Benzothiadiazepine compound and application thereof

Abstract

The invention belongs to the technical field of medicines, relates to a benzothiadiazepine compound and application thereof, and further relates to a preparation method of the benzothiadiazepine compound and a pharmaceutical composition containing the benzothiadiazepine compound. The present disclosure specifically relates to compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, and uses thereof.

Description

A benzothiadiazepine compound and its use

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to and the benefits of Chinese Patent Application No. 202310608988.9, Chinese Patent Application No. 202410160508.1, and Chinese Patent Application No. 202410622891.8 filed with the National Intellectual Property Administration of China, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure belongs to the field of medical technology, and relates to a benzothiadiazepine compound and a use thereof. The present disclosure also relates to a preparation method of the benzothiadiazepine compound and a pharmaceutical composition containing the compound. Background Art

[0004] NTCP (sodium taurocholate cotransporting polypeptide) refers to the sodium-taurocholate cotransporter, encoded by the SLC10A1 gene. NTCP is the primary protein that transports sodium ions and bile acids on the hepatocyte membrane. It plays a crucial role in the enterohepatic circulation of bile acids and is a potential target for antiviral and cholestatic indications. NTCP is located in the basolateral domain (blood side) of hepatocytes in humans, rats, and other species and is not detected in any other tissues.

[0005] The HBV envelope protein is composed of three proteins: the large envelope protein (LHBs), the middle envelope protein (MHBs), and the small envelope protein (SHBs), which include the preS1, preS2, and S regions. Scientists have discovered that HBV and HDV enter hepatocytes by binding to NTCP, which has the HBV preS1 surface protein domain. Furthermore, in vitro knockout of NTCP significantly inhibits HBV / HDV infection of hepatocytes. Therefore, the antiviral mechanism of action of the NTCP inhibitors currently under investigation relies on specific binding and blockade of the hepatocyte surface protein NTCP. This NTCP-mediated inhibition can prevent HBV and HDV from entering cells, thereby preventing hepatocyte infection. Furthermore, regarding bile acid metabolism, NTCP inhibition reduces bile acid entry into the liver, thereby increasing the circulating bile acid pool. This elevated bile acid pool can act as an FXR stimulator. Furthermore, NTCP inhibition significantly improves hepatic fat accumulation and steatosis, alleviating liver damage.

[0006] Detailed Description of the Invention

[0007] In one aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] X is selected from C(R a R b ) or NR c or

[0010] L is selected from a bond, O, S, (C(R a R b )) p 、(NR c ) q or (C(R a R b )) i -(NR c ) j ;

[0011] R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 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 Ra3 、-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, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may optionally be further substituted with one or more substituents;

[0012] Or, R 1 and R 2 and the carbon atoms to which they are attached together to form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclyl may be further substituted with one or more substituents;

[0013] Alternatively, when X is selected from (NR c ) q When R 2 and R c and together with the carbon atom and nitrogen atom to which they are attached form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents;

[0014] R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 The cycloalkyl or 3-14 membered heterocyclyl may be further substituted with one or more substituents;

[0015] R c Selected from hydrogen, hydroxyl, amino, thiol, C 1-12 Alkyl or C 1-12 Alkoxy, the amino, C 1-12 Alkyl or C1-12 The alkoxy group may optionally be further substituted with one or more substituents;

[0016] Alternatively, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together to form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclyl may be further substituted with one or more substituents;

[0017] Alternatively, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and together with the nitrogen atom to which they are attached form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents;

[0018] Alternatively, when L is selected from (C(R a R b )) i -(NR c ) j When R a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents;

[0019] R 3 Selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2- 12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH2) n R al 、-(CH2) n ORal 、-(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, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl may optionally be further substituted with one or more substituents;

[0020] A is selected from

[0021] Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may optionally be further substituted with one or more substituents;

[0022] R 4 Selected from C 3-14Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may optionally be further substituted with one or more substituents;

[0023] R 5 and R 5’ are each 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 with one or more substituents;

[0024] R a1 、R a2 or R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, 6-14 membered aryl or 5-14 membered heteroaryl, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-104 membered aryl or 5-14 membered heteroaryl may optionally be further substituted with one or more substituents;

[0025] p, q, i or j are each independently selected from 1, 2 or 3;

[0026] m is selected from 0, 1 or 2;

[0027] n and n1 are each independently selected from 0, 1, 2, 3 or 4;

[0028] The conditions are:

[0029] When A is selected from L is a bond, and R 1 and R 2 Each independently selected from hydrogen or unsubstituted C 1-12 When alkyl, R 4 It is not a substituted or unsubstituted phenyl group.

[0030] In some embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0031] in,

[0032] X is selected from C(R a R b ) or NR c ;

[0033] L is selected from a bond, O, S, (C(R a R b )) p 、(NR c ) q or (C(R a R b )) i -(NR c ) j ;

[0034] R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 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 Ra2 ) 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, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further optionally substituted by one or more R aa replace;

[0035] Or, R 1 and R 2 and the carbon atoms to which they are attached together to form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may optionally be further substituted by one or more R bb replace;

[0036] Alternatively, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and nitrogen atom to which they are attached together form a 3-14 membered heterocyclic group, which may optionally be further substituted by one or more R bb replace;

[0037] R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may be further optionally substituted by one or more R cc replace;

[0038] R c Selected from hydrogen, hydroxyl, amino, thiol, C 1-12 Alkyl or C 1-12 Alkoxy, the amino, C1-12 Alkyl or C 1-12 The alkoxy group may optionally be further substituted with one or more R e replace;

[0039] Alternatively, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together to form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may be further optionally substituted by one or more R d1 replace;

[0040] Alternatively, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and the nitrogen atom to which they are attached together form a 3-14 membered heterocyclic group, which may optionally be further substituted by one or more R d2 replace;

[0041] Alternatively, when L is selected from (C(R a R b )) i -(NR c ) j When R a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form a 3-14 membered heterocyclic group, which may optionally be further substituted by one or more R d3 replace;

[0042] R 3 Selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2- 12 Alkenyl, C 2-12 Alkynyl, C 3-14Cycloalkyl, 3-14 membered heterocyclyl, 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, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl may optionally be further substituted with one or more R f replace;

[0043] A is selected from

[0044] Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further optionally substituted by one or more R g replace;

[0045] R 4 Selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further optionally substituted by one or more R h replace;

[0046] R 5 and R 5’ are each 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 with one or more R i replace;

[0047] R a1 、R a2 or R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, 6-14 membered aryl or 5-14 membered heteroaryl, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-104 membered aryl or 5-14 membered heteroaryl may optionally be further substituted with one or more R j replace;

[0048] R aa 、R bb 、R cc 、R d1 、R d2 、R d3 、R e 、R f 、R g 、R h 、R i and R jare each independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, =O, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, -(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 Cycloalkyl or 3-14 membered heterocycloalkyl may optionally be further substituted with one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano;

[0049] p, q, i or j are each independently selected from 1, 2 or 3;

[0050] m is selected from 0, 1 or 2;

[0051] n and n1 are each independently selected from 0, 1, 2, 3 or 4;

[0052] The conditions are:

[0053] When A is selected from L is a bond, and R 1 and R 2 are each independently selected from hydrogen or unsubstituted C 1-12 When alkyl, R 4 It is not a substituted or unsubstituted phenyl group.

[0054] In some embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0055] in,

[0056] X is selected from C(R a R b ) or NR c ;

[0057] L is selected from a bond, O, S, (C(R a R b )) p 、(NR c ) q or (C(R a R b )) i -(NR c ) j ;

[0058] R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 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 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may optionally be further substituted with one or more R aa replace;

[0059] Or, R 1 and R 2 and the carbon atoms to which they are attached together to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 The cycloalkyl or 3-12 membered heterocyclic group may be further optionally substituted by one or more R bb replace;

[0060] Alternatively, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and nitrogen atom to which they are attached together form a 3-12 membered heterocyclic group, which may be further optionally substituted by one or more R bb replace;

[0061] R aand R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 The cycloalkyl or 3-12 membered heterocyclic group may be further optionally substituted by one or more R cc replace;

[0062] R c Selected from hydrogen, hydroxyl, amino, thiol, 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 substituted with one or more R e replace;

[0063] Alternatively, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together to form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 The cycloalkyl or 3-12 membered heterocyclic group may be further optionally substituted by one or more R d replace;

[0064] Alternatively, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and the nitrogen atom to which they are attached together form a 3-12 membered heterocyclic group, which may optionally be further substituted by one or more R d replace;

[0065] Alternatively, when L is selected from (C(R a Rb )) i -(NR c ) j When R a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form a 3-12 membered heterocyclic group, which may be further optionally substituted by one or more R d replace;

[0066] R 3 Selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 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 Ra3 , the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may optionally be further substituted with one or more R f replace;

[0067] A is selected from

[0068] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may optionally be further substituted with one or more R g replace;

[0069] R 4 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may optionally be further substituted with one or more R h replace;

[0070] R 5 and R 5’ are each 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 substituted with one or more R i replace;

[0071] R a1 、R a2 or R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the amino, C 1-6 Alkyl, C1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may optionally be further substituted with one or more R j replace;

[0072] R aa 、R bb 、R cc 、R d 、R e 、R f 、R g 、R h 、R i and R j are each independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -(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 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl may be further optionally substituted by one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano;

[0073] p, q, i or j are each independently selected from 1, 2 or 3;

[0074] m is selected from 0, 1 or 2;

[0075] n and n1 are each independently selected from 0, 1, 2, 3 or 4;

[0076] The conditions are:

[0077] When A is selected from L is a bond, and R 1 and R 2 are each independently selected from hydrogen or unsubstituted C 1-12 When alkyl, R 4 It is not a substituted or unsubstituted phenyl group.

[0078] In some embodiments, the R d Selected from R d1 、R d2 or R d3 .

[0079] In some embodiments, the R d1 、R d2 or R d3 It can be R d .

[0080] In some embodiments, R aa 、R bb 、R cc 、R d1 、R d2 、R d3 、R e 、R f 、R g 、R h 、R i and R jare each independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, =O, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, -(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 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 The cycloalkyl or 3-14 membered heterocycloalkyl may optionally be further substituted with one or more substituents selected from deuterium, =0, halogen, hydroxy, amino or cyano.

[0081] In some embodiments, R aa 、R bb 、R cc 、R d 、Re 、R f 、R g 、R h 、R i and R j are each independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -(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 group and the 3-6 membered heterocyclyl group may be further optionally substituted by one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano.

[0082] In some embodiments, R aa 、R bb 、R cc 、R d 、R e 、R f 、R g 、R h 、R i and R j are each independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -(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 3-6The cycloalkyl group and the 3-6 membered heterocyclyl group may be further optionally substituted by one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano.

[0083] In some embodiments, the "one or more" is each independently selected from 1, 2, 3, 4, 5, or 6.

[0084] In some embodiments, the "one or more" are each independently selected from 1, 2, 3, 4 or 5.

[0085] In some embodiments, the "one or more" are each independently selected from 1, 2, 3 or 4.

[0086] In some embodiments, the "one or more" are each independently selected from 1, 2, or 3.

[0087] In some embodiments, the "hetero" is each independently selected from oxygen, sulfur, nitrogen, and phosphorus heteroatoms, 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 the phosphorus atom is optionally oxidized to P(O) or P(O)2, and other variables are as defined in the present disclosure.

[0088] In some embodiments, the "hetero" is each independently selected from oxygen, sulfur, and nitrogen heteroatoms, 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 the present disclosure.

[0089] In some embodiments, R a and R b are each independently selected from hydrogen, deuterium, 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 substituted with one or more R cc replace.

[0090] In some embodiments, R a and R b are each independently selected from hydrogen, deuterium, 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 with one or more R cc replace.

[0091] In some embodiments, R a and R b Each independently selected from hydrogen or C 1-3 Alkyl, the C1-3 The alkyl group may optionally be further substituted with one or more R cc replace.

[0092] In some embodiments, R a and R b are each independently selected from hydrogen or methyl.

[0093] In some embodiments, R a Selected from hydrogen, R b is selected from methyl; or R a Selected from methyl, R b Selected from hydrogen.

[0094] In some embodiments, R a and R b are all selected from hydrogen.

[0095] In some embodiments, R a and R b are all selected from methyl.

[0096] In some embodiments, R c Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more R e replace.

[0097] In some embodiments, R c Selected from hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be further substituted with one or more R e replace.

[0098] In some embodiments, R c is selected from hydrogen or methyl optionally substituted by deuterium.

[0099] In some embodiments, R c is selected from hydrogen, methyl or -CD3.

[0100] In some embodiments, R c Selected from methyl.

[0101] In some embodiments, R c Selected from hydrogen.

[0102] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) jWhen R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be further optionally substituted by one or more R d or R d1 replace.

[0103] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may optionally be further substituted with one or more R d or R d1 replace.

[0104] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl optionally being further substituted by one or more R d or R d1 replace.

[0105] In some embodiments, when L is selected from (C(R a R b ))p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, which may optionally be further replaced by one or more R d or R d1 replace.

[0106] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl or azetidinyl group, which may optionally be further substituted by one or more R d or R d1 replace.

[0107] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group, which may optionally be further substituted by one or more R d or R d1 replace.

[0108] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same carbon atom a and R band together with the carbon atom to which they are attached form a cyclopropyl group which may optionally be further substituted with one or more R d or R d1 replace.

[0109] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on different carbon atoms a and R b and together with the carbon atom to which they are attached form a cyclobutyl group which may optionally be further substituted with one or more R d or R d1 replace.

[0110] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j , the “same or different carbon atoms” are “two same or two different carbon atoms”; or, the “same carbon atom” is “two same carbon atoms”; or, the “different carbon atoms” are “two different carbon atoms”.

[0111] In some embodiments, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When the carbon atoms are the same or different, they are “two the same or two different carbon atoms at both ends”; or, the same carbon atoms are “two the same carbon atoms at both ends”; or, the different carbon atoms are “two different carbon atoms at both ends”.

[0112] In some embodiments, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms cand the nitrogen atom to which they are attached together form a 3-6 membered heterocyclic group, which may optionally be further substituted by one or more R d or R d2 replace.

[0113] In some embodiments, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and the nitrogen atom to which they are attached together form a 1,3-diazetidinyl, imidazolidinyl or piperazinyl group, which may optionally be further substituted by one or more R d or R d2 replace.

[0114] In some embodiments, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and together with the nitrogen atom to which they are attached form a 1,3-diazetidinyl group, which may optionally be further substituted with one or more R d or R d2 replace.

[0115] In some embodiments, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When , the “different nitrogen atoms” refer to “two different nitrogen atoms”.

[0116] In some embodiments, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When , the “different nitrogen atoms” refer to “two different nitrogen atoms at both ends”.

[0117] In some embodiments, when L is selected from (C(R aR b )) i -(NR c ) j When R a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form a 3-6 membered heterocyclic group, which may be further optionally substituted by one or more R d or R d3 replace.

[0118] In some embodiments, when L is selected from (C(R a R b )) i -(NR c ) j When R a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form an azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl or piperazinyl group, wherein the azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl or piperazinyl group may be further optionally substituted by one or more R d or R d3 replace.

[0119] In some embodiments, when L is selected from (C(R a R b )) i -(NR c ) j When R a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form an azetidinyl group, which may optionally be further substituted by one or more R d or R d3 replace.

[0120] In some embodiments, when L is selected from (C(R a R b )) i -(NR c ) j When the "R on the carbon atom a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom connected to it" is "R on a carbon atom a and the carbon atom to which it is attached, R on a nitrogen atom c and the nitrogen atom to which it is attached."

[0121] In some embodiments, when L is selected from (C(R a R b )) i -(NR c ) j When the "R on the carbon atom a and R on the carbon and nitrogen atoms connected to it c and the nitrogen atom connected to it" is "R on a carbon atom at one end a and the carbon atom connected to it, and the R on a nitrogen atom at the other end. c and the nitrogen atom to which it is attached."

[0122] In some embodiments, X is selected from NR c .

[0123] In some embodiments, X is selected from CH2, CH(CH3), C(CH3)2, or N(CH3), said X being optionally substituted with one or more deuteriums.

[0124] In some embodiments, X is selected from CH2, CH(CH3), C(CH3)2, or N(CH3).

[0125] In some embodiments, X is selected from

[0126] In some embodiments, X is selected from NH, N(CH2D), N(CHD2), or N(CD3).

[0127] In some embodiments, X is selected from NH or N(CD3).

[0128] In some embodiments, X is selected from CH2, N(CH3), NH, N(CD3) or

[0129] In some embodiments, X is selected from CH2 or N(CH3).

[0130] In some embodiments, X is selected from N(CD3) or N(CH3).

[0131] In some embodiments, X is selected from N(CH3).

[0132] In some embodiments, L is selected from a bond, (C(R a R b )) p or (C(R a R b )) i -(NR c ) j .

[0133] In some embodiments, p, q, i, or j are each independently selected from 1 or 2.

[0134] In some embodiments, i and j are each selected from 1.

[0135] In some embodiments, q is 2.

[0136] In some embodiments, L is selected from a bond, -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 .

[0137] In some embodiments, 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 -.

[0138] In some embodiments, L is selected from a bond.

[0139] In some embodiments, L is selected from a bond, CH2, CH(CH3), C(CH3)2, wherein each r is independently selected from 1, 2, 3 or 4. In some embodiments, wherein each r is independently selected from 1 or 2.

[0140] In some embodiments, L is selected from a bond, CH2, CH(CH3), C(CH3)2,

[0141] In some embodiments, L is selected from a bond, CH2, C(CH3)2,

[0142] In some embodiments, 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 .

[0143] In some embodiments, 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 .

[0144] In some embodiments, structural fragment LR 4 Selected from -R 4 、-CH2R 4 、-C(CH3)2R 4 、

[0145] In some embodiments, R cc 、R d1 、R d2 、R d3 and R e Each independently selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3The alkoxy group may optionally be further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.

[0146] In some embodiments, R cc 、R d1 、R d2 、R d3 and R e Each is independently selected from deuterium, halogen or hydroxyl.

[0147] In some embodiments, R cc 、R d1 、R d2 、R d3 and R e are each independently selected from F.

[0148] In some embodiments, R cc 、R d and R e Each independently 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 with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.

[0149] In some embodiments, R cc 、R d and R e Each is independently selected from deuterium, halogen or hydroxyl.

[0150] In some embodiments, R cc 、R d and R e are each independently selected from F.

[0151] In some embodiments, R 1 and R 2 Each independently selected from hydrogen, deuterium, halogen, hydroxyl, NH2, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or -(CH2) n OR al , the C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further substituted with one or more R aa In some embodiments, R 1 and R 2 Each independently selected from -(CH2) n R al .

[0152] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy or -(CH2) n OR al , the C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further substituted with one or more R aa replace.

[0153] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl, -(CH2) n R al or -(CH2) n OR al , the C 1-6 The alkyl group may be further substituted with one or more R aa replace.

[0154] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl or -(CH2) n OR al , the C 1-6 The alkyl group may be further substituted with one or more R aa replace.

[0155] In some embodiments, n and n1 are each independently selected from 0, 1 or 2.

[0156] In some embodiments, n is selected from 1 or 2.

[0157] In some embodiments, n is selected from 0.

[0158] In some embodiments, R 1 and R 2 Each 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, tert-butyl groups may be further optionally replaced by one or more R aa In some embodiments, R 1 and R 2 Each independently selected from -CH2R al .

[0159] In some embodiments, R1 and R 2 Each independently selected from hydrogen, n-butyl, -CH2R al 、-CH2OR al 、-CH2CH2OR al , the n-butyl group may optionally be further replaced by one or more R aa replace.

[0160] In some embodiments, R 1 and R 2 and the carbon atoms to which they are attached together to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be further optionally substituted by one or more R bb replace.

[0161] In some embodiments, R 1 and R 2 and the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, said cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl optionally being further substituted by one or more R bb replace.

[0162] In some embodiments, R 1 and R 2 and together with the carbon atom to which they are attached form a cyclopentyl group which may optionally be further substituted with one or more R bb replace.

[0163] In other embodiments, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and nitrogen atom to which they are attached together form a 3-6 membered heterocyclic group, which may be further optionally substituted by one or more R bb replace.

[0164] In other embodiments, when X is selected from (NR c ) q When R 2 and R cand the carbon atom and nitrogen atom to which they are attached together form an azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl or piperazinyl group, which may optionally be further substituted by one or more R bb replace.

[0165] In other embodiments, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and nitrogen atom to which they are attached together form a pyrrolidinyl or piperidinyl group, which may optionally be further substituted by one or more R bb replace.

[0166] In some embodiments, R a1 、R a2 or R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be further optionally substituted by one or more R j In some embodiments, R a1 、R a2 or R a3 Each is independently selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl may be further optionally substituted by one or more R j replace.

[0167] In some embodiments, R a1 、R a2 or R a3 are each independently selected from hydrogen, 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 substituted with one or more R j In some embodiments, R a1 、R a2 or R a3 are each independently selected from phenyl, which may optionally be further substituted by one or more R j replace.

[0168] In some embodiments, Ra1 、R a2 or R a3 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or phenyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl or phenyl group may optionally be further substituted with one or more R j replace.

[0169] In some embodiments, R a1 、R a2 or R a3 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or phenyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or phenyl may be further optionally replaced by one or more R j replace.

[0170] In some embodiments, R a1 、R a2 or R a3 Each independently selected from methyl, ethyl, cyclopropyl or phenyl, said methyl, ethyl, cyclopropyl or phenyl optionally further substituted by one or more R j replace.

[0171] In some embodiments, R a1 、R a2 or R a3 Each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted by one or more R j replace.

[0172] In some embodiments, R a1 、R a2 or R a3 Each independently selected from hydrogen, methyl, ethyl, tert-butyl or cyclopentyl, said methyl, ethyl, tert-butyl or cyclopentyl optionally being further substituted by one or more R j replace.

[0173] In some embodiments, R aa 、R bb and R j Each independently selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C1-3 The alkoxy group may optionally be further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.

[0174] In some embodiments, R aa 、R bb and R j are each independently selected from deuterium, halogen or hydroxy. 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. bb In other embodiments, R bb Selected from ethyl.

[0175] In some embodiments, R aa 、R bb and R j are each independently selected from F.

[0176] In some embodiments, R a1 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more R j replace.

[0177] In some embodiments, R a1 Selected from C 1-3 alkyl.

[0178] In some embodiments, R a1 is selected from methyl, ethyl, cyclopropyl or phenyl, which may be further substituted with one or more F.

[0179] In some embodiments, R a1 is selected from methyl, ethyl, cyclopropyl or 2-fluorophenyl.

[0180] In some embodiments, R a1 Selected from methyl or ethyl.

[0181] In some embodiments, R j Selected from F or -(CH2) n S(O) m R al .

[0182] In some embodiments, R j Select F or -SR al .

[0183] In some embodiments, Rj Selected from F or -SCH3.

[0184] In some embodiments, R 1 and R 2 and the carbon atom to which they are attached form a cyclopentyl group.

[0185] In other embodiments, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and nitrogen atom to which they are attached together 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.

[0186] In other embodiments, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and nitrogen atom to which they are attached together form a pyrrolidinyl or piperidinyl group, which may optionally be further substituted with an ethyl group; R 1 In other embodiments, when X is selected from (NR c ) q When R 2 and R c Together with the carbon and nitrogen atoms to which they are attached, R 1 In other embodiments, when X is selected from (NR c ) q When R 2 and R c Together with the carbon and nitrogen atoms to which they are attached, R 1 Selected from H.

[0187] In some embodiments, R 1 and R 2 Each 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, tert-butyl groups may be further substituted with one or more F groups, R a1 Selected from methyl or ethyl.

[0188] In some embodiments, R 1 and R 2Each independently selected from hydrogen, n-butyl, -CH2R al 、-CH2OR al 、-CH2CH2OR al , the n-butyl group may optionally be further substituted by one or more F, R a1 is selected from methyl, ethyl or cyclopropyl.

[0189] In some embodiments, R 1 and R 2 Each independently selected from hydrogen, n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3, wherein the n-butyl group may be further substituted with one or more F.

[0190] In some embodiments, R 1 and R 2 Each is independently selected from hydrogen, n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3, wherein the n-butyl group may be further substituted with one or more F.

[0191] In some embodiments, R 1 and R 2 are each independently selected from hydrogen or n-butyl, which may be further substituted with one or more F. In some embodiments, R 1 and R 2 Each independently selected from hydrogen, n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3.

[0192] In some embodiments, R 1 and R 2 Each independently selected from hydrogen, n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3.

[0193] In some embodiments, R 1 Selected from H.

[0194] In some embodiments, R 1 Selected from H, R 2 Selected from n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3.

[0195] In some embodiments, R 1 Selected from H, R 2 Selected from n-butyl, -CH2OCH2CH3 or -CH2CH2OCH3.

[0196] In some embodiments, R 1 Selected from H, R 2 Selected from n-butyl.

[0197] In some embodiments, R 1 Selected from H, R 2 Selected from

[0198] In some embodiments, R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy 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 substituted with one or more R f In other embodiments, 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 substituted with one or more R f In some embodiments, R 3 Selected from -(CH2) n OR al .

[0199] In some embodiments, R 3 Selected from halogen, hydroxy, NH2, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or -(CH2) n S(O) m R al , the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted with one or more R f replace.

[0200] In some embodiments, R 3 Selected from methyl, ethyl, methoxy, ethoxy or -(CH2) n S(O) m R al The methyl, ethyl, methoxy, ethoxy groups may be further optionally replaced by one or more R f In other embodiments, R3 Selected from cyclopropyl, cyclobutyl or -(CH2) n NR a2 R a3 The cyclopropyl or cyclobutyl group may optionally be further replaced by one or more R f replace.

[0201] In some embodiments, R 3 Selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -(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 replaced by one or more R f replace.

[0202] In some embodiments, 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 replaced by one or more R f replace.

[0203] In some embodiments, 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 replaced by one or more R f replace.

[0204] In some embodiments, 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 replaced by one or more R f replace.

[0205] In some embodiments, R fSelected 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 with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.

[0206] In some embodiments, R f Selected from deuterium, halogen or hydroxyl.

[0207] In some embodiments, R f Selected from F.

[0208] In some embodiments, R 3 Selected from -(CH2) n S(O) m R al In other embodiments, R 3 Selected from cyclopropyl or -(CH2) n NR a2 R a3 .

[0209] In some embodiments, m is selected from 0.

[0210] In some embodiments, R a1 Selected from methyl.

[0211] In other embodiments, R a2 or R a3 are each independently selected from H or methyl.

[0212] In other embodiments, R a2 or R a3 are all selected from methyl.

[0213] In some embodiments, R 3 In other embodiments, R 3 Selected from cyclopropyl or -N(CH3)2.

[0214] In other embodiments, R 3 Selected from methyl, CF3CH2O- or

[0215] In other embodiments, A is selected from

[0216] In some embodiments, A is selected from

[0217] In some embodiments, R 5 and R 5’are each 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 substituted with one or more R i replace.

[0218] In some embodiments, R 5 and R 5’ are each independently selected from hydrogen, deuterium, halogen or C 1-3 Alkyl; the C 1-3 The alkyl group may optionally be further substituted with one or more R i replace.

[0219] In some embodiments, R 5 and R 5’ are each independently selected from hydrogen, deuterium, halogen, NH2, methyl, ethyl, methoxy or ethoxy, wherein the methyl, ethyl, methoxy or ethoxy group may be further optionally substituted by one or more R i In other embodiments, R 5 and R 5’ are each independently selected from hydrogen, deuterium, halogen or methyl, which methyl group may optionally be further replaced by one or more R i In other embodiments, R 5 and R 5’ are all selected from methyl.

[0220] In some embodiments, R 5 is selected from hydrogen, deuterium or halogen.

[0221] In some embodiments, R 5 is selected from hydrogen or F. In other embodiments, R 5 is selected from methyl, which may optionally be further replaced by one or more R i replace.

[0222] In some embodiments, R 5 In some other embodiments, R 5 Selected from CF3.

[0223] In some embodiments, 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 with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.

[0224] In some embodiments, R i Selected from deuterium, halogen or hydroxyl.

[0225] In some embodiments, R i Selected from F.

[0226] In some embodiments, A is selected from In some embodiments, A is selected from R 4 Not for

[0227] In some embodiments, A is selected from

[0228] In some embodiments, A is selected from Or in other embodiments, A is selected from Ring B is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, said C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may optionally be further substituted with one or more R g replace.

[0229] In some embodiments, A is selected from Or in other embodiments, A is selected from Ring B is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl may optionally be further substituted with one or more R g replace.

[0230] In some embodiments, A is selected from Or in other embodiments, A is selected from Ring B is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl may be further optionally substituted with one or more R g replace.

[0231] In some embodiments, A is selected from Or in other embodiments, A is selected from Ring B is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl may be further optionally substituted by one or more R g In other embodiments, ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, and the ring B may optionally be further substituted with one or more R g replace.

[0232] In some embodiments, A is selected from Or in other embodiments, A is selected from Ring B is selected from phenyl, pyrrolyl, furyl, thienyl or pyridyl, and the phenyl, pyrrolyl, furyl, thienyl or pyridyl group may be further optionally substituted by one or more R g In other embodiments, ring B is selected from cyclopropyl, cyclobutyl, cyclohexyl, azetidinyl, piperidinyl or thiazolyl, and the ring B may be further optionally substituted with one or more R g replace.

[0233] In some embodiments, A is selected from When , the two bonds to ring B are bonded to different ring atoms. Alternatively, the two bonds to ring B are bonded to the same ring atom.

[0234] In some embodiments, A is selected from Or in other embodiments, A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g In other embodiments, ring B is selected from The ring B may optionally be further substituted with one or more R g replace.

[0235] In some embodiments, A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R gIn other embodiments, A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g replace.

[0236] In other embodiments, A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g replace.

[0237] In some embodiments, A is selected from Ring B is selected from The ring B may optionally be further substituted with one or more R g replace.

[0238] In other embodiments, A is selected from

[0239] In other embodiments, A is selected from

[0240] In some embodiments, 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 with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.

[0241] In some embodiments, R g is selected from halogen, hydroxy, NH2, methyl, ethyl, methoxy or ethoxy, wherein the methyl, ethyl, methoxy or ethoxy group may be further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino or cyano.

[0242] In some embodiments, R g is selected from halogen, hydroxy, NH2, methyl, ethyl, methoxy or ethoxy, wherein the methyl, ethyl, methoxy or ethoxy group may be further substituted with one or more substituents selected from halogen.

[0243] In some embodiments, R g is selected from halogen, hydroxy, NH2, methyl, ethyl, methoxy or ethoxy, wherein the methyl, ethyl, methoxy or ethoxy group may be further substituted with one or more F groups.

[0244] In some embodiments, R g is selected from F, methyl or trifluoromethyl.

[0245] In some embodiments, R g Selected from F.

[0246] In some embodiments, A is selected from Ring B is selected from

[0247] In other embodiments, A is selected from Ring B is selected from

[0248] In other embodiments, A is selected from Ring B is selected from

[0249] In some embodiments, A is selected from Ring B is selected from

[0250] In some embodiments, A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g In other embodiments, A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g replace.

[0251] In some embodiments, A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g replace.

[0252] In some embodiments, A is selected from Structural unit Selected from

[0253] In other embodiments, A is selected from Structural unit Selected from

[0254] In some embodiments, A is selected from Structural unit Selected from

[0255] In other embodiments, A is selected from Structural unit Selected from The ring B may optionally be further substituted with one or more R g replace.

[0256] In other embodiments, A is selected from Structural unit Selected from

[0257] In other embodiments, A is selected from Structural unit Selected from

[0258] In some embodiments, R 4 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-10 membered heteroaryl, the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 The aryl or 5-10 membered heteroaryl group may optionally be further substituted with one or more R h replace.

[0259] In some embodiments, R 4 Selected from C 5-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-12 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-12 The aryl or 5-10 membered heteroaryl group may optionally be further substituted with one or more R h In some embodiments, R 4 Selected from C 8-10 Cycloalkyl, the C 8-10 The cycloalkyl group may optionally be further substituted with one or more R h In some embodiments, R 4 Selected from C 8-10 Polycyclic cycloalkyl, the C 8-10 The polycyclic cycloalkyl group may optionally be further substituted with one or more R h In some embodiments, R 4 Selected from C 8-10Polycyclic cycloalkyl, wherein the polycyclic ring is bicyclic, tricyclic or tetracyclic, and the C 8-10 The polycyclic cycloalkyl group may optionally be further substituted with one or more R h replace.

[0260] In some embodiments, R 4 Selected from C 5-8 Cycloalkyl, C 6-11 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, C 6-11 The aryl or 5-10 membered heteroaryl group may optionally be further substituted with one or more R h replace.

[0261] In some embodiments, R 4 Selected from C 5-8 Cycloalkyl, phenyl, C 9-11 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, phenyl, C 9-11 The aryl or 5-10 membered heteroaryl group may optionally be further substituted with one or more R h replace.

[0262] In some embodiments, R 4 Selected from C 5-8 Cycloalkyl, C 9-11 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, C 9-11 The aryl or 5-10 membered heteroaryl group may optionally be further substituted with one or more R h replace.

[0263] In some embodiments, R 4Selected from phenyl, indolinyl, isoindolinyl, benzodioxolane, benzopyrazolidine, benzimidazolidine, benzotetrahydrothiophene, benzotetrahydrofuran, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyran, benzothiazolidine, benzisothiazolidine, benzoxazolidine, benzisoxazolidine, benzopiperidine, benzopiperazine, benzomorpholine, benzothiazinane, pyrrolyl, pyrazolyl, imidazolyl, oxazole yl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuran ring group, benzothiophene ring group, benzothiazole ring group, benzoxazole ring group, indolyl, isoindolyl, benzimidazolyl ring group, indazolyl, pyrrolo[2,3-b]pyridine ring group, pyrrolo[2,3-c]pyridine ring group, pyrrolo[3,2-c]pyridine ring group, pyrrolo[3,2-b]pyridine ring group, imidazo[4,5-b]pyridine cyclic group, imidazo[4,5-c]pyridine ring group, imidazo[1,2-a]pyridine ring group, imidazo[1,5-a]pyridine ring group, pyrazolo[4,3-d]pyridine ring group, pyrazolo[4,3-c]pyridine ring group, pyrazolo[3,4-c]pyridine ring group, pyrazolo[1,5-a]pyridine ring group, thieno[3,2-b]pyridine ring group, thieno[2,3-b]pyridine ring group, purinyl, indolizinyl, quinolyl, isoquinolyl, pyrrolo[1,2-a]pyridine ring group, ] pyridazine ring group, imidazo[1,2-c]pyrimidine ring group, pyrazolo[1,5-a]pyrazine ring group, pyrrolo[1,2-a]pyrazine ring group, 2,3-dihydrofuro[2,3-b]pyridine ring group, 2,3-dihydrofuro[3,2-b]pyridine ring group, 2,3-dihydrofuro[3,2-c]pyridine ring group, 2,3-dihydrofuro[2,3-c]pyridine ring group, bicyclo[1.1.1]pentanyl or bicyclo[2.2.2]octyl group, wherein R 4 Optionally, it may be further represented by one or more R h In some embodiments, R 4 is selected from 2,3-dihydrobenzo[b][1,4]dioxinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein R 4 Optionally, it may be further represented by one or more R h replace.

[0264] In other embodiments, R 4 is selected from cyclobutyl, cyclopentyl, cyclohexyl, 1,2-dihydropyridyl, adamantyl, benzocyclobutyl, benzocyclopentyl or benzocyclohexyl, wherein R 4 Optionally, it may be further represented by one or more R h replace.

[0265] In some embodiments, R4 is selected from phenyl, indolinyl, isoindolinyl, benzopyrazolidine ring group, benzotetrahydrofuran ring group, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyran ring group, benzopiperidine ring group, furyl, thienyl, pyridyl, benzothiophene ring group, benzothiazole ring group, benzoxazole ring group, indolyl, benzimidazole ring group, thieno[3,2-b]pyridine ring group, thieno[2,3-b]pyridine ring group, quinolyl, isoquinolyl, 2,3-dihydrofuro[2,3-b]pyridine ring group, 2,3-dihydrofuro[3,2-b]pyridine ring group, 2,3-dihydrofuro[3,2-c]pyridine ring group or bicyclo[1.1.1]pentanyl, wherein R 4 Optionally, it may be further represented by one or more R h replace.

[0266] In other embodiments, R 4 is selected from cyclobutyl, 1,2-dihydropyridyl, adamantyl or benzocyclobutyl, wherein R 4 Optionally, it may be further represented by one or more R h replace.

[0267] In some embodiments, R 4 is selected from indolinyl, isoindolinyl, benzopyrazolidine ring group, benzotetrahydrofuran ring group, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyran ring group, benzopiperidine ring group, furyl, thienyl, pyridyl, benzothiophene ring group, benzothiazole ring group, benzoxazole ring group, indolyl, benzimidazole ring group, thieno[3,2-b]pyridine ring group, thieno[2,3-b]pyridine ring group, quinolinyl, isoquinolinyl, 2,3-dihydrofuro[2,3-b]pyridine ring group, 2,3-dihydrofuro[3,2-b]pyridine ring group, 2,3-dihydrofuro[3,2-c]pyridine ring group or bicyclo[1.1.1]pentanyl, wherein R 4 Optionally, it may be further represented by one or more R h replace.

[0268] In some embodiments, R 4is selected from the group consisting of cyclobutyl, 1,2-dihydropyridyl, adamantyl, benzocyclobutyl, phenyl, indolyl, isoindolyl, benzopyrazolidine ring group, benzotetrahydrofuran ring group, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyran ring group, benzodioxolanyl, benzotetrahydropyran ring group, benzopiperidine ring group, furyl, thienyl, pyridyl, benzothiophene ring group, benzothiazole ring group, benzoxazole ring group, indolyl, benzimidazole ring group, thieno[3, 2-b] pyridine ring group, thieno[2,3-b] pyridine ring group, quinolyl, isoquinolyl, 2,3-dihydrofuro[2,3-b] pyridine ring group, 2,3-dihydrofuro[3,2-b] pyridine ring group, 2,3-dihydrobenzo[b][1,4]dioxinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2,3-dihydrofuro[3,2-c] pyridine ring group or bicyclo[1.1.1]pentanyl, wherein R 4 Optionally, it may be further represented by one or more R h replace.

[0269] In some embodiments, when R 4 When the structure fragment LR contains an aromatic ring structure (such as a phenyl ring structure) or a heteroaromatic ring (such as a thiophene ring structure), the structure fragment LR 4 In the middle, L and R 4 The aromatic ring or heteroaromatic ring is connected.

[0270] In some embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h In some embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h In other embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h replace.

[0271] In some embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h replace.

[0272] In some embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h replace.

[0273] In some embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h substituted, and L is selected from C(R a R b ) or -C(R a R b )-C(R a R b )-.

[0274] In some embodiments, R h Selected from deuterium, halogen, hydroxyl, 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 may be further optionally substituted with one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano. h Selected from -(CH2) n P(O)R a2 R a3 In other embodiments, R h Selected from -(CH2) n O(CH2) n S(O) m R al .

[0275] In some embodiments, R h Selected from halogen, hydroxy, =O, C 1-6 Alkyl, C1-6 Alkoxy, 3-6 membered heterocycloalkyl, -(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 heterocycloalkyl group may optionally be further substituted with one or more substituents selected from deuterium, =0, halogen, hydroxy, amino or cyano.

[0276] In some embodiments, R h Selected from halogen, hydroxy, =O, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocycloalkyl, -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 heterocycloalkyl group may optionally be further substituted with one or more substituents selected from deuterium, =0, halogen, hydroxy, amino or cyano.

[0277] In some embodiments, R h Selected from halogen, =O, C 1-6 Alkyl, C 1-6 Alkoxy, 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 1-6The alkyl or 3-6 membered heterocycloalkyl group may optionally be further substituted with one or more substituents selected from deuterium, =0, halogen, hydroxy, amino or cyano.

[0278] In some embodiments, n1 is selected from 0.

[0279] In some embodiments, R h selected from halogen, =0, methyl, ethyl, isopropyl, methoxy, ethoxy, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, 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, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl optionally may be further substituted with one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano.

[0280] In some embodiments, R h Selected from halogen, hydroxy, =O, methyl, methoxy, pyrrolidinyl, -C(O)R al 、-NR a2 C(O)R a3 、-OCH2SR al or -P(O)R a2 R a3 , the methyl, methoxy or pyrrolidinyl group may optionally be further substituted by one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano.

[0281] In some embodiments, R a2 Selected from hydrogen.

[0282] In some embodiments, 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 substituted with one or more R j replace.

[0283] In some embodiments, R a3is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl may be further optionally substituted by one or more R j replace.

[0284] In some embodiments, R a3 Selected from tert-butyl or cyclopentyl.

[0285] In some embodiments, R h Selected from F, =O, methyl, pyrrolidinyl, -C(O)CH3, Or -C(O)NHC(CH3)3, the methyl or pyrrolidinyl group may be further substituted with one or more substituents selected from =O or halogen. In other embodiments, R h Selected from Or methoxy, said methoxy optionally may be further substituted by one or more halogens. In other embodiments, R h Selected from hydroxyl or -OCH2SCH3.

[0286] In some embodiments, R h Selected from F, =O, methyl, pyrrolidinyl, -C(O)CH3, or -C(O)NHC(CH3)3, wherein the methyl or pyrrolidinyl group may be further substituted with one or more substituents selected from =O or F. In other embodiments, R h Selected from Or methoxy, said methoxy optionally further may be substituted with one or more F or Cl. In other embodiments, R h Selected from or methoxy, which may optionally be further substituted with one or more F.

[0287] In some embodiments, R h Selected from F, hydroxy, =O, methyl, methoxy, pyrrolidinyl, -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.

[0288] In some embodiments, R h Selected from F, =O, methyl, trifluoromethyl, -C(O)CH3, Or -C(O)NHC(CH3)3. In other embodiments, R h Selected from In other embodiments, R h Selected from hydroxyl, CH3SCH2O- or

[0289] In some embodiments, R 4 Selected from

[0290] In other embodiments, R 4 Selected from

[0291] In some embodiments, R 4 Selected from

[0292] In some embodiments, R 4 Selected from

[0293] In some embodiments, R 4 Selected from

[0294] In some embodiments, 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 )-.

[0295] In some embodiments, R 4 Selected from and L is selected from a bond.

[0296] In some embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h replace.

[0297] In some embodiments, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h is substituted, and L is selected from a bond.

[0298] In other embodiments, R 4 Selected from

[0299] In the above, a dashed line, such as "---", represents a bond to the rest of the structural formula (eg, Formula (I)).

[0300] In some embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the compound of formula (I-1), the compound of formula (I-2), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0301] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , X and Ring B are as defined in the present disclosure.

[0302] In some embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the compound of formula (II-1), the compound of formula (II-2), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0303] Among them, R 2 、R 3 、R 4 、R 5 , X and Ring B are as defined in the present disclosure.

[0304] In some embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the compound of formula (III-1), the compound of formula (III-2), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0305] Among them, R 1 、R 2 、R 3 、R 4 、R 5 and Ring B are as defined in the present disclosure.

[0306] In some embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the compound of formula (IV-1), the compound of formula (IV-2), its stereoisomers, or pharmaceutically acceptable salts thereof:

[0307] Among them, R 1 、R 2 、R 4 、R 5 and Ring B are as defined in the present disclosure.

[0308] In some embodiments, the compound of formula (I) of the present disclosure, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the group consisting of a compound of formula (Ia), a compound of formula (I-1a), a compound of formula (I-2a), a compound of formula (II-1a), a compound of formula (II-2a), a compound of formula (III-1a), a compound of formula (III-2a), a compound of formula (IV-1a), a compound of formula (IV-2a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0309] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , X and Ring B are as defined in the present disclosure.

[0310] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0311] In some embodiments, the compounds of the present disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0312] In some embodiments, the compounds of the present disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0313] In another aspect, the present disclosure provides a pharmaceutical composition comprising the above-mentioned compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0314] In another aspect, the present disclosure provides a method for treating or preventing a disease, comprising administering a therapeutically effective amount of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0315] In another aspect, the present disclosure provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for treating or preventing a disease.

[0316] In another aspect, the present disclosure provides use of the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating or preventing a disease.

[0317] In another aspect, the present disclosure provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof for treating or preventing a disease.

[0318] In some embodiments, the disease is selected from a disease associated with inhibition of sodium taurocholate co-transporting peptide (NTCP) and / or inhibition of sodium-dependent bile acid transporter (ASBT).

[0319] In some embodiments, the disease associated with inhibition of sodium taurocholate co-transporting peptide (NTCP) and / or inhibition of sodium-dependent bile acid transporter (ASBT) is selected from conditions, disorders and diseases requiring inhibition of bile acid circulation, such as cardiovascular disease, fatty acid metabolism and glucose utilization disorders, gastrointestinal disease and liver disease.

[0320] In some embodiments, the inhibition of sodium taurocholate co-transporting peptide (NTCP) and / or the inhibition of sodium-dependent bile acid transporter (ASBT) is selected from the group consisting of selective inhibition of sodium taurocholate co-transporting peptide (NTCP), or simultaneous inhibition of sodium taurocholate co-transporting peptide (NTCP) and sodium-dependent bile acid transporter (ASBT).

[0321] The compounds disclosed herein have good inhibitory activity against NTCP and / or ASBT and can selectively inhibit NTCP and / or ASBT. The compounds disclosed herein also have good in vitro and in vivo efficacy and in vitro and in vivo pharmacokinetic properties.

[0322] definition

[0323] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0324] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0325] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present disclosure, which are prepared by reacting the compounds of the present disclosure with relatively nontoxic acids or bases. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in a neat solution or a suitable inert solvent. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in a neat solution or a suitable inert solvent. Certain specific compounds of the present disclosure contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0326] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0327] The compounds of the present disclosure may exist in specific stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0328] Unless otherwise specified, use a solid wedge key and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter.

[0329] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0330] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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 another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure.

[0331] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0332] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted 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 be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0333] 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 includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, based on chemical achievable basis.

[0334] The “substituents” described herein include, but are not limited to, the terms “alkyl”, “alkenyl”, “alkynyl”, “spirocycloalkyl”, “fused cycloalkyl”, “bridged cycloalkyl”, “heterocyclyl”, “spiroheterocyclyl”, “fused heterocyclyl”, “bridged heterocyclyl”, “alkoxy”, “cycloalkyl”, “heterocycloalkyl”, “heteroaryl”, “alkyl ring”, “heteroalkyl ring”, “heteroaryl ring”, etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the “substituents” include deuterium, tritium, -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azide, sulfoxide, sulfone, sulfoneamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester groups, etc., which are optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -N HC(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, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

[0335] In some embodiments herein, the “substituent” is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1- 12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -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- 12Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0336] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1- 3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0337] As used herein, m and n are integers within a given range. For example, "3-12 membered" means that the group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 members. For example, "5-10 membered" means that the group may have 5, 6, 7, 8, 9, or 10 members.

[0338] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0339] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0340] When the listed linking groups do not specify their linking direction, their linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0341] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0342] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0343] The term "hydroxy" refers to an -OH group.

[0344] The term "amino" refers to a -NH2 group.

[0345] The term "mercapto" refers to a -SH group.

[0346] The term "cyano" refers to a -CN group.

[0347] The term "nitro" refers to a -NO2 group.

[0348] The term "alkyl" refers to a group of the formula C n H 2n+1The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "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 has the same definition as above.

[0349] The term "alkoxy" refers to an -O-alkyl group.

[0350] The term "alkylamino" refers to an -NH-alkyl group.

[0351] The term "dialkylamino" refers to -N(alkyl)2.

[0352] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0353] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and 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), 1,3-butadiynyl (-C≡C≡CH), and the like.

[0354] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls; preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0355] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0356] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0357] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0358] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0359] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group can be optionally substituted or unsubstituted.

[0360] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon; wherein the ring atoms may further be boron or P(O) p(wherein p is an integer from 0 to 2). It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups; the spirocyclic, fused ring and bridged heterocyclic groups involved are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring. Non-limiting examples of heterocyclic groups include:

[0361] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0362] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0363] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0364] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl ring. It should be understood that the fused system formed after fusion belongs to the category of "heterocyclyl" defined in the present disclosure. Non-limiting examples of "heterocyclyl" also include: wait.

[0365] The term "aryl" refers to a group of 6 to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) aromatic rings having a conjugated π electron system, preferably 6 to 10 members, the aromatic rings can be phenyl rings and naphthyl rings, more preferably phenyl rings, the aromatic rings can be fused to heteroaryl, heterocyclic or cycloalkyl rings, wherein the ring connected to the parent structure is an aromatic ring, it should be understood that the fused system formed after fusion belongs to the category of "aryl" defined in the present disclosure, non-limiting examples of "aryl" include: phenyl, naphthyl,

[0366] The term "heteroaryl" refers to a heteroaromatic system containing 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 members, more preferably 5 or 6 members, and can be, for example, an imidazolyl ring, a furyl ring, a thienyl ring, a thiazolyl ring, a pyrazolyl ring, an oxazolyl ring, a pyrrolyl ring, a triazolyl ring, a tetrazolyl ring, a pyridyl ring, a pyrimidinyl ring, a thiadiazole ring, or a pyrazinyl ring, preferably a triazolyl ring, a thienyl ring, an imidazolyl ring, a pyrazolyl ring, a pyrimidinyl ring or a thiazolyl ring; more preferably a triazolyl ring, a pyrrolyl ring, a thienyl ring, a thiazolyl ring or a pyrimidinyl ring. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaromatic ring. It should be understood that the fused system formed after fusion belongs to the category of "heteroaryl" defined in the present disclosure. Non-limiting examples of "heteroaryl" include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl,

[0367] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0368] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0369] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0370] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0371] The term "therapeutically effective amount" means (i) treating a particular disease, condition, or disorder, or (ii) alleviating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0372] The term "prophylactically effective amount" means an amount of a compound of the present disclosure that prevents or delays the specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "prophylactically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and this disclosure.

[0373] The therapeutic or prophylactic dose of the disclosed compounds may depend, for example, on the specific use for treatment or prevention, the manner in which the compound is administered, the patient's health and condition, and the discretion of the prescribing physician. The proportion or concentration of the disclosed compounds in a pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compounds may be provided in 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 of body weight per day. The dose is likely to depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose may be obtained by extrapolation from a dose-response curve derived from an in vitro or animal model test system.

[0374] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0375] A "pharmaceutical composition" refers to a composition containing one or more compounds described herein, their isomers, or pharmaceutically acceptable salts thereof, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0376] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0377] 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.

[0378] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0379] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0380] The raw materials or intermediates used in the embodiments of the present disclosure can be obtained from commercial sources or prepared by methods of the prior art.

[0381] An important consideration in synthetic route planning in the art is the selection of appropriate protecting groups for reactive functional groups (such as the amino group in the present disclosure). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0382] In some embodiments, some of the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0383] Route 1:

[0384] Route 2:

[0385] Route 3:

[0386] Among them, R 2 、R 4 and Ring B are as defined in the present disclosure. DETAILED DESCRIPTION

[0387] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of the present disclosure. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in this disclosure are commercially available and can be used without further purification.

[0388] 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 examples, and the resulting compounds can be characterized using known instruments or methods, including but not limited to mass spectrometry, nuclear magnetic resonance, and the like.

[0389] This disclosure uses the following abbreviations:

[0390] Boc represents tert-butyloxycarbonyl;

[0391] Example 1: Preparation of Compound 1

[0392] At 0°C, Boc-norleucine (25.00g), aniline (10.07g), triethylamine (21.88g), and 1-propylphosphoric anhydride (41.30g) were added to N,N-dimethylformamide (90mL) and stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 1A (26.12g). MS (ESI): m / z 329.41 [M+Na] + .

[0393] Intermediate 1A (26.12 g) was stirred in 1,4-dioxane (250 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (106 mL) at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 1B (16.43 g). MS (ESI): m / z 207.37 [M+H] + .

[0394] At 0°C, intermediate 1B (10.00 g) and a tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 60.5 mL) were added to tetrahydrofuran (100 mL) and stirred at 75°C. After the reaction was complete, methanol (50 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 60°C for 1 hour. The solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH approximately 9) with saturated sodium bicarbonate aqueous solution. The residue was 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] + .

[0395] 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 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] + .

[0396] Intermediate 1D (2.50 g), potassium carbonate (1.24 g), and copper powder (0.31 g) were stirred in N,N-dimethylformamide (25 mL) at 115°C. After the reaction was complete, the mixture was filtered and the filtrate poured into water. The mixture was extracted 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 afford Intermediate 1E (1.88 g). MS (ESI): m / z 439.10 [M+H] + .

[0397] Intermediate 1E (1.88 g), cesium carbonate (1.24 g), and iodomethane (3.04 g) were stirred in N-methylpyrrolidone (10 mL) at room temperature. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 1F (2.07 g). MS (ESI): m / z 452.98 [M+H] + .

[0398] Intermediate 1F (2.07 g) and sodium thiomethoxide (1.60 g) were added to N,N-dimethylformamide (25 mL) and stirred at 80°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 1G (1.71 g). MS (ESI): m / z 407.21 [M+H] + .

[0399] Intermediate 1G (1.71 g) was subjected to chiral preparation (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] + .

[0400] Intermediate 1H (0.50 g), triethylamine (0.19 g), and trifluoromethanesulfonic anhydride (0.42 g) were stirred in dichloromethane (15 mL) at 0°C. After the reaction was complete, the reaction solution 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] + .

[0401] 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 stirred in 1,4-dioxane (15 mL) and water (1.5 mL) at 100°C under nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure and the intermediate 1K (0.52 g) was isolated by column chromatography (elution system: dichloromethane / methanol). MS (ESI): m / z 531.25 [M+H] + .

[0402] Intermediate 1K (200 mg) and lithium hydroxide monohydrate (32 mg) were stirred in 1,4-dioxane (6 mL) and water (2 mL) 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 obtain compound 1 (160 mg). MS (ESI): m / z 517.1289 [M+H] + .

[0403] 1 H NMR (500MHz, DMSO-d6) δ7.97(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=16.1Hz, 1H),3.82(d,J=8.3Hz,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=6.7Hz,3H).

[0404] Example 2: Preparation of Compound 2

[0405] Referring to the preparation method of compound 1 in Example 1, intermediate 1I was used to replace intermediate 1H to obtain compound 2 (80 mg). MS (ESI): m / z 517.1289 [M+H] + .

[0406] 1 H NMR (500MHz, DMSO-d6) δ7.90(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. 1Hz,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=6.8Hz,3H).

[0407] Example 3: Preparation of Compound 3

[0408] At 0°C, Boc-D-norleucine (3.0 g), 3-aminothiophene hydrochloride (1.8 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.9 g), and triethylamine (7.2 mL) were added to N,N-dimethylformamide (80 mL) and stirred at room temperature. After the reaction was complete, the reaction mixture was poured into ice water, stirred, and filtered. The filter cake was washed with water and dried to obtain Intermediate 3A (4.0 g). MS (ESI): m / z 313.09 [M+H] + .

[0409] Intermediate 3A (4.0 g) and trifluoroacetic acid (10 mL) were added to dichloromethane (30 mL) at 0°C and the reaction was stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution under ice-water bath. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 3B (3.3 g). MS (ESI): m / z 213.11 [M+H] + .

[0410] At 0°C, intermediate 3B (3.3 g) and a tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 22 mL) were added to tetrahydrofuran (60 mL) and the mixture was stirred at 75°C. After the reaction was complete, methanol (20 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 60°C for 1 hour. The solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution. The residue 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 3C (1.2 g). MS (ESI): m / z 199.15 [M+H] + .

[0411] 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) and 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 3D (2.10 g). MS (ESI): m / z 524.91 [M+H] + .

[0412] Intermediate 3D (2.10 g), potassium carbonate (0.99 g), and copper powder (0.25 g) were stirred in N,N-dimethylformamide (50 mL) at 115°C. After the reaction was complete, the mixture was filtered and the filtrate poured into water and extracted 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 3E (1.30 g). MS (ESI): m / z 445.02 [M+H] + .

[0413] Intermediate 3E (1.30 g), cesium carbonate (1.90 g), and iodomethane (2.00 g) were stirred in N-methylpyrrolidone (40 mL) at room temperature. After the reaction was complete, the reaction solution was poured into water and extracted 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 3F (1.30 g). MS (ESI): m / z 459.01 [M+H] + .

[0414] Intermediate 3F (1.30 g) and sodium thiomethoxide (0.98 g) were added to N,N-dimethylformamide (30 mL) and stirred at 80°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 3G (0.80 g). MS (ESI): m / z 413.13 [M+H] + .

[0415] To Intermediate 3G (200 mg) in N,N-dimethylformamide (10 mL) at 0°C, sodium hydride (97 mg, 60% w / w) was slowly added. After addition, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (263 mg) in N,N-dimethylformamide (1 mL) was added dropwise. After addition, the mixture was stirred at 70°C. After the reaction was complete, saturated aqueous ammonium chloride was added 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 afford Intermediate 3H (160 mg). MS (ESI): m / z 529.17 [M+H] + .

[0416] Intermediate 3H (160.0 mg) and lithium hydroxide monohydrate (32 mg) were stirred in 1,4-dioxane (8 mL) and water (2 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated, and the aqueous phase was extracted 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 (C18 column, elution system: acetonitrile / water) to obtain compound 3 (70 mg). MS (ESI): m / z 501.0980 [M+H] + .

[0417] 1 H NMR (500MHz, DMSO-d6) δ7.55(d,J=18.5Hz,1H),7.46(s,1H),7.36(dd,J=3.1,5.1Hz,1H),7.18(s,1H),6.57(d,J=4.5Hz,1H),6.39(s ,1H),3.86(d,J=15.0Hz,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).

[0418] Example 4: Preparation of Compound 4

[0419] Referring to the preparation method of compound 3 in Example 3, Boc-L-norleucine was substituted for Boc-D-norleucine to obtain compound 4 (60 mg). MS (ESI): m / z 501.0987 [M+H] + .

[0420] 1 H NMR (500MHz, DMSO-d6) δ7.36-7.35(m,2H),7.21(d,J=18.3Hz,1H),7.17(s,1H),6.55(d,J=4.8Hz,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).

[0421] Example 5: Preparation of Compound 5

[0422] Referring to the preparation method of compound 3 in Example 3, 4-methoxybenzylamine was used to replace 3-aminothiophene hydrochloride to obtain compound 5 (100 mg). MS (ESI): m / z 539.1686 [M+H] + .

[0423] 1 H NMR(500MHz,DMSO-d6)δ7.48(d,J=18.7Hz,1H),7.39(s,1H),7.32(d,J=8.3Hz,2H ),6.92(d,J=8.5Hz,2H),6.84(s,1H),4.66(d,J=14.4Hz,1H),4.43(d,J=14.4Hz, 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=7.1Hz,3H).

[0424] Example 6: Preparation of Compound 6

[0425] Referring to the preparation method of compound 3 in Example 3, 2,3-dihydrobenzofuran-5-amine was used to replace 3-aminothiophene hydrochloride to obtain compound 6 (30 mg). MS (ESI): m / z 537.1530 [M+H] + .

[0426] 1 H NMR(500MHz,DMSO-d6)δ7.33(s,1H),7.20(d,J=18.2Hz,1H),6.86(s,1H),6.78(s ,1H),6.64(d,J=8.5Hz,1H),6.58(d,J=9.1Hz,1H),4.46(t,J=8.6Hz,2H),3.93(d ,J=15.8Hz,1H),3.72(d,J=9.0Hz,1H),3.21(m,1H),3.11(t,J=8.6Hz,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=6.6Hz,3H).

[0427] Example 7: Preparation of Compound 7

[0428] Referring to 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] + .

[0429] 1 H NMR(500MHz,DMSO-d6)δ7.49(d,J=18.6Hz,1H),7.36(s,1H),6.99(s,1H),3.66(s,1H),3.39(m,2H),2.54(s,3H),2.51(s,3 H),2.45(s,1H),2.11(d,J=8.6Hz,3H),1.94(d,J=8.5Hz,3H),1.57-1.43(m,2H),1.40-1.31(m,4H),0.92(t,J=6.0Hz,3H).

[0430] Example 8: Preparation of Compound 8

[0431] Referring to 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-L-norleucine was replaced with Boc-D-norleucine to obtain compound 8 (10 mg). MS (ESI): m / z 485.1579 [M+H] + .

[0432] 1 H NMR(500MHz,DMSO-d6)δ7.26(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=8.6Hz,3H),1.93(d,J=8.3Hz,3H),1.57-1.43(m,2H),1.40-1.30(m,4H),0.92(t,J=6.9Hz,3H).

[0433] Example 9: Preparation of Compound 9

[0434] Referring to the preparation method of compound 3 in Example 3, 2,3-dihydrobenzofuran-6-amine was used to replace 3-aminothiophene hydrochloride to obtain compound 9 (40 mg). MS (ESI): m / z 537.1533 [M+H] + .

[0435] 1H NMR(500MHz,DMSO-d6)δ13.58(brs,1H),7.74(d,J=18.6Hz,1H),7.53(s,1H),7.12 (s,1H),6.99(d,J=8.7Hz,1H),6.11(s,2H),4.49-4.45(m,2H),3.99(d,J=16.0Hz, 1H),3.83-3.82(m,1H),3.21(m,1H),3.05(t,J=8.6Hz,2H),2.49(s,3H),2.41(s,3 H),1.62-1.56(m,1H),1.53-1.47(m,1H),1.39-1.29(m,4H),0.91(t,J=6.8Hz,3H).

[0436] Example 10: Preparation of Compound 10

[0437] 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 hours. Iodomethane (9.71 g) was added, and the mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 10A (5.60 g). MS (ESI): m / z 248.10 [M+H] + .

[0438] At 0°C, intermediate 10A (5.60 g) and trifluoroacetic acid (20 mL) were added to dichloromethane (80 mL) and stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain intermediate 10B (5.91 g). MS (ESI): m / z 148.15 [M+H] + .

[0439] 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 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] - .

[0440] Intermediate 10C (2.50 g) and sodium hydroxide (0.53 g) were stirred in tetrahydrofuran (40 mL) and water (10 mL) at room temperature. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 3) with 1 M dilute hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 10D (2.30 g). MS (ESI): m / z 457.97 [M+H] - .

[0441] Intermediate 10D (2.30 g), aniline (0.47 g), N,N-diisopropylethylamine (1.93 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.28 g) were stirred in N,N-dimethylformamide (45 mL) at room temperature. After the reaction was complete, the reaction solution was poured into saturated aqueous ammonium chloride and extracted 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 10E (1.08 g). MS (ESI): m / z 534.87 [M+H] + .

[0442] At 0°C, intermediate 10E (1.08 g) and a tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 2.5 mL) were added to tetrahydrofuran (40 mL) and the mixture was stirred at 75°C. After the reaction was complete, methanol (20 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 60°C for 1 hour. The solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution. The residue 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 10F (1.04 g). MS (ESI): m / z 520.94 [M+H] + .

[0443] Referring to the preparation method of compound 3 in Example 3, intermediate 10F was used to replace intermediate 3D to obtain compound 10 (25 mg). MS (ESI): m / z 497.1213 [M+H] + .

[0444] 1H NMR (500MHz, DMSO-d6) δ7.43(s,1H),7.37(d,J=18.3Hz,1H),7.19-7.15(m,3H),6.74(t,J=7.3Hz,1H),6.67(d,J=8.1Hz,2H),4.1 2(d,J=16.2Hz,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).

[0445] Example 11: Preparation of Compound 11

[0446] At room temperature, 1-benzyl-2-methyl-(R)-aziridine-1,2-dicarboxylate (4.50 g) was dissolved in chloroform (40 ml), and ethanol (67 ml) and boron trifluoride etherate (2.4 ml) were added sequentially with stirring. After the addition, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water and extracted with dichloromethane. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 11A (5.10 g).

[0447] Intermediate 11A (5.10 g) and palladium carbon (2.00 g, palladium content 10%, water content 50%) were dissolved in methanol (40 mL) and replaced with hydrogen three times. The mixture was stirred at room temperature and reacted. After completion of the reaction, the mixture was filtered and concentrated to obtain Intermediate 11B (2.89 g).

[0448] Referring to the preparation method of compound 10 in Example 10, intermediate 11B was used to replace intermediate 10B to obtain compound 11 (100 mg). MS (ESI): m / z 497.1219 [M+H] + .

[0449] 1 H NMR (500MHz, DMSO-d6) δ7.74(d,J=18.6Hz,1H),7.56(s,1H),7.23-7.15(m,3H),6.76(t,J=7.2Hz,1H),6.70(d,J= 8.00Hz,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=6.9Hz,3H).

[0450] Example 12: Preparation of Compound 12

[0451] Intermediate 3E (1.00 g), cesium carbonate (1.10 g), and p-methoxybenzyl bromide (0.80 g) were stirred in N-methylpyrrolidone (20 mL) at room temperature. After the reaction was complete, the reaction solution was poured into water and extracted 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 12A (1.00 g). MS (ESI): m / z 565.12 [M+H] + .

[0452] Intermediate 12A (1.00 g) and sodium thiomethoxide (0.62 g) were added to N,N-dimethylformamide (35 mL) and stirred at 80°C. After the reaction was complete, the reaction solution was poured into water and extracted 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: dichloromethane / methanol) to obtain Intermediate 12B (0.90 g). MS (ESI): m / z 519.20 [M+H] + .

[0453] To Intermediate 12B (900 mg) in N,N-dimethylacetamide (20 mL) at 0°C, sodium hydride (347 mg, 60% w / w) was slowly added. After addition, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (941 mg) in N,N-dimethylformamide (2 mL) was added dropwise. After addition, the mixture was stirred at 70°C. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 12C (560 mg). MS (ESI): m / z 635.27 [M+H] + .

[0454] Intermediate 12C (560 mg) and lithium hydroxide monohydrate (93 mg) were stirred in 1,4-dioxane (20 mL) and water (5 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 12D (460 mg). MS (ESI): m / z 607.20 [M+H] + .

[0455] Intermediate 12D (460 mg) was stirred in trifluoroacetic acid (40 mL) at 55°C. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to a weakly acidic pH of approximately 5 with sodium bicarbonate solution. The phases were separated, and the aqueous phase was extracted 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 (C18 column, elution system: acetonitrile / water) to obtain compound 12 (140 mg). MS (ESI): m / z 487.0831 [M+H] + .

[0456] 1 H NMR(500MHz,DMSO-d6)δ13.61(brs,1H),7.54-7.51(m,2H),7.40(d,J=9.3Hz,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=15.2Hz,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=7.2Hz,3H).

[0457] Example 13: Preparation of Compound 13

[0458] Referring to the preparation method of Compound 1 in Example 1, Compound 13 (80 mg) was obtained by replacing (5-(methoxycarbonyl)thiophene-3-yl)boronic acid with 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester. MS (ESI): m / z 517.1304 [M+H] + .

[0459] 1 H NMR (500MHz, DMSO-d6) δ12.89 (s, 1H), 8.39 (d, J = 1.5Hz, 1H), 7.73 (s, 1H), 7. 62(d,J=1.5Hz,1H),7.24(t,J=7.9Hz,2H),7.13(s,1H),6.84(dd,J=8.2,4.9H z,3H),4.11(d,J=16.0Hz,1H),3.79(d,J=11.6Hz,1H),3.44(s,1H),2.57(s,3 H), 2.36 (s, 3H), 1.63-1.54 (m, 2H), 1.41-1.28 (m, 4H), 0.91 (t, J = 6.9Hz, 3H).

[0460] Example 14: Preparation of Compound 14

[0461] Referring to 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] + .

[0462] 1 H NMR (500MHz, DMSO-d6) δ7.95(d,J=4.2Hz,1H),7.62(s,1H),7.24(dd,J=8.5,7.1Hz,2H),7.15(s,1H),6.86-6.78(m,3H),4.11(d,J=16 .1Hz,1H),3.81(d,J=11.4Hz,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=6.8Hz,3H).

[0463] Example 15: Preparation of Compound 15

[0464] Referring to the preparation method of Compound 1 in Example 1, Compound 15 (100 mg) was obtained by substituting 2-methoxycarbonylpyridine-4-boronic acid pinacol ester for (5-(methoxycarbonyl)thiophen-3-yl)boronic acid. MS (ESI): m / z 510.1530 [M+H] - .

[0465] 1 H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.11(s,1H),7.72-7.68(m,1H),7.65(s,1H),7.24(t,J=7.8Hz,2H),7.18(s,1H),6.86-6.83(m,3H), 4.13(d,J=16.2Hz,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=6.8Hz,3H).

[0466] Example 16: Preparation of Compound 16

[0467] Referring to the preparation method of compound 10 in Example 10, D-norleucine methyl ester hydrochloride was used to replace intermediate 10B, and 1-methyl-5-aminoindole was used to replace aniline to obtain compound 16 (40 mg). MS (ESI): m / z 548.1699 [M+H] + .

[0468] 1 H NMR (500MHz, Methanol-d4) δ7.45(s,1H),7.37-7.31(m,3H),7.18-7.14(m,1H),6.97(dd,J=8.7,2.2Hz,1H),6.60(s,1H),6.38(d,J=3.0Hz ,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=7.0Hz,3H).

[0469] Example 17: Preparation of Compound 17

[0470] Referring to 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] + .

[0471] 1 H NMR(500MHz,Methanol-d4)δ8.49(s,1H),7.59(s,1H),7.56(d,J=9.0Hz,1H),7 .38(d,J=17.5Hz,1H),7.10(s,1H),7.02-6.98(m,1H),6.91(dd,J=9.0,2.3Hz,1 H),4.20(d,J=16.0Hz,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=7.0Hz,3H).

[0472] Example 18: Preparation of Compound 18

[0473] Intermediate 1H (100 mg), methyl trans-3-hydroxycyclobutanecarboxylate (35 mg), diethyl azodicarboxylate (129 mg), and triphenylphosphine (194 mg) were reacted in tetrahydrofuran (5 mL) under microwave evaporation at 60°C. After completion of the reaction, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain Intermediate 18A (140 mg). MS (ESI): m / z 519.19 [M+H] + .

[0474] Referring to the preparation method of compound 3 in Example 3, intermediate 18A was used to replace intermediate 3H to obtain compound 18 (78 mg). MS (ESI): m / z 505.1832 [M+H] + .

[0475] 1 H NMR(500MHz,Methanol-d4)δ7.24(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),3.2 7(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=7.10Hz,3H).

[0476] Example 19: Preparation of Compound 19

[0477] Referring to the preparation method of compound 18 in Example 18, compound 19 (56 mg) was obtained by replacing trans-3-hydroxycyclobutanecarboxylic acid methyl ester with cis-3-hydroxycyclobutanecarboxylic acid methyl ester. MS (ESI): m / z 505.1836 [M+H] + .

[0478] 1H NMR(500MHz,Methanol-d4)δ7.17-7.14(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=7.10Hz,3H).

[0479] Example 20: Preparation of Compound 20

[0480] Referring to the preparation method of Compound 3 in Example 3, 2-methyl-6-aminobenzoxazole was used to replace 3-aminothiophene hydrochloride, and lithium aluminum hydride tetrahydrofuran solution (2.5 mol / L) was used to replace the tetrahydrofuran solution (2.0 mol / L) of borane dimethyl sulfide complex to obtain Compound 20 (15 mg). MS (ESI): m / z 550.1487 [M+H] + .

[0481] 1 H NMR(500MHz, Methanol-d4)δ7.60(s,1H),7.51(d,J=17.4Hz,1H),7.41(d,J=8.8Hz,1H),7.14(s,1H),6.95(s,1H),6.77(dd,J=1.8,8.8Hz,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=7.15Hz,3H).

[0482] Example 21: Preparation of Compound 21

[0483] Referring to the preparation method of compound 19 in Example 19, intermediate 3G was substituted for intermediate 1H to obtain compound 21 (18 mg). MS (ESI): m / z 511.1390 ​​[M+H] + .

[0484] 1H NMR(500MHz,Methanol-d4)δ7.24-7.22(m,1H),7.10(s,1H),7.07(s,1H),6.52(d ,J=5.15Hz,1H),6.21(s,1H),5.00-4.95(m,1H),3.98(m,1H),3.86(d,J=15.75Hz, 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=7.00Hz,3H).

[0485] Example 22: Preparation of Compound 22

[0486] Referring to the preparation method of compound 3 in Example 3, 4-amino-1-methylpyridine-ethanone was used to replace 3-aminothiophene hydrochloride to obtain compound 22 (15 mg). MS (ESI): m / z 526.1489 [M+H] + .

[0487] 1 H NMR (500MHz, DMSO-d6) δ13.61(s,1H),7.79(d,J=18.5Hz,1H),7.55(s,1H),7.37(d,J=7.7Hz,1H),7.26(s,1H),5.45(d,J=61.2Hz,2H),4.18-3.7 5(m,2H),3.27(s,3H),3.22-3.13(m,1H),2.48(s,3H),2.44(s,3H),1.7 4-1.59(m,1H),1.50-1.44(s,1H),1.39-1.30(s,4H),0.93-0.90(m,3H).

[0488] Example 23: Preparation of Compound 23

[0489] Referring to the preparation method of compound 3 in Example 3, cis-3-methoxycyclobutylamine hydrochloride was used to replace 3-aminothiophene hydrochloride to obtain compound 23 (45 mg). MS (ESI): m / z 503.1688 [M+H] + .

[0490] 1H NMR (500MHz, Methanol-d4) δ7.26 (s, 1H), 7.04 (d, J = 19.3Hz, 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),2.3 0-2.15(m,1H),1.95(s,1H),1.65-1.35(m,8H),0.97(t,J=6.7Hz,3H).

[0491] Example 24: Preparation of Compound 24

[0492] Intermediate 1H (200 mg), triphenylphosphine (380 mg), diethyl azodicarboxylate (257 mg), and methyl 1-(hydroxymethyl)cyclopropanecarboxylate (147 mg) were reacted in tetrahydrofuran (2 mL) under microwave evaporation at 80°C. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the reaction solution was separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain Intermediate 24A (250 mg). MS (ESI): m / z 519.47 [M+H] + .

[0493] Intermediate 24A (250 mg) and lithium hydroxide monohydrate (60 mg) were stirred in 1,4-dioxane (20 mL) and water (5 mL) 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 24 (243 mg). MS (ESI): m / z 505.1840 [M+H] + .

[0494] 1 H NMR (500MHz, Methanol-d4) δ7.37(s,1H),7.20-7.09(m,2H),7.02(s,1H),6.73(t,J=7.3Hz,1H),6.63(d,J=8.2Hz,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),1.4 9-1.37(m,4H),1.35-1.33(m,2H),1.17-1.14(m,2H),0.96(t,J=6.9Hz,3H).

[0495] Example 25: Preparation of Compound 25

[0496] Referring to the preparation method of compound 3 in Example 3, 2-methyl-5-amino-2,3-dihydrobenzofuran was used to replace 3-aminothiophene hydrochloride to obtain compound 25 (170 mg). MS (ESI): m / z 551.1690 [M+H] + .

[0497] 1 H NMR (500MHz, Methanol-d4) δ7.46 (s, 1H), 7.37 (d, J = 17.6Hz, 1H), 6.92 (dd, J = 6.3, 2.4Hz ,1H),6.81(dt,J=8.6,2.5Hz,1H),6.72(s,1H),6.65(dd,J=8.5,1.0Hz,1H),4.93-4.88(m ,1H),3.90(d,J=13.6Hz,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=1.2Hz,3H),1.71-1.63(m,1H),1.48-1.34(m,8H),0.93(t,J=7.0Hz,3H).

[0498] Example 26: Preparation of Compound 26

[0499] 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-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (146 mg), and cesium carbonate (998 mg) were dissolved in 1,4-dioxane (20 mL) and the atmosphere was purged with nitrogen. The reaction was then microwaved at 110°C. After completion of the reaction, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 26A (67 mg). MS (ESI): m / z 532.49 [M+H] + .

[0500] Intermediate 26A (67 mg) and lithium hydroxide monohydrate (53 mg) were stirred in 1,4-dioxane (20 mL) and water (5 mL) 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 obtain compound 26 (18 mg). MS (ESI): m / z 518.2147 [M+H] + .

[0501] 1 H NMR (500MHz, Methanol-d4) δ7.53 (s, 1H), 7.21-7.15 (m, 2H), 7.00 (s, 1H), 6.78 (t, J = 7.3Hz, 1H), 6.71 ( d,J=8.1Hz,2H),4.07(d,J=16.0Hz,1H),3.94(s,1H),3.45(d,J=11.2Hz,1H),3.35-3.32(m,1H),3.10( d,J=11.4Hz,1H),2.81(t,J=10.5Hz,1H),2.76-2.69(m,2H),2.56(s,3H),2.28(s,3H),2.09-2.06(m,1 H),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=6.9Hz,3H).

[0502] Example 27: Preparation of Compound 27

[0503] Intermediate 1J (2.00 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.61 g), and triethylamine (0.75 g) were added to 1,4-dioxane (50 mL) and introduced into a stream of carbon monoxide to a pressure of 15 atm. The reaction was allowed to proceed at 100°C. After completion of the reaction, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 27A (1.20 g). MS (ESI): m / z 449.45 [M+H] + .

[0504] Intermediate 27A (0.80 g) and lithium hydroxide monohydrate (0.75 g) were stirred in 1,4-dioxane (40 mL) and water (10 mL) at room temperature. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 4) with 1 M dilute hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 27B (0.73 g). MS (ESI): m / z 435.46 [M+H] + .

[0505] Intermediate 27B (200 mg), methyl 1-aminocyclopropylcarboxylate (64 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (262 mg), and triethylamine (233 mg) were added to N,N-dimethylformamide (20 mL) and stirred at room temperature. After the reaction was complete, the reaction mixture was poured into ice water, stirred, and filtered. The filter cake was washed with water and dried to obtain Intermediate 27C (240 mg). MS (ESI): m / z 532.45 [M+H] + .

[0506] Intermediate 27C (240 mg) and lithium hydroxide monohydrate (189 mg) were stirred in 1,4-dioxane (20 mL) and water (5 mL) 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 obtain compound 27 (120 mg). MS (ESI): m / z 518.1789 [M+H] + .

[0507] 1 H NMR(500MHz,Methanol-d4)δ7.99(s,1H),7.30(t,J=7.9Hz,2H),7.00-6.97(m,3H),6.91(s,1H),4.09(d,J=14.9Hz,1H),3. 80-1.71(m,2H),2.73(s,3H),2.19(s,3H),1.73-1.66(m,1H),1.58-1.34(m,7H),1.25-1.23(m,2H),0.94(t,J=7.0Hz,3H).

[0508] Example 28: Preparation of Compound 28

[0509] Referring to the preparation method of compound 27 in Example 27, methyl 2-amino-2-methylpropionate was used to replace methyl 1-aminocyclopropylcarboxylate to obtain compound 28 (80 mg). MS (ESI): m / z 520.1943 [M+H] + .

[0510] 1 H NMR(500MHz,Methanol-d4)δ7.91(s,1H),7.28(t,J=7.9Hz,2H),6.98-6.96(m,3H),6.93(s,1H),4.10(d,J=15.5Hz,1H),3.8 2-3.63(m,2H),2.71(s,3H),2.22(s,3H),1.72-1.65(m,1H),1.58(d,J=4.9Hz,6H),1.55-1.34(m,5H),0.94(t,J=7.0Hz,3H).

[0511] Example 29: Preparation of Compound 29

[0512] Referring to the preparation method of Compound 26 of Example 26, (S)-piperidine-3-carboxylic acid methyl ester was substituted with (R)-piperidine-3-carboxylic acid methyl ester to obtain Compound 29 (18 mg). MS (ESI): m / z 518.2154 [M+H] + .

[0513] 1 H NMR(500MHz,Methanol-d4)δ7.54(s,1H),7.19-7.16(m,2H),7.00(s,1H),6.78(t,J=7.3Hz,1H) ,6.71(d,J=8.1Hz,2H),4.07(d,J=16.0Hz,1H),3.94(s,1H),3.40-3.37(m,1H),3.35-3.32(m,1 H),3.16(d,J=10.8Hz,1H),2.80-2.68(m,3H),2.56(s,3H),2.28(s,3H),2.10-2.07(m,1H),1.9 1-1.87(m,1H),1.80-1.71(m,1H),1.64-1.54(m,3H),1.49-1.38(m,4H),0.96(t,J=6.9Hz,3H).

[0514] Example 30: Preparation of Compound 30

[0515] Referring to the preparation method of Compound 24 in Example 24, 1-(hydroxymethyl)cyclopropanecarboxylic acid methyl ester was replaced with (1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester to obtain Compound 30 (200 mg). MS (ESI): m / z 505.1831 [M+H] + .

[0516] 1 H NMR(500MHz,Methanol-d4)δ7.34(s,1H),7.17-7.14(m,2H),7.03(s,1H),6.74(t,J=7 .25Hz,1H),6.64(t,J=8.15Hz,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=7.10Hz,3H).

[0517] Example 31: Preparation of Compound 31

[0518] Referring to the preparation method of compound 26 in Example 26, methyl 3-fluoroazetidine-3-carboxylate hydrochloride was used to replace (S)-piperidine-3-carboxylic acid methyl ester to obtain compound 31 (235 mg). MS (ESI): m / z 508.1748 [M+H] + .

[0519] 1 H NMR (500MHz, Methanol-d4) δ7.22-7.07(m,4H),6.72(t,J=7.30Hz,1H),6.62(d,J=8.15Hz,2H),4.57-4.48(m,2H),4.33-4.24(m,2 H),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=7.10Hz,3H).

[0520] Example 32: Preparation of Compound 32

[0521] Referring to the preparation method of Compound 24 in Example 24, Compound 32 (150 mg) was obtained by replacing 1-(hydroxymethyl)cyclopropanecarboxylic acid methyl ester with (1S,2R)-2-(hydroxymethyl)cyclopropanecarboxylic acid methyl ester. MS (ESI): m / z 505.1833 [M+H] + .

[0522] 1 H NMR (500MHz, DMSO-d6) δ12.23(s,1H),7.24(s,1H),7.14(t,J=7.6Hz,2H),7.03(s,1H),6.69(t,J= 7.2Hz,1H),6.56(d,J=7.6Hz,2H),4.42-4.39(m,1H),4.20(t,J=8.7Hz,1H),4.01(d,J=15.9Hz,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=6.50Hz,3H).

[0523] Example 33: Preparation of Compound 33

[0524] Referring to the preparation method of Compound 24 in Example 24, 1-(hydroxymethyl)cyclopropanecarboxylic acid methyl ester was replaced with (1R,2R)-2-(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester to obtain Compound 33 (250 mg). MS (ESI): m / z 505.1836 [M+H] + .

[0525] 1 H NMR(500MHz,Methanol-d4)δ7.35(s,1H),7.18-7.14(m,2H),7.03(s,1H),6.74(t,J= 7.3Hz,1H),6.64(d,J=6.6Hz,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=7.1Hz,3H).

[0526] Example 34: Preparation of Compound 34

[0527] Referring to the preparation method of compound 1 in Example 1, D-Boc-norleucine was used to replace Boc-norleucine to obtain compound 34F (1.00 g). MS (ESI): m / z 453.39 [M+H] + .

[0528] Intermediate 34F (1.00 g), potassium cyclopropyltrifluoroborate (0.55 g), potassium carbonate (0.76 g), and tetrakistriphenylphosphine palladium (0.51 g) were stirred in 1,4-dioxane (50 mL) and water (10 mL) under nitrogen at 100°C. After the reaction was complete, the reaction solution was evaporated under reduced pressure to remove most of the residue, then extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain Intermediate 34G (0.91 g). MS (ESI): m / z 415.32 [M+H] + .

[0529] Intermediate 34G (914 mg) was dissolved in dichloromethane (50 mL) and cooled at -5°C. Boron tribromide etherate (3.0 mL, 2 mol / L) was slowly added dropwise to the reaction mixture. The mixture was stirred at room temperature. After completion of the reaction, the mixture was quenched with 20 mL of methanol, concentrated under reduced pressure, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 34H (200 mg). MS (ESI): m / z 401.51 [M+H] + .

[0530] To Intermediate 34H (200 mg) in N,N-dimethylformamide (10 mL) at 0°C, sodium hydride (140 mg, 60% w / w) was slowly added. After addition, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (650 mg) in N,N-dimethylformamide (1 mL) was added dropwise. After addition, the mixture was stirred at 85°C. After the reaction was complete, saturated aqueous ammonium chloride was added 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 isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 34I (178 mg). MS (ESI): m / z 517.49 [M+H] + .

[0531] Intermediate 34I (178.0 mg) and lithium hydroxide monohydrate (58 mg) were stirred in 1,4-dioxane (10 mL) and water (2.5 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 34 (60 mg). MS (ESI): m / z 489.1868 [M+H] + .

[0532] 1 H NMR (500MHz, Methanol-d4) δ7.59 (s, 1H), 7.53 (d, J = 17.6Hz, 1H), 7.20-7.17 (m, 2H ),6.83(s,1H),6.80(t,J=7.3Hz,1H),6.69(d,J=8.2Hz,2H),4.07(d,J=16.0Hz,1H ),3.92(s,1H),2.59(s,3H),2.22-2.16(m,1H),1.63-1.53(m,2H),1.48-1.34(m,4 H),1.06-1.04(m,1H),0.95(t,J=6.9Hz,3H),0.91-0.86(m,2H),0.70-0.64(m,2H).

[0533] Example 35: Preparation of Compound 35

[0534] Referring to the preparation method of Compound 24 in Example 24, Compound 35 (140 mg) was obtained by replacing 1-(hydroxymethyl)cyclopropanecarboxylic acid methyl ester with cis-4-hydroxycyclohexanecarboxylic acid methyl ester. MS (ESI): m / z 533.2151 [M+H] + .

[0535] 1H NMR(500MHz,Methanol-d4)δ7.37(s,1H),7.17-7.14(m,2H),7.02(s,1H),6.74 (t,J=7.30Hz,1H),6.64(d,J=8.15Hz,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=7.10Hz,3H).

[0536] Example 36: Preparation of Compound 36

[0537] Referring to the preparation method of Compound 24 of Example 24, Compound 36 (180 mg) was obtained by replacing 1-(hydroxymethyl)cyclopropanecarboxylic acid methyl ester with trans-4-hydroxycyclohexanecarboxylic acid methyl ester. MS (ESI): m / z 533.2150 [M+H] + .

[0538] 1 H NMR (500MHz, DMSO-d6) δ12.08(s,1H),7.28(s,1H),7.18-7.11(m,2H),7.04(s,1H),6.69(t,J=7.2Hz,1H),6.57(d,J=8.1Hz,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),1.9 3-1.59(m,9H),1.52-1.45(m,1H),1.36-1.30(m,3H),0.93-0.90(m,3H).

[0539] Example 37: Preparation of Compound 37

[0540] Intermediate 1J (1.00 g), pinacol borate (0.94 g), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (0.27 g), and potassium acetate (0.36 g) were reacted in 1,4-dioxane (50 mL) at 100°C after nitrogen substitution. After completion of the reaction, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 37A (0.69 g). MS (ESI): m / z 517.28 [M+H] + .

[0541] Referring to the preparation method of Compound 1 in Example 1, 2-bromothiazole-5-carboxylic acid methyl ester was substituted for (5-(methoxycarbonyl)thiophen-3-yl)boronic acid. After reacting with Intermediate 37A, compound 37 (33 mg) was obtained by further conversion. MS (ESI): m / z 518.1247 [M+H] + .

[0542] 1 H NMR (500MHz, DMSO-d6) δ8.44(s,1H),8.39(s,1H),7.35(t,J=7.6Hz,2H),7.11(d,J=8.1Hz,2H),7.06(t,J=7.4Hz,1H),6.93(s,1H),4.10( d,J=15.4Hz,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=7.0Hz,3H).

[0543] Example 38: Preparation of Compound 38

[0544] Under nitrogen protection, triphenylphosphine (3.76 g) and carbon tetrabromide (2.38 g) were dissolved in dichloromethane (40 ml), followed by the slow dropwise addition of ethyl 3,3,3-trifluoropyruvate (1.00 g). After the addition, the mixture was stirred under ice. After completion of the reaction, the reaction solution was concentrated and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 38A (1.20 g).

[0545] Under nitrogen at -50°C, isopropylmagnesium chloride (2M, 1.8 mL) was slowly added to a solution of Intermediate 38A (1.20 g) in diethyl ether (40 mL). The mixture was stirred for 15 min, followed by the addition of methanol (6 mL). The mixture was slowly warmed to room temperature and stirred. After the reaction was complete, water was added to quench the reaction, followed by extraction with diethyl ether. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 38B (0.28 g).

[0546] Potassium carbonate (67 mg), tetrakistriphenylphosphine palladium (56 mg), Intermediate 38B (100 mg), and Intermediate 37A (460 mg) were reacted in dioxane (15 ml) and water (3 ml) under nitrogen in an oil bath at 100°C. After completion of the reaction, 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]+ .

[0547] Intermediate 38C (115 mg) and lithium hydroxide monohydrate (20 mg) were stirred in 1,4-dioxane (10 mL) and water (2.5 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 38 (30 mg). MS (ESI): m / z 529.1430 [M+H] + .

[0548] 1 H NMR (500MHz, DMSO-d6) δ7.96(d,J=84.0Hz,1H),7.72-7.42(m,1H),7.27-7.21(m,2H),7.12(d,J=4.2Hz,1H),6.88-6.80(m,3H),4.08(d,J=16.1Hz, 1H),3.86-3.73(m,1H),2.53(s,3H),2.42(d,J=3.9Hz,3H),1.61-1.53(m ,2H),1.34(d,J=8.8Hz,2H),1.24(d,J=6.7Hz,3H),0.90(t,J=6.5Hz,3H).

[0549] Example 39: Preparation of Compound 39

[0550] Referring to the preparation method of Compound 37 in Example 37, 2-bromothiazole-5-carboxylic acid methyl ester was substituted with 5-bromothiophene-2-carboxylic acid methyl ester to obtain Compound 39 (130 mg). MS (ESI): m / z 517.1292 [M+H] + .

[0551] 1 H NMR(500MHz, Methanol-d4)δ7.80(s,1H),7.75(d,J=3.8Hz,1H),7.30-7.27(m,3H),6.98-6.94(m,4H),4.12(d,J=15.3Hz,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=7.0Hz,3H).

[0552] Example 40: Preparation of Compound 40

[0553] Referring to the preparation method of compound 3 in Example 3, 2-(dimethylphosphino)aniline was used to replace 3-aminothiophene hydrochloride to obtain compound 40 (300 mg). MS (ESI): m / z 571.1525 [M+H] + .

[0554] 1 H NMR (500MHz, DMSO-d6) δ13.52(s,1H),8.04(dd,J=12.4,7.7Hz,1H),7.81(t,J=7.8Hz,1H),7.59-7.53(m,4H),5.88(s,1H),4.24-4.22(m,1 H),3.99(d,J=13.5Hz,1H),3.42(d,J=14.4Hz,1H),2.64(s,3H),1.94(s,3H),1.73(t,J=13.1Hz,4H),1.43-1.14(m,7H),0.97-0.73(m,3H).

[0555] Example 41: Preparation of Compound 41

[0556] Referring to the preparation method of compound 3 in Example 3, 4-(dimethylphosphino)aniline was used to replace 3-aminothiophene hydrochloride to obtain compound 41 (80 mg). MS (ESI): m / z 571.1501 [M+H] + .

[0557] 1 H NMR(500MHz,DMSO-d6)δ13.63(s,1H),7.77(d,J=18.5Hz,1H),7.58(s,1H), 7.52(dd,J=10.9,8.5Hz,2H),7.28(s,1H),6.69(d,J=8.2Hz,2H),4.10(d,J =16.1Hz,1H),3.94-3.88(m,1H),3.25(s,1H),2.47(d,J=11.1Hz,6H),1.72 -1.62(m,1H),1.58-1.48(M,7H),1.40-1.31(m,4H),0.93(d,J=6.9Hz,3H).

[0558] Example 42: Preparation of Compound 42

[0559] 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 at 80°C in an open atmosphere. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and intermediate 42A (250 mg) was isolated by column chromatography (elution system: petroleum ether / ethyl acetate). MS (ESI): m / z 485.21 [M+H] + .

[0560] Referring to the preparation method of compound 3 in Example 3, intermediate 42A was used to replace intermediate 3F to obtain compound 42 (12 mg). MS (ESI): m / z 527.1141 [M+H] + .

[0561] 1 H NMR(500MHz, Methanol-d4)δ7.37(s,1H),7.31-7.26(m,2H),6.86(s,1H),6.82(d,J=5.15Hz,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),1.3 5-1.62(m,5H),0.84-0.78(m,4H),0.69-0.63(m,1H),0.57-0.45(m,2H).

[0562] Example 43: Preparation of Compound 43

[0563] Intermediate 27B (100 mg), taurine (57.6 mg), triethylamine (70 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (131 mg) were dissolved in DMF. After addition, the reaction mixture was stirred at room temperature. After completion of the reaction, the reaction solution was poured into water and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phase was washed sequentially 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] + .

[0564] 1H NMR(500MHz,MeOD)δ7.84(s,1H),7.20(t,J=7.8Hz,2H),6.89-6.87(m,3H),6.83(s,1H),3.99(d,J=14 .2Hz,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).

[0565] Example 44: Preparation of Compound 44

[0566] Referring to the preparation method of compound 3 in Example 3, 1-adamantanamine was used to replace 3-aminothiophene hydrochloride to obtain compound 44 (65 mg). MS (ESI): m / z 553.2203 [M+H] + .

[0567] 1 H NMR (500MHz, Methanol-d4) δ7.44(s,1H),7.38(d,J=17.6Hz,1H),7.21(s,1H),3.91-3.87(m,1H),3.43(d,J=15.9Hz,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=6.4Hz,3H).

[0568] Example 45: Preparation of Compound 45

[0569] 2-Adamantane ketone (10.00 g), hydroxylamine hydrochloride (9.30 g), and sodium acetate (10.90 g) were added to methanol (200 mL) and stirred at 65°C. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 45A (11.10 g).

[0570] To 45A (11.00 g) in tetrahydrofuran (250 mL) was slowly added a 2.5 M solution of lithium aluminum tetrahydride in tetrahydrofuran (80 mL) at 0°C. After the addition was complete, the reaction was stirred at 65°C. After the reaction was complete, ice water (8 mL), aqueous sodium hydroxide solution (8 mL, 15%), and ice water (24 mL) were slowly added to the reaction mixture in an ice bath. After stirring for 10 minutes, anhydrous sodium sulfate (30 g) was added, and the mixture was filtered through celite. The filtrate was concentrated to obtain intermediate 45B (8.80 g). MS (ESI): m / z 152.31 [M+H] + .

[0571] At 0°C, Boc-norleucine (8.80 g), Intermediate 45B (6.33 g), triethylamine (15.40 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (21.70 g) were added to N,N-dimethylformamide (100 mL) and stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 45C (12.11 g). MS (ESI): m / z 365.31 [M+H] + .

[0572] Intermediate 45C (7.00 g) was reacted with trifluoroacetic acid (20 mL) in dichloromethane (100 mL) with stirring at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 45D (4.60 g). MS (ESI): m / z 265.25 [M+H] + .

[0573] 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 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 obtain Intermediate 45E (7.40 g). MS (ESI): m / z 591.06 [M+H] + .

[0574] Intermediate 45E (7.40 g) and a tetrahydrofuran solution of borane dimethyl sulfide complex (2 M, 18.9 mL) were added to tetrahydrofuran (50 mL) at 0°C and stirred at 75°C. After the reaction was complete, methanol (50 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 60°C for 1 hour. The solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 45F (5.30 g). MS (ESI): m / z 579.05 [M+H] + .

[0575] Intermediate 45F (2.00 g), potassium tert-butoxide (0.97 g), and copper powder (1.32 g) were stirred in N,N-dimethylacetamide (100 mL) at 95°C. After the reaction was complete, the mixture was filtered and the filtrate poured into water and extracted 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 45G (0.81 g). MS (ESI): m / z 497.08 [M+H] + .

[0576] Intermediate 45G (0.40 g), cesium carbonate (0.31 g), and iodomethane (0.33 g) were stirred in N-methylpyrrolidone (10 mL) at room temperature. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 45H (0.22 g). MS (ESI): m / z 511.02 [M+H] + .

[0577] Intermediate 45H (0.18 g) and sodium thiomethoxide (0.74 g) were added to N,N-dimethylformamide (25 mL) and stirred at 80°C. After the reaction was complete, the reaction solution was poured into saturated aqueous ammonium chloride and extracted 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 45I (0.15 g). MS (ESI): m / z 465.21 [M+H] + .

[0578] To Intermediate 45I (120 mg) in N,N-dimethylacetamide (6 mL) at 0°C, sodium hydride (62 mg, 60% w / w) was slowly added. After addition, 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 addition, the mixture was stirred at 80°C. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 45J (100 mg). MS (ESI): m / z 581.23 [M+H] + .

[0579] Intermediate 45J (100 mg) and lithium hydroxide monohydrate (108.4 mg) were stirred in 1,4-dioxane (8 mL) and water (4 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 45 (70 mg). MS (ESI): m / z 553.2208 [M+H] + .

[0580] 1 H NMR (500MHz, Methanol-d4) δ7.40 (s, 1H), 7.29 (d, J = 17.6Hz, 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=6.8Hz,3H).

[0581] Example 46: Preparation of Compound 46

[0582] Intermediate 45G (0.40 g), cesium carbonate (0.30 g), and 4-methoxybenzyl chloride (0.11 g) were stirred in DMF (10 mL) at room temperature. After the reaction was complete, the reaction solution was poured into water and extracted 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 46A (0.21 g). MS (ESI): m / z 617.14 [M+H] + .

[0583] Referring to 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] + .

[0584] 1 H NMR (500MHz, Methanol-d4) δ7.46 (s, 1H), 7.26 (d, J = 17.6Hz, 1H), 6.99 (s, 1H), 3.57 -3.49(m,3H),2.37(s,3H),2.32(d,J=12.3Hz,1H),2.20-2.15(m,2H),2.09-2.06(m ,1H),2.02(d,J=12.5Hz,1H),1.91-1.88(m,1H),1.80-1.70(m,4H),1.68-1.61(m,3 H),1.46-1.44(m,1H),1.40-1.21(m,7H),1.11-1.08(m,1H),0.84(t,J=7.2Hz,3H).

[0585] Example 47: Preparation of Compound 47

[0586] Referring to the preparation method of compound 45 of Example 45, 3,4-(methylenedioxy)aniline was used to replace intermediate 45B to obtain compound 47 (100 mg). MS (ESI): m / z 539.1331 [M+H] + .

[0587] 1H NMR (500MHz, Methanol-d4) δ7.42 (s, 1H), 7.30 (d, J = 17.6Hz, 1H), 6.82 (s, 1H), 6. 64(d,J=8.4Hz,1H),6.40(d,J=2.2Hz,1H),6.30(dd,J=2.2,8.4Hz,1H),5.80(dd, J=1.0,7.3Hz,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=7.0Hz,3H).

[0588] Example 48: Preparation of Compound 48

[0589] Referring to the preparation method of compound 45 of Example 45, 4-aminobenzocyclobutene was used to replace intermediate 45B to obtain compound 48 (190 mg). MS (ESI): m / z 521.1568 [M+H] + .

[0590] 1 H NMR (500MHz, Methanol-d4) δ7.41(s,1H),7.32(d,J=17.6Hz,1H),6.80(d,J=7.4Hz,1H),6.81(s,1H),6.63(dd,J=1.6,8.0Hz,1H),6.57(s,1H),3.92( d,J=15.6Hz,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=7.0Hz,3H).

[0591] Example 49: Preparation of Compound 49

[0592] Referring to the preparation method of compound 24 in Example 24, methyl hydroxytrimethylacetate was used to replace methyl 1-(hydroxymethyl)cyclopropanecarboxylate to obtain compound 49 (200 mg). MS (ESI): m / z 507.1981 [M+H] + .

[0593] 1H NMR (500MHz, Methanol-d4) δ7.38 (s, 1H), 7.22-7.15 (m, 2H), 7.04 (s, 1H), 6.77-6.74 (m, 1H), 6.66 (d, J = 8.2Hz, 2H), 4.15 (s, 2H), 4.13-3.9 6(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=2.7Hz,6H),0.99(t,J=7.2Hz,3H).

[0594] Example 50: Preparation of Compound 50

[0595] Referring to the preparation method of compound 3 in Example 3, 3-aminothiophene hydrochloride was replaced with 4-fluoroaniline to obtain intermediate 50G (1.04 g). MS (ESI): m / z 425.16 [M+H] + .

[0596] Referring again to the preparation method of Compound 24 of Example 24, methyl hydroxytrimethylacetate was used to replace methyl 1-(hydroxymethyl)cyclopropanecarboxylate to obtain Compound 50 (230 mg). MS (ESI): m / z 525.1878 [M+H] + .

[0597] 1 H NMR(500MHz,Methanol-d4)δ7.24(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=2.2Hz,6H),0.86(t,J=7.0Hz,3H).

[0598] Example 51: Preparation of Compound 51

[0599] Referring to the preparation method of compound 45 of Example 45, 1-adamantanemethane was used to replace intermediate 45B to obtain compound 51 (29 mg). MS (ESI): m / z 567.2375 [M+H] + .

[0600] 1H NMR (500MHz, DMSO-d6) δ13.53(s,1H),7.49(d,J=18.7Hz,1H),7.38(s,1H),7.24(s,1H),3.98(s,1H),3.77(d,J=14.7Hz,1H),3.09-3.01 (m,2H),2.72(d,J=14.8Hz,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).

[0601] Example 52: Preparation of Compound 52

[0602] Referring to the preparation method of compound 46 in Example 46, intermediate 51E was used to replace intermediate 45G to obtain compound 52 (30 mg). MS (ESI): m / z 553.2209 [M+H] + .

[0603] 1 H NMR (500MHz, DMSO-d6) δ13.50(s,1H),7.43(s,1H),7.36(d,J=18.7Hz,1H),7.25(s,1H),6.98(d,J=9.4Hz,1H),3.81(d,J=14.8Hz,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=7.2Hz,3H).

[0604] Example 53: Preparation of Compound 53

[0605] At 0°C, BOC-D-proline (7.00 g), aniline (13.48 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.55 g), and triethylamine (18.2 mL) were added to N,N-dimethylformamide (80 mL) and stirred at room temperature. After the reaction was complete, the reaction mixture was poured into ice water, stirred, and filtered. The filter cake was washed with water and dried to obtain Intermediate 53A (7.60 g). MS (ESI): m / z 291.13 [M+H] + .

[0606] Intermediate 53A (7.60 g) and trifluoroacetic acid (30 mL) were added to dichloromethane (100 mL) at 0°C and the reaction was stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution under ice-water bath, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 53B (5.0 g). MS (ESI): m / z 191.12 [M+H] + .

[0607] Intermediate 53B (5.0 g) and a tetrahydrofuran solution of borane dimethyl sulfide complex (2 M, 38 mL) were added to tetrahydrofuran (100 mL) at 0°C and the mixture was stirred at 75°C. After the reaction was complete, methanol (30 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 60°C for 2 hours. The solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution. The residue 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 53C (4.5 g). MS (ESI): m / z 177.14 [M+H] + .

[0608] Intermediate 53C (3.0 g), Intermediate K (1.6 g), and N,N-diisopropylethylamine (3.44 mL) were added to tetrahydrofuran (100 mL) at 0°C and 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 53D (3.0 g). MS (ESI): m / z 502.96 [M+H] + .

[0609] Intermediate 53D (3.0 g), potassium tert-butoxide (1.67 g), and copper powder (2.27 g) were stirred in N,N-dimethylformamide (25 mL) under microwave heating at 115°C. After completion of the reaction, the mixture was filtered, and the filtrate was poured into water and extracted 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 afford Intermediate 53E (0.25 g). MS (ESI): m / z 388.25 [M+H] + ;53F(2.0g), MS(ESI):m / z 423.10[M+H] + .

[0610] Intermediate 53F (2.0 g) and sodium thiomethoxide (3.32 g) were added to N,N-dimethylformamide (30 mL) and stirred at 100°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 53G (1.50 g). MS (ESI): m / z 377.18 [M+H] + .

[0611] To Intermediate 53G (400 mg) in N,N-dimethylformamide (25 mL) was slowly added sodium hydride (255 mg, 60% w / w) at 0°C. After addition, 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 addition, the mixture was stirred at 90°C. After completion of the reaction, saturated aqueous ammonium chloride was added 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 isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 53H (250 mg). MS (ESI): m / z 493.16 [M+H] + .

[0612] Intermediate 53H (250 mg) and lithium hydroxide monohydrate (64 mg) were stirred in 1,4-dioxane (20 mL) and water (5 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated, and the aqueous phase was extracted 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 (C18 column, elution system: acetonitrile / water) to obtain compound 53 (55 mg). MS (ESI): m / z 465.0953 [M+H] + .

[0613] 1 H NMR (500MHz, Methanol-d4) δ7.49 (s, 1H), 7.38 (d, J = 17.4Hz, 1H), 7.11 (t, J = 7.6Hz, 2H), 7.02 (s, 1H), 6.74-6.68 (m, 3H), 4.18 (dd, J = 15.8, 2.4Hz,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).

[0614] Example 54: Preparation of Compound 54

[0615] Referring to the preparation method of compound 53 in Example 53, intermediate 53E was used to replace intermediate 53F to obtain compound 54 (100 mg). MS (ESI): m / z 462.1497 [M+H] + .

[0616] 1 H NMR (500MHz, DMSO) δ7.59(d,J=18.5Hz,1H),7.11(t,J=7.7Hz,2H),7.03(d,J=2.8Hz,1H),6.93(d,J=2.9Hz,1H),6.67(t,J=7.2Hz,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).

[0617] Example 55: Preparation of Compound 55

[0618] Referring to the preparation method of compound 53 in Example 53, BOC-D-homoproline was used to replace BOC-D-proline to obtain compound 55 (30 mg). MS (ESI): m / z 479.1112 [M+H] + .

[0619] 1 H NMR (500MHz, Methanol-d4) δ7.56 (s, 1H), 7.49 (d, J = 17.4Hz, 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).

[0620] Example 56: Preparation of Compound 56

[0621] Intermediate 55F (100 mg), triethylamine (233 mg), and trifluoromethanesulfonic anhydride (520 mg) were stirred in dichloromethane (15 mL) at 0°C. After the reaction was complete, the reaction solution was poured into water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to isolate Intermediate 56A (120 mg). MS (ESI): m / z 523.08 [M+H] + .

[0622] Intermediate 56A (120 mg), methyl 4-(4,4,5,5-tetramethyl-2-1,3-dioxaboryl)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 stirred in 1,4-dioxane (20 mL) and water (4 mL) at 100°C under nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure and the reaction solution was isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to obtain Intermediate 56B (45 mg). MS (ESI): m / z 515.16 [M+H] + .

[0623] Intermediate 56B (45 mg) and lithium hydroxide monohydrate (15 mg) were stirred in 1,4-dioxane (20 mL) and water (5 mL) at room temperature. After the reaction was complete, the reaction solution was adjusted to acidity (pH approximately 4) with 1 M 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] + .

[0624] 1 H NMR(500MHz,MeOD)δ7.76(dd,J=47.3,1.5Hz,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=16.0,1 0.7Hz,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).

[0625] Example 57: Preparation of Compound 57

[0626] 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'-tetramethyluronium hexafluorophosphate (6.63 g), and triethylamine (4.07 g) were added to N,N-dimethylformamide (100 mL) and stirred at room temperature. After the reaction was complete, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the intermediate 57A (4.10 g). MS (ESI): m / z 361.15 [M+H] + .

[0627] Intermediate 57A (4.10 g) and trifluoroacetic acid (10 mL) were added to dichloromethane (50 mL) at 0°C and the mixture was stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution under ice-water bath. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 57B (3.00 g). MS (ESI): m / z 261.17 [M+H] + .

[0628] Intermediate 57B (3.00 g), Intermediate K (5.00 g), and triethylamine (4.66 g) were added to tetrahydrofuran (80 mL) at 0°C and 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 obtain Intermediate 57C (6.25 g). MS (ESI): m / z 587.00 [M+H] + .

[0629] Intermediate 57C (500 mg), cesium carbonate (830 mg), cuprous iodide (16 mg), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (12 mg) were stirred in N,N-dimethylformamide (30 mL) at 100°C. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 57D (380 mg). MS (ESI): m / z 506.99 [M+H] + .

[0630] Intermediate 57D (250 mg) and a tetrahydrofuran solution of borane dimethyl sulfide complex (2M, 4.6 mL) were added to tetrahydrofuran (3 mL) at 0°C and stirred at 75°C. After the reaction was complete, methanol (5 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 65°C for 1 hour, and the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 57E (230 mg). MS (ESI): m / z 492.88 [M+H] + .

[0631] Intermediate 57E (200 mg) and sodium thiomethoxide (850 mg) were added to N,N-dimethylformamide (10 mL) and stirred at 80°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 57F (120 mg). MS (ESI): m / z 447.11 [M+H] + .

[0632] To Intermediate 57F (100 mg) in N,N-dimethylacetamide (6 mL) at 0°C, sodium hydride (43 mg, 60% w / w) was slowly added. After addition, 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 addition, the mixture was stirred at 70°C. After the reaction was complete, saturated aqueous ammonium chloride was added 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 isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 57G (90 mg). MS (ESI): m / z 563.22 [M+H] + .

[0633] Intermediate 57G (90 mg) and lithium hydroxide monohydrate (132 mg) were stirred in 1,4-dioxane (8 mL) and water (4 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (C18 column, elution system: acetonitrile / water) to obtain compound 57 (35 mg). MS (ESI): m / z 535.1390 ​​[M+H] + .

[0634] 1H NMR(500MHz,MeOD)δ7.40(s,1H),7.30(d,J=17.5Hz,1H),6.80(s,1H),6.71-6.69(m,1H),6.61 -6.59(m,1H),6.50(dd,J=8.5,2.0Hz,1H),4.77-4.74(m,1H),3.99-3.95(m,1H),3.88(d,J=15 .5Hz,1H),3.59(dd,J=15.6,10.4Hz,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).

[0635] Example 58: Preparation of Compound 58

[0636] Methyl 4-bromopicolinate (12.00 g), potassium ethylene trifluoroborate (11.16 g), potassium phosphate (35.40 g), bistriphenylphosphine palladium dichloride (3.90 g), and water (20 mL) were added to 1,4-dioxane (100 mL) and stirred at 100°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 58A (8.40 g). MS (ESI): m / z 164.02 [M+H] + .

[0637] Intermediate 58A (4.00 g), ammonium formate (6.18 g), glacial acetic acid (7.36 g), and palladium hydroxide on carbon (12.05 g, 10% palladium content, 50% water content, w / w) were reacted in tetrahydrofuran (40 mL) and methanol (40 mL) at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered, and the filtrate was adjusted to pH ~8 with saturated aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate, and 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 afford Intermediate 58B (2.20 g). MS (ESI): m / z 172.30 [M+H] + .

[0638] Intermediate 58B (2.00 g), Intermediate K (5.07 g), and triethylamine (5.91 g) were added to tetrahydrofuran (60 mL) at 0°C and 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] + .

[0639] Intermediate 58C (4.60 g) and lithium hydroxide monohydrate (3.87 g) were stirred in 1,4-dioxane (20 mL) and water (20 mL) at room temperature. After the reaction was complete, the reaction solution was poured into ethyl acetate and adjusted to acidity (pH approximately 4) with 1M dilute hydrochloric acid solution. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 58D (4.41 g). MS (ESI): m / z 483.90 [M+H] + .

[0640] At 0°C, Intermediate 58D (4.40 g), aniline (0.85 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.48 g), and triethylamine (2.75 g) were added to N,N-dimethylformamide (100 mL) and stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate. 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] + .

[0641] Referring to the preparation method of Compound 57 of Example 57, Intermediate 58E was used to replace Intermediate 57C to obtain Compound 58 (48 mg). MS (ESI): m / z 507.1416.[M+H] + .

[0642] 1H NMR(500MHz,DMSO-d6)δ13.59(brs,1H),7.73(d,J=18.6Hz,1H),7.53(s,1H),7.23(s,1H),7.19-7. 13(m,2H),6.71(t,J=7.2Hz,1H),6.67-6.61(m,2H),4.14-4.08(m,2H),3.56(dd,J=16.2,11.0Hz,1H ),3.39-3.37(m,1H),2.59-2.51(m,1H),2.43(s,3H),2.04(d,J=13.6Hz,1H),1.73(d,J=12.7Hz,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=7.4Hz,3H).

[0643] Example 59: Preparation of Compound 59

[0644] (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 dichloromethane (15 mL) and stirred at room temperature. After the reaction was complete, the pH was adjusted to 3-5 with dilute hydrochloric acid (1 mol / L). The mixture was extracted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 59A (2.45 g). MS (ESI): m / z 244.14 [M+H] + .

[0645] Referring to the preparation method of compound 45 of Example 45, intermediate 59A was substituted for Boc-D-norleucine, and aniline was substituted for intermediate 45B to obtain compound 59 (26 mg). MS (ESI): m / z 493.1260 [M+H] + .

[0646] 1H NMR (500MHz, Methanol-d4) δ7.47 (s, 1H), 7.35 (d, J = 17.3Hz, 1H), 7.11-7.01 (m, 3H), 6. 67(t,J=7.3Hz,1H),6.59(d,J=8.2Hz,2H),4.12(dd,J=10.9,4.3Hz,1H),4.03(d,J=16.0 Hz,1H),3.50(dd,J=16.0,10.8Hz,1H),3.44-3.39(m,1H),2.54-2.47(m,1H),2.30(s,3 H),1.82(d,J=10.1Hz,1H),1.69-1.62(m,1H),1.51-1.42(m,3H),0.85(d,J=5.2Hz,3H).

[0647] Example 60: Preparation of Compound 60

[0648] 4-Bromo-2-(trifluoromethyl)thiophene (970 mg), palladium acetate (181 mg), cesium carbonate (3.94 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (466 mg), and benzophenone imine (730 mg) were dissolved in 1,4-dioxane (40 mL) and the atmosphere was replaced with nitrogen. The reaction was then microwaved at 110°C. After completion of the reaction, the mixture was filtered, concentrated, and separated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 60A (630 mg).

[0649] Intermediate 60A (630 mg) and a solution of hydrochloric acid in dioxane (4.5 mL, 4 mol / L) were stirred in 1,4-dioxane (20 mL) and water (4 mL) at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, the mixture was slurried with dichloromethane, and filtered to obtain Intermediate 60B (370 mg).

[0650] Referring to the preparation method of Compound 45 of Example 45, Intermediate 60B was substituted for Intermediate 45B, and (R)-1-N-Boc-piperidine-2-carboxylic acid was substituted for Boc-D-norleucine to obtain Compound 60 (20 mg). MS (ESI): m / z 553.0558 [M+H] + .

[0651] 1H NMR (500MHz, Methanol-d4) δ7.55(s,1H),7.47(d,J=17.4Hz,1H),7.27(s,1H),6.94(s,1H),6.47(d,J=1.8Hz,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).

[0652] Example 61: Preparation of Compound 61

[0653] Referring to the preparation method of compound 45 of Example 45, chroman-7-amine was used to replace intermediate 45B to obtain compound 61 (60 mg). MS (ESI): m / z 551.1680 [M+H] + .

[0654] 1 H NMR (500MHz, Methanol-d4) δ7.44(s,1H),7.37(d,J=17.4Hz,1H),6.99(s,1H),6.77(d,J=8.4Hz,1H),6.17(dd,J=2.0,8.3Hz,1H),6.07 (d,J=1.6Hz,1H),4.03-3.97(m,2H),3.90(d,J=15.6Hz,1H),3.79(s,1H),3.28(s,1H),2.58(t,J=6.4Hz,2H),2.51(s,3H),2.26(s,3H), 1.87-1.82(m,2H),1.57-1.49(m,1H),1.48-1.41(m,1H),1.38-1.28(m,4H),0.86(t,J=7.0Hz,3H).

[0655] Example 62: Preparation of Compound 62

[0656] Referring to the preparation method of compound 3 in Example 3, chroman-6-amine hydrochloride was used in place of 3-aminothiophene hydrochloride to obtain compound 62 (90 mg). MS (ESI): m / z 551.1699 [M+H] + .

[0657] 1H NMR(500MHz,Methanol-d4)δ7.47(s,1H),7.35(d,J=17.6Hz,1H),6.80(s,1H) ,6.77-6.69(m,2H),6.67(d,J=8.6Hz,1H),4.20-4.04(m,2H),3.93(d,J=15.4H z,1H),3.75(s,1H),3.64(d,J=13.6Hz,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=6.9Hz,3H).

[0658] Example 63: Preparation of Compound 63

[0659] Referring to 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] + .

[0660] 1 H NMR (500MHz, Methanol-d4) δ7.42 (s, 1H), 7.26 (d, J = 17.5Hz, 1H), 6.74 (s, 1H), 6.65-6.54(m,3H),4.14(d,J=15.3Hz,1H),4.02(dd,J=5.9,4.4Hz,2H),3.40-3 .30(m,1H),3.13(d,J=14.1Hz,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=7.2Hz,3H).

[0661] Example 64: Preparation of Compound 64

[0662] Referring to 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] + .

[0663] 1H NMR (500MHz, Methanol-d4) δ7.45 (s, 1H), 7.30 (d, J = 17.5Hz, 1H), 6.84 (s, 1H), 6.62(d,J=8.4Hz,1H),6.39(d,J=2.3Hz,1H),6.29(dd,J=2.3,8.4Hz,1H),5.79( dd,J=1.0,6.6Hz,2H),4.15(d,J=15.4Hz,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).

[0664] Example 65: Preparation of Compound 65

[0665] Referring to the preparation method of compound 3 in Example 3, 4-amino-1,3-benzodioxole was used to replace 3-aminothiophene hydrochloride to obtain compound 65 (90 mg). MS (ESI): m / z 539.1313 [M+H] + .

[0666] 1 H NMR (500MHz, Methanol-d4) δ7.38 (s, 1H), 7.30 (d, J = 17.5Hz, 1H), 6.72 (s, 1H), 6.66(t,J=8.1Hz,1H),6.47(d,J=7.7Hz,1H),6.32(d,J=8.4Hz,1H),5.83(d,J=1 .1Hz,1H),5.77(s,1H),4.12-4.06(m,1H),3.63(s,2H),2.64(s,3H),2.17(s,3 H),1.61-1.53(m,1H),1.42-1.33(m,2H),1.32-1.16(m,3H),0.86-0.76(m,3H).

[0667] Example 66: Preparation of Compound 66

[0668] Referring to the preparation method of compound 45 of Example 45, 6-fluorobenzo[d][1,3]dihydroxy-5-amine was used to replace intermediate 45B to obtain compound 66 (90 mg). MS (ESI): m / z 557.1222 [M+H] + .

[0669] 1H NMR (500MHz, Methanol-d4) δ7.35 (s, 1H), 7.24 (d, J = 17.7Hz, 1H), 6.77-6.71 (m, 2H), 6.38 (s, 1H), 5.94-5.89 (m, 2H), 3.9 7-3.89(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=7.0Hz,3H).

[0670] Example 67: Preparation of Compound 67

[0671] Referring to the preparation method of compound 45 of Example 45, 2,3-dihydrobenzo[b][1,4]dioxane-6-amine was used to replace intermediate 45B to obtain compound 67 (16 mg). MS (ESI): m / z 553.1478 [M+H] + .

[0672] 1 H NMR (500MHz, Methanol-d4) δ7.37(s,1H),7.18(d,J=17.6Hz,1H),6.85(s,1H),6.62(d,J=8.5Hz,1H),6.29-6.22(m,2H),4.12-4.07(m,4H),3.83 (d,J=15.7Hz,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=6.9Hz,3H).

[0673] Example 68: Preparation of Compound 68

[0674] Referring to the preparation method of compound 45 of Example 45, 5-amino-2,2-difluoro-1,3-benzodioxole was used to replace intermediate 45B to obtain compound 68 (68 mg). MS (ESI): m / z 575.1135 [M+H] + .

[0675] 1H NMR (500MHz, Methanol-d4) δ7.46(s,1H),7.30(d,J=17.4Hz,1H),7.02(s,1H),6.90(d,J=8.8Hz,1H),6.51(s,1H),6.34(dd,J=2.0,8. 8Hz,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=7.0Hz,3H).

[0676] Example 69: Preparation of Compound 69

[0677] Sodium hydride (2.68 g), 5-nitroindoline (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 sanded and 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] + .

[0678] Intermediate 69A (3.50 g) and palladium carbon (2.00 g, 10% palladium content, 50% water content) were dissolved in methanol (20 mL). After hydrogen substitution, the mixture was stirred at room temperature. After completion of the reaction, the mixture was filtered and concentrated to afford Intermediate 69B (3.0 g). MS (ESI): m / z 148.95 [M+H] + .

[0679] Referring to the preparation method of compound 45 of Example 45, intermediate 69B was substituted for intermediate 45B to obtain compound 69 (12.5 mg). MS (ESI): m / z 550.1485 [M+H] + .

[0680] Example 70: Preparation of Compound 70

[0681] Referring to the preparation method of compound 3 in Example 3, 2,3-dihydrobenzo[b][1,4]dioxane-5-amine was used to replace 3-aminothiophene hydrochloride to obtain compound 70 (240 mg). MS (ESI): m / z 553.22 [M+H] + .

[0682] 1H NMR(500MHz, Methanol-d4)δ7.30(s,1H),7.20(d,J=17.7Hz,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=15.7,3.7Hz,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=7.0Hz,3H).

[0683] Example 71: Preparation of Compound 71

[0684] At 0°C, a solution of sodium hydroxide (3.21 g, 60% w / w) in dimethyl sulfoxide (30 mL) was slowly added dropwise to the solution. After addition, the mixture was stirred at room temperature for 1.5 hours. A solution of (S)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (6.50 g) in dimethyl sulfoxide (30 mL) was added to the stirred solution. After addition, the mixture was stirred in an oil bath. After completion, the reaction was quenched with aqueous sodium bicarbonate (5%) and washed with toluene. The aqueous phase was acidified (pH approximately 3) with dilute hydrochloric acid (1 mol / L) and extracted with methyl tert-butyl ether. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 71A (9.00 g). MS (ESI): m / z 256.34 [M+H] + .

[0685] At 0°C, 71A (6.00 g), aniline (2.30 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.50 g), and triethylamine (13.40 g) were added to N,N-dimethylformamide (100 mL) and stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water and extracted 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 71B (5.8 g). MS (ESI): m / z 331.20 [M+H] + .

[0686] Intermediate 71B (5.80 g) and palladium hydroxide on carbon (6.5 g, 10% palladium content, 50% water content, w / w) were dissolved in tetrahydrofuran (20 mL) and methanol (20 mL), replaced with hydrogen, and stirred at room temperature. After completion, the reaction 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'(1.9g). MS(ESI):m / z 333.22[M+H] + .

[0687] Intermediate 71C (3.50 g) and trifluoroacetic acid (15 mL) were added to dichloromethane (80 mL) at 0°C and the reaction was stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The mixture was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 71D (2.40 g). MS (ESI): m / z 233.23 [M+H] + .

[0688] At 0°C, Intermediate 71D (2.40 g), Intermediate K (4.00 g), and triethylamine (3.00 g) were added to tetrahydrofuran (70 mL) and 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 obtain Intermediate 71E (5.30 g). MS (ESI): m / z 559.03 [M+H] + .

[0689] 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 stirred in N,N-dimethylformamide (70 mL) at 110°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 71F (750 mg). MS (ESI): m / z 479.35 [M+H] + .

[0690] At 0°C, intermediate 71F (750 mg) and a tetrahydrofuran solution of borane dimethyl sulfide complex (1 mL, 10 mol / L) were added to tetrahydrofuran (25 mL) and stirred at 75°C. After the reaction was complete, methanol (5 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 65°C for 1 hour, and the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 71G (700 mg). MS (ESI): m / z 465.12 [M+H] + .

[0691] Intermediate 71G (700 mg) and sodium thiomethoxide (740 mg) were added to N,N-dimethylformamide (20 mL) and stirred at 80°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 71H (650 mg). MS (ESI): m / z 419.25 [M+H] + .

[0692] To Intermediate 71H (650 mg) in N,N-dimethylacetamide (40 mL) at 0°C, sodium hydride (373 mg, 60% w / w) was slowly added. After addition, 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 addition, the mixture was stirred at 90°C. After the reaction was complete, saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted 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 afford Intermediate 71I (300 mg). MS (ESI): m / z 535.24 [M+H] + .

[0693] Intermediate 71I (300 mg) and lithium hydroxide monohydrate (118 mg) were stirred in 1,4-dioxane (25 mL) and water (5 mL) 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, and the aqueous phase was extracted 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 (C18 column, elution system: acetonitrile / water) to obtain compound 71 (100 mg). MS (ESI): m / z 507.1421 [M+H] + .

[0694] 1H NMR (500MHz, DMSO-d6) δ13.66(brs,1H),7.67(dd,J=18.6,1.9Hz,1H),7.52(d,J=1.9Hz,1H),7.23(d,J=1 .8Hz,1H),7.17-7.13(m,2H),6.71(t,J=7.2Hz,1H),6.64(d,J=8.1Hz,2H),4.19-4.06(m,2H),3.59-3.53 (m,1H),3.38(d,J=12.1Hz,1H),2.58-2.52(m,1H),2.43(s,3H),2.04(d,J=13.2Hz,1H),1.73(d,J=12.8H z,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=7.4Hz,3H).

[0695] Example 72: Preparation of Compound 72

[0696] Referring to the preparation method of Compound 71 of Example 71, (S)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid was substituted with (R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid to obtain Compound 72 (240 mg). MS (ESI): m / z 507.1422 [M+H] + .

[0697] 1 H NMR(500MHz,DMSO-d6)δ7.48-7.45(m,2H),7.22(s,1H),7.20-7.08(m,2H),6.71(t,J =7.3Hz,1H),6.63(d,J=8.3Hz,2H),4.16-4.03(m,2H),3.56(dd,J=16.1,11.0Hz,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=7.4Hz,3H).

[0698] Example 73: Preparation of Compound 73

[0699] Compound 73 (90 mg) was prepared from intermediate 72C' by referring to the preparation method of compound 72 in Example 72. MS (ESI): m / z 507.1428 [M+H] + .

[0700] 1 H NMR(500MHz,DMSO-d6)δ13.55(brs,1H),7.67(d,J=18.6Hz,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=14.2Hz,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=7.4Hz,3H).

[0701] Example 74: Preparation of Compound 74

[0702] Compound 74 (195 mg) was prepared from intermediate 71C' by referring to the preparation method of compound 72 in Example 72. MS (ESI): m / z 507.1420 [M+H] + .

[0703] 1 H NMR(500MHz,DMSO-d6)δ13.56(brs,1H),7.67(d,J=18.6Hz,1H),7.52(s,1H),7.21(dd ,J=8.8,7.1Hz,2H),7.09(s,1H),6.80(d,J=7.8Hz,3H),4.19(d,J=14.2Hz,1H),3.60-3 .48(m,2H),3.21(s,1H),2.97(s,1H),2.37(s,3H),1.92(d,J=12.3Hz,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=7.4Hz,3H).

[0704] Example 75: Preparation of Compound 75

[0705] Referring to the preparation method of compound 45 of Example 45, 5-fluorobenzo[d][1,3]dioxa-4-amine was used to replace intermediate 45B to obtain intermediate 75F (600 mg). MS (ESI): m / z 515.2 [M+H] + .

[0706] Intermediate 75F (0.60 g) and sodium thiomethoxide (0.45 g) were added to N,N-dimethylformamide (15 mL) and stirred at 100°C. After the reaction was complete, the reaction solution was poured into water and extracted 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: dichloromethane / methanol) to obtain Intermediate 75G (0.40 g). MS (ESI): m / z 517.3 [M+H] + .

[0707] Referring to the preparation method of compound 66 in Example 66, intermediate 75G was substituted for intermediate 66G to obtain compound 75 (120 mg). MS (ESI): m / z 605.1287 [M+H] + .

[0708] 1H NMR (500MHz, CDCl3) δ7.86(brs,1H),7.56(s,1H),7.35(d,J=16.8Hz,1H),6.92(dd,J=9.1,5.3Hz,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=6.8Hz,3H).

[0709] Example 76: Preparation of Compound 76

[0710] Referring to the preparation method of Compound 45 of Example 45, 2,2-dimethylbenzo-1,3-dioxol-5-amine was used to replace Intermediate 45B to obtain Compound 76 (130 mg). MS (ESI): m / z 567.1636 [M+H] + .

[0711] 1H NMR (500MHz, Methanol-d4) δ7.39(s,1H),7.31(d,J=17.6Hz,1H),6.76(s,1H),6.54(d,J=8.4Hz,1H),6.34(d,J=2.2Hz,1H),6.29(dd,J=2. 2,8.4Hz,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=7.0Hz,3H).

[0712] Example 77: Preparation of Compound 77

[0713] Referring to the preparation method of Example 72, Compound 72 was prepared by replacing aniline with benzo[d][1,3]dioxol-5-amine and starting from Intermediate 77B' to obtain Compound 77 (180 mg). MS (ESI): m / z 551.1323 [M+H] + .

[0714] 1 H NMR (500MHz, Methanol-d4) δ7.55 (s, 1H), 7.48 (d, J = 17.4Hz, 1H), 7.08 (s, 1H), 6.70 (d, J = 8. 4Hz,1H),6.41(d,J=2.4Hz,1H),6.30(dd,J=2.4,8.5Hz,1H),5.88(dd,J=0.8,7.3Hz,2H),4.2 2-4.18(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).

[0715] Example 78: Preparation of Compound 78

[0716] Compound 78 (280 mg) was prepared from intermediate 77A by referring to the preparation method of compound 72 in Example 72. MS (ESI): m / z 551.1321 [M+H] + .

[0717] 1H NMR(500MHz,Methanol-d4)δ7.50(s,1H),7.36(d,J=17.4Hz,1H),6.82(d,J=8.3Hz,1H),6 .70-6.67(m,2H),6.62(dd,J=1.8,8.2Hz,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=10.4Hz,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=7.4Hz,3H).

[0718] Example 79: Preparation of Compound 79

[0719] Referring to the preparation method of compound 12 in Example 12, intermediate 70E was used to replace intermediate 3E to obtain compound 79 (88 mg). MS (ESI): m / z 539.1322 [M+H] + .

[0720] 1 H NMR(500MHz,DMSO-d6)δ13.47(brs,1H),7.78(d,J=7.6Hz,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,4 H),3.91(d,J=15.2Hz,1H),3.56(dd,J=15.9,8.1Hz,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=6.8Hz,3H).

[0721] Example 80: Preparation of Compound 80

[0722] Referring to the preparation method of compound 70 in Example 70, deuterated iodomethane was used to replace iodomethane to obtain compound 80 (50 mg). MS (ESI): m / z 556.1666 [M+H] + .

[0723] 1H NMR(500MHz, Methanol-d4)δ7.28(s,1H),7.11(d,J=17.8Hz,1H),6.77(t,J=8.0Hz,1H),6.72-6.68(m,2H),6.24(s,1H),4.21-4.04(m,5H),3 .65(dd,J=15.7,3.6Hz,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=6.9Hz,3H).

[0724] Example 81: Preparation of Compound 81

[0725] Referring to the preparation method of compound 47 in Example 47, deuterated iodomethane was used to replace iodomethane to obtain compound 81 (250 mg). MS (ESI): m / z 542.11 [M+H] + .

[0726] 1 H NMR(500MHz,Methanol-d4)δ7.53(s,1H),7.43(d,J=17.6Hz,1H),6.93(s,1H) ,6.75(d,J=8.4Hz,1H),6.52(d,J=2.3Hz,1H),6.42(dd,J=8.4,2.4Hz,1H),5. 92(dd,J=7.5,1.2Hz,2H),3.96(d,J=15.8Hz,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=6.8Hz,3H).

[0727] Example 82: Preparation of Compound 82

[0728] 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) and stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 3-5 with dilute hydrochloric acid (1 mol / L). The mixture was extracted with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 82A (6.44 g). MS (ESI): m / z 230.13 [M+H] + .

[0729] 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'-tetramethyluronium hexafluorophosphate (15.26 g) were added to N,N-dimethylformamide (50 mL) at 0°C and stirred at room temperature. After the reaction was complete, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 82B (7.39 g). MS (ESI): m / z 305.18 [M+H] + .

[0730] Intermediate 82B (4.00 g) and trifluoroacetic acid (15.00 g) were stirred in dichloromethane (50 mL) at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 82C (2.68 g). MS (ESI): m / z 205.16 [M+H] + .

[0731] At 0°C, Intermediate 82C (2.68 g), Intermediate K (4.76 g), and triethylamine (5.32 g) were added to tetrahydrofuran (50 mL) and 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 obtain Intermediate 82D (5.50 g). MS (ESI): m / z 530.95 [M+H] + .

[0732] 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 stirred in N,N-dimethylformamide (60 mL) at 110°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 82E (2.00 g). MS (ESI): m / z 450.98 [M+H] + .

[0733] Intermediate 82E (2.00 g), cesium carbonate (2.90 g), and iodomethane (1.26 g) were stirred in N-methylpyrrolidone (20 mL) at room temperature. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 82F (1.27 g). MS (ESI): m / z 464.99 [M+H] + .

[0734] Intermediate 82F (1.27 g) and a tetrahydrofuran solution of borane dimethyl sulfide complex (10 mol / L, 4 mL) were added to tetrahydrofuran (25 mL) at 0°C and stirred at 75°C. After the reaction was complete, methanol (14 mL) was added to the reaction solution to quench the reaction. The reaction was stirred at 60°C for 2 hours. The solvent was evaporated under reduced pressure, and the residue was adjusted to alkaline (pH approximately 9) with saturated aqueous sodium bicarbonate solution. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Intermediate 82G (0.43 g). MS (ESI): m / z 451.13 [M+H] + .

[0735] Intermediate 82G (0.43 g) and sodium thiomethoxide (1.34 g) were added to N,N-dimethylformamide (20 mL) and stirred at 60°C. After the reaction was complete, the reaction solution was poured into saturated aqueous ammonium chloride and extracted 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 82H (0.31 g). MS (ESI): m / z 405.19 [M+H] + .

[0736] At 0°C, sodium hydride (166 mg, 60% w / w) was slowly added to Intermediate 82H (160 mg) in N,N-dimethylacetamide (12 mL). After addition, the mixture was stirred at 0°C for 10 minutes. A solution of ethyl 3-bromo-2,2-difluoropropionate (550 mg) in N,N-dimethylacetamide (4 mL) was added dropwise. After addition, the mixture was stirred at 80°C. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography (elution system: petroleum ether / ethyl acetate) to afford Intermediate 82I (130 mg). MS (ESI): m / z 521.23 [M+H] + .

[0737] Intermediate 82I (130 mg) and lithium hydroxide monohydrate (63 mg) were stirred in 1,4-dioxane (15 mL) and water (5 mL) 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, and the aqueous phase was extracted 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 (C18 column, elution system: acetonitrile / water) to obtain compound 82 (60 mg). MS (ESI): m / z 493.1270 [M+H] + .

[0738] 1 H NMR (500MHz, Methanol-d4) δ7.37 (s, 1H), 7.28 (d, J = 17.5Hz, 1H), 7.07-6.98 (m,2H),6.89(s,1H),6.69-6.61(m,3H),4.05(d,J=15.9Hz,1H),3.81(d,J=9 .1Hz,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).

[0739] Example 83: Preparation of Compound 83

[0740] Referring to the preparation method of Compound 1 in Example 1, Intermediate 47G was substituted for Intermediate 1H, and (5-(methoxycarbonyl)thiophen-3-yl)boronic acid was substituted for (4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid to obtain Compound 83 (106 mg). MS (ESI): m / z 579.1091 [M+H]+.

[0741] 1H NMR(500MHz,Methanol-d4)δ7.61(d,J=4.3Hz,1H),7.50(s,1H),6.73-6.66(m ,2H),6.58(d,J=2.3Hz,1H),6.49(dd,J=8.3,2.3Hz,1H),5.85(dd,J=7.0,1.2H z,2H),3.84(d,J=15.1Hz,1H),3.76-3.71(m,1H),3.67-3.62(m,1H),2.68(s, 3H), 2.11 (s, 3H), 1.64-1.56 (m, 1H), 1.44-1.23 (m, 5H), 0.84 (t, J = 6.9Hz, 3H).

[0742] Example 84: Preparation of Compound 84

[0743] Referring to the preparation method of Compound 82 of Example 82, aniline was replaced by 4-(chlorodifluoromethoxy)aniline, and Intermediate 82A was replaced by Boc-D-norleucine to obtain Compound 84 (85 mg). MS (ESI): m / z 595.0961 [M+H] + .

[0744] 1 H NMR(500MHz,Methanol-d4)δ7.50(s,1H),7.41(d,J=17.4Hz,1H),7.09(s,1H),7.01(d,J=9.0Hz,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=7.0Hz,3H).

[0745] Example 85: Preparation of Compound 85

[0746] Referring to the preparation method of Example 72, Compound 72 was prepared by replacing aniline with 5-amino-1,4-benzodioxane and starting from Intermediate 71C' to obtain Compound 85 (146 mg). MS (ESI): m / z 565.1460 [M+H] + .

[0747] 1H NMR(500MHz,DMSO-d6)δ13.42(brs,1H),7.48-7.40(m,2H),6.96-6.86(m,2H),6.79( dd,J=7.1,2.3Hz,1H),6.05(s,1H),4.33-4.16(m,5H),4.01(s,1H),3.89(d,J=12.6Hz ,1H),2.84(t,J=12.1Hz,1H),2.07(s,3H),1.78(d,J=13.0Hz,1H),1.57(d,J=11.5Hz ,1H),1.48-1.30(m,2H),1.29-1.14(m,2H),1.13-1.04(m,1H),0.82(t,J=7.4Hz,3H).

[0748] Example 86: Preparation of Compound 86

[0749] Compound 86 (80 mg) was prepared from intermediate 85C' by referring to the preparation method of compound 72 in Example 72. MS (ESI): m / z 565.1461 [M+H] + .

[0750] 1 H NMR (500 MHz, Methanol-d4) 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

[0751] Referring to the preparation method of Example 72, Compound 72 was prepared by substituting N-Boc-4-oxo-D-proline for (R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid and starting from Intermediate 87C' to obtain Compound 87 (150 mg). MS (ESI): m / z 493.1274 [M+H] + .

[0752] 1H NMR(500MHz,DMSO-d6)δ13.64(brs,1H),7.66(d,J=18.5Hz,1H),7.53(s,1H),7.19(td,J= 7.3,1.8Hz,2H),7.14(s,1H),6.84-6.68(m,3H),4.23(dd,J=15.9,2.4Hz,1H),4.10-4.00( m,1H),3.63-3.49(m,1H),3.23-3.02(m,1H),2.63(t,J=9.7Hz,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=7.4Hz,3H).

[0753] Example 88: Preparation of Compound 88

[0754] Compound 88 (90 mg) was prepared from intermediate 87C by referring to the preparation method of compound 72 in Example 72. MS (ESI): m / z 493.1257 [M+H] + .

[0755] 1 H NMR(500MHz,DMSO-d6)δ13.58(brs,1H),7.72(d,J=18.6Hz,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=15.8,2.3Hz,1H),4.07(t,J=9.3Hz,1H),3.26(t,J=9.5Hz,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=7.4Hz,3H).

[0756] Example 89: Preparation of Compound 89

[0757] Referring to the preparation method of Compound 1 in Example 1, Compound 89 (100 mg) was obtained by substituting 70G for 1I and replacing (5-(methoxycarbonyl)thiophen-3-yl)boronic acid with (4-fluoro-5-(methoxycarbonyl)thiophen-3-yl)boronic acid. MS (ESI): m / z 593.1241 [M+H] + .

[0758] 1 H NMR(500MHz, Methanol-d4)δ7.66(d,J=4.1Hz,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),4.3 5-4.16(m,4H),3.77(dd,J=15.7,4.0Hz,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=7.0Hz,3H).

[0759] Example 90: Preparation of Compound 90

[0760] Intermediate 47F (500 mg), potassium carbonate (417 mg), cyclopropylboronic acid (130 mg), tetrakis(triphenylphosphine)palladium (232 mg), and water (2 mL) were dissolved in 1,4-dioxane (10 mL). After nitrogen replacement, the mixture was reacted in an oil bath at 100°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 90A (367 mg). MS (ESI): m / z 459.22 [M+H] + .

[0761] Intermediate 90A (300 mg) and sodium thiomethoxide (321 mg) were added to N,N-dimethylformamide (20 mL) and stirred in a microwave at 90°C. After the reaction was complete, the reaction solution was poured into water and extracted 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 90B (180 mg). MS (ESI): m / z 445.24 [M+H] + .

[0762] Referring to the preparation method of compound 3 in Example 3, intermediate 90B was used to replace intermediate 3G to obtain compound 90 (87 mg). MS (ESI): m / z 533.1759.[M+H] + .

[0763] 1H NMR (500MHz, Methanol-d4) δ7.53 (s, 1H), 7.49 (d, J = 17.7Hz, 1H), 6.70 (d, J = 8.4Hz, 1H), 6. 67(s,1H),6.41(d,J=2.4Hz,1H),6.31(dd,J=8.4,2.4Hz,1H),5.88(dd,J=8.0,1.2Hz,2H), 3.92(d,J=15.8Hz,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=6.9Hz,3H),0.68-0.58(m,2H).

[0764] Example 91: Preparation of Compound 91

[0765] Referring to the preparation method of compound 90 in Example 90, trimethylcyclotriboroxane was used to replace cyclopropylboronic acid to obtain compound 91 (50 mg). MS (ESI): m / z 507.1591 [M+H] + .

[0766] 1 H NMR (500MHz, Methanol-d4) δ7.44 (s, 1H), 7.37 (d, J = 17.6Hz, 1H), 6.91 (s, 1H), 6. 61(d,J=8.4Hz,1H),6.34(d,J=2.4Hz,1H),6.27(dd,J=8.4,2.4Hz,1H),5.78(dd, J=8.0,1.2Hz,2H),3.82(d,J=15.8Hz,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=6.9Hz,3H).

[0767] Example 92: Preparation of Compound 92

[0768] Referring to the preparation method of Compound 45 of Example 45, 6-amino-3H-spiro[benzofuran-2,1'-cyclopropane]-3-one was used to replace Intermediate 45B to obtain Compound 92 (25 mg). MS (ESI): m / z 563.1676 [M+H] + .

[0769] 1 H NMR (500MHz, Methanol-d4) δ7.45 (s, 1H), 7.32 (d, J = 17.5Hz, 1H), 6.99 (s, 1H), 6.92 (d,J=8.2Hz,1H),6.18(dd,J=8.1,2.3Hz,1H),6.08-6.04(m,1H),3.91(d,J=16.1Hz, 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=6.8Hz,3H),0.64-0.58(m,2H).

[0770] Example 93: Preparation of Compound 93

[0771] Referring to the preparation method of Compound 82 of 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-norleucine to obtain Compound 93 (50 mg). MS (ESI): m / z 567.1626 [M+H] + .

[0772] 1 H NMR (500MHz, Methanol-d4) δ7.27 (s, 1H), 7.11 (d, J = 17.7Hz, 1H), 6.54-6.50 (m, 2H), 6.26 (s, 1H), 4.15-4.04 (m, 5H), 3.6 3(dd,J=15.6,3.6Hz,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=6.8Hz,3H).

[0773] Example 94: Preparation of Compound 94

[0774] Referring to the preparation method of Compound 82 of 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-norleucine to obtain Compound 94 (80 mg). MS (ESI): m / z 571.1382 [M+H] + .

[0775] 1H NMR(500MHz, Methanol-d4)δ7.33(s,1H),7.24(d,J=17.6Hz,1H),6.50-6.44(m,2H),6.37(s,1H),4.20-4.07(m,4H),3.93(t,J=13.6Hz ,1H),3.74(dd,J=15.8,3.4Hz,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=6.9Hz,3H).

[0776] Experimental Example 1 FITC-preS1 peptide binding experiment

[0777] 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.

[0778] 50,000 Huh-7D-NTCP cells were seeded in a 96-well plate (Eppendorf, 30730119) and incubated at 37°C under 5% CO2 for 24 hours. Compound stock solutions were prepared using DMSO (Sigma, D2650) and compound dilutions were performed using DMEM medium (VivaCell, C3113-0500). A total of 8 concentration points were set, with the highest concentration point being 20 μM, and the dilutions were performed in 3-fold increments. The culture supernatant was discarded, and then 90 μL of DMEM medium containing the compound was added to the wells. At the same time, 90 μL of DMEM medium was added to the wells as a negative control and incubated at 37°C for 1 hour. Myrcludex B-FITC (HBV / 2-48 with lysine (K) at the C-terminus, Hefei Kesheng Jingpeptide Biotechnology Co., Ltd., was diluted in DMEM medium (VivaCell, C3113-0500) myr (C)-FITC) was added to the wells to a concentration of 100 nM. Subsequently, 10 μL of DMEM medium containing Myrcludex B-FITC was added to all wells and incubated at 37°C for 1 hour.

[0779] The supernatant was discarded, and the cells were washed with 200 μL of PBS (Gibco, C20012500BT). 50 μL of trypsin (Gibco, 12604-021) was added to the well, and the plate was incubated in a CO2 incubator at 37°C for 15 minutes. After digestion, 150 μL of PBS (Gibco, C20012500BT) containing 5% FBS (Gibco, 2409126CP) was added to terminate the digestion. After pipetting and mixing, the resuspended cells were transferred to a 96U bottom plate (Nunc, 249944). After centrifugation at 1500 rpm for 3 minutes using a centrifuge (Thermo, ST8R), the supernatant was removed, and 40 μL of PBS (Gibco, C20012500BT) was added to resuspend the cells. The cells were then collected using a flow cytometer (Sartorius, IQue3) and the geometric mean fluorescence intensity of FITC was detected to calculate the affinity of the compound to Huh-7D-NTCP cells. Calculation formula: Inhibition rate (%) = (1-compound (GMFI) / negative control (GMFI)) × 100%, IC calculated by GraphPad prism curve fitting 50 value.

[0780] The experimental results are shown in Table 1, where A represents: 0nM<IC 50 ≤500nM; B represents: 500nM<IC 50 ≤1000nM; C represents: 1000nM<IC 50 ≤5000nM; D represents: 5000nM<IC 50 .

[0781] Table 1: FACS analysis of affinity between compounds and Huh-7D-NTCP cells

[0782] Test Example 2: In vitro CYP450 enzyme inhibition activity

[0783] The human liver microsome incubation system was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.2 mg / ml), mixed CYP450 specific substrates, test compounds and NADPH+MgCl2 solution, and incubated at 37°C and 300 rpm for 0.5 hours. A positive control group and a negative control group were also set up. The positive control group was the system in which the specific inhibitor was substituted for the test compound, and the negative control group was the system in which the solvent was substituted for the test compound. After incubation, the sample was added with acetonitrile solution containing internal standard to prepare the supernatant through protein precipitation, which was 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 disclosed compounds have good stability in human liver microsomes, with a residual amount of >80% after 60 minutes.

[0784] The experimental results are shown in Table 2.

[0785] Table 2 Liver microsome stability

[0786] Experimental Example 3: Pharmacokinetics in mice

[0787] ICR mice weighing 18-22 g were acclimated for 3-5 days and then randomly divided into groups of 9 mice each. The test compound solution was orally administered at a dose of 10 mg / kg.

[0788] Blood was collected from the eye socket at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare the plasma samples to be tested.

[0789] 30 μL of the plasma sample to be tested and the standard sample were aspirated and added to an acetonitrile solution containing an internal standard for protein precipitation. The resulting supernatant was diluted and used for LC / MS / MS analysis. A non-compartmental model was used for fitting. The disclosed compounds exhibited favorable pharmacokinetic properties and high bioavailability, with relative bioavailability exceeding 75%.

[0790] The test results are shown in Table 3.

[0791] Table 3 Pharmacokinetics in mice

[0792] Test Example 4: In vitro assay of hNTCP transporter and hASBT transporter

[0793] hNTCP transporter in vitro assay

[0794] HEK293-hNTCP cells (human NTCP overexpressing cells) were 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 the logarithmic growth phase were digested with trypsin (Gbico, 12604-021) and plated to adjust the cell density to 4×10 5 cells / ml, 500 μL / well of cell suspension, cultured in a 37°C, 5% CO2 saturated humidity incubator, and allowed to adhere to the wall for 24 h. Experiments were performed when the confluence was ≥90%.

[0795] The next day, the cell supernatant was discarded, and 250 μL of preincubation solution (negative group: blank vehicle; test group: compound; final concentrations: 100 nM, 30 nM, 10 nM, 5 nM, 3 nM, 1 nM, and 0.3 nM) was added to each well, mixed, and preincubated at 37°C for 30 min. The preincubation solution was then removed. 250 μL of incubation solution (negative group: blank vehicle; test group: compound; both containing 5 μM sodium deuterated taurate (MD-1020-10mg, Guangzhou Puen Scientific Instrument Co., Ltd.)) was added to each well, mixed, and preincubated at 37°C for 2 min. The incubation solution was then removed. The reaction was terminated by adding 500 μL of ice-cold PBS (Gbico, C20012500BT), and the cells were washed twice, for a total of three times. 150 μL of cell lysis buffer (Thermo, 89900) was added to each well and lysed on ice for 20 min. After lysis, transfer the entire lysate to a 1.5 mL centrifuge tube (AXYGEN, MCT-150-CS) and centrifuge (Thermo, ST8R) at 4°C, 4000 rpm, for 10 min to obtain the supernatant. Aspirate 100 μL of the supernatant and add 400 μL of glacial acetonitrile containing an internal standard to precipitate the resulting supernatant, which was diluted for LC-MS / MS analysis.

[0796] hASBT transporter in vitro assay

[0797] HEK293-hASBT cells (human ASBT overexpressing cells) were 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 the logarithmic growth phase were digested with trypsin (Gbico, 12604-021) and plated to adjust the cell density to 4×10 5cells / ml, 500 μL / well of cell suspension, cultured in a 37°C, 5% CO2 saturated humidity incubator, and allowed to adhere to the wall for 24 h. Experiments were performed when the confluence was ≥90%.

[0798] The next day, the cell supernatant was discarded, and 250 μL of preincubation solution (negative group: blank vehicle; test group: compound; final concentrations: 30 μM, 10 μM, 3 μM, 2 μM, 1 μM, 300 nM, 100 nM) was added to each well. Mix thoroughly, incubate at 37°C for 30 min, and then remove the preincubation solution. 250 μL of incubation solution (negative group: blank vehicle; test group: compound; both containing 5 μM sodium deuterated taurate (MD-1020-10mg, Guangzhou Puen Scientific Instrument Co., Ltd.)) was added to each well. Mix thoroughly, incubate at 37°C for 2 min, and then remove the incubation solution. The reaction was terminated by adding 500 μL of ice-cold PBS (Gbico, C20012500BT), followed by two washes, for a total of three washes. 150 μL of cell lysis buffer (Thermo, 89900) was added to each well and lysed on ice for 20 min. After lysis, transfer the entire lysate to a 1.5 mL centrifuge tube (AXYGEN, MCT-150-CS) and centrifuge (Thermo, ST8R) at 4°C, 4000 rpm, for 10 min to obtain the supernatant. Aspirate 100 μL of the supernatant and add 400 μL of glacial acetonitrile containing an internal standard to precipitate the resulting supernatant, which was diluted for LC-MS / MS analysis.

[0799] The results of in vitro assays for hNTCP transporter and hASBT transporter are shown in Table 4, where A represents 0 nM < IC 50 ≤10nM; B represents: 10nM<IC 50 ≤100nM; C represents: 100nM<IC 50 ≤1000nM; D represents: 1000nM<IC 50 .

[0800] Table 4 In vitro assays for hNTCP transporter and hASBT transporter

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, X is selected from C(R a R b ) or NR c ; L is selected from a bond, O, S, (C(R a R b )) p ,(NR c ) q or (C(R a R b )) i -(NR c ) j ; R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH 2 ) n R al 、-(CH 2 ) n OR al 、-(CH 2 ) n C(O)R al 、-(CH 2 ) n C(O)OR al 、-(CH 2 ) n S(O) m R al 、-(CH 2 ) n NR a2 R a3 、-(CH 2 ) n NR a2 C(O)OR a3 、-(CH 2 ) n NR a2 C(O)(CH 2 ) nl R a3 、-(CH 2 ) n NR a2 C(O)NR a2 R a3 、-(CH 2 ) n C(O)NR a2 (CH 2 ) nl R a3 、-OC(R al R a2 ) n (CH 2 ) nl R a3 or -(CH 2 ) 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, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more substituents; Or, R 1 and R 2 Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclyl may be further optionally substituted by one or more substituents; Alternatively, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and the nitrogen atom to which they are attached together form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents; R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 The cycloalkyl or 3-14 membered heterocyclyl may be further optionally substituted by one or more substituents; R c Selected from hydrogen, hydroxyl, amino, thiol, 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 with one or more substituents; Alternatively, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclyl may be further optionally substituted by one or more substituents; Alternatively, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and together with the nitrogen atom to which they are attached form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents; Alternatively, when L is selected from (C(R a R b )) i -(NR c ) j When R a and the R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form a 3-14 membered heterocyclic group, which may be further substituted with one or more substituents; R 3 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2- 12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH 2 ) n R al 、-(CH 2 ) n OR al 、-(CH 2 ) n C(O)R al 、-(CH 2 ) n C(O)OR al 、-(CH 2 ) n S(O) m R al 、-(CH 2 ) n NR a2 R a3 、-(CH 2 ) n NR a2 C(O)OR a3 、-(CH 2 ) n NR a2 C(O)(CH 2 ) nl R a3 、-(CH 2 ) n NR a2 C(O)NR a2 R a3 、-(CH 2 ) n C(O)NR a2 (CH 2 ) nl R a3 、-OC(R al R a2 ) n (CH 2 ) nl R a3 or -(CH 2 ) 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, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl may be further substituted with one or more substituents; A is selected from Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more substituents; R 4 Selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more substituents; R 5 and R 5’ are each independently selected from hydrogen, deuterium, halogen, amino, C 1-12 Alkyl or C 1-12 Alkoxy; the amino group, C 1- 12 Alkyl or C 1-12 The alkoxy group may optionally be further substituted with one or more substituents; R a1 , R a2 or R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-104 membered aryl or 5-14 membered heteroaryl may be further substituted with one or more substituents; p, q, i or j are 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 from L is a bond, and R 1 and R 2 are each independently selected from hydrogen or unsubstituted C 1-12 When alkyl, R 4 It is not substituted or unsubstituted phenyl.

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, in, X is selected from C(R a R b ) or NR c ; L is selected from a bond, O, S, (C(R a R b )) p ,(NR c ) q or (C(R a R b )) i -(NR c ) j ; R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH 2 ) n R al 、-(CH 2 ) n OR al 、-(CH 2 ) n C(O)R al 、-(CH 2 ) n C(O)OR al 、-(CH 2 ) n S(O) m R al 、-(CH 2 ) n NR a2 R a3 、-(CH 2 ) n NR a2 C(O)OR a3 、-(CH 2 ) n NR a2 C(O)(CH 2 ) nl R a3 、-(CH 2 ) n NR a2 C(O)NR a2 R a3 、-(CH 2 ) n C(O)NR a2 (CH 2 ) nl R a3 、-OC(R al R a2 ) n (CH 2 ) nl R a3 or -(CH 2 ) 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, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further optionally substituted with one or more R aa replace; Or, R 1 and R 2 Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may be further optionally substituted by one or more R bb replace; Alternatively, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and the nitrogen atom to which they are attached together form a 3-14 membered heterocyclic group, which may be further optionally substituted by one or more R bb replace; R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may be further optionally substituted with one or more R cc replace; R c Selected from hydrogen, hydroxyl, amino, thiol, 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 with one or more R e replace; Alternatively, when L is selected from (C(R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group may be further optionally substituted with one or more R d1 replace; Alternatively, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and the nitrogen atom to which they are attached together form a 3-14 membered heterocyclic group, which may be further optionally substituted by one or more R d2 replace; Alternatively, when L is selected from (C(R a R b )) i -(NR c ) j When R a and the R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form a 3-14 membered heterocyclic group, wherein the 3-14 membered heterocyclic group may be further optionally substituted by one or more R d3 replace; R 3 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, amino, mercapto, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, C 2- 12 Alkenyl, C 2-12 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-14 membered heteroaryl, -(CH 2 ) n R al 、-(CH 2 ) n OR al 、-(CH 2 ) n C(O)R al 、-(CH 2 ) n C(O)OR al 、-(CH 2 ) n S(O) m R al 、-(CH 2 ) n NR a2 R a3 、-(CH 2 ) n NR a2 C(O)OR a3 、-(CH 2 ) n NR a2 C(O)(CH 2 ) nl R a3 、-(CH 2 ) n NR a2 C(O)NR a2 R a3 、-(CH 2 ) n C(O)NR a2 (CH 2 ) nl R a3 、-OC(R al R a2 ) n (CH 2 ) nl R a3 or -(CH 2 ) 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, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more R f replace; A is selected from Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further optionally substituted with one or more R g replace; R 4 Selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl may be further optionally substituted with one or more R h replace; R 5 and R 5’ are each independently selected from hydrogen, deuterium, halogen, amino, C 1-12 Alkyl or C 1-12 Alkoxy; the amino group, C 1- 12 Alkyl or C 1-12 The alkoxy group may optionally be further substituted with one or more R i replace; R a1 , R a2 or R a3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl or 5-14 membered heteroaryl, the amino, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-14 The cycloalkyl, 3-14 membered heterocyclyl, 6-104 membered aryl or 5-14 membered heteroaryl may be further optionally substituted with one or more R 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 are each independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, thiol, =O, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, -(CH 2 ) n R al 、-(CH 2 ) n OR al 、-(CH 2 ) n C(O)R al 、-(CH 2 ) n C(O)OR al 、-(CH 2 ) n S(O) m R al 、-(CH 2 ) n O(CH 2 ) n S(O) m R al 、-(CH 2 ) n P(O)R a2 R a3 、-(CH 2 ) n NR a2 R a3 、-(CH 2 ) n NR a2 C(O)OR a3 、-(CH 2 ) n NR a2 C(O)(CH 2 ) nl R a3 、-(CH 2 ) n NR a2 C(O)NR a2 R a3 、-(CH 2 ) n C(O)NR a2 (CH 2 ) nl R a3 、-OC(R al R a2 ) n (CH 2 ) nl R a3 or -(CH 2 ) n NR a2 S(O) m R a3 , the C 1-12 Alkyl, C 1-12 Alkoxy, C 3-14 Cycloalkyl or 3-14 membered heterocycloalkyl may optionally be further substituted with one or more substituents selected from deuterium, =0, halogen, hydroxyl, amino or cyano; p, q, i or j are 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 from L is a bond, and R 1 and R 2 are each independently selected from hydrogen or unsubstituted C 1-12 When alkyl, R 4 It is not substituted or unsubstituted phenyl.

3. The compound of formula (I) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, R a and R b are each independently selected from hydrogen, deuterium, 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 substituted with one or more R cc Substituted; preferably, R a and R b are each independently selected from hydrogen, deuterium, 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 with one or more R cc Substituted; preferably, R a and R b are each independently selected from hydrogen or methyl.

4. The compound of formula (I) according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, R c Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be further substituted with one or more R e Substituted; preferably, R c Selected from hydrogen or C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be further substituted with one or more R e Substituted; preferably, R c Selected from hydrogen, methyl or -CD 3 .

5. The compound of formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, when L is selected from (C (R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be further optionally substituted with one or more R d Substitution; preferably, when L is selected from (C (R a R b )) p or (C(R a R b )) i -(NR c ) j When R on the same or different carbon atoms a and R b and the carbon atoms to which they are attached together form a cyclopropyl or cyclobutyl group, which cyclopropyl or cyclobutyl group may optionally be further substituted by one or more R d replace; Alternatively, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and the nitrogen atom to which they are attached together form a 3-6 membered heterocyclic group, which may be further optionally substituted by one or more R d Substituted; preferably, when L is selected from (NR c ) q or (C(R a R b )) i -(NR c ) j When R on different nitrogen atoms c and the nitrogen atom to which they are attached together form a 1,3-diazetidinyl group, which may optionally be further substituted by one or more R d Substituted; or, when L is selected from (C(R a R b )) i -(NR c ) j When R a and the R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group may be further optionally substituted by one or more R d Substitution; preferably, when L is selected from (C (R a R b )) i -(NR c ) j When R a and the R on the carbon and nitrogen atoms connected to it c and the nitrogen atom to which it is attached together form an azetidinyl group, which may optionally be further substituted by one or more R d replace; Alternatively, L is selected from a bond, 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 a bond; or preferably, L is selected from a bond, CH 2 , C(CH 3 ) 2 , 6. A compound of formula (I) according to any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from CH 2 、N(CH 3 )、NH、N(CD 3 )or Preferably, X is selected from N(CH 3 ).

7. The compound of formula (I) according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, NH 2 , mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) n R al or -(CH 2 ) n OR al , the C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further substituted with one or more R aa Substituted; preferably, R 1 and R 2 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) n R al or -(CH 2 ) n OR al , the C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further substituted with one or more R aa Substituted; preferably, R 1 and R 2 are each independently selected from hydrogen, C 1-6 Alkyl, -(CH 2 ) n R al or -(CH 2 ) n OR al , the C 1-6 The alkyl group may be further substituted with one or more R aa Substituted; preferably, R 1 and R 2 are each independently selected from hydrogen, n-butyl, -CH 2 R al 、-CH 2 OR al 、-CH 2 CH 2 OR al , the n-butyl group may be further optionally substituted by one or more F, R a1 is selected from methyl, ethyl or cyclopropyl; preferably, R 1 and R 2 Each independently selected from hydrogen, n-butyl, -CH 2 OCH 2 CH 3 or -CH 2 CH 2 OCH 3 , the n-butyl group may be further optionally substituted by one or more F; preferably, R 1 and R 2 Each is independently selected from hydrogen or n-butyl, which may be further substituted by one or more F; preferably, R 1 and R 2 Each independently selected from hydrogen, n-butyl, -CH 2 OCH 2 CH 3 or -CH 2 CH 2 OCH 3 ; Or, R 1 and R 2 Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may be further optionally substituted with one or more R bb Substituted; preferably, R 1 and R 2 and together with the carbon atom to which they are attached form a cyclopentyl group, which cyclopentyl group may optionally be further substituted with one or more R bb replace; Alternatively, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and nitrogen atom to which they are attached together form a 3-6 membered heterocyclic group, which may be further optionally substituted by one or more R bb Substituted; preferably, when X is selected from (NR c ) q When R 2 and R c and the carbon atom and the nitrogen atom to which they are attached together form a pyrrolidinyl or piperidinyl group, which may optionally be further substituted by one or more R bb replace.

8. The compound of formula (I) according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -(CH 2 ) n OR al 、-(CH 2 ) n NR a2 R a3 or -(CH 2 ) n S(O) m R al , the amino group, C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be further substituted with one or more R f Substituted; preferably, R 3 Selected from halogen, hydroxyl, NH 2 , cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -(CH 2 ) n OR al 、-(CH 2 ) n NR a2 R a3 or -(CH 2 ) n S(O) m R al , the C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted with one or more R f Substituted; preferably, R 3 is selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -(CH 2 ) n OR al 、-(CH 2 ) n NR a2 R a3 -(CH 2 ) n S(O) m R al The methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl group may be further optionally substituted by one or more R f Substituted; preferably, R 3 Selected from -(CH 2 ) n S(O) m R al ; Preferably, R 3 Selected from-SCH 3 .

9. The compound of formula (I) according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 5 and R 5’ are each independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl or C 1-3 Alkoxy; the amino group, C 1-3 Alkyl or C 1-3 The alkoxy group may optionally be further substituted with one or more R i Substituted; preferably, R 5 and R 5’ are each independently selected from hydrogen, deuterium, halogen, NH 2 , methyl, ethyl, methoxy or ethoxy, wherein the methyl, ethyl, methoxy or ethoxy group may be further substituted by one or more R i Substituted; preferably, R 5 Selected from hydrogen or F; preferably, A is selected from 10. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein A is selected from Ring B is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with one or more R g Substituted; preferably, A is selected from Ring B is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl may be further optionally substituted with one or more R g replace.

11. The compound of formula (I) according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 Aryl or 5-10 membered heteroaryl, the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-12 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with one or more R h Substituted; preferably, R 4 Selected from C 5-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-12 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-12 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with one or more R h Substituted; preferably, R 4 Selected from C 5-8 Cycloalkyl, C 6-11 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, C 6-11 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with one or more R h Substituted; preferably, R 4 Selected from C 5-8 Cycloalkyl, phenyl, C 9-11 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, phenyl, C 9-11 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with one or more R h Substituted; preferably, R 4 Selected from C 5-8 Cycloalkyl, C 9-11 Aryl or 5-10 membered heteroaryl, the C 5-8 Cycloalkyl, C 9-11 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with one or more R h replace; Or, R 4 is selected from the group consisting of cyclobutyl, 1,2-dihydropyridyl, adamantyl, benzocyclobutyl, phenyl, indolyl, isoindolyl, benzopyrazolidine ring group, benzotetrahydrofuran ring group, 3H-spiro[benzofuran-2,1'-cyclopropane], benzotetrahydropyran ring group, benzodioxolanyl, benzotetrahydropyran ring group, benzopiperidine ring group, furanyl, thienyl, pyridyl, benzothiophene ring group, benzothiazole ring group, benzoxazole ring group, indolyl, benzimidazole ring group, thieno[3, 2-b]pyridine ring group, thieno[2,3-b]pyridine ring group, quinolyl, isoquinolyl, 2,3-dihydrofuro[2,3-b]pyridine ring group, 2,3-dihydrofuro[3,2-b]pyridine ring group, 2,3-dihydrobenzo[b][1,4]dioxinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2,3-dihydrofuro[3,2-c]pyridine ring group or bicyclo[1.1.1]pentyl, wherein R 4 Optionally, it may be further represented by one or more R h Substituted; preferably, R 4 Selected from The R 4 Optionally, it may be further represented by one or more R h replace.

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

13. The following compound, its stereoisomer or its pharmaceutically acceptable salt: Preferably, it is selected from the following compounds, their stereoisomers or pharmaceutically acceptable salts:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating or preventing a disease; optionally, the disease is selected from cardiovascular disease, fatty acid metabolism and glucose utilization disorders, gastrointestinal disease and liver disease.

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