H), 2.53 (s, 3H), 2.53-2.46 (m,2H), 2.32 (s, 3H), 1.61-1.53 ​​(m, 2H), 1.49-1.34 (m, 4H), 0.96 (t, J = 7.10 Hz, 3H). Example 20: Preparation of Compound 20

[0434] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 2-methyl-6-aminobenzoxazole, and the tetrahydrofuran solution of the boronane dimethyl sulfide complex (2.0 mol / L) was replaced with a tetrahydrofuran solution of lithium aluminum hydride (2.5 mol / L) to obtain compound 20 (15 mg). MS (ESI): m / z 550.1487 [M+H] + .

[0435] 1 H NMR (500 MHz, Methanol- d 4) δ 7.60 (s, 1H), 7.51 (d, J = 17.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 6.95 (s, 1H), 6.77 (dd, J = 1.8, 8.8 Hz,1H), 4.14-4.11 (m, 1H), 3.98-3.97 (m, 1H), 3.49-3.37 (m, 1H), 2.61 (s, 3H),2.57 (s, 3H), 2.36 (s, 3H), 1.65-1.56 (m, 2H), 1.49-1.38 (m, 4H), 0.96 (t, J =7.15 Hz, 3H). Example 21: Preparation of compound 21

[0436] Following the preparation method of compound 19 in Example 19, intermediate 1H was replaced with intermediate 3G to obtain compound 21 (18 mg). MS (ESI): m / z 511.1390 ​​[M+H] + .

[0437] 1 H NMR (500 MHz, Methanol- d 4) δ 7.24-7.22 (m, 1H), 7.10 (s, 1H), 7.07(s, 1H), 6.52 (d, J = 5.15 Hz, 1H), 6.21 (s, 1H), 5.00-4.95 (m, 1H), 3.98 (m,1H), 3.86 (d, J= 15.75 Hz, 1H), 3.35 (m, 1H), 3.21-3.15 (m, 1H), 2.79-2.73 (m,2H), 2.56 (s, 3H), 2.52-2.49 (m, 2H), 2.33 (s, 3H), 1.62-1.51 (m, 2H), 1.50-1.35 (m, 4H), 0.96 (t, J = 7.00 Hz, 3H). Example 22: Preparation of compound 22

[0438] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 4-amino-1-methylpyridine-acetone to obtain compound 22 (15 mg). MS (ESI): m / z 526.1489 [M+H] + .

[0439] 1 H NMR (500 MHz, DMSO- d 6) δ 13.61 (s, 1H), 7.79 (d, J = 18.5 Hz, 1H),7.55 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.26 (s, 1H), 5.45 (d, J = 61.2 Hz, 2H),4.18-3.75 (m, 2H), 3.27 (s, 3H), 3.22-3.13 (m, 1H), 2.48 (s, 3H), 2.44 (s,3H), 1.74-1.59 (m, 1H), 1.50-1.44 (s, 1H), 1.39-1.30 (s, 4H), 0.93-0.90 (m, 3H). Example 23: Preparation of compound 23

[0440] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with cis-3-methoxycyclobutamine hydrochloride to obtain compound 23 (45 mg). MS (ESI): m / z 503.1688 [M+H] + .

[0441] 1 H NMR (500 MHz, Methanol- d4) δ 7.26 (s, 1H), 7.04 (d, J = 19.3 Hz, 1H), 6.74 (s, 1H), 4.45-4.39 (m, 1H), 3.86 (s, 3H), 3.82-3.75 (m, 1H), 3.23-3.16(m, 1H), 3.07 (s, 1H), 2.86-2.81 (m, 2H), 2.53 (s, 2H), 2.44 (s, 3H), 2.30-2.15 (m, 1H), 1.95 (s, 1H), 1.65-1.35 (m, 8H), 0.97 (t, J = 6.7 Hz, 3H). Example 24: Preparation of compound 24

[0442] Intermediate 1H (200 mg), triphenylphosphine (380 mg), diethyl azodicarbonate (257 mg), and methyl 1-(hydroxymethyl)cyclopropanecarboxylate (147 mg) were reacted in tetrahydrofuran (2 mL) by microwave at 80 °C. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and intermediate 24A (250 mg) was obtained by column chromatography (elution system: petroleum ether / ethyl acetate). MS (ESI): m / z 519.47 [M+H] + .

[0443] Intermediate 24A (250 mg), lithium hydroxide monohydrate (60 mg), and water were reacted in 1,4-dioxane (20 mL) and water (5 mL) at room temperature with stirring. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to obtain compound 24 (243 mg). MS (ESI): m / z 505.1840 [M+H] + .

[0444] 1 H NMR (500 MHz, Methanol- d 4) δ 7.37 (s, 1H), 7.20-7.09 (m, 2H), 7.02(s, 1H), 6.73 (t, J = 7.3 Hz, 1H), 6.63 (d, J= 8.2 Hz, 2H), 4.33-4.25 (m, 2H), 4.08-3.94 (m, 2H), 3.28-3.25 (m, 1H), 2.54 (s, 3H), 2.31 (s, 3H), 1.70-1.54(m, 2H), 1.49-1.37 (m, 4H), 1.35-1.33 (m, 2H), 1.17-1.14 (m, 2H), 0.96 (t, J =6.9 Hz, 3H). Example 25: Preparation of Compound 25

[0445] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 2-methyl-5-amino-2,3-dihydrobenzofuran to obtain compound 25 (170 mg). MS (ESI): m / z 551.1690 [M+H] + .

[0446] 1 H NMR (500 MHz, Methanol- d 4) δ 7.46 (s, 1H), 7.37 (d, J = 17.6 Hz, 1H), 6.92 (dd, J = 6.3, 2.4 Hz, 1H), 6.81 (dt, J = 8.6, 2.5 Hz, 1H), 6.72 (s, 1H), 6.65 (dd, J = 8.5, 1.0 Hz, 1H), 4.93-4.88 (m, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.74 (s, 2H), 3.30-3.23 (m, 1H), 2.82-2.77 (m, 1H), 2.75 (s, 3H), 2.23 (d, J =1.2 Hz, 3H), 1.71-1.63 (m, 1H), 1.48-1.34 (m, 8H), 0.93 (t, J = 7.0 Hz, 3H). Example 26: Preparation of Compound 26

[0447] Intermediate 1J (550 mg), (S)-piperidine-3-carboxylic acid methyl ester (219 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (160 mg), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (146 mg), and cesium carbonate (998 mg) were reacted in 1,4-dioxane (20 mL) under nitrogen purging and microwaved at 110 °C. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to give intermediate 26A (67 mg). MS (ESI): m / z 532.49 [M+H] + .

[0448] Intermediate 26A (67 mg) and lithium hydroxide monohydrate (53 mg) were reacted in 1,4-dioxane (20 mL) and water (5 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to give compound 26 (18 mg). MS (ESI): m / z 518.2147 [M+H] + .

[0449] 1 H NMR (500 MHz, Methanol- d 4) δ 7.53 (s, 1H), 7.21-7.15 (m, 2H), 7.00 (s, 1H), 6.78 (t, J = 7.3 Hz, 1H), 6.71 (d, J = 8.1 Hz, 2H), 4.07 (d, J = 16.0 Hz,1H), 3.94 (s, 1H), 3.45 (d, J = 11.2 Hz, 1H), 3.35-3.32 (m, 1H), 3.10 (d, J =11.4 Hz, 1H), 2.81 (t, J= 10.5 Hz, 1H), 2.76-2.69 (m, 2H), 2.56 (s, 3H), 2.28(s, 3H), 2.09-2.06 (m, 1H), 1.90-1.85 (m, 1H), 1.80-1.71 (m, 1H), 1.66-1.55(m, 3H), 1.48-1.33 (m, 4H), 0.96 (t, J = 6.9 Hz, 3H). Example 27: Preparation of Compound 27

[0450] Intermediate 1J (2.00 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.61 g), and triethylamine (0.75 g) were reacted in 1,4-dioxane (50 mL) under carbon monoxide pressure of 15 atm at 100 °C. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to give intermediate 27A (1.20 g). MS (ESI): m / z 449.45 [M+H] + .

[0451] Intermediate 27A (0.80 g) and lithium hydroxide monohydrate (0.75 g) were reacted in 1,4-dioxane (40 mL) and water (10 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 27B (0.73 g). MS (ESI): m / z 435.46 [M+H] + .

[0452] Intermediate 27B (200 mg), methyl 1-aminocyclopropylformate (64 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (262 mg), and triethylamine (233 mg) were added to N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water and dried to give intermediate 27C (240 mg). MS (ESI): m / z 532.45 [M+H] + .

[0453] Intermediate 27C (240 mg), lithium hydroxide monohydrate (189 mg), and 1,4-dioxane (20 mL) and water (5 mL) were reacted at room temperature with stirring. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to give compound 27 (120 mg). MS (ESI): m / z 518.1789 [M+H] + .

[0454] 1 H NMR (500 MHz, Methanol- d 4) δ7.99 (s, 1H), 7.30 (t, J = 7.9 Hz, 2H),7.00-6.97 (m, 3H), 6.91 (s, 1H), 4.09 (d, J 0.94 (t, J = 7.0 Hz, 3H). Example 28: Preparation of Compound 28

[0455] Following the preparation method of compound 27 in Example 27, methyl 1-aminocyclopropylcarbamate was replaced with methyl 2-amino-2-methylpropionate to obtain compound 28 (80 mg). MS (ESI): m / z 520.1943 [M+H] + .

[0456] 1 H NMR (500 MHz, Methanol- d 4) δ 7.91 (s, 1H), 7.28 (t, J = 7.9 Hz, 2H), 6.98-6.96 (m, 3H), 6.93 (s, 1H), 4.10 (d, J = 15.5 Hz, 1H), 3.82-3.63 (m, 2H), 2.71 (s, 3H), 2.22 (s, 3H), 1.72-1.65 (m, 1H), 1.58 (d, J= 4.9 Hz, 6H), 1.55-1.34 (m, 5H), 0.94 (t, J = 7.0 Hz, 3H). Example 29: Preparation of compound 29

[0457] Following the preparation method of compound 26 in Example 26, (S)-piperidine-3-carboxylic acid methyl ester was replaced with (R)-piperidine-3-carboxylic acid methyl ester to obtain compound 29 (18 mg). MS (ESI): m / z 518.2154 [M+H] + .

[0458] 1 H NMR (500 MHz, Methanol- d 4) δ 7.54 (s, 1H), 7.19-7.16 (m, 2H), 7.00 (s, 1H), 6.78 (t, J = 7.3 Hz, 1H), 6.71 (d, J = 8.1 Hz, 2H), 4.07 (d, J = 16.0 Hz,1H), 3.94 (s, 1H), 3.40-3.37 (m, 1H), 3.35-3.32 (m, 1H), 3.16 (d, J = 10.8 Hz,1H), 2.80-2.68 (m, 3H), 2.56 (s, 3H), 2.28 (s, 3H), 2.10-2.07 (m, 1H), 1.91-1.87 (m, 1H), 1.80-1.71 (m, 1H), 1.64-1.54 (m, 3H), 1.49-1.38 (m, 4H), 0.96(t, J = 6.9 Hz, 3H). Example 30: Preparation of compound 30

[0459] Following the preparation method of compound 24 in Example 24, methyl 1-(hydroxymethyl)cyclopropanecarboxylate was replaced with ethyl (1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylate to obtain compound 30 (200 mg). MS (ESI): m / z 505.1831 [M+H] + .

[0460] 1H NMR (500 MHz, Methanol- d 4) δ 7.34 (s, 1H), 7.17-7.14 (m, 2H), 7.03(s, 1H), 6.74 (t, J = 7.25 Hz, 1H), 6.64(t, J = 8.15 Hz, 2H), 4.22-4.19 (m, 1H), 4.06-3.98 (m, 3H), 3.28-3.22 (m, 1H), 2.53 (s, 3H), 2.32 (s, 3H), 1.91-1.84(m, 1H), 1.76-1.72 (m, 1H), 1.60-1.53 ​​(m, 2H), 1.50-1.34 (m, 4H), 1.25-1.21(m, 1H), 1.13-1.09 (m, 1H), 0.96 (t, J = 7.10 Hz, 3H). Example 31: Preparation of compound 31

[0461] Following the preparation method of compound 26 in Example 26, (S)-piperidine-3-carboxylic acid methyl ester was replaced with methyl 3-fluoroacetidine-3-carboxylic acid hydrochloride to obtain compound 31 (235 mg). MS (ESI): m / z 508.1748 [M+H] + .

[0462] 1 H NMR (500 MHz, Methanol- d 4) δ 7.22-7.07 (m, 4H), 6.72 (t, J = 7.30 Hz, 1H), 6.62 (d, J = 8.15 Hz, 2H), 4.57-4.48 (m, 2H), 4.33-4.24 (m, 2H), 4.05-3.97(m, 2H), 3.28-3.22 (m, 1H), 2.54 (s, 3H), 2.36 (s, 3H), 1.61-1.55 (m, 2H),1.48-1.33 (m, 4H), 0.96 (t, J = 7.10 Hz, 3H). Example 32: Preparation of compound 32

[0463] Following the preparation method of compound 24 in Example 24, methyl 1-(hydroxymethyl)cyclopropanecarboxylate was replaced with methyl (1S,2R)-2-(hydroxymethyl)cyclopropanecarboxylate to obtain compound 32 (150 mg). MS (ESI): m / z 505.1833 [M+H] + .

[0464] 1 H NMR (500 MHz, DMSO-d6) δ 12.23 (s, 1H), 7.24 (s, 1H), 7.14 (t, J =7.6 Hz, 2H), 7.03 (s, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 7.6 Hz, 2H),4.42-4.39 (m, 1H), 4.20 (t, J = 8.7 Hz, 1H), 4.01 (d, J = 15.9 Hz, 1H), 3.94-3.82(m, 1H), 3.19 (s, 1H), 2.45 (s, 3H), 2.34 (s, 3H), 1.83-1.75 (m, 2H), 1.62-1.59 (m, 1H), 1.53-1.46 (m, 1H), 1.39-1.30 (m, 4H), 1.20-1.16 (m, 1H), 1.02-0.99 (m, 1H), 0.91 (t, J = 6.50 Hz, 3H). Example 33: Preparation of compound 33

[0465] Following the preparation method of compound 24 in Example 24, methyl 1-(hydroxymethyl)cyclopropanecarboxylate was replaced with ethyl (1R,2R)-2-(hydroxymethyl)cyclopropanecarboxylate to obtain compound 33 (250 mg). MS (ESI): m / z 505.1836 [M+H] + .

[0466] 1 H NMR (500 MHz, Methanol- d 4) δ 7.35 (s, 1H), 7.18-7.14 (m, 2H), 7.03(s, 1H), 6.74 (t, J= 7.3 Hz, 1H), 6.64(d, J = 6.6 Hz, 2H), 4.24-4.21 (m, 1H), 4.07-3.98 (m, 3H), 3.28-3.22 (m, 1H), 2.54 (s, 3H), 2.33 (s, 3H), 1.91-1.85(m, 1H), 1.76-1.73 (m, 1H), 1.61-1.54 (m, 2H), 1.49-1.35 (m, 4H), 1.25-1.21(m, 1H), 1.13-1.09 (m, 1H), 0.96 (t, J = 7.1 Hz, 3H). Example 34: Preparation of compound 34

[0467] Following the preparation method of compound 1 in Example 1, compound 34F (1.00 g) was obtained by replacing Boc-leucine with D-Boc-leucine. MS (ESI): m / z 453.39 [M+H] + .

[0468] Intermediate 34F (1.00 g), potassium cyclopropyltrifluoroborate (0.55 g), potassium carbonate (0.76 g), and tetraphenylphosphine palladium (0.51 g) were reacted in 1,4-dioxane (50 mL) and water (10 mL) under nitrogen protection with stirring at 100 °C. After the reaction was complete, most of the residue was evaporated under reduced pressure, followed by extraction with dichloromethane, drying to anhydrous sodium sulfate, filtration, concentration, and separation by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 34G (0.91 g). MS (ESI): m / z 415.32 [M+H] + .

[0469] Intermediate 34G (914 mg) was dissolved in dichloromethane (50 mL) and cooled to -5°C. Boron tribromide diethyl ether solution (3.0 mL, 2 mol / L) was slowly added dropwise. After addition, the mixture was stirred at room temperature. Once the reaction was complete, it was quenched with 20 mL of methanol, concentrated under reduced pressure, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 34H (200 mg). MS (ESI): m / z 401.51 [M+H] + .

[0470] At 0°C, intermediate 34H (200 mg) was added to 10 mL of N,N-dimethylformamide, and sodium hydride (140 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (650 mg) in 1 mL of N,N-dimethylformamide was added dropwise. After the addition was complete, the mixture was stirred at 85°C. After the reaction was complete, a saturated ammonium chloride aqueous solution was added sequentially to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 34I (178 mg). MS (ESI): m / z 517.49 [M+H] + .

[0471] Intermediate 34I (178.0 mg) and lithium hydroxide monohydrate (58 mg) were reacted in 1,4-dioxane (10 mL) and water (2.5 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 34 (60 mg). MS (ESI): m / z 489.1868 [M+H] + .

[0472] 1 H NMR (500 MHz, Methanol- d 4) δ 7.59 (s, 1H), 7.53 (d, J = 17.6 Hz, 1H),7.20-7.17 (m, 2H), 6.83 (s, 1H), 6.80 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.2 Hz, 2H), 4.07 (d, J 0.95 (t, J = 6.9 Hz,3H), 0.91-0.86 (m, 2H), 0.70-0.64 (m, 2H). Example 35: Preparation of compound 35

[0473] Following the preparation method of compound 24 in Example 24, methyl 1-(hydroxymethyl)cyclopropanecarboxylate was replaced with methyl cis-4-hydroxycyclohexanecarboxylate to obtain compound 35 (140 mg). MS (ESI): m / z 533.2151 [M+H] + .

[0474] 1 H NMR (500 MHz, Methanol- d 4) δ 7.37 (s, 1H), 7.17-7.14 (m, 2H), 7.02(s, 1H), 6.74 (t, J = 7.30 Hz, 1H), 6.64 (d, J = 8.15 Hz, 2H), 4.45-4.39 (m, 1H), 4.05-3.98 (m, 2H), 3.27 (m, 1H), 2.54 (s, 3H), 2.44-2.37 (m, 1H), 2.30 (s,3H), 2.21-2.15 (m, 2H), 2.11-2.08 (m, 2H), 1.69-1.56 (m, 6H), 1.51-1.33 (m,4H), 0.96 (t, J = 7.10 Hz, 3H). Example 36: Preparation of compound 36

[0475] Following the preparation method of compound 24 in Example 24, methyl 1-(hydroxymethyl)cyclopropanecarboxylate was replaced with methyl trans-4-hydroxycyclohexanecarboxylate to obtain compound 36 (180 mg). MS (ESI): m / z 533.2150 [M+H] + .

[0476] 1 H NMR (500 MHz, DMSO- d 6) δ 12.08 (s, 1H), 7.28 (s, 1H), 7.18-7.11 (m,2H), 7.04 (s, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.57 (d, J= 8.1 Hz, 2H), 4.76 (s,1H), 3.89 (s, 1H), 3.21 (s, 1H), 2.44 (s, 3H), 2.39-2.35 (m, 1H), 2.34 (s,3H), 1.93-1.59 (m, 9H), 1.52-1.45 (m, 1H), 1.36-1.30 (m, 3H), 0.93-0.90 (m, 3H). Example 37: Preparation of compound 37

[0477] Intermediate 1J (1.00 g), pinacol diboronate (0.94 g), 1,1-bis(diphenylphosphine)diberamic acid palladium dichloride (0.27 g), and potassium acetate (0.36 g) were reacted in 1,4-dioxane (50 mL) at 100 °C after nitrogen purging. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to give intermediate 37A (0.69 g). MS (ESI): m / z 517.28 [M+H] + .

[0478] Following the preparation method of Compound 1 in Example 1, methyl 2-bromothiazol-5-carboxylate was used to replace (5-(methoxycarbonyl)thiophene-3-yl)boronic acid in the reaction with intermediate 37A, and further conversion yielded compound 37 (33 mg). MS (ESI): m / z 518.1247 [M+H] + .

[0479] 1 H NMR (500 MHz, DMSO- d 6) δ 8.44 (s, 1H), 8.39 (s, 1H), 7.35 (t, J = 7.6Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.93 (s, 1H), 4.10(d, J = 15.4 Hz, 1H), 3.93-3.88 (m, 1H), 3.75 (m, 1H), 2.80 (s, 3H), 2.27 (s,3H), 1.75-1.70 (m, 1H), 1.56-1.33 (m, 5H), 0.94 (t, J = 7.0 Hz, 3H). Example 38: Preparation of compound 38

[0480] Under nitrogen protection in an ice bath, triphenylphosphine (3.76 g) and carbon tetrabromide (2.38 g) were added to dichloromethane (40 ml), followed by the slow dropwise addition of ethyl 3,3,3-trifluoropyruvate (1.00 g). After the addition was complete, the reaction mixture was stirred in an ice bath. Once the reaction was complete, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 38A (1.20 g).

[0481] -50 o Under nitrogen protection, isopropyl magnesium chloride (2M, 1.8 mL) was slowly added to a solution of intermediate 38A (1.20 g) in diethyl ether (40 mL), and stirred for 15 min. Then methanol (6 mL) was added. The mixture was slowly brought to room temperature and stirred. After the reaction was complete, the reaction was quenched with water, extracted with diethyl ether, and the organic phase was washed successively with water and saturated brine. The phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 38B (0.28 g).

[0482] Potassium carbonate (67 mg), tetraphenylphosphine palladium (56 mg), intermediate 38B (100 mg), and intermediate 37A (460 mg) were reacted in dioxane (15 ml) and water (3 ml) under nitrogen protection in an oil bath at 100 °C. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 38C (117 mg). MS (ESI): m / z 557.30 [M+H] + .

[0483] Intermediate 38C (115 mg) and lithium hydroxide monohydrate (20 mg) were reacted in 1,4-dioxane (10 mL) and water (2.5 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 38 (30 mg). MS (ESI): m / z 529.1430 [M+H] + .

[0484] 1 H NMR (500 MHz, DMSO- d 6) δ 7.96 (d, J= 84.0 Hz, 1H), 7.72-7.42 (m,1H), 7.27-7.21 (m, 2H), 7.12 (d, J = 4.2 Hz, 1H), 6.88-6.80 (m, 3H), 4.08 (d, J =16.1 Hz, 1H), 3.86-3.73 (m, 1H), 2.53 (s, 3H), 2.42 (d, J = 3.9 Hz, 3H), 1.61-1.53 ​​(m, 2H), 1.34 (d, J = 8.8 Hz, 2H), 1.24 (d, J = 6.7 Hz, 3H), 0.90 (t, J = 6.5Hz, 3H). Example 39: Preparation of compound 39

[0485] Following the preparation method of compound 37 in Example 37, methyl 2-bromothiophene-2-carboxylate was replaced with methyl 5-bromothiophene-2-carboxylate to obtain compound 39 (130 mg). MS (ESI): m / z 517.1292 [M+H] + .

[0486] 1 H NMR (500 MHz, Methanol- d 4) δ 7.80 (s, 1H), 7.75 (d, J = 3.8 Hz,1H),7.30-7.27 (m, 3H), 6.98-6.94 (m, 4H), 4.12 (d, J = 15.3 Hz, 1H), 3.80 (s, 1H), 3.66-3.65 (m, 1H), 2.71 (s, 3H), 2.24 (s, 3H), 1.72-1.65 (m, 1H), 1.59-1.48(m, 1H), 1.48-1.33 (m , 4H), 0.94 (t, J = 7.0 Hz, 3H). Example 40: Preparation of Compound 40

[0487] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 2-(dimethyloxophospho)aniline to obtain compound 40 (300 mg). MS (ESI): m / z 571.1525 [M+H] + .

[0488] 1 H NMR (500 MHz, DMSO- d 6) δ 13.52 (s, 1H), 8.04 (dd, J = 12.4, 7.7 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.59-7.53 (m, 4H), 5.88 (s, 1H), 4.24-4.22 (m,1H), 3.99 (d, J = 13.5 Hz, 1H), 3.42 (d, J = 14.4 Hz, 1H), 2.64 (s, 3H), 1.94 (s,3H), 1.73 (t, J = 13.1 Hz, 4H), 1.43-1.14 (m, 7H), 0.97-0.73 (m, 3H). Example 41: Preparation of compound 41

[0489] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 4-(dimethyloxophospho)aniline to obtain compound 41 (80 mg). MS (ESI): m / z 571.1501 [M+H] + .

[0490] 1 H NMR (500 MHz, DMSO- d 6) δ 13.63 (s, 1H), 7.77 (d, J = 18.5 Hz, 1H),7.58 (s, 1H), 7.52 (dd, J = 10.9, 8.5 Hz, 2H), 7.28 (s, 1H), 6.69 (d, J = 8.2 Hz, 2H), 4.10 (d, J = 16.1 Hz, 1H), 3.94-3.88 (m, 1H), 3.25 (s, 1H), 2.47 (d, J=11.1 Hz, 6H), 1.72-1.62 (m, 1H), 1.58-1.48 (M, 7H), 1.40-1.31 (m, 4H), 0.93(d, J = 6.9 Hz, 3H). Example 42: Preparation of compound 42

[0491] Intermediate 3E (800 mg), cyclopropylboronic acid (617 mg), anhydrous copper acetate (391 mg), 2,2'-bipyridine (1400 mg), and sodium carbonate (381 mg) were reacted in 1,2-dichloroethane in an open environment at 80 °C. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and intermediate 42A (250 mg) was obtained by column chromatography (elution system: petroleum ether / ethyl acetate). MS (ESI): m / z 485.21 [M+H] + .

[0492] Following the preparation method of compound 3 in Example 3, intermediate 3F was replaced with intermediate 42A to obtain compound 42 (12 mg). MS (ESI): m / z 527.1141 [M+H] + .

[0493] 1 H NMR (500 MHz, Methanol- d 4) δ 7.37 (s, 1H), 7.31-7.26 (m, 2H), 6.86 (s, 1H), 6.82 (d, J = 5.15 Hz, 1H), 4.18-4.13 (m, 1H), 3.98-3.95 (m, 1H), 3.68(s, 1H), 2.38 (s, 1H), 2.20 (s, 3H), 1.79-1.71 (m, 1H), 1.47-1.40 (m, 1H), 1.35-1.62 (m, 5H), 0.84-0.78 (m, 4H), 0.69-0.63 (m, 1H), 0.57-0.45 (m, 2H). Example 43: Preparation of compound 43

[0494] Intermediate 27B (100 mg), taurine (57.6 mg), triethylamine (70 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (131 mg) were dissolved in DMF. After addition, the mixture was stirred at room temperature. Once the reaction was complete, the reaction solution was poured into water and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with dichloromethane, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 43 (75 mg). MS (ESI): m / z 542.1463 [M+H] + .

[0495] 1 H NMR (500 MHz, MeOD) δ 7.84 (s, 1H), 7.20 (t, J = 7.8 Hz, 2H), 6.89-6.87 (m, 3H), 6.83 (s, 1H), 3.99 (d, J = 14.2 Hz, 1H), 3.69-3.54 (m, 4H), 3.03(s, 2H), 2.62 (s, 3H), 2.12 (s, 3H), 1.22 – 1.15 (m, 6H), 0.84 (t, 3H). Example 44: Preparation of compound 44

[0496] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 1-adamantaneamine to obtain compound 44 (65 mg). MS (ESI): m / z 553.2203 [M+H] + .

[0497] 1 H NMR (500 MHz, Methanol- d 4) δ 7.44 (s, 1H), 7.38 (d, J = 17.6 Hz, 1H),7.21 (s, 1H), 3.91-3.87 (m, 1H), 3.43 (d, J= 15.9 Hz, 1H), 2.54-2.48 (m, 4H), 2.37 (s, 3H), 2.13-2.07 (m, 6H), 1.79-1.77 (m, 3H), 1.72-1.65 (m, 6H), 1.52-1.36 (m, 6H), 0.97 (t, J = 6.4 Hz, 3H). Example 45: Preparation of compound 45

[0498] 10.00 g of 2-adamantanone, 9.30 g of hydroxylamine hydrochloride, and 10.90 g of sodium acetate were added to 200 mL of methanol, and the mixture was stirred at 65 °C. After the reaction was complete, the solvent was removed by vacuum distillation. The residue was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 45A (11.10 g).

[0499] At 0°C, 11.00 g of 45A was slowly added to 250 mL of tetrahydrofuran, followed by a 2.5 M, 80 mL solution of lithium aluminum hydride in tetrahydrofuran. After the addition was complete, the mixture was stirred at 65°C. Once the reaction was complete, under ice bath conditions, 8 mL of ice water, 8 mL of 15% sodium hydroxide aqueous solution, and 24 mL of ice water were slowly added sequentially. After stirring for 10 minutes, 30 g of anhydrous sodium sulfate was added. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated to obtain intermediate 45B (8.80 g). MS (ESI): m / z 152.31 [M+H] + .

[0500] At 0 °C, Boc-leucine (8.80 g), intermediate 45B (6.33 g), triethylamine (15.40 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (21.70 g) were added to N,N-dimethylformamide (100 mL), and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 45C (12.11 g). MS (ESI): m / z 365.31 [M+H] + .

[0501] Intermediate 45C (7.00 g) was reacted with trifluoroacetic acid (20 mL) in dichloromethane (100 mL) at room temperature with stirring. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 45D (4.60 g). MS (ESI): m / z 265.25 [M+H] + .

[0502] At 0 °C, intermediate 45D (3.99 g), intermediate K (5.50 g), and triethylamine (6.11 g) were added to tetrahydrofuran (100 mL), and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 45E (7.40 g). MS (ESI): m / z 591.06 [M+H] + .

[0503] At 0 °C, intermediate 45E (7.40 g) and a tetrahydrofuran solution (2 M, 18.9 mL) of a boronane dimethyl sulfide complex were added to 50 mL of tetrahydrofuran. The mixture was stirred at 75 °C until complete. After the reaction was complete, methanol (50 mL) was added to quench the reaction mixture, and the mixture was stirred at 60 °C for 1 hour. The solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 45F (5.30 g). MS (ESI): m / z 579.05 [M+H] + .

[0504] Intermediate 45F (2.00 g), potassium tert-butoxide (0.97 g), and copper powder (1.32 g) were reacted in N,N-dimethylacetamide (100 mL) with stirring at 95 °C. After the reaction was complete, the mixture was filtered, the filtrate was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 45G (0.81 g). MS (ESI): m / z 497.08 [M+H] + .

[0505] Intermediate 45G (0.40 g), cesium carbonate (0.31 g), and iodomethane (0.33 g) were reacted in 10 mL of N-methylpyrrolidone at room temperature with stirring. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 45H (0.22 g). MS (ESI): m / z 511.02 [M+H]+ .

[0506] Intermediate 45H (0.18 g) and sodium methanethiol (0.74 g) were added to N,N-dimethylformamide (25 mL), and the mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 45I (0.15 g). MS (ESI): m / z 465.21 [M+H] + .

[0507] At 0 °C, intermediate 45I (120 mg) was added to N,N-dimethylacetamide (6 mL), and sodium hydride (62 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0 °C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (280 mg) in N,N-dimethylacetamide (6 mL) was added dropwise. After the addition was complete, the mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 45J (100 mg). MS (ESI): m / z 581.23 [M+H] + .

[0508] Intermediate 45J (100 mg), lithium hydroxide monohydrate (108.4 mg), and water were reacted in 1,4-dioxane (8 mL) and water (4 mL) at room temperature with stirring. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 45 (70 mg). MS (ESI): m / z 553.2208 [M+H] + .

[0509] 1 H NMR (500 MHz, Methanol- d 4) δ 7.40 (s, 1H), 7.29 (d, J= 17.6 Hz, 1H),7.01 (s, 1H), 4.06-4.00 (m, 1H), 3.60 (s, 1H), 3.20-3.18 (m, 1H), 2.46-2.41(m, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 2.23-2.18 (m, 2H), 2.04-2.01 (m, 2H),1.91-1.88 (m, 1H), 1.79-1.71 (m, 4H), 1.68-1.60 (m, 3H), 1.48-1.45 (m, 1H),1.40-1.27 (m, 6H), 1.11-1.08 (m, 1H), 0.86 (t, J = 6.8 Hz, 3H). Example 46: Preparation of Compound 46

[0510] Intermediate 45G (0.40 g), cesium carbonate (0.30 g), and 4-methoxybenzyl chloride (0.11 g) were reacted in DMF (10 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 46A (0.21 g). MS (ESI): m / z 617.14 [M+H] + .

[0511] Following the preparation method of compound 12 in Example 12, intermediate 12A was replaced with intermediate 46A to obtain compound 46 (80 mg). MS (ESI): m / z 539.2056 [M+H] + .

[0512] 1 H NMR (500 MHz, Methanol- d 4) δ 7.46 (s, 1H), 7.26 (d, J = 17.6 Hz, 1H), 6.99 (s, 1H), 3.57-3.49 (m, 3H), 2.37 (s, 3H), 2.32 (d, J = 12.3 Hz, 1H), 2.20-2.15 (m, 2H), 2.09-2.06 (m, 1H), 2.02 (d, J= 12.5 Hz, 1H), 1.91-1.88 (m, 1H), 1.80-1.70 (m, 4H), 1.68-1.61 (m, 3H), 1.46-1.44 (m, 1H), 1.40-1.21 (m, 7H), 1.11-1.08 (m, 1H), 0.84 (t, J = 7.2 Hz, 3H). Example 47: Preparation of Compound 47

[0513] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 3,4-(methylenedioxy)aniline to obtain compound 47 (100 mg). MS (ESI): m / z 539.1331 [M+H] + .

[0514] 1 H NMR (500 MHz, Methanol- d 4) δ 7.42 (s, 1H), 7.30 (d, J = 17.6 Hz, 1H), 6.82 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 6.30 (dd, J =2.2, 8.4 Hz, 1H), 5.80 (dd, J = 1.0, 7.3 Hz, 2H), 3.86-3.83 (m, 1H), 3,76-3.71(m, 1H), 3.45-3.39 (m, 1H), 2.58 (s, 3H), 2.22 (s, 3H), 1.59-1.52 (m, 1H),1.46-1.25 (m, 5H), 0.85 (t, J = 7.0 Hz, 3H). Example 48: Preparation of Compound 48

[0515] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 4-aminobenzocyclobutene to obtain compound 48 (190 mg). MS (ESI): m / z 521.1568 [M+H] + .

[0516] 1 H NMR (500 MHz, Methanol- d 4) δ 7.41 (s, 1H), 7.32 (d, J = 17.6 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.81 (s, 1H), 6.63 (dd, J = 1.6, 8.0 Hz, 1H), 6.57 (s,1H), 3.92 (d, J = 15.6 Hz, 2H), 3. 71 (m, 1H), 3.45-3.39 (m, 1H), 3.00 (s, 3H), 2.57 (s, 3H), 2.18 (s, 3H), 1.58-1.51 (m, 1H), 1.44-1.21 (m, 5H), 0.84 (t, J =7.0 Hz, 3H). Example 49: Preparation of Compound 49

[0517] Following the preparation method of compound 24 in Example 24, methyl 1-(hydroxymethyl)cyclopropanecarboxylate was replaced with methyl hydroxytrimethylacetate to obtain compound 49 (200 mg). MS (ESI): m / z 507.1981 [M+H] + .

[0518] 1 H NMR (500 MHz, Methanol- d 4) δ 7.38 (s, 1H), 7.22-7.15 (m, 2H), 7.04 (s, 1H), 6.77-6.74 (m, 1H), 6.66 (d, J = 8.2 Hz, 2H), 4.15 (s, 2H), 4.13-3.96(m, 2H), 3.32-3.17 (m, 1H), 2.57 (s, 3H), 2.33 (s, 3H), 1.64-1.57 (m, 2H),1.52-1.40 (m, 4H), 1.39 (d, J = 2.7 Hz, 6H), 0.99 (t, J = 7.2 Hz, 3H). Example 50: Preparation of Compound 50

[0519] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 4-fluoroaniline to obtain intermediate 50 G (1.04 g). MS (ESI): m / z 425.16 [M+H] + .

[0520] Referring again to the preparation method of compound 24 in Example 24, methyl 1-(hydroxymethyl)cyclopropanecarboxylate was replaced with methyl hydroxytrimethylacetate to obtain compound 50 (230 mg). MS (ESI): m / z 525.1878 [M+H] + .

[0521] 1 H NMR (500 MHz, Methanol- d 4) δ 7.24 (s, 1H), 6.88 (s, 1H), 6.84-6.78(m, 2H), 6.55-6.53 (m, 2H), 4.02 (s, 2H), 3.91-3.85 (m, 2H), 3.20-3.11 (m,1H), 2.45 (s, 3H), 2.20 (s, 3H), 1.51-1.42 (m, 2H), 1.38-1.28 (m, 4H), 1.26(d, J = 2.2 Hz, 6H), 0.86 (t, J = 7.0 Hz, 3H). Example 51: Preparation of compound 51

[0522] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 1-adamantanemethylamine to obtain compound 51 (29 mg). MS (ESI): m / z 567.2375 [M+H] + .

[0523] 1 H NMR (500 MHz, DMSO- d 6) δ 13.53 (s, 1H), 7.49 (d, J = 18.7 Hz, 1H),7.38 (s, 1H), 7.24 (s, 1H), 3.98 (s, 1H), 3.77 (d, J = 14.7 Hz, 1H), 3.09-3.01(m, 2H), 2.72 (d, J= 14.8 Hz, 1H), 2.53 (s, 3H), 2.40 (s, 3H), 1.90-1.86 (m, 3H), 1.62-1.54 (m, 6H), 1.48-1.28 (m, 12H), 0.92-0.90 (m, 3H). Example 52: Preparation of compound 52

[0524] Following the preparation method of compound 46 in Example 46, intermediate 45G was replaced with intermediate 51E to obtain compound 52 (30 mg). MS (ESI): m / z 553.2209 [M+H] + .

[0525] 1 H NMR (500 MHz, DMSO- d 6) δ 13.50 (s, 1H), 7.43 (s, 1H), 7.36 (d, J =18.7 Hz, 1H), 7.25 (s, 1H), 6.98 (d, J = 9.4 Hz, 1H), 3.81 (d, J = 14.8 Hz, 1H),3.51-3.44 (m, 1H), 3.38-3.35 (m, 1H), 2.70-2.64 (m, 2H), 2.52 (s, 3H), 1.87(s, 3H), 1.62-1.53 ​​(m, 6H), 1.51-1.27 (m, 12H), 0.89 (t, J = 7.2 Hz, 3H). Example 53: Preparation of compound 53

[0526] At 0 °C, BOC-D-proline (7.00 g), aniline (13.48 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (18.55 g), and triethylamine (18.2 mL) were added to N,N-dimethylformamide (80 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water and dried to give intermediate 53A (7.60 g). MS (ESI): m / z 291.13 [M+H] + .

[0527] At 0°C, intermediate 53A (7.60 g) and trifluoroacetic acid (30 mL) were added to dichloromethane (100 mL), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution under ice-water bath conditions. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 53B (5.0 g). MS (ESI): m / z 191.12 [M+H] + .

[0528] At 0 °C, intermediate 53B (5.0 g) and a tetrahydrofuran solution (2 M, 38 mL) of a boronane dimethyl sulfide complex were added to 100 mL of tetrahydrofuran. The mixture was stirred at 75 °C until complete. After the reaction was complete, methanol (30 mL) was added to quench the reaction mixture, and the mixture was stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 53C (4.5 g). MS (ESI): m / z 177.14 [M+H] + .

[0529] At 0 °C, intermediate 53C (3.0 g), intermediate K (1.6 g), and N,N-diisopropylethylamine (3.44 mL) were added to tetrahydrofuran (100 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 53D (3.0 g). MS (ESI): m / z 502.96 [M+H] + .

[0530] Intermediate 53D (3.0 g), potassium tert-butoxide (1.67 g), and copper powder (2.27 g) were reacted in N,N-dimethylformamide (25 mL) under microwave heating and stirring at 115 °C. After the reaction was complete, the mixture was filtered, the filtrate was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 53E (0.25 g). MS (ESI): m / z 388.25 [M+H] + ; 53F (2.0 g), MS (ESI): m / z 423.10 [M+H] + .

[0531] Intermediate 53F (2.0 g) and sodium methanethiol (3.32 g) were added to N,N-dimethylformamide (30 mL), and the mixture was stirred at 100 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 53G (1.50 g). MS (ESI): m / z 377.18 [M+H] + .

[0532] At 0°C, intermediate 53G (400 mg) was added to N,N-dimethylformamide (25 mL), and sodium hydride (255 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (1.2 g) in N,N-dimethylformamide (1 mL) was added dropwise. After the addition was complete, the mixture was stirred at 90°C. After the reaction was complete, a saturated ammonium chloride aqueous solution was added sequentially, followed by extraction with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 53H (250 mg). MS (ESI): m / z 493.16 [M+H] + .

[0533] Intermediate 53H (250 mg) and lithium hydroxide monohydrate (64 mg) were reacted in 1,4-dioxane (20 mL) and water (5 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 53 (55 mg). MS (ESI): m / z 465.0953 [M+H] + .

[0534] 1 H NMR (500 MHz, Methanol- d 4) δ 7.49 (s, 1H), 7.38 (d, J = 17.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 2H), 7.02 (s, 1H), 6.74-6.68 (m, 3H), 4.18 (dd, J= 15.8,2.4 Hz, 1H), 4.06-4.03 (m, 1H), 3.45-3.40 (m, 1H), 3.06-2.99 (m, 2H), 2.26(s, 3H), 2.18-2.10 (m, 1H), 1.96-1.79 (m, 2H), 1.71-1.65 (m, 1H). Example 54: Preparation of compound 54

[0535] Following the preparation method of compound 53 in Example 53, intermediate 53F was replaced with intermediate 53E to obtain compound 54 (100 mg). MS (ESI): m / z 462.1497 [M+H] + .

[0536] 1 H NMR (500 MHz, DMSO) δ 7.59 (d, J = 18.5 Hz, 1H), 7.11 (t, J = 7.7 Hz, 2H), 7.03 (d, J = 2.8 Hz, 1H), 6.93 (d, J = 2.9 Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H),6.45 (s, 2H), 4.24-3.96 (m, 2H), 3.44-3.29 (m, 1H), 3.15-2.95 (m, 2H), 2.69(s, 6H), 2.20-2.10 (m, 1H), 2.03-1.88 (m, 2H), 1.84-1.67 (m, 1H). Example 55: Preparation of compound 55

[0537] Following the preparation method of compound 53 in Example 53, compound 55 (30 mg) was obtained by replacing BOC-D-proline with BOC-D-homoproline. MS (ESI): m / z 479.1112 [M+H] + .

[0538] 1 H NMR (500 MHz, Methanol- d 4) δ 7.56 (s, 1H), 7.49 (d, J= 17.4 Hz, 1H),7.19-7.13 (m, 3H), 6.79-6.68 (m, 3H), 4.18-4.06 (m, 2H), 3.68-3.60 (m, 1H),3.49-3.47 (m, 1H), 2.63-2.57 (m, 1H), 2.39 (s, 3H), 1.96-1.85 (m, 1H), 1.79-1.75 (m, 1H), 1.66-1.54 (m, 2H), 0.91-0.87 (m, 2H). Example 56: Preparation of compound 56

[0539] Intermediate 55F (100 mg), triethylamine (233 mg), and trifluoromethanesulfonic anhydride (520 mg) were reacted in 15 mL of dichloromethane at 0 °C with stirring. After the reaction was complete, the reaction mixture was poured into water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and intermediate 56A (120 mg) was obtained. MS (ESI): m / z 523.08 [M+H] + .

[0540] Intermediate 56A (120 mg), methyl 4-(4,4,5,5-tetramethyl-2-1,3,-dioxoboryl)thiophene 2-carboxylate (85 mg), tripotassium phosphate (89 mg), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (16 mg) were reacted in 1,4-dioxane (20 mL) and water (4 mL) under nitrogen protection with stirring at 100 °C. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure, and intermediate 56B (45 mg) was obtained by column chromatography (elution system: petroleum ether / ethyl acetate). MS (ESI): m / z 515.16 [M+H] + .

[0541] Intermediate 56B (45 mg) and lithium hydroxide monohydrate (15 mg) were reacted in 1,4-dioxane (20 mL) and water (5 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to obtain compound 56 (27 mg). MS (ESI): m / z 501.0972 [M+H] + .

[0542] 1 H NMR (500 MHz, MeOD) δ 7.76 (dd, J = 47.3, 1.5 Hz, 2H), 7.63 (s, 1H), 7.16-7.04 (m, 3H), 6.79-6.56 (m, 3H), 4.10-4.01 (m, 2H), 3.59 (dd, J = 16.0,10.7 Hz, 1H), 3.39-3.34 (m, 1H), 2.57-2.52 (m, 1H), 2.23 (s, 3H), 1.91-1.75(m, 2H), 1.73-1.63 (m, 1H), 1.60-1.47 (m, 2H), 1.42-1.29 (m, 1H). Example 57: Preparation of Compound 57

[0543] At 0 °C, BOC-D-homoproline (3.07 g), 2-methyl-5-amino-2,3-dihydrobenzofuran (2.00 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (6.63 g), and triethylamine (4.07 g) were added to N,N-dimethylformamide (100 mL). The mixture was stirred at room temperature until complete. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 57A (4.10 g). MS (ESI): m / z 361.15 [M+H] + .

[0544] At 0°C, intermediate 57A (4.10 g) and trifluoroacetic acid (10 mL) were added to dichloromethane (50 mL), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution under ice-water bath conditions. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 57B (3.00 g). MS (ESI): m / z 261.17 [M+H] + .

[0545] At 0 °C, intermediate 57B (3.00 g), intermediate K (5.00 g), and triethylamine (4.66 g) were added to tetrahydrofuran (80 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 57C (6.25 g). MS (ESI): m / z 587.00 [M+H] + .

[0546] Intermediate 57C (500 mg), cesium carbonate (830 mg), cuprous iodide (16 mg), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (12 mg) were reacted in N,N-dimethylformamide (30 mL) with stirring at 100 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 57D (380 mg). MS (ESI): m / z 506.99 [M+H] + .

[0547] At 0 °C, intermediate 57D (250 mg) and a tetrahydrofuran solution (2 M, 4.6 mL) of a boronane dimethyl sulfide complex were added to tetrahydrofuran (3 mL). After the addition was complete, the mixture was stirred at 75 °C. Once the reaction was complete, methanol (5 mL) was added to quench the reaction mixture, and the mixture was stirred at 65 °C for 1 hour. The solvent was removed under reduced pressure, and the residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 57E (230 mg). MS (ESI): m / z 492.88 [M+H] + .

[0548] Intermediate 57E (200 mg) and sodium methanethiol (850 mg) were added to N,N-dimethylformamide (10 mL), and the mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 57F (120 mg). MS (ESI): m / z 447.11 [M+H] + .

[0549] At 0°C, intermediate 57F (100 mg) was added to N,N-dimethylacetamide (6 mL), and sodium hydride (43 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (194 mg) in N,N-dimethylformamide (6 mL) was added dropwise. After the addition was complete, the mixture was stirred at 70°C. After the reaction was complete, a saturated ammonium chloride aqueous solution was added sequentially to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 57G (90 mg). MS (ESI): m / z 563.22 [M+H] + .

[0550] Intermediate 57G (90 mg), lithium hydroxide monohydrate (132 mg), and 1,4-dioxane (8 mL) and water (4 mL) were reacted at room temperature with stirring. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 57 (35 mg). MS (ESI): m / z 535.1390 ​​[M+H] + .

[0551] 1 H NMR (500 MHz, MeOD) δ 7.40 (s, 1H), 7.30 (d, J = 17.5 Hz, 1H), 6.80(s, 1H), 6.71-6.69 (m, 1H), 6.61-6.59 (m, 1H), 6.50 (dd, J = 8.5, 2.0 Hz, 1H),4.77-4.74 (m, 1H), 3.99-3.95 (m, 1H), 3.88 (d, J = 15.5 Hz, 1H), 3.59 (dd, J =15.6, 10.4 Hz, 1H), 3.38-3.34 (m, 1H), 3.17-3.11 (m, 1H), 2.68-2.58 (m, 2H), 2.19 (s, 3H), 1.81-1.74 (m, 2H), 1.68-1.64 (m, 1H), 1.58-1.48 (m, 2H), 1.30-1.25 (m, 4H). Example 58: Preparation of Compound 58

[0552] 12.00 g of methyl 4-bromopyridinecarboxylate, 11.16 g of potassium trifluoroborate, 35.40 g of potassium phosphate, 3.90 g of palladium dichloride (triphenylphosphine), and 20 mL of water were added to 1,4-dioxane (100 mL). The mixture was stirred at 100 °C until complete. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 58A (8.40 g). MS (ESI): m / z 164.02 [M+H] + .

[0553] Intermediate 58A (4.00 g), ammonium formate (6.18 g), glacial acetic acid (7.36 g), and palladium hydroxide on carbon (12.05 g, palladium content 10%, water content 50%, w / w) were reacted in tetrahydrofuran (40 mL) and methanol (40 mL) at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was adjusted to pH ~8 with a saturated sodium bicarbonate aqueous solution. Extraction was performed with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 58B (2.20 g). MS (ESI): m / z 172.30 [M+H] + .

[0554] At 0 °C, intermediates 58B (2.00 g), K (5.07 g), and triethylamine (5.91 g) were added to tetrahydrofuran (60 mL), and the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 58C (4.61 g). MS (ESI): m / z 497.89 [M+H] + .

[0555] Intermediate 58C (4.60 g) and lithium hydroxide monohydrate (3.87 g) were reacted in 1,4-dioxane (20 mL) and water (20 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 58D (4.41 g). MS (ESI): m / z 483.90 [M+H]+ .

[0556] At 0 °C, intermediate 58D (4.40 g), aniline (0.85 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.48 g), and triethylamine (2.75 g) were added to N,N-dimethylformamide (100 mL). The mixture was stirred at room temperature until complete. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 58E (3.05 g). MS (ESI): m / z 558.93 [M+H] + .

[0557] Following the preparation method of compound 57 in Example 57, intermediate 57C was replaced with intermediate 57E to obtain compound 58 (48 mg). MS (ESI): m / z 507.1416. [M+H] + .

[0558] 1 H NMR (500 MHz, DMSO- d 6) δ 13.59 (brs, 1H), 7.73 (d, J = 18.6 Hz, 1H),7.53 (s, 1H), 7.23 (s, 1H), 7.19-7.13 (m, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.67-6.61 (m, 2H), 4.14-4.08 (m, 2H), 3.56 (dd, J = 16.2, 11.0 Hz, 1H), 3.39-3.37(m, 1H), 2.59-2.51 (m, 1H), 2.43 (s, 3H), 2.04 (d, J = 13.6 Hz, 1H), 1.73 (d, J =12.7 Hz, 1H), 1.44-1.37 (m, 1H), 1.33-1.25 (m, 1H), 1.23-1.17 (m, 2H), 1.16-1.07 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H).

[0559] Example 59: Preparation of compound 59

[0560] (2R,4R)-4-methyl-2-piperidinic acid (1.50 g), di-tert-butyl dicarbonate (2.52 g), and triethylamine (3.18 g) were added to 15 mL of dichloromethane, and the mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 3-5 with dilute hydrochloric acid (1 mol / L), and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 59A (2.45 g). MS (ESI): m / z 244.14 [M+H] + .

[0561] Following the preparation method of compound 45 in Example 45, intermediate 59 (26 mg) was obtained by replacing Boc-D-leucine with intermediate 59A and intermediate 45B with aniline. MS (ESI): m / z 493.1260 [M+H] + .

[0562] 1 H NMR (500 MHz, Methanol- d 4) δ 7.47 (s, 1H), 7.35 (d, J = 17.3 Hz, 1H),7.11-7.01 (m, 3H), 6.67 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.2 Hz, 2H), 4.12 (dd, J = 10.9, 4.3 Hz, 1H), 4.03 (d, J = 16.0 Hz, 1H), 3.50 (dd, J = 16.0, 10.8 Hz, 1H),3.44-3.39 (m, 1H), 2.54-2.47 (m, 1H), 2.30 (s, 3H), 1.82 (d, J = 10.1 Hz, 1H),1.69-1.62 (m, 1H), 1.51-1.42 (m, 3H), 0.85 (d, J = 5.2 Hz, 3H). Example 60: Preparation of Compound 60

[0563] 4-Bromo-2-(trifluoromethyl)thiophene (970 mg), palladium acetate (181 mg), cesium carbonate (3.94 g), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (466 mg), and benzophenone imine (730 mg) were reacted in 1,4-dioxane (40 mL) under nitrogen purging and microwaved at 110 °C. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 60A (630 mg).

[0564] Intermediate 60A (630 mg), a dioxane solution in hydrochloric acid (4.5 ml, 4 mol / L) was added to 1,4-dioxane (20 mL) and water (4 mL), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation, the mixture was slurried in dichloromethane, filtered, and intermediate 60B (370 mg) was obtained.

[0565] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with intermediate 60B, and Boc-D-leucine was replaced with (R)-1-N-Boc-piperidine-2-carboxylic acid to obtain compound 60 (20 mg). MS (ESI): m / z 553.0558 [M+H] + .

[0566] 1 H NMR (500 MHz, Methanol- d 4) δ 7.55 (s, 1H), 7.47 (d, J = 17.4 Hz, 1H),7.27 (s, 1H), 6.94 (s, 1H), 6.47 (d, J = 1.8 Hz, 1H), 4.33-4.20 (m, 1H), 3.93-3.90 (m, 1H), 3.76-3.71 (m, 1H), 3.52-3.44 (m, 1H), 2.61-2.55 (m, 1H), 2.44(s, 3H), 1.99-1.89 (m, 2H), 1.65-1.60 (m, 2H), 1.40-1.35 (m, 2H). Example 61: Preparation of Compound 61

[0567] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with benzodihydropyran-7-amine to obtain compound 61 (60 mg). MS (ESI): m / z 551.1680 [M+H] + .

[0568] 1 H NMR (500 MHz, Methanol- d 4) δ 7.44 (s, 1H), 7.37 (d, J = 17.4 Hz, 1H), 6.99 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.17 (dd, J = 2.0, 8.3 Hz, 1H), 6.07 (d, J = 1.6 Hz, 1H), 4.03-3.97 (m, 2H), 3.90 (d, J = 15.6 Hz, 1H), 3.79 (s, 1H), 3.28(s, 1H), 2.58 (t, J 0.86 (t, J = 7.0Hz, 3H). Example 62: Preparation of compound 62

[0569] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with benzodihydropyran-6-amine hydrochloride to obtain compound 62 (90 mg). MS (ESI): m / z 551.1699 [M+H] + .

[0570] 1 H NMR (500 MHz, Methanol- d 4) δ 7.47 (s, 1H), 7.35 (d, J = 17.6 Hz, 1H), 6.80 (s, 1H), 6.77-6.69 (m, 2H), 6.67 (d, J = 8.6 Hz, 1H), 4.20-4.04 (m, 2H), 3.93 (d, J = 15.4 Hz, 1H), 3.75 (s, 1H), 3.64 (d, J= 13.6 Hz, 1H), 2.77-2.68 (m,5H), 2.25 (s, 3H), 2.00-1.90 (m, 2H), 1.73-1.59 (m, 1H), 1.56-1.31 (m, 5H), 0.93 (t, J = 6.9 Hz, 3H). Example 63: Preparation of compound 63

[0571] Following the preparation method of compound 12 in Example 12, intermediate 3E was replaced with intermediate 62E to obtain compound 63 (45 mg). MS (ESI): m / z 537.1516 [M+H] + .

[0572] 1 H NMR (500 MHz, Methanol- d 4) δ 7.42 (s, 1H), 7.26 (d, J = 17.5 Hz, 1H),6.74 (s, 1H), 6.65-6.54 (m, 3H), 4.14 (d, J = 15.3 Hz, 1H), 4.02 (dd, J = 5.9,4.4 Hz, 2H), 3.40-3.30 (m, 1H), 3.13 (d, J = 14.1 Hz, 1H), 2.63 (dd, J = 7.6, 5.7Hz, 2H), 2.17 (s, 3H), 1.96-1.78 (m, 2H), 1.51-1.34 (m, 2H), 1.34-1.25 (m,4H), 0.82 (t, J = 7.2 Hz, 3H). Example 64: Preparation of Compound 64

[0573] Following the preparation method of compound 12 in Example 12, intermediate 3E was replaced with intermediate 47E to obtain compound 64 (32 mg). MS (ESI): m / z 525.1168 [M+H] + .

[0574] 1 H NMR (500 MHz, Methanol- d4) δ 7.45 (s, 1H), 7.30 (d, J = 17.5 Hz, 1H), 6.84 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 6.29 (dd, J =2.3, 8.4 Hz, 1H), 5.79 (dd, J = 1.0, 6.6 Hz, 2H), 4.15 (d, J = 15.4 Hz, 1H),3.41-3.36 (m, 1H), 3,07-3.03 (m, 1H), 2.22 (s, 3H), 1.45-1.38 (m, 3H), 1.37-1.22 (m, 3H), 0.83 (t, J = 7.2Hz, 3H). Example 65: Preparation of Compound 65

[0575] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 4-amino-1,3-benzodioxometalate to obtain compound 65 (90 mg). MS (ESI): m / z 539.1313 [M+H] + .

[0576] 1 H NMR (500 MHz, Methanol- d 4) δ 7.38 (s, 1H), 7.30 (d, J = 17.5 Hz, 1H), 6.72 (s, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.47 (d, J = 7.7 Hz, 1H), 6.32 (d, J = 8.4Hz, 1H), 5.83 (d, J = 1.1 Hz, 1H), 5.77 (s, 1H), 4.12-4.06 (m, 1H), 3.63 (s,2H), 2.64 (s, 3H), 2.17 (s, 3H), 1.61-1.53 ​​(m, 1H), 1.42-1.33 (m, 2H) , 1.32-1.16 (m, 3H), 0.86-0.76 (m, 3H). Example 66: Preparation of Compound 66

[0577] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 6-fluorobenzo[d][1,3]dihydroxy-5-amine to obtain compound 66 (90 mg). MS (ESI): m / z 557.1222 [M+H] + .

[0578] 1 H NMR (500 MHz, Methanol- d 4) δ 7.35 (s, 1H), 7.24 (d, J = 17.7 Hz, 1H), 6.77-6.71 (m, 2H), 6.38 (s, 1H), 5.94-5.89 (m, 2H), 3.97-3.89 (m, 1H), 3.58-3.54 (m, 2H), 2.75 (s, 3H), 2.11 (s, 3H), 1.64-1.57 (m, 1H), 1.40-1.21 (m,5H), 0.83 (t, J = 7.0 Hz, 3H). Example 67: Preparation of Compound 67

[0579] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 2,3-dihydrobenzo[b][1,4]dioxane-6-amine to obtain compound 67 (16 mg). MS (ESI): m / z 553.1478 [M+H] + .

[0580] 1 H NMR (500 MHz, Methanol- d 4) δ 7.37 (s, 1H), 7.18 (d, J = 17.6 Hz, 1H), 6.85 (s, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.29-6.22 (m, 2H), 4.12-4.07 (m, 4H), 3.83 (d, J= 15.7 Hz, 1H), 3.72 (s, 1H), 3.34 (s, 1H), 2.53 (s, 3H), 2.21 (s,3H), 1.53 (d, 1H), 1.57-1.49 (m, 1H), 1.43-1.23 (m, 5H), 0.85 (t, J = 6.9 Hz, 3H). Example 68: Preparation of Compound 68

[0581] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 5-amino-2,2-difluoro-1,3-benzodioxometalate to obtain compound 68 (68 mg). MS (ESI): m / z 575.1135 [M+H] + .

[0582] 1 H NMR (500 MHz, Methanol- d 4) δ 7.46 (s, 1H), 7.30 (d, J = 17.4 Hz, 1H),7.02 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.51 (s, 1H), 6.34 (dd, J = 2.0, 8.8 Hz,1H), 3.93-3.84 (m, 2H), 3.30-3.24 (m, 1H), 2.47 (s, 3H), 2.29 (s, 3H), 1.51-1.47 (m, 2H), 1.40-1.28 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H). Example 69: Preparation of Compound 69

[0583] Sodium hydrogen (2.68 g), 5-nitrodihydroindole (5.00 g), and iodomethane (6.48 g) were reacted in N,N-dimethylformamide (40 mL) at 0 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was prepared into a slurry. The slurry was then separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 69A (3.50 g). MS (ESI): m / z 179.02 [M+H] + .

[0584] Intermediate 69A (3.50 g) and palladium on carbon (2.00 g, palladium content 10%, water content 50%) were reacted in methanol (20 mL) with hydrogen purging followed by stirring at room temperature. After the reaction was complete, the mixture was filtered, concentrated, and used to obtain intermediate 69B (3.0 g). MS (ESI): m / z 148.95 [M+H] + .

[0585] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with intermediate 69B to obtain compound 69 (12.5 mg). MS (ESI): m / z 550.1485 [M+H] + .

[0586] Example 70: Preparation of Compound 70

[0587] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 2,3-dihydrobenzo[b][1,4]dioxane-5-amine to obtain compound 70 (240 mg). MS (ESI): m / z 553.22 [M+H] + .

[0588] 1 H NMR (500 MHz, Methanol- d 4) δ 7.30 (s, 1H), 7.20 (d, J = 17.7 Hz, 1H), 6.79-6.76 (m, 1H), 6.73-6.69 (m, 2H), 6.23 (s, 1H), 4.20-4.10 (m, 5H), 3.65(dd, J = 15.7, 3.7 Hz, 1H), 3.54-3.48 (m, 1H), 2.85 (s, 3H), 2.03 (s, 3H), 1.67-1.61 (m, 1H), 1.41-1.21 (m, 5H), 0.82 (t, J = 7.0 Hz, 3H). Example 71: Preparation of Compound 71

[0589] At 0 °C, sodium hydrogen hydrate (3.21 g, 60% w / w) was dissolved in dimethyl sulfoxide (30 mL). A solution of ethyltriphenylphosphonium bromide (29.8 g) in dimethyl sulfoxide (80 mL) was slowly added dropwise to the solution. After the addition was complete, the mixture was stirred at room temperature for 1.5 hours. A solution of (S)-1-(tert-butoxycarbonyl)-4-oxopiperidin-2-carboxylic acid (6.50 g) in dimethyl sulfoxide (30 mL) was added to the stirred mixture. After the addition was complete, the mixture was stirred in an oil bath. The reaction was quenched with a 5% aqueous solution of sodium bicarbonate, washed with toluene, and the aqueous phase was adjusted to acidity (pH approximately 3) with dilute hydrochloric acid (1 mol / L). The phase was extracted with methyl tert-butyl ether, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 71A (9.00 g). MS (ESI): m / z 256.34 [M+H] + .

[0590] At 0 °C, 71A (6.00 g), aniline (2.30 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (9.50 g), and triethylamine (13.40 g) were added to N,N-dimethylformamide (100 mL). The mixture was stirred at room temperature until complete. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 71B (5.8 g). MS (ESI): m / z 331.20 [M+H] + .

[0591] Intermediate 71B (5.80 g) and palladium hydroxide on carbon (6.5 g, palladium content 10%, water content 50%, w / w) were reacted in tetrahydrofuran (20 mL) and methanol (20 mL) under hydrogen purging and stirring at room temperature. After the reaction was complete, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 71C (3.5 g). MS (ESI): m / z 333.20 [M+H] + ;71C' (1.9 g). MS (ESI): m / z 333.22 [M+H] + .

[0592] At 0°C, intermediate 71C (3.50 g) and trifluoroacetic acid (15 mL) were added to dichloromethane (80 mL), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed under reduced pressure. The mixture was then adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate solution under ice-water bath conditions. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 71D (2.40 g). MS (ESI): m / z 233.23 [M+H] + .

[0593] At 0 °C, intermediate 71D (2.40 g), intermediate K (4.00 g), and triethylamine (3.00 g) were added to tetrahydrofuran (70 mL). The mixture was stirred at room temperature until complete. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 71E (5.30 g). MS (ESI): m / z 559.03 [M+H] + .

[0594] Intermediate 71E (3.00 g), tripotassium phosphate (3.40 g), cuprous iodide (102 mg), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (76 mg) were reacted in N,N-dimethylformamide (70 mL) with stirring at 110 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 71F (750 mg). MS (ESI): m / z 479.35 [M+H] + .

[0595] At 0 °C, intermediate 71F (750 mg) and a tetrahydrofuran solution (1 mL, 10 mol / L) of a boron dimethyl sulfide complex were added to 25 mL of tetrahydrofuran. The mixture was stirred at 75 °C until complete. After the reaction was complete, methanol (5 mL) was added to quench the reaction mixture, and the mixture was stirred at 65 °C for 1 hour. The solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 71G (700 mg). MS (ESI): m / z 465.12 [M+H] + .

[0596] Intermediate 71G (700 mg) and sodium methanethiol (740 mg) were added to N,N-dimethylformamide (20 mL), and the mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 71H (650 mg). MS (ESI): m / z 419.25 [M+H] + .

[0597] At 0 °C, intermediate 71H (650 mg) was added to N,N-dimethylacetamide (40 mL), and sodium hydride (373 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0 °C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (1.7 g) in N,N-dimethylformamide (6 mL) was added dropwise. After the addition was complete, the mixture was stirred at 90 °C. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 71I (300 mg). MS (ESI): m / z 535.24 [M+H] + .

[0598] Intermediate 71I (300 mg), lithium hydroxide monohydrate (118 mg), and 1,4-dioxane (25 mL) and water (5 mL) were reacted at room temperature with stirring. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with dilute hydrochloric acid (1 mol / L). The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 71 (100 mg). MS (ESI): m / z 507.1421 [M+H] + .

[0599] 1 H NMR (500 MHz, DMSO- d 6) δ 13.66 (brs, 1H), 7.67 (dd, J = 18.6, 1.9 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.17-7.13 (m, 2H), 6.71(t, J = 7.2 Hz, 1H), 6.64 (d,J = 8.1 Hz, 2H), 4.19-4.06 (m, 2H), 3.59-3.53 (m,1H), 3.38 (d, J = 12.1 Hz, 1H), 2.58-2.52 (m, 1H), 2.43 (s, 3H), 2.04 (d, J =13.2 Hz, 1H), 1.73 (d, J = 12.8 Hz, 1H), 1.47-1.38 (m, 1H), 1.33-1.26 (m, 1H), 1.25-1.18 (m, 2H), 1.17-1.08 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H). Example 72: Preparation of compound 72

[0600] Following the preparation method of compound 71 in Example 71, (S)-1-(tert-butoxycarbonyl)-4-oxopiperidin-2-carboxylic acid was replaced with (R)-1-(tert-butoxycarbonyl)-4-oxopiperidin-2-carboxylic acid to obtain compound 72 (240 mg). MS (ESI): m / z 507.1422 [M+H] + .

[0601] 1 H NMR (500 MHz, DMSO- d 6) δ 7.48-7.45 (m, 2H), 7.22 (s, 1H), 7.20-7.08(m, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.3 Hz, 2H), 4.16-4.03 (m, 2H), 3.56 (dd, J = 16.1, 11.0 Hz, 1H), 3.40-3.35 (m, 1H), 2.61-2.52 (m, 1H), 2.43(s, 3H), 2.11-1.98 (m, 1H), 1.78-1.68 (m, 1H), 1.43-1.35 (m, 1H), 1.25-1.18(m, 2H), 1.16-1.08 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H). Example 73: Preparation of Compound 73

[0602] Compound 73 (90 mg) was prepared from intermediate 72C' according to the preparation method of compound 72 in Example 72. MS (ESI): m / z 507.1428 [M+H] + .

[0603] 1 H NMR (500 MHz, DMSO- d 6) δ 13.55 (brs, 1H), 7.67 (d, J = 18.6 Hz, 1H),7.52 (s, 1H), 7.26-7.16 (m, 2H), 7.09 (s, 1H), 6.82-6.79 (m, 3H), 4.19 (d, J =14.2 Hz, 1H), 3.68-3.46 (m, 2H), 3.21 (s, 1H), 2.97 (s, 1H), 2.37 (s, 3H),1.96-1.85 (m, 1H), 1.85-1.72 (m, 1H), 1.52-1.44 (m, 1H), 1.45-1.34 (m, 1H),1.33-1.19 (m, 3H), 0.86 (t, J = 7.4 Hz, 3H). Example 74: Preparation of Compound 74

[0604] Compound 74 (195 mg) was prepared from intermediate 71C' according to the preparation method of compound 72 in Example 72. MS (ESI): m / z 507.1420 [M+H] + .

[0605] 1 H NMR (500 MHz, DMSO- d 6) δ 13.56 (brs, 1H), 7.67 (d, J = 18.6 Hz, 1H),7.52 (s, 1H), 7.21 (dd, J = 8.8, 7.1 Hz, 2H), 7.09 (s, 1H), 6.80 (d, J = 7.8 Hz, 3H), 4.19 (d, J= 14.2 Hz, 1H), 3.60-3.48 (m, 2H), 3.21 (s, 1H), 2.97 (s, 1H), 2.37 (s, 3H), 1.92 (d, J = 12.3 Hz, 1H), 1.83-1.76 (m, 1H), 1.52-1.45 (m, 1H), 1.42-1.36 (m, 1H), 1.32-1.23 (m, 3H), 0.86 (t, J = 7.4 Hz, 3H). Example 75: Preparation of Compound 75

[0606] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 5-fluorobenzo[d][1,3]dioxa-4-amine to obtain intermediate 75F (600 mg). MS (ESI): m / z 515.2 [M+H] + .

[0607] Intermediate 75F (0.60 g) and sodium methanethiol (0.45 g) were added to N,N-dimethylformamide (15 mL), and the mixture was stirred at 100 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: dichloromethane / methanol) to obtain intermediate 75G (0.40 g). MS (ESI): m / z 517.3 [M+H] + .

[0608] Following the preparation method of compound 66 in Example 66, intermediate 66G was replaced with intermediate 75G to obtain compound 75 (120 mg). MS (ESI): m / z 605.1287 [M+H] + .

[0609] 1H NMR (500 MHz, CDCl3) δ 7.86 (brs, 1H), 7.56 (s, 1H), 7.35 (d, J =16.8 Hz, 1H), 6.92 (dd, J= 9.1, 5.3 Hz, 1H), 6.74-6.66 (m, 2H), 5.20 (s, 2H), 4.14 (s, 1H), 3.49-3.29 (m, 2H), 2.60 (s, 3H), 2.26-2.23 (m, 6H), 1.53-1.29(m, 7H), 0.92 (t, J = 6.8 Hz, 3H).

[0610] Example 76: Preparation of Compound 76

[0611] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 2,2-dimethylbenzo-1,3-dioxacyclopenten-5-amine to obtain compound 76 (130 mg). MS (ESI): m / z 567.1636 [M+H] + .

[0612] 1 H NMR (500 MHz, Methanol- d 4) δ 7.39 (s, 1H), 7.31 (d, J = 17.6 Hz, 1H), 6.76 (s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 2.2 Hz, 1H), 6.29 (dd, J =2.2, 8.4 Hz, 1H), 3.86-3.65 (m, 2H), 3.53-3.42 (m, 1H), 2.59 (s, 3H), 2.19(s, 3H), 1.58-1.51 (m, 7H), 1.44-1.24 (m, 5H), 0.84 (t, J = 7.0 Hz, 3H). Example 77: Preparation of Compound 77

[0613] Following the preparation method of compound 72 in Example 72, aniline was replaced with benzo[d][1,3]dioxane-5-amine, and compound 77 (180 mg) was prepared starting from intermediate 77B'. MS (ESI): m / z 551.1323 [M+H] + .

[0614] 1H NMR (500 MHz, Methanol- d 4) δ 7.55 (s, 1H), 7.48 (d, J = 17.4 Hz, 1H),7.08 (s, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.30 (dd, J =2.4, 8.5 Hz, 1H), 5.88 (dd, J = 0.8, 7.3 Hz, 2H), 4.22-4.18 (m, 1H), 4.02-3.99(m, 1H), 3.63-3.51 (m, 2H), 2.70-2.56 (m, 1H), 2.38 (s, 3H), 1.95-1.92 (m,1H), 1.86-1.83 (m, 1H), 1.59-1.49 (m, 1H), 1.38-1.21 (m, 4H), 0.94 (t, J = 7.4Hz, 3H). Example 78: Preparation of Compound 78

[0615] Compound 78 (280 mg) was prepared from intermediate 77A according to the preparation method of compound 72 in Example 72. MS (ESI): m / z 551.1321 [M+H] + .

[0616] 1 H NMR (500 MHz, Methanol- d 4) δ 7.50 (s, 1H), 7.36 (d, J = 17.4 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.70-6.67 (m, 2H), 6.62 (dd, J = 1.8, 8.2 Hz, 1H), 5.97(s, 2H), 4.18-4.14 (m, 1H), 4.04-3.96 (m, 1H), 3.88-3.80 (m, 1H), 3.46-3.39(m, 1H), 2.89 (t, J= 10.4 Hz, 1H), 2.25 (s, 3H), 1.88-1.84 (m, 1H), 1.75-1.72(m, 1H), 1.52-1.44 (m, 1H), 1.43-1.26 (m, 4H), 0.92 (t, J = 7.4 Hz, 3H). Example 79: Preparation of Compound 79

[0617] Following the preparation method of compound 12 in Example 12, intermediate 3E was replaced with intermediate 70E to obtain compound 79 (88 mg). MS (ESI): m / z 539.1322 [M+H] + .

[0618] 1 H NMR (500 MHz, DMSO- d 6) δ 13.47 (brs, 1H), 7.78 (d, J = 7.6 Hz, 1H),7.49-7.24 (m, 2H), 6.85-6.81 (m, 2H), 6.79-6.74 (m, 1H), 6.26 (s, 1H), 4.32-4.24 (m, 4H), 3.91 (d, J = 15.2 Hz, 1H), 3.56 (dd, J = 15.9, 8.1 Hz, 1H), 2.13(s, 3H), 1.71-1.45 (m, 1H), 1.46-1.31 (m, 2H), 1.33-1.09 (m, 4H), 0.83 (q, J =6.8 Hz, 3H). Example 80: Preparation of Compound 80

[0619] Following the preparation method of compound 70 in Example 70, compound 80 (50 mg) was obtained by replacing iodomethane with deuterated iodomethane. MS (ESI): m / z 556.1666 [M+H] + .

[0620] 1 H NMR (500 MHz, Methanol- d 4) δ 7.28 (s, 1H), 7.11 (d, J= 17.8 Hz, 1H), 6.77 (t, J = 8.0 Hz, 1H), 6.72-6.68 (m, 2H), 6.24 (s, 1H), 4.21-4.04 (m, 5H), 3.65 (dd, J = 15.7, 3.6 Hz, 1H), 3.54-3.47 (m, 1H), 2.03 (s, 3H), 1.68-1.58 (m,1H), 1.41-1.30 (m, 2H), 1.29-1.21 (m, 3H), 0.83 (t, J = 6.9 Hz, 3H). Example 81: Preparation of Compound 81

[0621] Following the preparation method of compound 47 in Example 47, compound 81 (250 mg) was obtained by replacing iodomethane with deuterated iodomethane. MS (ESI): m / z 542.11 [M+H] + .

[0622] 1 H NMR (500 MHz, Methanol- d 4) δ 7.53 (s, 1H), 7.43 (d, J = 17.6 Hz, 1H), 6.93 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 6.42 (dd, J =8.4, 2.4 Hz, 1H), 5.92 (dd, J = 7.5, 1.2 Hz, 2H), 3.96 (d, J = 15.8 Hz, 1H), 3.84(s, 1H), 3.59-3.49 (m, 1H), 2.33 (s, 3H), 1.70-1.60 (m, 1H), 1.57-1.34 (m,5H), 0.96 (t, J = 6.8 Hz, 3H). Example 82: Preparation of Compound 82

[0623] D-3-(cyclopropyl)alanine (3.25 g), di-tert-butyl dicarbonate (3.85 g), and potassium carbonate (6.37 g) were added to THF (35 mL) and H₂O (35 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the pH of the reaction solution was adjusted to 3-5 with dilute hydrochloric acid (1 mol / L). The solution was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 82A (6.44 g). MS (ESI): m / z 230.13 [M+H] + .

[0624] At 0 °C, intermediate 82A (6.13 g), aniline (3.00 g), N,N-diisopropylethylamine (6.92 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (15.26 g) were added to N,N-dimethylformamide (50 mL). The mixture was stirred at room temperature until complete. After the reaction was complete, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 82B (7.39 g). MS (ESI): m / z 305.18 [M+H] + .

[0625] Intermediate 82B (4.00 g) and trifluoroacetic acid (15.00 g) were reacted in dichloromethane (50 mL) with stirring at room temperature. After the reaction was complete, the solvent was removed from the reaction mixture under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 82C (2.68 g). MS (ESI): m / z 205.16 [M+H] + .

[0626] At 0 °C, intermediate 82C (2.68 g), intermediate K (4.76 g), and triethylamine (5.32 g) were added to tetrahydrofuran (50 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 82D (5.50 g). MS (ESI): m / z 530.95 [M+H] + .

[0627] Intermediate 82D (3.00 g), tripotassium phosphate (3.60 g), cuprous iodide (216 mg), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (160 mg) were reacted in N,N-dimethylformamide (60 mL) with stirring at 110 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 82E (2.00 g). MS (ESI): m / z 450.98 [M+H] + .

[0628] Intermediate 82E (2.00 g), cesium carbonate (2.90 g), and iodomethane (1.26 g) were reacted in N-methylpyrrolidone (20 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 82F (1.27 g). MS (ESI): m / z 464.99 [M+H] + .

[0629] At 0°C, intermediate 82F (1.27 g) and a tetrahydrofuran solution (10 mol / L, 4 mL) of a boronane dimethyl sulfide complex were added to 25 mL of tetrahydrofuran. The mixture was stirred at 75°C until complete. After the reaction was complete, methanol (14 mL) was added to quench the reaction mixture, and the mixture was stirred at 60°C for 2 hours. The solvent was removed under reduced pressure. The residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 82G (0.43 g). MS (ESI): m / z 451.13 [M+H] + .

[0630] Intermediate 82G (0.43 g) and sodium methanethiol (1.34 g) were added to N,N-dimethylformamide (20 mL), and the mixture was stirred at 60 °C. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 82H (0.31 g). MS (ESI): m / z 405.19 [M+H] + .

[0631] At 0 °C, intermediate 82H (160 mg) was added to 12 mL of N,N-dimethylacetamide, and sodium hydride (166 mg, 60% w / w) was slowly added. After the addition was complete, the mixture was stirred at 0 °C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (550 mg) in 4 mL of N,N-dimethylacetamide was added dropwise. After the addition was complete, the mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 82I (130 mg). MS (ESI): m / z 521.23 [M+H] + .

[0632] Intermediate 82I (130 mg) and lithium hydroxide monohydrate (63 mg) were reacted in 1,4-dioxane (15 mL) and water (5 mL) at room temperature with stirring. After the reaction was complete, the reaction mixture was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with dilute hydrochloric acid (1 mol / L). The phases were separated; the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 82 (60 mg). MS (ESI): m / z 493.1270 [M+H] + .

[0633] 1 H NMR (500 MHz, Methanol- d 4) δ 7.37 (s, 1H), 7.28 (d, J = 17.5 Hz, 1H),7.07-6.98 (m, 2H), 6.89 (s, 1H), 6.69-6.61 (m, 3H), 4.05 (d, J = 15.9 Hz, 1H), 3.81 (d, J = 9.1 Hz, 1H), 3.33-3.21 (m, 1H), 2.48 (s, 3H), 2.16 (s, 3H), 1.61-1.55 (m, 1H), 1.14-1.07 (m, 1H), 0.72-0.65 (m, 1H), 0.42-0.34 (m, 2H), 0.02--0.05 (m, 2H). Example 83: Preparation of Compound 83

[0634] Following the preparation method of Compound 1 in Example 1, intermediate 1H was replaced with intermediate 47G, and (5-(methoxycarbonyl)thiophen-3-yl)boronic acid was replaced with (4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid to obtain Compound 83 (106 mg). MS (ESI): m / z 579.1091 [M+H]+.

[0635] 1 H NMR (500 MHz, Methanol- d 4) δ 7.61 (d, J = 4.3 Hz, 1H), 7.50 (s, 1H), 6.73-6.66 (m, 2H), 6.58 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.3, 2.3 Hz, 1H), 5.85(dd, J = 7.0, 1.2 Hz, 2H), 3.84 (d, J 0.84 (t, J = 6.9 Hz, 3H). Example 84: Preparation of Compound 84

[0636] Following the preparation method of compound 82 in Example 82, aniline was replaced with 4-(chlorodifluoromethoxy)aniline, and intermediate 82A was replaced with Boc-D-ortholeucine to obtain compound 84 (85 mg). MS (ESI): m / z 595.0961 [M+H] + .

[0637] 1 H NMR (500 MHz, Methanol- d 4) δ 7.50 (s, 1H), 7.41 (d, J = 17.4 Hz, 1H),7.09 (s, 1H), 7.01 (d, J= 9.0 Hz, 2H), 6.67-6.61 (m, 2H), 3.99-3.90 (m, 2H), 3.30-3.23 (m, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 1.54-1.48 (m, 2H), 1.41-1.26(m, 4H), 0.86 (t, J = 7.0 Hz, 3H). Example 85: Preparation of Compound 85

[0638] Following the preparation method of compound 72 in Example 72, compound 85 (146 mg) was prepared starting from intermediate 71C' by replacing aniline with 5-amino-1,4-benzodioxane. MS (ESI): m / z 565.1460 [M+H] + .

[0639] 1 H NMR (500 MHz, DMSO- d 6) δ 13.42 (brs, 1H), 7.48-7.40 (m, 2H), 6.96-6.86 (m, 2H), 6.79 (dd, J = 7.1, 2.3 Hz, 1H), 6.05 (s, 1H), 4.33-4.16 (m, 5H), 4.01 (s, 1H), 3.89 (d, J = 12.6 Hz, 1H), 2.84 (t, J = 12.1 Hz, 1H), 2.07 (s, 3H), 1.78 (d, J = 13.0 Hz, 1H), 1.57 (d, J = 11.5 Hz, 1H), 1.48-1.30 (m, 2H), 1.29-1.14 (m, 2H), 1.13-1.04 (m, 1H), 0.82 (t, J = 7.4 Hz, 3H). Example 86: Preparation of Compound 86

[0640] Compound 86 (80 mg) was prepared from intermediate 85C' according to the preparation method of compound 72 in Example 72. MS (ESI): m / z 565.1461 [M+H] + .

[0641] 1 H NMR (500 MHz, Methanol- d 4) δ 7.36 (s, 1H), 7.25 (d, J = 17.6 Hz, 1H), 6.68-6.61 (m, 3H), 6.57 (s, 1H), 4.26-4.14 (m, 4H), 4.09-4.06 (m, 1H), 3.68-3.63 (m, 1H), 3.58-3.54 (m, 1H), 3.49-3.45 (m, 1H), 2.64-2.59 (m, 1H), 2.12(s, 3H), 1.76-1.69 (m, 2H), 1.46-1.39 (m, 1H), 1.25-1.09 (m, 4H), 0.79 (t, J =7.4 Hz, 3H). Example 87: Preparation of compound 87

[0642] Following the preparation method of compound 72 in Example 72, compound 87 (150 mg) was prepared from intermediate 87C' by replacing (R)-1-(tert-butoxycarbonyl)-4-oxopiperidin-2-carboxylic acid with N-Boc-4-oxo-D-proline. MS (ESI): m / z 493.1274 [M+H] + .

[0643] 1 H NMR (500 MHz, DMSO- d 6) δ 13.64 (brs, 1H), 7.66 (d, J = 18.5 Hz, 1H),7.53 (s, 1H), 7.19 (td, J = 7.3, 1.8 Hz, 2H), 7.14 (s, 1H), 6.84-6.68 (m, 3H), 4.23 (dd, J = 15.9, 2.4 Hz, 1H), 4.10-4.00 (m, 1H), 3.63-3.49 (m, 1H), 3.23-3.02 (m, 1H), 2.63 (t, J= 9.7 Hz, 1H), 2.47-2.41 (m, 1H), 2.39 (s, 3H), 2.27-2.15 (m, 1H), 1.38-1.27 (m, 2H), 1.23-1.14 (m, 1H), 0.83 (t, J = 7.4 Hz, 3H). Example 88: Preparation of Compound 88

[0644] Compound 88 (90 mg) was prepared from intermediate 87C according to the preparation method of compound 72 in Example 72. MS (ESI): m / z 493.1257 [M+H] + .

[0645] 1 H NMR (500 MHz, DMSO- d 6) δ 13.58 (brs, 1H), 7.72 (d, J = 18.6 Hz, 1H),7.55 (s, 1H), 7.23 (s, 1H), 7.20-7.09 (m, 2H), 6.74-6.65 (m, 3H), 4.24 (dd, J =15.8, 2.3 Hz, 1H), 4.07 (t, J = 9.3 Hz, 1H), 3.26 (t, J = 9.5 Hz, 1H), 3.09-2.94(m, 2H), 2.42 (s, 3H), 2.26-2.13 (m, 1H), 1.99-1.87 (m, 1H), 1.84-1.73 (m,1H), 1.46-1.31 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). Example 89: Preparation of Compound 89

[0646] Following the preparation method of Compound 1 in Example 1, 70G was used instead of 1I, and (4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid was used instead of (5-(methoxycarbonyl)thiophen-3-yl)boronic acid to obtain Compound 89 (100 mg). MS (ESI): m / z 593.1241 [M+H] + .

[0647] 1H NMR (500 MHz, Methanol- d 4) δ 7.66 (d, J = 4.1 Hz, 1H), 7.54 (s, 1H), 6.98-6.91 (m, 1H), 6.91-6.80 (m, 2H), 6.32 (s, 1H), 4.47 (dd, J = 15.7, 11.6Hz, 1H), 4.35-4.16 (m, 4H), 3.77 (dd, J = 15.7, 4.0 Hz, 1H), 3.65-3.53 (m, 1H), 3.03 (s, 3H), 2.08 (s, 3H), 1.88-1.74 (m, 1H), 1.59-1.33 (m, 5H), 0.95 (t, J =7.0 Hz, 3H). Example 90: Preparation of Compound 90

[0648] Intermediate 47F (500 mg), potassium carbonate (417 mg), cyclopropylboronic acid (130 mg), tetrakis(triphenylphosphine)palladium (232 mg), and water (2 mL) were reacted in 1,4-dioxane (10 mL) under nitrogen purging in an oil bath at 100 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 90A (367 mg). MS (ESI): m / z 459.22 [M+H] + .

[0649] Intermediate 90A (300 mg) and sodium methanethiol (321 mg) were added to N,N-dimethylformamide (20 mL). After the addition was complete, the mixture was stirred in a microwave at 90°C. Once the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 90B (180 mg). MS (ESI): m / z 445.24 [M+H] + .

[0650] Following the preparation method of compound 3 in Example 3, intermediate 3G was replaced with intermediate 90B to obtain compound 90 (87 mg). MS (ESI): m / z 533.1759. [M+H] + .

[0651] 1 H NMR (500 MHz, Methanol- d 4) δ 7.53 (s, 1H), 7.49 (d, J = 17.7 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.31 (dd, J =8.4, 2.4 Hz, 1H), 5.88 (dd, J = 8.0, 1.2 Hz, 2H), 3.92 (d, J = 15.8 Hz, 1H), 3.82(m, 1H), 3.45 (m, 1H), 2.66 (s, 3H), 2.18-2.12 (m, 1H), 1.69-1.60 (m, 1H),1.56-1.33 (m, 5H), 1.08-0.99 (m, 2H), 0.94 (t, J = 6.9 Hz, 3H), 0.68-0.58 (m,2H). Example 91: Preparation of Compound 91

[0652] Following the preparation method of compound 90 in Example 90, compound 91 (50 mg) was obtained by replacing cyclopropylboronic acid with trimethylcyclotriboroxane. MS (ESI): m / z 507.1591 [M+H] + .

[0653] 1 H NMR (500 MHz, Methanol- d 4) δ 7.44 (s, 1H), 7.37 (d, J = 17.6 Hz, 1H), 6.91 (s, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 6.27 (dd, J =8.4, 2.4 Hz, 1H), 5.78 (dd, J = 8.0, 1.2 Hz, 2H), 3.82 (d, J= 15.8 Hz, 1H), 3.73(m, 1H), 3.43-3.33 (m, 1H), 2.56 (s, 3H), 2.15 (s, 3H),1.60-1.46 (m, 1H),1.45-1.22 (m, 5H), 0.84 (t, J = 6.9 Hz, 3H). Example 92: Preparation of compound 92

[0654] Following the preparation method of compound 45 in Example 45, intermediate 45B was replaced with 6-amino-3H-spirocyclic [benzofuran-2,1'-cyclopropane]-3-one to obtain compound 92 (25 mg). MS (ESI): m / z 563.1676 [M+H] + .

[0655] 1 H NMR (500 MHz, Methanol- d 4) δ 7.45 (s, 1H), 7.32 (d, J = 17.5 Hz, 1H), 6.99 (s, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.18 (dd, J = 8.1, 2.3 Hz, 1H), 6.08-6.04(m, 1H), 3.91 (d, J = 16.1 Hz, 1H), 3.82 (m, 1H), 3.27 (m, 1H), 3.11 (s, 2H), 2.51 (s, 3H), 2.27 (s, 3H), 1.57-1.40 (m, 2H), 1.37-1.25 (m, 4H), 1.02-0.94(m, 2H), 0.86 (t, J = 6.8 Hz, 3H), 0.64-0.58 (m, 2H). Example 93: Preparation of Compound 93

[0656] Following the preparation method of compound 82 in Example 82, aniline was replaced with 7-methyl-5-amino-2,3-dihydrobenzo[b][1,4]dioxane, and intermediate 82A was replaced with Boc-D-ortholeucine to obtain compound 93 (50 mg). MS (ESI): m / z 567.1626 [M+H] + .

[0657] 1 H NMR (500 MHz, Methanol- d 4) δ 7.27 (s, 1H), 7.11 (d, J = 17.7 Hz, 1H), 6.54-6.50 (m, 2H), 6.26 (s, 1H), 4.15-4.04 (m, 5H), 3.63 (dd, J = 15.6, 3.6 Hz,1H), 3.51 (s, 1H), 2.82 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.45-1.19 (m,6H), 0.82 (t, J = 6.8 Hz, 3H). Example 94: Preparation of Compound 94

[0658] Following the preparation method of compound 82 in Example 82, aniline was replaced with 7-fluoro-5-amino-2,3-dihydrobenzo[b][1,4]dioxane, and intermediate 82A was replaced with Boc-D-ortholeucine to obtain compound 94 (80 mg). MS (ESI): m / z 571.1382 [M+H] + .

[0659] 1 H NMR (500 MHz, Methanol- d 4) δ 7.33 (s, 1H), 7.24 (d, J = 17.6 Hz, 1H), 6.50-6.44 (m, 2H), 6.37 (s, 1H), 4.20-4.07 (m, 4H), 3.93 (t, J = 13.6 Hz, 1H), 3.74 (dd, J = 15.8, 3.4 Hz, 1H), 3.54 (s, 1H), 2.78 (s, 3H), 2.11 (s, 3H), 1.67-1.56 (m, 1H), 1.44-1.22 (m, 5H), 0.83 (t, J = 6.9 Hz, 3H). Example 95: Preparation of Compound 95

[0660] Intermediate 72A (1.10 g) and palladium hydroxide on carbon (6.5 g, palladium content 10%, water content 50%, w / w) were reacted in tetrahydrofuran (10 mL) and methanol (10 mL) under hydrogen purging and stirring at room temperature. After the reaction was complete, the mixture was filtered and concentrated to obtain intermediate 95A (1.01 g). The sample was not purified and was directly fed into the next reaction step.

[0661] Intermediate 95A (900 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1729 mg), triethylamine (1770 mg), and 3-aminothiophene hydrochloride (569 mg) were reacted in N,N-dimethylformamide (40 mL) with stirring at room temperature. After the reaction was complete, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 95B (375 mg). MS (ESI): m / z 329.00 [M+H] + .

[0662] Following the preparation method of compound 73 in Example 73, intermediate 72C' was replaced with intermediate 95B to obtain compound 95 (79 mg). MS (ESI): m / z 513.0997 [M+H] + .

[0663] 1 H NMR (500 MHz, Methanol- d 4) δ 13.53 (brs, 1H), 7.61 (d, J = 18.6 Hz,1H), 7.46 (s, 1H), 7.43-7.41 (m, 1H), 7.07 (s, 1H), 6.76 (d, J = 4.6 Hz, 1H), 6.67 (s, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.67 (m, 1H), 3.40 (m, 2H), 2.86 (s,1H), 2.36 (s, 3H), 1.88-1.85 (m, 1H), 1.81-1.77 (m, 1H), 1.49-1.42 (m, 1H),1.36-1.29 (m, 1H), 1.27-1.21 (m, 3H), 0.85 (t, J = 7.3 Hz, 3H). Example 96: Preparation of Compound 96

[0664] Following the preparation method of compound 45 in Example 45, intermediate 82A was used to replace Boc-D-leucine, and intermediate 45B was used to replace 3-aminothiophene hydrochloride to obtain compound 96 (150 mg). MS (ESI): m / z 499.0838 [M+H] + .

[0665] 1 H NMR (500 MHz, Methanol- d 4) δ 7.31 (s, 1H), 7.22 (d, J = 15.15 Hz, 1H), 7.11 (d, J = 5.20 Hz, 1H), 6.92 (s, 1H), 6.50 (d, J = 5.20 Hz, 1H), 3.87-3.79 (m, 2H), 3.42-3.37 (m, 1H), 2.51 (s, 3H), 2.16 (s, 3H), 1.62-1.57 (m,1H), 1.12-1.06 (m, 1H), 0.71-0.64 (m, 1H), 0.40-0.33 (m, 2H), 0.03- -0.06 (m, 2H). Example 97: Preparation of Compound 97

[0666] Following the preparation method of compound 45 in Example 45, intermediate 82A was used to replace Boc-D-leucine, and 3,4-(methylenedioxy)aniline was used to replace intermediate 45B to obtain compound 97 (150 mg). MS (ESI): m / z 537.1164 [M+H] + .

[0667] 1 H NMR (500 MHz, Methanol- d 4) δ 7.32 (s, 1H), 7.23 (d, J = 17.5 Hz, 1H), 6.71 (s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.27 (dd, J=8.4, 2.4 Hz, 1H), 5.81-5.65 (m, 2H), 3.88 (d, J = 15.8 Hz, 1H), 3.72 (d, J = 9.1Hz, 1H), 3.58-3.39 (m, 1H), 2.58 (s, 3H), 2.13 (s, 3H), 1.69-1.49 (m, 1H), 1.15-0.98 (m, 1H), 0.79-0.60 (m, 1H), 0.45-0.28 (m, 2H), 0.12- -0.15 (m, 2H). Example 98: Preparation of Compound 98

[0668] Following the preparation method of compound 45 in Example 45, intermediate 82A was used to replace Boc-D-leucine, and intermediate 45B was used to replace 45B with 4-aminobenzocyclobutene to obtain compound 98 (400 mg). MS (ESI): m / z 519.1405 [M+H] + .

[0669] 1 H NMR (500 MHz, Methanol- d 4) δ 7.50 (s, 1H), 7.41 (d, J = 17.55 Hz, 1H), 6.92 (d, J = 7.95 Hz, 1H), 6.88 (s, 1H), 6.78 (dd, J = 1.20, 7.90 Hz, 1H),6.72 (s, 1H), 4.15-4.09 (m, 1H), 3.90-3.85 (m, 1H), 3.65 (m, 1H), 3.11 (s,4H), 2.75 (s, 3H), 2.27 (s, 3H), 1.80-1.74 (m, 1H), 1.29-1.22 (m, 1H), 0.85-0.80 (m, 1H), 0.54-0.52 (m, 2H), 0.21-0.09 (m, 2H). Example 99: Preparation of Compound 99

[0670] 5-Nitropyrazole-3-carboxylic acid ethyl ester (8.50 g) and 10% palladium on carbon (4.00 g, palladium content 10%, water content 50%, w / w) were reacted in methanol (100 mL), purged with hydrogen, and stirred at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give intermediate 99A (7.00 g).

[0671] At 0 °C, Boc-D-leucine (11.68 g), intermediate 99A (7.00 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (20.94 g), and triethylamine (19 mL) were added to N,N-dimethylformamide (150 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with water and dried to obtain intermediate 99B (7.50 g). MS (ESI): m / z 313.95 [M-56+H] + .

[0672] Intermediate 99B (2.30 g), potassium carbonate (4.30 g), and 1,2-dibromoethane (2.41 g) were reacted in acetone (50 mL) with stirring in an oil bath at 70 °C. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and intermediate 99C (2.00 g) was obtained by column chromatography (elution system: petroleum ether / ethyl acetate). MS (ESI): m / z 419.10 [M-56+H] + .

[0673] At -5°C, intermediate 99C (1.90 g) was slowly added dropwise to anhydrous dichloromethane (50 mL) under nitrogen protection with lithium aluminum hydride solution (4 mL, 2.0 mol / L). After the addition was complete, the mixture was stirred at -5°C. Once the reaction was complete, a saturated ammonium chloride aqueous solution was slowly added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 99D (1.10 g). MS (ESI): m / z 433.07 [M+H] + .

[0674] Intermediate 99D (0.45 g) and potassium carbonate (0.36 g) were reacted in acetonitrile (50 mL) and stirred in an oil bath at 80 °C. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give intermediate 99E (0.37 g). MS (ESI): m / z 353.10 [M+H] + .

[0675] Following the preparation method of compound 3 in Example 3, intermediate 3A was replaced with intermediate 99E to obtain compound 99 (2 mg). MS (ESI): m / z 541.1583 [M+H]+ .

[0676] Example 100: Preparation of Compound 100

[0677] Following the preparation method of Compound 1 in Example 1, 82H was used instead of 1H, and (4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid was used instead of (5-(methoxycarbonyl)thiophen-3-yl)boronic acid to obtain Compound 100 (75 mg). MS (ESI): m / z 533.1045 [M+H] + .

[0678] 1 H NMR (500 MHz, Methanol- d 4) δ 7.72 (d, J = 4.3 Hz, 1H), 7.66 (s, 1H), 7.36-7.21 (m, 2H), 7.05-6.98 (m, 3H), 6.95 (t, J = 7.4 Hz, 1H), 4.25 (d, J = 15.9Hz, 1H), 3.94-3.88 (m, 1H), 3.75-3.72 (m, 1H), 2.76 (s, 3H), 2.24 (s, 3H), 1.89-1.72 (m, 1H), 0.96-0.73 (m, 2H), 0.58-0.54 (m, 2H), 0.23-0.16 (m, 1H), 0.17 – 0.04 (m, 1H). Example 101: Preparation of Compound 101

[0679] Following the preparation method of compound 20 in Example 20, intermediate Boc-D-leucine was replaced with intermediate 82A to obtain compound 101 (100 mg). MS (ESI): m / z 548.1322 [M+H] + .

[0680] 1H NMR (500 MHz, Methanol- d4) δ 7.59 (s, 1H), 7.51 (d, J = 17.4 Hz,1H), 7.42 (d, J = 8.7 Hz, 1H), 7.14 (s, 1H), 6.98 (s, 1H), 6.79 (dd, J = 8.7,2.3 Hz, 1H), 4.24 (d, J = 16.2 Hz, 1H), 4.07 (s, 1H), 3.47 (m, 1H), 2.65 (s,3H), 2.56 (s, 3H), 2.36 (s, 3H), 1.78-1.73 (m, 1H), 1.35-1.28 (m, 1H), 0.90 –0.87 (m, 1H), 0.62-0.55 (m, 2H), 0.22-0.17 (m, 2H). Example 102: Preparation of compound 102

[0681] 4-Bromothiazole (3.00 g), 3-(BOC-amino)phenylboronic acid pinacol ester (6.42 g), potassium carbonate (5.06 g), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.87 g), chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.44 g), and water (10 mL) were reacted in 1,4-dioxane (50 mL) with stirring at 100 °C. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 102A (4.09 g). MS (ESI): m / z 277.02 [M+H] + .

[0682] Intermediate 105A (4.00 g) was reacted with dichloromethane (20 mL) and a 1,4-dioxane solution of hydrogen chloride (14.5 mL, 4 mol / L) at room temperature with stirring. After the reaction was complete, the reaction solution was concentrated, and the residue was adjusted to alkalinity (pH approximately 9) with a saturated aqueous sodium bicarbonate solution. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 105B (2.22 g). MS (ESI): m / z 177.19 [M+H] + .

[0683] Following the preparation method of compound 20 in Example 20, 2-methyl-6-aminobenzoxazole was replaced with intermediate 102B to obtain compound 102 (34 mg). MS (ESI): m / z 578.1241 [M+H] + .

[0684] 1 H NMR (500 MHz, Methanol- d 4) δ 9.01 (d, J = 2.0 Hz, 1H), 7.79 (d, J =1.9 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 17.4 Hz, 1H), 7.42 (s, 1H), 7.37 (d,J = 7.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.19 (s, 1H), 6.76-6.65 (m, 1H), 4.19 (d, J = 16.3 Hz, 1H), 4.01 (s, 1H), 3.45-3.35 (m, 1H), 2.61 (s, 3H),2.38 (s, 3H), 1.66-1.61 (m, 2H), 1.51-1.36 (m, 4H), 0.95 (t, J = 7.1 Hz, 3H). Example 103: Preparation of compound 103

[0685] Intermediate 47G (1.00 g) and N-chlorosuccinimide (0.30 g) were reacted in tetrahydrofuran (50 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to give intermediate 103A (0.82 g). MS (ESI): m / z 485.12 [M+H]+.

[0686] Following the preparation method of compound 3 in Example 3, intermediate 3G was replaced with intermediate 103A to obtain compound 103 (334 mg). MS (ESI): m / z 573.0912 [M+H] + .

[0687] 1 H NMR (500 MHz, Methanol- d 4) δ 7.50 (s, 1H), 7.33 (d, J= 17.65 Hz,1H), 7.04 (s, 1H), 6.94 (s, 1H), 6.36 (s, 1H), 6.05-6.03 (m, 2H), 4.13-4.06(m, 1H), 3,76-3.71 (m, 1H), 3.56-3.53 (m, 1H), 2.87 (s, 3H), 2.19 (s, 3H),1.73-1.67 (m, 1H), 1.49-1.33 (m, 5H), 0.93 (t, J = 7.00 Hz, 3H). Example 104: Preparation of Compound 104

[0688] Intermediate 47F (2.2 g) and 10% palladium on carbon (0.8 g, palladium content 10%, water content 50%, w / w) were reacted in tetrahydrofuran (20 mL), purged with hydrogen, and stirred at room temperature. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give intermediate 104A (1.6 g). MS (ESI): m / z 419.19 [M+H] + .

[0689] Following the preparation method of compound 3 in Example 3, intermediate 3F was replaced with intermediate 104A to obtain compound 104 (38 mg). MS (ESI): m / z 493.1432 [M+H] + .

[0690] 1 H NMR (500 MHz, Methanol- d 4) δ 7.47 (d, 1H), 7.25 (d, 1H), 7.17 (dd,1H), 7.06 (d, 1H), 6.59 (d, 1H), 6.30 (d, 1H), 6.21 (dd, 1H), 5.77 (dd, 2H),3.86-3.73 (m, 2H), 3.32 (m, 1H), 2.53 (s, 3H), 1.52 (s, 1H), 1.43-1.23 (m,5H), 0.85 (t, 3H). Example 105: Preparation of compound 105

[0691] Intermediate 104B (1.51 g) and N-bromosuccinimide (0.56 g) were reacted in tetrahydrofuran (50 mL) with stirring at -20 °C. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to give intermediate 105A (1.36 g). MS (ESI): m / z 483.1 [M+H] + .

[0692] Intermediate 105A (0.70 g), zinc cyanide (0.20 g), and tetraphenylphosphine palladium (0.25 g) were reacted in N,N-dimethylformamide (30 mL) with stirring at 120 °C. After the reaction was complete, water was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 105B (0.47 g). MS (ESI): m / z 430.20 [M+H] + .

[0693] Following the preparation method of compound 3 in Example 3, intermediate 3G was replaced with intermediate 105B to obtain compound 105 (220 mg). MS (ESI): m / z 518.1398 [M+H] + .

[0694] 1 H NMR (500 MHz, Methanol- d 4) δ 7.52 (d, J = 3.00 Hz, 1H), 7.43 (d, J =17.60 Hz, 1H), 7.19-7.16 (m, 1H), 6.97 (s, 1H), 6.85 (d, J = 8.90 Hz, 1H), 6.79(s, 1H), 5.99-5.98 (m, 2H), 3.89-3.86 (m, 1H), 3,76-3.68 (m, 2H), 2.68 (s,3H), 1.61-1.54 (m, 1H), 1.45-1.22 (m, 5H), 0.84 (t, J = 6.95 Hz, 3H). Example 106: Preparation of Compound 106

[0695] Intermediate 104B (0.31 g) and N-chlorosuccinimide (90 mg) were reacted in dichloromethane (50 mL) at -15 °C with stirring. After completion, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 106A (1.10 g). MS (ESI): m / z 439.16 [M+H] + .

[0696] Following the preparation method of compound 3 in Example 3, intermediate 3G was replaced with intermediate 106A to obtain compound 106 (41 mg). MS (ESI): m / z 527.1033 [M+H] + .

[0697] 1 H NMR (500 MHz, Methanol- d 4) δ 7.56 (d, 1H), 7.41 (d, 1H), 7.16 (dd,1H), 7.03 (s, 1H), 6.92 (s, 1H), 6.65 (d, 1H), 6.05 (d, 2H), 4.06 (s, 1H), 3.77 (s, 1H), 3.65-3.53 (m, 1H), 2.89 (s, 3H), 1.81 – 1.65 (m, 1H), 1.53-1.30 (m, 5H), 0.95 (t, 3H). Example 107: Preparation of Compound 107

[0698] Following the preparation method of compound 47 in Example 47, N-Boc-D-leucine was replaced with N-Boc-D-valine to obtain compound 107 (165 mg). MS (ESI): m / z 525.1147 [M+H] + .

[0699] 1 H NMR (500 MHz, Methanol- d 4) δ 7.47 (s, 1H), 7.39 (d, J = 17.40 Hz,1H), 6.81 (s, 1H), 6.76 (d, J = 9.05 Hz, 1H), 6.59 (s, 1H), 6.50 (d, J= 8.10 Hz, 1H), 5.92 (dd, J = 0.95, 7.75 Hz, 2H), 4.17-4.14 (m, 1H), 3.78 (m, 1H), 3.27-3.23 (m, 1H), 2.78 (s, 3H), 2.27 (s, 3H), 2.00-1.91 (m, 1H), 1.07-0.99 (m,6H). Example 108: Preparation of Compound 108

[0700] Following the preparation method of compound 105 in Example 105, zinc cyanide was replaced with 2-fluorophenylborate pinacol ester to obtain compound 108 (185 mg). MS (ESI): m / z 587.1645 [M+H] + .

[0701] 1 H NMR (500 MHz, Methanol- d 4) δ 7.44 (d, J = 3.00 Hz, 1H), 7.38 (d, J =17.70 Hz, 1H), 7.34-7.30 (m, 1H), 7.18-7.08 (m, 4H), 6.87-6.81 (m, 1H), 6.79-6.76 (m, 2H), 6.04 (s, 2H), 3.85-3.74 (m, 1H), 3.48-3.42 (m, 1H), 3.27-3.23(m, 1H), 2.58 (s, 3H), 1.59-1.53 ​​(m, 1H), 1.35-1.21 (m, 5H), 0.90 (t, J = 7.00Hz, 3H). Example 109: Preparation of compound 109

[0702] Following the preparation method of compound 47 in Example 47, iodomethane was replaced with iodoethane to obtain compound 109 (53 mg). MS (ESI): m / z 553.1471 [M+H] + .

[0703] 1 H NMR (500 MHz, Methanol- d4) δ 7.35 (s, 1H), 7.27 (d, J = 17.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 6.64-6.54 (m, 1H), 6.46 (dd, J = 8.4, 2.4Hz, 1H), 5.89-5.77 (m, 2H), 3.88 (s, 2H), 3.50 (s, 1H), 3.26-3.22 (m, 1H), 2.92 (dd, J = 14.4, 7.1 Hz, 1H), 2.15 (s, 3H), 1.71-1.65 (m, 1H), 1.50-1.35 (m,2H), 1.30-1.17 (m, 3H), 1.10 (t, J = 7.0 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H). Example 110: Preparation of compound 110

[0704] Following the preparation method of compound 47 in Example 47, sodium ethanethiol was substituted for sodium methanethiol to obtain compound 110 (500 mg). MS (ESI): m / z 553.1482 [M+H] + .

[0705] 1 H NMR (500 MHz, Methanol- d 4) δ 7.41 (s, 1H), 7.31 (d, J = 17.5 Hz, 1H), 6.83 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.32 (dd, J =8.5, 2.4 Hz, 1H), 5.83-5.76 (m, 2H), 3.83 (d, J = 15.8 Hz, 1H), 3.70 (s, 1H), 3.47 (s, 1H), 2.73 (q, J= 7.4 Hz, 2H), 2.59 (s, 3H), 1.58-1.53 ​​(m, 1H), 1.47-1.19 (m, 5H), 1.12 (t, J = 7.4 Hz, 3H), 0.84 (t, J = 6.9 Hz, 3H). Example 111: Preparation of compound 111

[0706] Methyl 2,3-dihydroxybenzoate (5.00 g), potassium 3-bromopropene carbonate (9.71 g), and potassium carbonate (16.44 g) were reacted in acetonitrile (50 mL) and stirred in an oil bath at 80 °C. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give intermediate 111A (7 g).

[0707] Under nitrogen protection, intermediate 111A (7.00 g) was reacted in toluene (50 mL) at 60 °C for 30 min. Then, tris(triphenylphosphine)carbonyl ruthenium(II) hydrochloride (800 mg) was added, and the reaction was continued at 60 °C for 20 h. The mixture was then brought to room temperature, and copper chloride (341 mg) was added. The mixture was stirred at room temperature for 30 min until the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 111B (6.20 g).

[0708] Under nitrogen protection, intermediate 111B (4.20 g) was reacted in toluene (30 mL) at 70 °C for 30 min. Then, GRELA second-generation catalyst (57 mg) was added, and the reaction was continued at 70 °C for another 30 min. The mixture was then brought to room temperature, and 1,4-bis(3-isocyanopropyl)piperazine (37 mg) was added. The mixture was stirred at room temperature for 30 min until the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 111C (3.30 g). MS (ESI): m / z 193.14 [M+H] + .

[0709] Intermediate 111C (3.30 g) and lithium hydroxide monohydrate (2.16 g) were reacted in 1,4-dioxane (40 mL) and water (10 mL) with stirring at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with dilute hydrochloric acid (1 mol / L). The phases were separated, the aqueous phase was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 111D (3.00 g).

[0710] Under nitrogen protection, intermediate 111D (3.00 g), triethylamine (7 mL), and diphenyl azidophosphate (6.95 g) were reacted in tert-butanol (20 mL) at 80 °C until complete. The mixture was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 111E (3.34 g). MS (ESI): m / z 249.96 [MH] + .

[0711] At 0°C, intermediate 111E (3.34 g) and trifluoroacetic acid (3.1 mL) were added to dichloromethane (30 mL), and the mixture was stirred at room temperature. After the reaction was complete, the mixture was concentrated, and the residue was adjusted to alkalinity (pH approximately 9) with a saturated sodium bicarbonate aqueous solution under an ice-water bath. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 111F (2.00 g).

[0712] Following the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with intermediate 111F to obtain compound 111 (145 mg). MS (ESI): m / z 551.1325 [M+H] + .

[0713] 1 H NMR (500 MHz, Methanol- d 4) δ 7.32 (s, 1H), 7.23 (d, 1H), 6.80 (t,1H), 6.72 (d ,1H), 6.53 – 6.45 (m, 1H), 6.39 (s, 1H), 6.09 – 5.83 (m, 2H),4.04 – 3.88 (m, 1H), 3.71 – 3.47 (m, 2H), 2.78 (s, 3H), 2.16 (s, 3H), 1.69 –1.56 (m, 1H), 1.32 (ddd, 5H), 0.84 (t, 3H). Example 112: Preparation of compound 112

[0714] Following the preparation method of intermediate 82H in Example 82, intermediate K was replaced with intermediate K1 to obtain intermediate 112E (100 mg). MS (ESI): m / z 406.23 [M+H] + .

[0715] Following the preparation method of compound 83 in Example 83, intermediate 47G was replaced with intermediate 112E to obtain compound 112 (30 mg). MS (ESI): m / z 534.0991 [M+H] + .

[0716] 1 H NMR (500 MHz, Methanol- d 4) δ 7.72 (s, 1H), 7.54 (d, 1H), 7.43 (t,2H), 7.35-7.18 (m, 3H), 4.75-4.69 (m, 1H), 4.04 (dd, 1H), 3.80-3.70 (m, 1H), 3.11 (s, 3H), 1.93-1.86 (m, 1H), 1.84 (s, 3H), 1.37-1.31 (m, 1H), 0.85-0.78(m, 1H), 0.54-0.43 (m, 2H), 0.21-0.16 (m, 1H), 0.10 – 0.05 (m, 1H).

[0717] Example 113: Preparation of compound 113

[0718] Following the preparation method of intermediate 82C in Example 82, aniline was replaced with p-fluoroaniline to obtain intermediate 113A, and further intermediate 113B (6.00 g) was obtained. MS (ESI): m / z 223.1 [M+H] + .

[0719] Following the preparation method of compound 112 in Example 112, intermediate 82C was replaced with intermediate 113B to obtain compound 113 (260 mg). MS (ESI): m / z 552.0889 [M+H] + .

[0720] 1 H NMR (500 MHz, Methanol- d4) δ 7.66-7.74 (m, 2H), 7.29-7.22 (m, 2H), 7.12-7.08 (m, 2H), 4.72-4.66 (m, 1H), 3.87 (dd, 1H), 3.74-7.67 (m, 1H), 3.04(s, 3H), 1.81 (s, 3H), 1.81-1.77 (m, 1H), 1.24-1.20 (m, 1H), 0.77-0.70 (m,1H), 0.47-0.36 (m, 2H), 0.14-0.09 (m, 1H), 0.02- -0.02(m, 1H). Example 114: Preparation of compound 114

[0721] Following the preparation method of intermediate 104B in Example 104, intermediate 47F was replaced with intermediate 113F to obtain intermediate 114B (444 mg).

[0722] Following the preparation method of compound 112 in Example 112, intermediate 112E was replaced with intermediate 112B to obtain compound 114 (150 mg). MS (ESI): m / z 506.1030 [M+H] + .

[0723] 1 H NMR (500 MHz, Methanol- d 4) δ 8.18 (d, 1H), 8.12 (d, 1H), 7.72 (d,1H), 7.12 – 7.08 (m, 2H), 6.96 (t, 2H), 4.47-4.41 (m, 1H), 3.84 (dd, 1H),3.60 – 3.53 (m, 1H), 2.90 (s, 3H), 1.70 – 1.65 (m, 1H), 1.14-1.12 (m, 1H), 0.64 – 0.60 (m, 1H), 0.36-0.25 (m, 2H), 0.03- -0.01 (m, 1H), -0.09- -0.14 (m,1H). Example 115: Preparation of compound 115

[0724] Referring to the preparation method of intermediate 112D in Example 112, intermediate K1 was replaced with intermediate K2 to obtain intermediate 115D (1.00g).

[0725] Intermediate 115D (1.0 g) and sodium methanethiol (0.21 g) were added to N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature until complete. After the reaction was finished, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 115E (0.58 g). MS (ESI): m / z 420.23 [M+H] + .

[0726] Intermediate 115E (0.58 g) was added dropwise to dichloromethane (20 mL) in an ice bath at 0°C. A 1 mol / L solution of boron tribromide in dichloromethane (4.5 mL) was slowly added. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the reaction solution was poured into ice water and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain intermediate 115F (0.42 g). MS (ESI): m / z 406.18 [M+H] + .

[0727] Following the preparation method of compound 112 in Example 112, intermediate 112E was replaced with intermediate 112F to obtain compound 115 (118 mg). MS (ESI): m / z 534.0976 [M+H] + .

[0728] 1 H NMR (500 MHz, Methanol- d 4) δ 7.77 (d, J = 4.1 Hz, 1H), 7.36 – 7.29(m, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.10 (s, 1H), 7.06 (t, J = 7.4 Hz, 1H), 4.23(dd, J = 15.9, 4.1 Hz, 1H), 4.05 (dd, J= 15.9, 11.7 Hz, 1H), 3.62-3.56 (m, 1H), 2.91 (s, 3H), 2.11 (s, 3H), 1.81-1.74 (m, 1H), 1.27 – 1.22 (m, 1H), 0.77-0.73(m, 1H), 0.49 – 0.36 (m, 2H), 0.12 (m, 1H), 0.03 – 0.04 (m, 1H). Example 116: Preparation of compound 116

[0729] Following the preparation method of compound 113 in Example 113, intermediate K1 was replaced with intermediate K2 to obtain compound 116 (60 mg). MS (ESI): m / z 552.0888 [M+H] + .

[0730] 1 H NMR (500 MHz, Methanol- d 4) δ 7.76 (d, J = 4.0 Hz, 1H), 7.22 (dd, J =8.9, 4.6 Hz, 2H), 7.09 (t, J = 8.6 Hz, 2H), 6.98 (s, 1H), 4.11 (d, J = 7.7 Hz,2H), 3.63-3.56 (m, 1H), 2.94 (s, 3H), 2.12 (s, 3H), 1.78 (ddd, J = 14.6, 8.7,6.4 Hz, 1H), 1.26-1.19 (m, 1H), 0.79-0.72 (m, 1H), 0.47-0.37 (m, 2H), 0.14-0.09 (m, 1H), 0.02 – -0.03 (m, 1H). Example 117: Preparation of Compound 117

[0731] Intermediate 115C (0.50 g), triethylamine (0.11 g), and palladium on carbon (0.10 g, palladium content 10%, water content 50%) were added to tetrahydrofuran (30 mL). After the addition was complete, the mixture was purged with hydrogen and stirred at room temperature. The reaction was completed, filtered, and concentrated to give intermediate 117A (0.41 g). MS (ESI): m / z 374.24 [M+H]+ .

[0732] Following the preparation method of Compound 1 in Example 1, 1H was replaced with intermediate 117A, and (5-(methoxycarbonyl)thiophen-3-yl)boronic acid was replaced with (4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid to obtain Compound 117 (28 mg). MS (ESI): m / z 488.1133 [M+H] + .

[0733] 1 H NMR (500 MHz, Methanol- d 4) δ 8.21 (d, J = 4.2 Hz, 1H), 7.65 (d, J = 8.7Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 4.25 (dd, J = 16.0, 4.0 Hz, 1H), 4.00-3.95 (m,1H), 3.62-3.55 (m, 1H), 2.89 (s, 3H), 1.81-1.75 (m, 1H), 1.30-1.11 (m, 1H),0.83-0.70 (m, 1H), 0.47-0.38 (m, 2H), 0.14-0.09 (m, 1H), 0.02- -0.02 (m, 1H). Example 118: Preparation of compound 118

[0734] Following the preparation method of compound 45 in Example 45, Boc-D-leucine was replaced with Boc-D-cyclopropylglycine, intermediate 45B was replaced with aniline, and intermediate K was replaced with intermediate K2 to obtain intermediate 118F (2.52 g). MS (ESI): m / z 438.06 [M+H] + .

[0735] Following the preparation method of compound 115 in Example 115, compound 115D was prepared by replacing intermediate 115D with intermediate 118F to obtain compound 118 (72 mg). MS (ESI): m / z 520.0812 [M+H] + .

[0736] 1 H NMR (500 MHz, Methanol- d 4) δ 7.91 (d, J = 4.0 Hz, 1H), 7.40 (dd, J =8.6, 7.3 Hz, 2H), 7.32 (s, 1H), 7.19-7.14 (m, 2H), 7.10 (t, J = 7.4 Hz, 1H), 4.38 (dd, J = 16.0, 3.5 Hz, 1H), 4.15 (dd, J = 15.9, 10.6 Hz, 1H), 2.99 (s, 3H), 2.91-2.84 (m, 1H), 2.27 (s, 3H), 1.23-1.18 (m, 1H), 0.72-0.65 (m, 2H), 0.50-0.46 (m, 1H), 0.30-0.26 (m, 1H). Example 119: Preparation of compound 119

[0737] Following the preparation method of compound 115 in Example 115, aniline was replaced with 3-methylthiophene hydrochloride to obtain compound 119 (30 mg). MS (ESI): m / z 540.0555 [M+H] + .

[0738] 1 H NMR (500 MHz, Methanol- d 4) δ 7.87 (d, J = 4.1 Hz, 1H), 7.56-7.50 (m,1H), 7.32 (s, 1H), 7.13-7.10 (m, 1H), 7.10-7.03 (m, 1H), 4.28-4.05 (m, 2H), 3.78-3.69 (m, 1H), 3.03 (s, 3H), 2.30 (s, 3H), 1.94-1.87 (m, 1H), 1.41-1.31(m, 1H), 0.93-0.85 (m, 1H), 0.59-0.50 (m, 2H), 0.28-0.20 (m, 1H), 0.14-0.09(m, 1H). Example 120: Preparation of Compound 120

[0739] Following the preparation method of compound 113 in Example 113, aniline was replaced with 3-aminothiophene hydrochloride to obtain compound 120 (31 mg). MS (ESI): m / z 540.0556 [M+H] + .

[0740] 1 H NMR (500 MHz, Methanol- d 4) δ 7.80-7.71 (m, 2H), 7.44 (dd, J = 5.2, 3.1 Hz, 1H), 7.25 (dd, J = 3.2, 1.5 Hz, 1H), 7.11 (dd, J = 5.2, 1.5 Hz, 1H), 4.68(dd, J = 15.8, 12.0 Hz, 1H), 4.14-4.01 (m, 1H), 3.85-3.75 (m, 1H), 3.08 (s,3H), 2.09 (s, 3H), 1.94-1.88 (m, 1H), 1.37-1.33 (m, 1H), 0.94-0.81 (m, 1H), 0.58-0.48 (m, 2H), 0.25-0.20 (m, 1H), 0.13-0.08 (m, 1H). Example 121: Preparation of compound 121

[0741] Following the preparation method of compound 115 in Example 115, intermediate 82A was replaced with N-tert-butoxycarbonyl-D-valine to obtain compound 121 (87 mg). MS (ESI): m / z 522.0959 [M+H] + .

[0742] 1 H NMR (500 MHz, Methanol- d 4) δ 7.86 (d, J = 4.0 Hz, 1H), 7.45 (t, J = 7.7Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.23-7.16 (m, 2H), 4.47 (dd, J= 15.9, 4.2 Hz,1H), 4.24-4.19 (m, 1H), 3.16-3.11 (m, 1H), 3.00 (s, 3H), 2.21 (s, 3H), 2.19-2.11 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H). Example 122: Preparation of compound 122

[0743] Following the preparation method of compound 121 in Example 121, aniline was replaced with 4-fluoroaniline to obtain compound 122 (89 mg). MS (ESI): m / z 540.0856 [M+H] + .

[0744] 1 H NMR (500 MHz, Methanol- d 4) δ 7.74 (d, J = 4.0 Hz, 1H), 7.26-7.22 (m,2H), 7.09 (t, J = 8.5 Hz, 2H), 6.94 (s, 1H), 4.25-4.13 (m, 2H), 3.05-3.00 (m,1H), 2.92 (s, 3H), 2.09 (s, 3H), 2.06-1.99 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H). Example 123: Preparation of compound 123

[0745] Following the preparation method of compound 112 in Example 112, intermediate 82C112A was replaced with intermediate 50B to obtain compound 123 (85 mg). MS (ESI): m / z 554.1070 [M+H] + .

[0746] 1 H NMR (500 MHz, DMSO- d 6) δ 13.46 (brs, 1H), 7.98 (d, J= 4.4 Hz, 1H),7.74 (s, 1H), 7.49-7.37 (m, 2H), 7.26 (t, J = 8.8 Hz, 2H), 4.54 (dd, J = 15.8,11.7 Hz, 1H), 3.90 (dd, J = 15.8, 4.0 Hz, 1H), 3.73-3.60 (m, 1H), 2.96 (s,3H), 1.86 (s, 3H), 1.73-1.62 (m, 1H), 1.51-1.25 (m, 5H), 0.88 (t, J = 7.0 Hz, 3H).

[0747] Example 124 Preparation of capsules containing the compounds disclosed herein Each capsule contains:

[0748] Experimental Example 1: FITC-preS1 Peptide Binding Experiment Huh-7D-NTCP cells were cultured in DMEM medium (VivaCell, C3113-0500) supplemented with 10% FBS (Gibco, 2409126CP) at 37°C under 5% CO2 conditions.

[0749] 50,000 Huh-7D-NTCP cells were seeded in 96-well plates (Eppendorf, 30730119) and incubated at 37°C with 5% CO2 for 24 hours. A stock solution of the compound was prepared using DMSO (Sigma, D2650), and the compound was diluted in DMEM medium (VivaCell, C3113-0500) to eight concentration points, with the highest concentration being 20 μM, serially diluted 3-fold. The culture supernatant was discarded, and 90 μL of DMEM medium containing the compound was added to each well. 90 μL of DMEM medium was also added as a negative control. The cells were incubated at 37°C for 1 hour. Myrcludex B-FITC (Hefei Kesheng Jingtai Biotechnology Co., Ltd., HBV / 2-48 with a C-terminal lysine (K)) was diluted in DMEM medium (VivaCell, C3113-0500). myr (C)-FITC was added to the wells to a concentration of 100 nM. Then, 10 μL of DMEM medium containing Myrcludex B-FITC was added to all wells and incubated at 37°C for 1 hour.

[0750] Discard the supernatant and wash with 200 μL PBS (Gibco, C20012500BT). 50 μL of trypsin (Gibco, 12604-021) was added to the wells, and the plate was incubated in a CO2 incubator at 37°C for 15 min for digestion. Then, 150 μL of PBS (Gibco, C20012500BT) containing 5% FBS (Gibco, 2409126CP) was added to terminate the digestion. After mixing by pipetting, the cells were resuspended and transferred to a 96U plate (Nunc, 249944). After centrifugation at 1500 rpm for 3 min using a Thermo, the supernatant was removed, and the cells were resuspended in 40 μL of PBS (Gibco, C20012500BT). The cells were then collected by flow cytometry (Sartorius, IQue3), and the geometric mean fluorescence intensity of FITC was detected. The affinity of the compound for Huh-7D-NTCP cells was calculated. Calculation formula: Inhibition rate (%) = (1 - Compound (GMFI) / Negative control (GMFI)) × 100%, IC50 calculated using GraphPad Prism curve fitting. 50 value.

[0751] The experimental results are shown in Table 1, where A represents: 0 nM < IC 50 ≤500 nM; B represents: 500 nM < IC 50 ≤1000nM; C represents: 1000 nM < IC 50 ≤5000 nM; D represents: 5000 nM < IC 50 .

[0752] Table 1: FACS assay of the affinity of compounds for Huh-7D-NTCP cells

[0753]

[0754] Experimental Example 2: In vitro CYP450 enzyme inhibitory activity The human liver microsome incubation system was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.2 mg / ml), CYP450 specific substrate, the test compound, and NADPH + MgCl2 solution, and incubating at 37°C and 300 rpm for 0.5 hours. A positive control and a negative control were also established. The positive control system used a specific inhibitor instead of the test compound, and the negative control system used a solvent instead of the test compound. After incubation, the sample was treated with acetonitrile solution containing an internal standard for protein precipitation to prepare a supernatant, which was then diluted and used for LC / MS / MS determination of the metabolites of the specific substrate. The inhibition rate was calculated using the formula (1 – (test group / negative control group)) × 100%. The compound disclosed in this study exhibits good stability in human liver microsomes, with a residual amount >80% after 60 min.

[0755] The test results are shown in Table 2.

[0756] Table 2 Hepatic Microsomal Stability

[0757] Experimental Example 3: Pharmacokinetics in Mice ICR mice, weighing 18-22 g, were acclimatized for 3-5 days and then randomly divided into groups of 9 mice each. The mice were administered the test compound solution by gavage at a dose of 10 mg / kg.

[0758] Blood was collected at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h from the orbital cavity to prepare plasma samples for testing.

[0759] Take 30 µL of the plasma sample and standard curve sample, add acetonitrile solution containing internal standard, and obtain the supernatant after protein precipitation. Dilute the supernatant and use it for LC / MS / MS analysis. A non-compartmental model was used for fitting. The disclosed compound exhibits good pharmacokinetic properties and high bioavailability, with a relative bioavailability exceeding 75%.

[0760] The test results are shown in Table 3.

[0761] Table 3. Pharmacokinetics in Mice

[0762] Experimental Example 4: In vitro assays of hNTCP and hASBT transporters hNTCP transporter in vitro assay HEK293-hNTCP cells (human NTCP overexpressing cells) were completely cultured in DMEM (Viva Cell, C3113-0500) containing 10% fetal bovine serum (Gibco, 10099-141) and 200 μg / ml G418 (Gbico, 10131-027) at 37°C in an incubator containing 5% CO2 / 95% air. Cells in logarithmic growth phase were digested with trypsin (Gbico, 12604-021) and plated to adjust the cell density to 4 × 10⁶ cells / mL. 5 Cells / ml, cell suspension 500μL / well, cultured in a 37°C, 5% CO2 saturated humidity incubator, and allowed to adhere for 24 hours. When the confluence is ≥90%, experiments can be carried out.

[0763] The following day, discard the cell supernatant and add 250 μL of pre-incubation solution to each well (the negative control group used the blank solvent, and the test group used the compound; final concentrations were 100 nM, 30 nM, 10 nM, 5 nM, 3 nM, 1 nM, and 0.3 nM). Mix well and pre-incubate at 37°C for 30 min, then remove the pre-incubation solution. Add 250 μL of incubation solution to each well (the negative control group used the blank solvent, and the test group used the compound, both containing 5 μM deuterated sodium taurate (Guangzhou Puen Scientific Instruments Co., Ltd., MD-1020-10 mg)), mix well, and pre-incubate at 37°C for 2 min, then remove the incubation solution. Add 500 μL of ice-cold PBS (Gbico, C20012500BT) to terminate the reaction, and wash twice more, for a total of three washes. Add 150 μL of cell lysis buffer (Thermo, 89900) to each well and lyse on ice for 20 min. After lysis, the entire lysate was transferred to a 1.5 mL centrifuge tube (AXYGEN, MCT-150-CS) and centrifuged at 4°C, 4000 rpm, for 10 min using a Thermo, ST8R centrifuge to obtain the supernatant. 100 μL of the supernatant was aspirated and 400 μL of icy acetonitrile containing the internal standard was added to precipitate the supernatant. This supernatant was then diluted and used for LC-MS / MS analysis.

[0764] hASBT transporter in vitro assay HEK293-hASBT cells (human ASBT overexpressing cells) were completely cultured in DMEM (Viva Cell, C3113-0500) containing 10% fetal bovine serum (Gibco, 10099-141) and 200 μg / ml G418 (Gbico, 10131-027) at 37°C in an incubator containing 5% CO2 / 95% air. Cells in logarithmic growth phase were digested with trypsin (Gbico, 12604-021) and plated to adjust the cell density to 4 × 10⁶ cells / year. 5Cells / ml, cell suspension 500μL / well, cultured in a 37°C, 5% CO2 saturated humidity incubator, and allowed to adhere for 24 hours. When the confluence is ≥90%, experiments can be carried out.

[0765] The following day, discard the cell supernatant and add 250 μL of pre-incubation solution to each well (the negative group used the blank solvent, and the test group used the compound. The final concentrations were as follows: 30 μM, 10 μM, 3 μM, 2 μM, 1 μM, 300 nM, and 100 nM). Mix well and pre-incubate at 37°C for 30 min, then remove the pre-incubation solution. Add 250 μL of incubation solution to each well (the negative group used the blank solvent, and the test group used the compound, both containing 5 μM sodium deuterated taurate (Guangzhou Puen Scientific Instruments Co., Ltd., MD-1020-10 mg)), mix well, and pre-incubate at 37°C for 2 min, then remove the incubation solution. Add 500 μL of ice-cold PBS (Gbico, C20012500BT) to terminate the reaction, and wash twice more, for a total of 3 washes. Add 150 μL of cell lysis buffer (Thermo, 89900) to each well and lyse on ice for 20 min. After lysis, the entire lysate was transferred to a 1.5 mL centrifuge tube (AXYGEN, MCT-150-CS) and centrifuged at 4°C, 4000 rpm, for 10 min using a Thermo, ST8R centrifuge to obtain the supernatant. 100 μL of the supernatant was aspirated and 400 μL of icy acetonitrile containing the internal standard was added to precipitate the supernatant. This supernatant was then diluted and used for LC-MS / MS analysis.

[0766] The results of in vitro assays of hNTCP and hASBT transporters are shown in Table 4, where A represents 0 nM < IC 50 ≤10 nM; B represents: 10 nM < IC 50 ≤100 nM; C represents: 100 nM < IC 50 ≤1000 nM; D represents: 1000 nM < IC 50 .

[0767] Table 4. In vitro assays of hNTCP and hASBT transporters

[0768] .

Claims

1. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, X is selected from C(R) a R b ) or NR c ; L is selected from bond, O, S, (C(R) a R b )) p 、(NR c ) q or (C(R) a R b )) i -(NR c ) j ; W 1 and W 2 Each is independently selected from CH or N; R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl or 5-14-membered heteroaryl groups may optionally be further substituted by one or more substituents; Or, R 1 and R 2 Together with the carbon atoms attached to them, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may optionally be further substituted with one or more substituents; Or, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form 3-14 membered heterocyclic groups, which may optionally be further substituted by one or more substituents; R a and R b Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, cyano, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may optionally be further substituted with one or more substituents; R c Selected from hydrogen, hydroxyl, amino, mercapto, C 1-12 Alkyl or C 1-12 alkoxy, the amino, C 1-12 Alkyl or C 1-12 The alkoxy group may optionally be further substituted by one or more substituents; Or, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups, wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may optionally be further substituted with one or more substituents; Or, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached to them, they form 3-14 membered heterocyclic groups, which may optionally be further substituted by one or more substituents; Or, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, they form a 3-14 membered heterocyclic group, which may optionally be further substituted by one or more substituents; R 3 Selected from hydrogen, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH2) n R al -(CH2) n OR al -(CH2) n C(O)R al -(CH2) n C(O)OR al -(CH2) n S(O) m R al -(CH2) n NR a2 R a3 -(CH2) n NR a2 C(O)OR a3 -(CH2) n NR a2 C(O)(CH2) nl R a3 -(CH2) n NR a2 C(O)NR a2 R a3 -(CH2) n C(O)NR a2 (CH2) nl R a3 -OC(R) al R a2 ) n (CH2) nl R a3 Or -(CH2) n NR a2 S(O) m R a3 The amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl or 5-10 membered heteroaryl may optionally be further substituted by one or more substituents; A is selected from , , , , , or ; Ring B is selected from C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 3-14 The cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl or 5-14-membered heteroaryl groups may optionally be further substituted by one or more substituents; R 4 Selected from C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl, or 5-14-membered heteroaryl, wherein C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl, 3-14-membered heterocyclic, 6-14-membered aryl or 5-14-membered heteroaryl groups may optionally be further substituted by one or more substituents; R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-12 Alkyl or C 1-12 Alkoxy; the amino, C 1-12 Alkyl or C 1-12 The alkoxy group may optionally be further substituted by one or more substituents; R a1 R a2 or R a3 Each is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, sulfhydryl, cyano, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl, or 5-14 membered heteroaryl, wherein the amino group, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-14 The cycloalkyl, 3-14 membered heterocyclic, 6-104 membered aryl or 5-14 membered heteroaryl may optionally be further substituted by one or more substituents; p, q, i, or j are each independently selected from 1, 2, or 3; m is selected from 0, 1, or 2; n and n1 are each independently selected from 0, 1, 2, 3 or 4; The conditions are: When A is selected L is the bond, and R 1 and R 2 Each is independently selected from hydrogen or unsubstituted C. 1-12 When alkyl, R 4 The phenyl group is either unsubstituted or non-substituted.

2. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, R a and R b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups. cc Replacement; preferred, R a and R b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further reacted with one or more R groups. cc Replacement; preferred, R a and R b Each is independently selected from hydrogen, methyl, or ethyl; preferably, R a and R b Each is independently selected from hydrogen or methyl.

3. The compound of formula (I) according to any one of claims 1-2, its stereoisomers or pharmaceutically acceptable salts thereof, R c Selected from hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further reacted with one or more R e Replacement; preferred, R c Selected from hydrogen or C 1-3 Alkyl, the C 1-3 Alkyl groups may optionally be further reacted with one or more R e Replacement; preferred, R c Selected from hydrogen, methyl, ethyl, or -CD3; preferably, R c Selected from hydrogen, methyl, or -CD3.

4. The compound of formula (I) according to any one of claims 1-3, its stereoisomers or pharmaceutically acceptable salts thereof, wherein L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 cycloalkyl or 3-6 membered heterocyclic groups may optionally be further reacted with one or more R d Replacement; preferably, when L is selected from (C(R) a R b )) p or (C(R) a R b )) i -(NR c ) j At the same or different carbon atoms, R a and R b Together with the carbon atoms attached to them, they form cyclopropyl or cyclobutyl groups, which may optionally be further reacted with one or more R groups. d replace; Or, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached to them, they form 3-6 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. d Replacement; preferably, when L is selected from (NR) c ) q or (C(R) a R b )) i -(NR c ) j At that time, R on different nitrogen atoms c Together with the nitrogen atoms attached thereto, they form 1,3-diazacyclobutane, which may optionally be further reacted with one or more R... d replace; Or, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, they form a 3-6 membered heterocyclic group, which may optionally be further bonded by one or more R atoms. d Replacement; preferably, when L is selected from (C(R) a R b )) i -(NR c ) j At that time, the R on the carbon atom a And the R atoms on the carbon and nitrogen atoms connected to it. c Together with the nitrogen atom attached thereto, it forms a nitrogen-containing heterocyclic butyl group, which may optionally be further reacted with one or more R... d replace; Alternatively, L can be selected from the key, C(R) a R b ), -C(R a R b )-C(R a R b )-、-C(R a R b )-NR c -、-C(R a R b )-C(R a R b )-C(R a R b )- or C(R a R b )-C(R a R b )-NR c Preferably, L is selected from C(R) a R b ), -C(R a R b )-C(R a R b - or -C(R) a R b )-NR c -; Preferably, L is selected from bond; or preferably, L is selected from bond, CH2, C(CH3)2, , or .

5. The compound of formula (I) according to any one of claims 1-4, its stereoisomers or pharmaceutically acceptable salts thereof, wherein X is selected from CH2, N(CH3), NH, N(CD3) or Preferably, X is selected from N(CH3).

6. The compound of formula (I) according to any one of claims 1-5, its stereoisomer, or a pharmaceutically acceptable salt thereof, R 1 and R 2 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, NH2, mercapto, cyano, and C. 1-6 Alkyl, C 1-6 Alkyl group, -(CH2) n R al -(CH2) n OR al -(CH2) n R al Or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group may optionally be further reacted with one or more R aa Replacement; preferred, R 1 and R 2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkyl group, -(CH2) n R al Or -(CH2) n OR al The C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further reacted with one or more R groups. aa Replacement; preferred, R 1 and R 2 Each is independently selected from hydrogen and C. 1-6 Alkyl group, -(CH2) n R al Or -(CH2) n OR al The C 1-6 Alkyl groups can be further reacted with one or more R aa Replacement; preferred, R 1 and R 2 Each is independently selected from hydrogen, isopropyl, n-butyl, cyclopropyl, -CH2R al -CH2OR al -CH2CH2OR al The n-butyl, isopropyl, and cyclopropyl groups may optionally be further substituted with one or more F groups, R a1 Selected from methyl, ethyl, or cyclopropyl; preferably, R 1 and R 2 Each is independently selected from hydrogen, isopropyl, n-butyl, cyclopropyl, -CH2OCH2CH3 or -CH2CH2OCH3, wherein the n-butyl, isopropyl, or cyclopropyl groups may optionally be further substituted with one or more F groups; preferably, R 1 and R 2 Each is independently selected from hydrogen or n-butyl, and the n-butyl group may be further substituted with one or more F groups; preferably, R 1 and R 2 Each is independently selected from hydrogen, isopropyl, n-butyl, cyclopropyl, , , , , -CH2OCH2CH3 or -CH2CH2OCH3; Or, R 1 and R 2 Together with the carbon atoms attached to them, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 cycloalkyl or 3-6 membered heterocyclic groups may optionally be further reacted with one or more R bb Replacement; preferred, R 1 and R 2 Together with the carbon atoms attached to them, they form a cyclopentyl group, which may optionally be further reacted with one or more R... bb replace; Or, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form 3-6 membered heterocyclic groups, which may optionally be further bonded by one or more R atoms. bb Replacement; preferably, when X is selected from (NR) c ) q At that time, R 2 and R c Together with the carbon and nitrogen atoms attached to them, they form a pyrrolidinyl or piperidinyl group, which may optionally be further reacted with one or more R groups. bb replace.

7. The compound of formula (I) according to any one of claims 1-6, its stereoisomers or pharmaceutically acceptable salts thereof, R 3 Selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, -(CH2) n OR al -(CH2) n NR a2 R a3 Or -(CH2) n S(O) m R al The amino group, C 1-6 Alkane, C 1-6 alkoxy or phenyl may optionally be further reacted with one or more R f Replacement; preferred, R 3 Selected from halogens, hydroxyl groups, NH2, cyano groups, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, phenyl, -(CH2) n OR al -(CH2) n NR a2 R a3 Or -(CH2) n S(O) m R al The C 1-3 Alkyl, C 1-3 alkoxy or phenyl may optionally be further reacted with one or more R f Replacement; preferred, R 3 Selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl, -(CH2) n OR al -(CH2) n NR a2 R a3 -(CH2) n S(O) m R al The methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, or phenyl group may optionally be further reacted with one or more R groups. f Replacement; preferred, R 3 Selected from -(CH2) n S(O) m R al Preferred, R 3 Selected from -SCH3.

8. The compound of formula (I) according to any one of claims 1-7, its stereoisomers or pharmaceutically acceptable salts thereof, R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl or C 1-3 Alkoxy; the amino, C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further reacted with one or more R groups. i Replacement; preferred, R 5 and R 5’ Each is independently selected from hydrogen, deuterium, halogen, NH2, methyl, ethyl, methoxy, or ethoxy, wherein the methyl, ethyl, methoxy, or ethoxy group may optionally be further reacted with one or more R groups. i Replacement; preferred, R 5 Selected from hydrogen or F; preferably, A is selected from... .

9. The compound of formula (I) according to any one of claims 1-8, its stereoisomers or pharmaceutically acceptable salts thereof, wherein A is selected from... , , or Ring B is selected from C. 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. g Replacement; preferred, A is selected from , , or Ring B is selected from C. 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups may optionally be further subjected to one or more R groups. g replace.

10. The compound of formula (I) according to any one of claims 1-9, its stereoisomer or a pharmaceutically acceptable salt thereof, R 4 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-10 heteroaryl, wherein C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h Replacement; preferred, R 4 Selected from C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-12 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, 5-8 membered heterocyclic, C 6-12 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h Replacement; preferred, R 4 Selected from C 5-8 cycloalkyl, C 6-11 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, C 6-11 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h Replacement; preferred, R 4 Selected from C 5-8 cycloalkyl, phenyl, C 9-11 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, phenyl, C 9-11 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h Replacement; preferred, R 4 Selected from C 5-8 cycloalkyl, C 9-11 Aryl or 5-10 heteroaryl, wherein C 5-8 cycloalkyl, C 9-11 Aryl or 5-10 heteroaryl groups may optionally be further reacted with one or more R groups. h replace; Or, R 4 Selected from cyclobutyl, 1,2-dihydropyridyl, adamantyl, benzocyclobutyl, phenyl, indololinyl, isoindololinyl, benzopyrazolidinecycloyl, benzotetrahydrofurancycloyl, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyrancycloyl, benzodioxolanecycloyl, benzotetrahydropyrancycloyl, benzopiperidinecycloyl, furanyl, thienyl, pyridyl, benzothienylcycloyl, benzothiazolecycloyl, benzooxazolylcycloyl, indolyl, benzoimidazolylcycloyl, thien[3, 2-b]pyridine cycloyl, thieno[2,3-b]pyridine cycloyl, quinolinyl, isoquinolinyl, 2,3-dihydrofurano[2,3-b]pyridine cycloyl, 2,3-dihydrofurano[3,2-b]pyridine cycloyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 6,7-dihydro-4H-pyrazol[5,1-c][1,4]oxazinyl, 2,3-dihydrofurano[3,2-c]pyridine cycloyl or bicyclic[1.1.1]pentyl, wherein R 4 Optionally, it can be further modified by one or more R h Replacement; preferred, R 4 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or The R 4 Optionally, it can be further modified by one or more R h replace.

11. A compound of formula (I) according to any one of claims 1-10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from compounds of formula (I-1), compounds of formula (I-2), stereoisomers thereof, or pharmaceutically acceptable salts thereof: in, R 1 R 2 R 3 R 4 R 5 The definitions of X and ring B are as described in any one of claims 1-10; Alternatively, selected from compounds of formula (II-1), compounds of formula (II-2), their stereoisomers, or pharmaceutically acceptable salts thereof: Among them, R 2 R 3 R 4 R 5 The definitions of X and ring B are as described in any one of claims 1-10; Alternatively, selected from compounds of formula (III-1), compounds of formula (III-2), their stereoisomers, or pharmaceutically acceptable salts thereof: Among them, R 1 R 2 R 3 R 4 R 5 The definition of ring B is as described in any one of claims 1-10; Alternatively, selected from compounds of formula (IV-1), compounds of formula (IV-2), their stereoisomers, or pharmaceutically acceptable salts thereof: Among them, R 1 R 2 R 4 R 5 The definition of ring B is as described in any one of claims 1-10.

12. The following compounds, their stereoisomers, or their pharmaceutically acceptable salts: ； Preferably, the compounds are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 。 13. A pharmaceutical composition comprising the compound of any one of claims 1-12, its stereoisomer, or a pharmaceutically acceptable salt thereof.

14. Use of the compound of any one of claims 1-12, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13 in the preparation of a medicament for treating or preventing disease.

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