Heterocyclic derivative as well as preparation method and application thereof

Abstract

The invention provides a compound as shown in a formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof. The compound provided by the invention is used as a CB1 receptor antagonist or inverse agonist, and the compound and the pharmaceutical composition thereof can be used for preparing drugs for treating and / or preventing CB1 receptor mediated diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a class of heterocyclic derivatives, their preparation methods, and their pharmaceutical uses as CB1 receptor antagonists or inverse agonists. Background Technology

[0002] Cannabinoid receptors CB1 and CB2 are key components of the endocannabinoid system. CB1 is expressed throughout the body and is widely distributed in the central nervous system (CNS), while CB2 is mainly expressed in the immune system and less frequently in the CNS.

[0003] As one of the most highly expressed G protein-coupled receptors (GPCRs) in the central nervous system, the cannabinoid receptor CB1 participates in numerous biological processes, including mood regulation, appetite and lipid metabolism, cognitive function, nociception, and cell growth and proliferation. It is a potential drug target for treating various diseases, including anxiety, obesity, pain, and neurodegenerative diseases. For example, rimonabant hydrochloride, a CB1 receptor antagonist, reduces appetite and nicotine cravings by blocking both central and peripheral CB1 receptor pathways. It can be used to treat obesity, nicotine cravings, hypertension, dyslipidemia, type 2 diabetes, and metabolic syndrome. It also lowers cholesterol and has the effect of preventing heart disease and diabetes in obese individuals. It was launched in Europe in 2006. Furthermore, basic and clinical studies have confirmed that rimonabant can effectively improve hyperglycemia, insulin resistance, and lipid metabolism disorders associated with obesity. However, its use is prohibited due to significant central nervous system-related side effects. Currently, no new CB1 receptor antagonists or inverse agonists have been approved for marketing. Summary of the Invention

[0004] In a first aspect, the present invention provides a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0005]

[0006] in,

[0007] X and Y are each independently selected from N or CR 5 ;

[0008] R 5 The group independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, -C(O)OH, -C(O)NH2, or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6Cycloalkyl or 3-6 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups, halogen groups or methyl groups;

[0009] R 1 R 2 Each is independently selected from the arbitrarily substituted: C 6-10 Aryl or 5-14 heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different R 6 replace;

[0010] R 6 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, nitro, halogen, and -OR. 7 -SR 7 -NR 7 R 7 -C(O)R 7 -C(O)OR 7 -C(O)NR 7 R 7 -OC(O)R 7 -C(=NR) 7 )R 7 ,-S(O) 1-2 R 7 -OS(O) 1-2 R 7 -S(O)2NR 7 R 7 -NR 7 S(O)2R 7 -NR 7 C(O)R 7 -NR 7 C(O)NR 7 R 7 -NR 7 S(O)2NR 7 R 7 -P(O)R 7 R 7 -P(O)(OR) 7 2. -B(OR) 7 2. Or optionally substituted with the following groups: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10Aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R groups. 7 replace;

[0011] R 7 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different hydrogens, deuterium, cyano, nitro, halogen, -R 8 -OR 8 -SR 8 -NR 8 R 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 8 R 8 -OC(O)R 8 -C(=NR) 8 )R 8 ,-S(O) 1-2 R 8 -S(O)2NR 8 R 8 -NR 8 S(O)2R 8 -NR 8 C(O)R 8 -NR 8 C(O)NR 8 R 8 -NR 8 S(O)2NR 8 R 8 -P(O)R 8 R 8 -P(O)(OR) 8 )2 or -B(OR 8 )2 replaces;

[0012] R 8 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or 3-12 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups or halogens.

[0013] R 3 Independently selected from -OR 9 -NR 9 R 9 -NR 9 S(O)2R 9 -NR 9 C(O)R 9 -NR 9 C(O)NR 9 R 9 -NR 9 S(O)2NR 9 R 9 The following groups, or optionally substituted groups: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R groups. 10 replace;

[0014] R 9 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; or, two R 9 Together with the N atom to which they are attached, they form an optionally substituted 4-11 membered heterocyclic group, which, in addition to the already included N atom, contains 0-2 (0, 1, or 2) heteroatoms selected from N, O, or S; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R atoms. 10 replace;

[0015] R10 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, nitro, halogen, oxo group, and -OR. 11 -SR 11 -SF5, -NR 11 R 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 11 R 11 -OC(O)R 11 -C(=NR) 11 )R 11 ,-S(O) 1-2 R 11 -S(O)2NR 11 R 11 -NR 11 S(O)2R 11 -NR 11 C(O)R 11 -NR 11 C(O)NR 11 R 11 -NR 11 S(O)2NR 11 R 11 -P(O)R 11 R 11 -P(O)(OR) 11 2. -B(OR) 11 2. Or optionally substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; or, when two R atoms are simultaneously attached to the same carbon atom. 10 At that time, two R 10 The carbon atoms connected thereto form optionally substituted 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl groups; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups, halogen groups, oxo groups, -C(O)OH groups, -CONH2 groups, C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)NHC 1-6 Alkyl, -C(O)N(C) 1-6Alkyl)2、-NHC(O)C 1-6 Alkyl, -NC 1-6 Alkyl C(O)C 1-6 Alkyl, -P(O)(C 1-6 Alkyl)2, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The C-terminals of halogenated alkoxy and hydroxyl groups (1 or 2) are... 1-6 Alkyl or hydroxyl-substituted (1 or 2) C 1-6 Alkyl substitution;

[0016] R 11 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g. 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuterium, cyano, nitro, halogen, -R 12 -OR 12 -SR 12 -NR 12 R 12 -C(O)R 12 -C(O)OR 12 -C(O)NR 12 R 12 -OC(O)R 12 -C(=NR) 12 )R 12 ,-S(O) 1-2 R 12 -S(O)2NR 12 R 12 -NR 12 S(O)2R 12 -NR 12 C(O)R 12 -NR 12 C(O)NR 12 R 12 -NR 12 S(O)2NR 12 R 12 -P(O)R 12 R 12 -P(O)(OR) 12 )2 or -B(OR12 )2 replaces;

[0017] R 12 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or 3-12 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups or halogens.

[0018] R 4 Selected from amino, halogen, cyano, carboxyl, -OR 13 -NR 13 R 13 -NR 13 S(O)2R 13 -NR 13 C(O)R 13 -COOR 13 -NR 13 C(O)NR 13 R 13 -NR 13 S(O)2NR 13 R 13 -NHC(=NH)NHC(O)R 13 -NHC(=NH)NHR 13 -NHC(=NH)R 13 -C(O)NR 13 R 13 -C(O)NR 13 S(O)2R 13 The following groups, or optionally substituted groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g. 0, 1, 2, 3, 4, 5 or 6) identical or different R groups. 14 replace;

[0019] R 13Each time it appears, it is independently selected from hydrogen, deuterium, hydroxyl, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; or, two R 13 Together with the N atom to which they are attached, they form an optionally substituted 4-6 membered heterocyclic group, which, in addition to the already included N atom, contains 0-2 (0, 1, or 2) heteroatoms selected from N, O, or S; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R atoms. 14 replace;

[0020] R 14 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, halogen, and -OR. 15 -SR 15 -NR 15 R 15 -C(O)R 15 -C(O)OR 15 -C(O)NR 15 R 15 -OC(O)R 15 -C(=NR) 15 )R 15 ,-S(O) 1-2 R 15 -NR 15 S(O) 1-2 R 15 -S(O)2NR 15 R 15 -NR 15 C(O)R 15 -NR 15 C(O)NR 15 R 15 -NR 15 S(O)2NR 15 R 15 -P(O)R 15 R 15 -P(O)(OR) 15 2. -B(OR) 15 2. Or optionally substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; or, when two R atoms are present on the same carbon atom. 14 At that time, two R 14 The carbon atoms connected thereto form optionally substituted 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl groups; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, cyano groups, nitro groups, halogens, -OR groups. 16 , Oxide group, -SR 16 -NR 16 R 16 -C(O)R 16 -C(O)OR 16 -C(O)NR 16 R 16 -OC(O)R 16 -C(=NR) 16 )R 16 ,-S(O) 1-2 R 16 -S(O)2NR 16 R 16 -NR 16 S(O)2R 16 -NR 16 C(O)R 16 -NR 16 C(O)NR 16 R 16 -NR 16 S(O)2NR 16 R 16 -P(O)R 16 R 16 -P(O)(OR) 16 2. -B(OR) 16 2. C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The C-terminals of halogenated alkoxy and hydroxyl groups (1 or 2) are... 1-6 Alkyl or hydroxyl-substituted (1 or 2) C 1-6 Alkyl substitution;

[0021] R 15 and R 16 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12Cycloalkyl or 3-12 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups or halogens;

[0022] The condition is that it does not contain the following compounds:

[0023]

[0024] In some embodiments, the heterocyclic group, heterocyclic alkyl group, or heteroaryl group comprises 1-4 (1, 2, 3, or 4) heteroatoms independently selected from N, O, or S; preferably N or O.

[0025] In some implementations, X is N and Y is N.

[0026] In some implementations, X is N and Y is CR. 5 .

[0027] In some implementations, X is CR 5 Y is N.

[0028] In some implementations, X is CR 5 Y is CR 5 .

[0029] In some implementation schemes, R 5 The group independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, -C(O)OH, -C(O)NH2, or optionally substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably, R 5 The group is independently selected from hydrogen, cyano, halogen, -C(O)OH, -C(O)NH2, or optionally substituted with the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, aziridinyl, or aziridine.

[0030] The optional substitution mentioned above refers to unsubstituted or optional substitution by 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogen, deuterium, hydroxyl, amino, mercapto, cyano, nitro, halogen or methyl groups;

[0031] More preferably, R 5 The group is independently selected from hydrogen, cyano, fluorine, chlorine, -C(O)OH, -C(O)NH2 or methyl; wherein the methyl group is optionally substituted by 0-3 (e.g. 0, 1, 2, 3) identical or different hydrogen, deuterium, hydroxyl, cyano, fluorine or chlorine groups;

[0032] More preferably, R 5 It is independently selected from hydrogen, cyano, fluorine, and methyl.

[0033] In some implementation schemes, R 1 and R 2 Each is independently selected from optionally substituted: phenyl or 5-6 membered heteroaryl;

[0034] Preferably, R 1 and R 2 Each is independently selected from optionally substituted: phenyl or 5-6-membered heteroaryl, wherein the 5-6-membered heteroaryl contains one or two heteroatoms each independently selected from O, S or N;

[0035] Preferably, R 1 and R 2 Each is independently selected from the optionally substituted: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiopheneyl, furanyl, pyrroloyl, thiazolyl, oxazolyl, pyrazolyl, or imidazolyl; preferably, R 1 and R 2 Each is independently selected from the optionally substituted: phenyl, pyridyl, thiophenyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, pyrazolyl, or imidazolyl; more preferably, R 1 and R 2 Each is independently selected from the optionally substituted: phenyl, pyridyl, thiophenyl, or thiazolyl; more preferably, R 1 and R 2 Each is independently selected from the optionally substituted: phenyl or pyridyl;

[0036] Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R 6 replace.

[0037] In some implementation schemes, R 6 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, halogen, and -OR. 7 -NR 7 R 7 -C(O)R 7 -C(O)NR 7 R 7 -C(=NR) 7 )R 7 ,-S(O) 1-2 R 7 -OS(O) 1-2 R 7 -S(O)2NR 7 R 7 -NR7 S(O)2R 7 -NR 7 C(O)R 7 -NR 7 C(O)NR 7 R 7 -NR 7 S(O)2NR 7 R 7 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-10 aryl, 3-6 membered heterocyclic or 5-10 membered heteroaryl; preferably, R 6 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, halogen, and -OR. 7 -NR 7 R 7 -C(O)NR 7 R 7 -OS(O) 1-2 R 7 The following groups, or optionally substituted groups: C 1-3 Alkyl, C 2-3 alkynyl group, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; more preferably, R 6 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, fluorine, chlorine, bromine, and -OR. 7 -C(O)NR 7 R 7 -OS(O) 1-2 R 7 The following groups, or optionally substituted groups: C 1-3 Alkyl, C 2-3 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; more preferably, R 6 Each time it appears, it is independently selected from hydrogen, cyano, fluorine, chlorine, and -OR. 7 -C(O)NR 7 R 7 -OS(O) 1-2 R 7 Or optionally substituted acetylene group; more preferably, R 6Each group, when appearing independently, is selected from hydrogen, cyano, fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, -C(O)NH2, -OS(O)2CH3, -OS(O)2CH2CH3, -OS(O)2CH2CH2CH3, -OS(O)2CH(CH3)2, or optionally substituted ethynyl groups; more preferably, R 6 Each time it appears, it is independently selected from hydrogen, cyano, chlorine or -C(O)NH2;

[0038] Preferably, the heterocyclic or heteroaryl group contains one or two heteroatoms independently selected from N, O or S;

[0039] Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R 7 replace.

[0040] In some implementation schemes, R 7 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic and 5-10 membered heteroaryl; preferably, R 7 Each time it appears, it is independently selected from hydrogen, optionally substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; more preferably, R 7 Each time it appears, it is independently selected from hydrogen, optionally substituted with the following groups: C 1-3 Alkyl, C 5-6 Cycloalkyl, phenyl, or 5-6 heteroaryl; more preferably, R 7 Each time it appears, it is independently selected from hydrogen, optionally substituted with the following groups: C 1-3 Alkyl, cyclopentyl, phenyl, thiophenyl, or pyridyl;

[0041] Preferably, the heterocyclic or heteroaryl group contains one or two heteroatoms independently selected from N, O or S;

[0042] The optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, deuterium, cyano, halogen (preferably F or Cl), -R 8 -OR 8 -SR 8 -NR8 R 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 8 R 8 -OC(O)R 8 -C(=NR) 8 )R 8 ,-S(O) 1-2 R 8 -S(O)2NR 8 R 8 -NR 8 S(O)2R 8 -NR 8 C(O)R 8 -NR 8 C(O)NR 8 R 8 -NR 8 S(O)2NR 8 R 8 -P(O)R 8 R 8 -P(O)(OR) 8 )2 or -B(OR 8 )2 replaces.

[0043] In some implementation schemes, R 8 Each time it appears, it is independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl or 3-6 membered heterocyclic group; preferably, R 8 Each time it appears, it is independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0044] Preferably, the heterocyclic group contains one or two heteroatoms independently selected from N, O or S;

[0045] The optional substitution refers to being unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, deuterium, hydroxyl, amino, mercapto, cyano, nitro or halogen (preferably F or Cl).

[0046] In some implementation schemes, R1 and R 2 Each of the following groups, independently selected from those with optional substitution: phenyl, pyridyl, or thiophene; the optional substitution refers to unsubstituted or optionally substituted (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R groups. 6 replace;

[0047] R 6 Each time it appears, it is independently selected from hydrogen, cyano, fluorine, chlorine, and -OR. 7 -C(O)NR 7 R 7 -OS(O) 1-2 R 7 Or acetylenic; wherein the acetylenic group is optionally surrounded by 1 R 7 replace;

[0048] R 7 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-3 Alkyl, C 5-6 Cycloalkyl, phenyl, and 5-6 heteroaryl groups; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different hydrogens, cyano groups, halogens (preferably F or Cl), or R groups. 8 Substitution; preferably, the heteroaryl group contains one or two heteroatoms independently selected from N, O or S;

[0049] R 8 Each time it appears, it is independently selected from hydrogen, deuterium, or C. 1-3 Alkyl; wherein the C 1-3 The alkyl group is optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) identical or different hydrogens, cyano groups, or halogens (preferably F or Cl).

[0050] In some implementation schemes, R 1 and R 2 Each of the following groups, independently selected from those with optional substitution: phenyl or pyridyl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-3 (e.g., 0, 1, 2 or 3; preferably 0 or 1) identical or different R groups. 6 replace;

[0051] R 6Each group, when appearing independently, is selected from hydrogen, cyano, fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, -C(O)NH2, -OS(O)2CH3, -OS(O)2CH2CH3, -OS(O)2CH2CH2CH3, -OS(O)2CH(CH3)2, or ethynyl; wherein the ethynyl group is optionally marked with an R 7 replace;

[0052] R 7 Each time it appears, it is independently selected from the following optionally substituted groups: C 1-3 Alkyl, cyclopentyl, phenyl, thiophene, or pyridyl; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-3 (e.g., 0, 1, 2, or 3; preferably 0 or 1) identical or different hydrogens, cyano, fluorine, chlorine, or R. 8 replace;

[0053] R 8 Independently selected from hydrogen or C 1-3 Alkyl; wherein the C 1-3 The alkyl group is optionally substituted with 0-3 (e.g., 0, 1, 2 or 3; preferably 0 or 1) identical or different hydrogen, cyano, fluorine or chlorine groups.

[0054] In some implementation schemes, R 1 and R 2 Each is independently selected from phenyl or pyridyl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-3 (e.g., 0, 1, 2 or 3; preferably 0 or 1) identical or different R groups. 6 replace;

[0055] R 6 Each of these groups is independently selected from hydrogen, cyano, fluorine, chlorine, methoxy, methyl, trifluoromethyl, or -C(O)NH2 each time it appears.

[0056] In some implementation schemes, R 1 and R 2 Each independently selected

[0057] In some implementation schemes, R 1 Selected from R 2 Selected from

[0058] In some implementation schemes, R 3 Independently selected from -OR 9 -NR 9 R 9 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl; preferably, R 3 Independently selected from -OR 9 -NR 9 R 9 The following groups, or optionally substituted groups: C 1-4 Alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocyclic or 5-10 membered heteroaryl; more preferably, R 3 Independently selected from -OR 9 -NR 9 R 9 The following groups, or optionally substituted groups: C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl; more preferably, R 3 Independently selected from -OR 9 -NR 9 R 9 Or optionally substituted with the following groups: phenyl, 4-6 membered heterocyclic group or 5-6 membered heteroaryl group; more preferably, R 3 Independently selected from -NR 9 R 9 Or optionally substituted with the following groups: phenyl, piperidinyl, pyridinyl, piperazine, aziridine, morpholinyl, pyrrolidinyl; more preferably, R 3 Independently selected from -NR 9 R 9 Or optionally substituted with the following groups: phenyl, in Indicate the connection site;

[0059] Preferably, the heterocyclic or heteroaryl group contains one or two heteroatoms, each independently selected from N, O or S;

[0060] Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R 10 replace.

[0061] In some implementation schemes, R 3 Selected from the optional replacements: in The connection site is indicated; the optional substitution refers to the absence of substitution or optional substitution by 0-2 identical or different R... 10 Replacement; more preferably, R 3 Selected from This is the connection site.

[0062] In some implementation schemes, R 9 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl; preferably, R 9 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, phenyl, 4-10 membered heterocyclic or 5-6 membered heteroaryl; preferably, R 9 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl, 4-9 membered heterocyclic or 5-6 membered heteroaryl; more preferably, R 9 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 4-6 Cycloalkyl, phenyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl;

[0063] Preferably, the heterocyclic or heteroaryl group contains one or two heteroatoms, each independently selected from N, O or S;

[0064] Or, two Rs 9 Together with the N atom to which they are connected, they form optionally substituted 4-10 membered heterocyclic groups (e.g., 4, 5, 6, 7, 8, 9, 10 members), which, in addition to the one N atom already included, contain 0-2 (0, 1, or 2) heteroatoms selected from N, O, or S; preferably, the heterocyclic group is a heterocyclic alkyl or heterocyclic alkenyl group; more preferably, the heterocyclic alkyl or heterocyclic alkenyl group is a monocyclic or bicyclic group; more preferably, the bicyclic group is a spirocyclic, fused (or fused) ring, or bridged ring. Form; More preferably, the helical ring is a 4-element / 4-element, 4-element / 5-element, 4-element / 6-element, 5-element / 5-element, or 5-element / 6-element helical ring, the fused ring is a 4-element / 4-element, 4-element / 5-element, 4-element / 6-element, 5-element / 5-element, or 5-element / 6-element fused ring, and the bridge ring is a two-ring bridge ring; wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R 10 replace.

[0065] In some implementation schemes, R 9 Each occurrence is independently selected from hydrogen or optionally substituted 4-6 membered heterocyclic groups; preferably hydrogen or optionally substituted tetrahydropyranyl; more preferably hydrogen or optionally substituted.

[0066] Or, two Rs 9 Together with the N atom to which they are connected, they form an optionally substituted 4-6 membered heterocyclic group, which, in addition to the one N atom already included, contains 0 or 1 heteroatom selected from N, O, or S; preferably, the two R atoms... 9 Together with the N atom to which they are connected, they form optionally substituted: 4- or 6-membered heterocyclic groups containing only one N atom; more preferably, two R atoms... 9 Together with the N atoms they are connected to, they form optionally substituted atoms: For connection sites; more preferably, two R 9 Together with the N atoms they are connected to, they form optionally substituted atoms: For connection sites;

[0067] The optional substitution refers to either not being substituted or optionally being replaced by 0-2 (preferably 0, 1, 2) identical or different Rs. 10 replace;

[0068] More preferably, two R 9 Together with the N atoms they are connected to, they form optional substitutions. This is the connection site.

[0069] In some implementation schemes, R 10 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, halogen, oxo group, -OR. 11 -SR 11 -SF5, -NR 11 R 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 11 R 11 -C(=NR) 11 )R 11 ,-S(O) 1-2 R 11 -S(O)2NR 11 R 11 -NR 11 S(O)2R 11 -NR11 C(O)R 11 -NR 11 C(O)NR 11 R 11 -NR 11 S(O)2NR 11 R 11 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; preferably, R 10 Each time it appears, it is independently selected from hydrogen, cyano, fluorine, chlorine, oxo, and -OR. 11 -SF5, -SR 11 -NR 11 R 11 -C(O)NR 11 R 11 -S(O)2R 11 -C(O)R 11 -C(O)OR 11 -S(O)2NR 11 R 11 -N(R) 11 )S(O)2R 11 -N(R) 11 )C(O)R 11 -C(O)NR 11 R 11 -S(O) 1-2 R 11 -NR 11 C(O)R 11 The following groups, or optionally substituted groups: C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl;

[0070] Preferably, the heterocyclic or heteroaryl group contains one or two heteroatoms, each independently selected from N, O or S;

[0071] Or, when two R exist simultaneously 10 When connected to the same carbon atom, the two R atoms 10 Together with the carbon atoms they are attached to, they form optionally substituted: 4-10 member (e.g., 4, 5, 6, 7, 8, 9, 10 member) cycloalkyl or 4-10 member (e.g., 4, 5, 6, 7, 8, 9, 10 member) heterocycloalkyl; preferably, when 2 R 10 When connected to the same carbon atom, the two R atoms 10 Together with the carbon atoms they are attached to, they form optionally substituted 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl;

[0072] Preferably, the heterocyclic alkyl group contains one or two heteroatoms, each independently selected from N, O or S;

[0073] More preferably, when two Rs exist simultaneously 10 When connected to the same carbon atom, the two R atoms 10 Together with the carbon atoms they are bonded to, they form optionally substituted compounds:

[0074] Wherein, the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, deuterium, hydroxyl, amino, cyano, halogen, oxo group, -C(O)OH, -CONH2, C 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2、-C(O)NHC 1-3 Alkyl, -C(O)N(C) 1-3 Alkyl)2、-NHC(O)C 1-3 Alkyl, -N(C) 1-3 Alkyl)C(O)C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 The C-terminals of halogenated alkoxy and hydroxyl groups (1 or 2) are... 1-3 Alkyl or hydroxyl-substituted (1 or 2) C 1-3 Alkyl substitution;

[0075] More preferably, when two Rs exist simultaneously 10 When connected to the same carbon atom, the two R atoms 10 Together with the carbon atoms they are bonded to, they form Where * represents a screw connection point.

[0076] In some implementation schemes, R 11 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; preferably, R 11 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl;

[0077] Preferably, the heterocyclic or heteroaryl group contains one or two heteroatoms, each independently selected from N, O or S;

[0078] The optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, deuterium, cyano, halogen (preferably F or Cl), -R 12 -OR 12 -NR 12 R 12 -C(O)NR 12 R 12 -C(=NR) 12 )R 12 ,-S(O) 1-2 R 12 -S(O)2NR 12 R 12 -NR 12 S(O)2R 12 -NR 12 C(O)R 12 -NR 12 C(O)NR 12 R 12 or -NR 12 S(O)2NR 12 R 12 Substitution; preferably, the optional substitution refers to being unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, cyano, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, -NH2, -C(O)NH2;

[0079] Preferably, R 11 Each time it appears, it is independently selected from hydrogen and C. 1-3 alkyl or cyclopropyl; wherein the C 1-3 The alkyl group is optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogens, cyano, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, -NH2, -C(O)NH2.

[0080] In some implementation schemes, R 12 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6Cycloalkyl or 3-6 membered heterocyclic groups; preferably, R 12 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably, R 12 Each time it appears, it is independently selected from hydrogen, deuterium, methyl, ethyl, methoxy, and cyclopropyl.

[0081] The optional substitution refers to being unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, deuterium, hydroxyl, amino, cyano or halogen groups.

[0082] In some implementation schemes, R 10 Each time it appears, it is independently selected from hydrogen, methyl, -C(O)NH2, -NHC2H5, -OCH(CH3)2, -C(O)OH, -S(O)2CF3, -OC2H5, -OCH3, -CF3, -NHC(O)CH3, F, -CN, -OH, -OCH2CHF2, -NHCH2CH2CF3, -NHcyclopropyl, and -NHCH(CH3)2; or, when two Rs are present simultaneously. 10 When connected to the same carbon atom, the two R atoms 10 Together with the carbon atoms they are bonded to, they form Where * represents the screw connection point; preferably, R 10 Each time it appears, it is independently selected from methyl, -C(O)NH2, -OCH3, -CN, -OCH(CH3)2, -NHC2H5, -C(O)OH, -OC2H5, -NHC(O)CH3, -CF3, -OCH2CHF2, -NHCH2CH2CF3, -NHcyclopropyl and -NHCH(CH3)2.

[0083] In some implementation schemes, R 3 Selected from the optional replacements: in The connection site is indicated; the optional substitution refers to the absence of substitution or optional substitution by 0-2 identical or different R... 10 Replacement; more preferably, R 3 Selected from For connection sites;

[0084] R 10Each time it appears, it is independently selected from methyl, -C(O)NH2, -OCH3, -CN, -OCH(CH3)2, -NHC2H5, -C(O)OH, -OC2H5, -NHC(O)CH3, -CF3, -OCH2CHF2, -NHCH2CH2CF3, -NHcyclopropyl and -NHCH(CH3)2.

[0085] In some implementation schemes, R 3 Independently selected from -OR 9 -NR 9 R 9 The following groups, or optionally substituted groups: phenyl, 4-6 membered heterocyclic group, or 5-6 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one or two heteroatoms each independently selected from N, O, or S; wherein the optional substitution refers to unsubstituted or optionally substituted groups with 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R groups. 10 replace;

[0086] R 9 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 3-6 Alkyl, C 4-6 Cycloalkyl, phenyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises one or two heteroatoms each independently selected from N, O or S; or, two R... 9 Together with the N atom to which they are connected, they form an optionally substituted 4-10 member heterocyclic group (e.g., 4, 5, 6, 7, 8, 9, 10 members), which, in addition to the one N atom already included, contains 0-2 (0, 1, or 2) heteroatoms selected from N, O, or S; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2) identical or different R atoms. 10 replace;

[0087] R 10 Each time it appears, it is independently selected from hydrogen, cyano, oxo, fluorine, chlorine, and -OR. 11 -SF5, -NR 11 R 11 -C(O)NR 11 R 11 -S(O)2R 11 -C(O)R 11 -C(O)OR 11 -NR 11 C(O)R 11 The following groups, or optionally substituted groups: C 1-3 Alkyl, C3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclic, or 5-6 membered heteroaryl; or, when two R atoms are simultaneously attached to the same carbon atom. 10 At that time, two R 10 Together with the carbon atoms they are attached to, they form optionally substituted: 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl; wherein the heterocycloyl or heteroaryl group comprises one or two heteroatoms each independently selected from N, O or S; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g. 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2) identical or different hydrogens, hydroxyl groups, amino groups, cyano groups, oxo groups, fluorine groups, chlorine groups, -C(O)OH, -CONH2, C 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2-substituted;

[0088] R 11 Each time it appears, it is independently selected from hydrogen or C. 1-3 Alkyl; wherein the C 1-3 The alkyl group is optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2) identical or different hydrogens, cyano groups, fluorine groups, chlorine groups, methyl groups, or ethyl groups.

[0089] In some implementation schemes, R 3 Selected from the following groups:

[0090] in Indicates a connection key.

[0091] In some implementations, in addition to the above definitions, R 3 It further includes the following groups: in Indicates a connection key.

[0092] In some implementation schemes, R 3 Selected from the following groups:

[0093] in Indicates a connection key.

[0094] In some implementations, in addition to the above definitions, R 3 It further includes the following groups: in Indicates a connection key.

[0095] In some implementation schemes, R 3 Selected from the following groups: in Indicates a connection key.

[0096] In some implementation schemes, R 4 Selected from amino, cyano, carboxyl, -OR 13 -NR 13 R 13 -NR 13 C(O)R 13 -COOR 13 -NHC(=NH)NHC(O)R 13 -NHC(=NH)NHR 13 -NHC(=NH)R 13 -C(O)NR 13 R 13 -NR 13 S(O)2R 13 -NR 13 C(O)NR 13 R 13 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, aryl, 3-10 membered heterocyclic or 5-6 membered heteroaryl; preferably, R 4 Independently selected from cyano, -OR 13 -NR 13 R 13 -NR 13 C(O)R 13 -COOR 13 -C(O)NR 13 R 13 -NR 13 S(O)2R 13 -NR 13 C(O)NR 13 R 13 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl; more preferably, R 4 Independently selected from cyano, -OR 13 -NR 13 R 13 -NR 13 C(O)R 13 -COOR 13 -C(O)NR13 R 13 -NR 13 S(O)2R 13 -NR 13 C(O)NR 13 R 13 The following groups, or optionally substituted groups: methyl, 5-6 membered heterocyclic or 5-membered heteroaryl;

[0097] Preferably, the heterocyclic or heteroaryl group contains one, two, or three heteroatoms, each independently selected from N, O, or S;

[0098] More preferably, R 4 Selected from amino, cyano, carboxyl, -OR 13 -NR 13 R 13 -NR 13 C(O)R 13 -COOR 13 -C(O)NR 13 R 13 -NR 13 S(O)2R 13 -NR 13 C(O)NR 13 R 13 The following groups, or optionally substituted groups: methyl, pyrrolyl, imidazolyl;

[0099] More preferably, R 4 Selected from cyano, -OR 13 -NR 13 R 13 -NR 13 C(O)R 13 or -C(O)NR 13 R 13 ;

[0100] Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R 14 replace.

[0101] In some implementation schemes, R 13 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, aryl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; preferably, R 13 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic or 5-6 membered heteroaryl; more preferably, R 13 Each time it appears, it is independently selected from hydrogen, or optionally substituted groups of the following: C 1-4 Alkyl, 5-6 membered heterocyclic or 5-membered heteroaryl; more preferably, R 13 Each time it appears, it is independently selected from hydrogen or optionally substituted C. 1-6 alkyl;

[0102] Preferably, the heterocyclic or heteroaryl group contains one, two, or three heteroatoms, each independently selected from N, O, or S;

[0103] Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R 14 replace.

[0104] In some implementation schemes, R 14 Each time it appears, it is independently selected from hydrogen, cyano, halogen, -OR 15 -C(O)OR 15 -C(O)NR 15 R 15 -NR 15 S(O) 1-2 R 15 -NR 15 R 15 -C(O)NR 15 R 15 -S(O) 1-2 R 15 -S(O)2NR 15 R 15 -NR 15 S(O) 1-2 R 15 ,,-NR 15 C(O)R 15 -NR 15 C(O)NR 15 R 15 -NR 15 S(O)2NR 15 R 15 -P(O)R 15 R 15 -P(O)(OR) 15 2. Or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6Cycloalkyl, aryl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; preferably, R 14 Each time it appears, it is independently selected from hydrogen, cyano, halogen, -OR 15 -C(O)OR 15 -C(O)NR 15 R 15 -NR 15 S(O) 1-2 R 15 -NR 15 R 15 -C(O)NR 15 R 15 -S(O)2NR 15 R 15 -NR 15 C(O)R 15 -NR 15 C(O)NR 15 R 15 -NR 15 S(O)2NR 15 R 15 -P(O)R 15 R 15 -P(O)(OR) 15 2. Or optionally substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; more preferably, R 14 Each occurrence is independently selected from -OR 15 -NR 15 S(O) 1-2 R 15 -C(O)NR 15 R 15 -NR 15 C(O)R 15 The following groups, or optionally substituted groups: C 1-6 alkyl;

[0105] Or, when two R atoms are connected to a single atom. 14 At that time, two R 14 Together with the atoms they are attached to, they form optionally substituted: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; more preferably, R 14 Each independently selected from -OR 15 -C(O)OR 15 -C(O)NR 15 R 15 -NR 15 S(O) 1-2 R15 The following groups, or optionally substituted groups: C 1-3 alkyl, in Indicates a connection key;

[0106] Preferably, the heterocyclic group, heterocyclic alkyl group, or heteroaryl group contains one, two, or three heteroatoms, each independently selected from N, O, or S;

[0107] Wherein, the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, cyano, halogen, -OR 16 , Oxide group, -SR 16 -NR 16 R 16 -C(O)NR 16 R 16 -S(O) 1-2 R 16 -S(O)2NR 16 R 16 -NR 16 S(O)2R 16 -NR 16 C(O)R 16 -NR 16 C(O)NR 16 R 16 -NR 16 S(O)2NR 16 R 16 -P(O)R 16 R 16 -P(O)(OR) 16 2. C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 The C-terminals of halogenated alkoxy and hydroxyl groups (1 or 2) are... 1-3 Alkyl or hydroxyl-substituted (1 or 2) C 1-3 Alkyl-substituted.

[0108] In some implementation schemes, R 15 and R 16 Each time it appears, it is independently selected from hydrogen, optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; preferably, R 15 and R 16 Each time it appears, it is independently selected from hydrogen, optionally substituted with the following groups: C 1-3Alkyl or C 1-3 Alkyl group; more preferably, R 15 and R 16 Each time it appears, it is independently selected from hydrogen, a 4-6 membered heterocyclic group (preferably a 4-6 membered heterocyclic alkyl group; more preferably a 4-5 membered heterocyclic alkyl group), or optionally substituted with the following groups: C 1-3 Alkyl; more preferably, R 15 Each time it appears, it is independently selected from hydrogen, oxetane, thionebutane, or optionally substituted groups of the following: C 1-3 alkyl;

[0109] Preferably, the heterocyclic group or heterocyclic alkyl group contains one or two heteroatoms, each independently selected from N, O or S;

[0110] The optional substitution refers to being unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, deuterium, hydroxyl, amino, mercapto, cyano or halogen groups.

[0111] In some implementation schemes, R 4 Independently selected from cyano, -OR 13 -NR 13 R 13 -NR 13 C(O)R 13 -COOR 13 The following groups, or optionally substituted groups: 5-6 membered heterocyclic groups or 5-membered heteroaryl groups; wherein, the optional substitution refers to unsubstituted or optionally substituted groups with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different R groups. 14 replace;

[0112] R 13 The following groups are independently selected from hydrogen, or optionally substituted: C 1-6 Alkyl, 5-6 membered heterocyclic or 5-membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g. 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different R 14 replace;

[0113] R 14 Each is independently selected from hydrogen, fluorine, and -OR 15 -C(O)OR 15 -NR 15 R 15 -C(O)NR 15 R 15 -S(O)2NR15 R 15 -NR 15 S(O)2R 15 -NR 15 C(O)R 15 -NR 15 C(O)NR 15 R 15 -NR 15 S(O)2NR 15 R 15 The following groups, or optionally substituted groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl; or, 2 Rs 14 The atoms connected to it are optionally substituted: 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogens, fluorines, -OR 16 , Oxide group, -NR 16 R 16 -C(O)NR 16 R 16 -S(O)2NR 16 R 16 -NR 16 S(O)2R 16 -NR 16 C(O)R 16 -NR 16 C(O)NR 16 R 16 -NR 16 S(O)2NR 16 R 16 -P(O)R 16 R 16 -P(O)(OR) 16 2. C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, hydroxyl-substituted C 1-3 alkyl or hydroxy substituted C 1-3 Alkyl substitution;

[0114] R 15 and R 16 Each of the following groups, independently selected from hydrogen and optionally substituted, is C 1-3 Alkyl or C 1-3Alkyl group; wherein the optional substitution refers to being unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different hydrogen, hydroxyl, amino, cyano or fluorine groups;

[0115] Preferably, the heterocyclic group, heterocyclic alkyl group, or heteroaryl group contains one, two, or three heteroatoms, each independently selected from N, O, or S.

[0116] In some implementation schemes, R 4 Selected from the following groups: cyano,

[0117] in, Indicates a connection key.

[0118] In some implementations, in addition to the above definitions, R 4 It further includes the following groups: in, Indicates a connection key.

[0119] In some implementation schemes, R 4 Selected from the following groups:

[0120] cyano,

[0121] in, Indicates a connection key.

[0122] In some implementations, in addition to the above definitions, R 4 It further includes the following groups:

[0123] in, Indicates a connection key.

[0124] In some implementation schemes, R 4 Selected from the following groups: cyano,

[0125] In the above embodiments of the present invention, except for the defined groups, the definitions of other groups are as described in the present invention, and will not be described one by one to save space.

[0126] The above embodiments of the present invention can be combined arbitrarily, and the resulting embodiments are all embodiments of the present invention.

[0127] In some embodiments, the present invention provides a compound as shown in formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0128]

[0129] Where Z is independently CH or N, and X, Y, R 3 R 4 and R 6 As described in compound (I);

[0130] Preferably, R 6 The number of digits is 0-5 (e.g., 0, 1, 2, 3, 4 or 5).

[0131] In some implementations, X is N and Y is N; or X is N and Y is CR. 5 ; or X is CR 5 Y is N; or X is CR 5 Y is CR 5 .

[0132] In some embodiments, the present invention provides a compound as shown in formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0133]

[0134] Where Z is CH or N, and X, Y, R 3 R 4 and R 6 As described in compound (I);

[0135] Preferably, R 6 The number of elements is either 1 or 2.

[0136] In some implementations, X is N and Y is N; or X is N and Y is CR. 5 ; or X is CR 5 Y is N; or X is CR 5 Y is CR 5 .

[0137] In some embodiments, the present invention provides a compound as shown in formula (IV) or (V), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0138]

[0139] Where Z is CH or N, and X, Y, R 13 R 3 and R 6 As described in compound (I);

[0140] Preferably, R 6 The number of elements is either 1 or 2.

[0141] In some implementations, X is N and Y is N; or X is N and Y is CR. 5 ; or X is CR 5 Y is N; or X is CR 5 Y is CR 5 .

[0142] In some embodiments, the present invention provides a compound as shown in formula (VI) or (VII), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0143]

[0144] Where Z is CH or N, and X, Y, R 4 R 6 R 9 and R 10 As described in compound (I);

[0145] Preferably, R 6 The number is 1 or 2;

[0146] Preferably, R 10 The number of elements is 0-3 (e.g., 0, 1, 2, or 3).

[0147] In some implementations, X is N, and Y is selected from N; or X is N, and Y is selected from CR. 5 ; or X is CR 5 Y is selected from N; or X is CR. 5 Y is selected from CR 5 .

[0148] In some embodiments, the present invention provides a compound of formula (VIII), formula (IX), formula (X) or formula (XI), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0149]

[0150] Where Z is CH or N, and X, Y, R 13 R 6 R 9 and R 10 As described in compound (I);

[0151] Preferably, R6 The number is 1 or 2;

[0152] Preferably, R 10 The number of elements is 0-3 (e.g., 0, 1, 2, or 3).

[0153] In some implementations, X is N and Y is N; or X is N and Y is CR. 5 ; or X is CR 5 Y is N; or X is CR 5 Y is CR 5 .

[0154] The following are examples of structures, including but not limited to compounds with the following structural formulas, their stereoisomers, or their pharmaceutically acceptable salts:

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound as described above, its stereoisomer, or a pharmaceutically acceptable salt thereof; preferably, the pharmaceutical composition comprises the compound as described above, its stereoisomer, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is used to block type I cannabinoid receptor (CB1), comprising the compound as described above, its stereoisomer, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is used to block type I cannabinoid receptor (CB1), comprising a therapeutically effective amount of the compound as described above, its stereoisomer, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier.

[0162] Thirdly, the present invention provides the use of the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the second aspect of the present invention, as medicines or in the preparation of medicines.

[0163] In some embodiments, the drug is a drug for preventing, alleviating, or treating cannabinoid receptor-mediated diseases or conditions; more preferably, the cannabinoid receptor is a type I cannabinoid receptor (CB1); preferably, the drug is a drug for preventing, alleviating, or treating metabolic diseases, metabolic disorders, or metabolic conditions; preferably, the disease or condition is selected from overweight or obesity, insulin resistance, diabetes (e.g., type 2 diabetes), hypertension, dyslipidemia, coronary heart disease, cirrhosis, fatty liver disease, chronic kidney disease, Prader-Willi syndrome (PWS syndrome), fibrosis, diabetic nephropathy, diabetic gastroparesis, tobacco dependence, high cholesterol, and cancer.

[0164] In some embodiments, the present invention provides the use of the compounds as described above, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the second aspect of the invention, in the preparation of medicaments for the prevention, mitigation, or treatment of cannabinoid receptor-mediated diseases or conditions. Preferably, the cannabinoid receptor is a type I cannabinoid receptor (CB1).

[0165] In some embodiments, the present invention provides the use of the compounds as described above, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the second aspect of the invention, in the preparation of medicaments for the prevention, mitigation, or treatment of metabolic diseases, metabolic disorders, or metabolic conditions.

[0166] In some embodiments, the present invention provides the use of the compounds as described above, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the second aspect of the invention, in the preparation of a medicament for the prevention, relief, or treatment of a disease or condition selected from overweight or obesity, insulin resistance, diabetes (e.g., type 2 diabetes), hypertension, dyslipidemia, coronary heart disease, cirrhosis, fatty liver disease, chronic kidney disease, Prader-Willi syndrome (PWS syndrome), fibrosis, diabetic nephropathy, diabetic gastroparesis, tobacco dependence, high cholesterol, and cancer.

[0167] In some implementations, the cannabinoid receptor-mediated diseases or conditions are selected from overweight or obesity, insulin resistance, diabetes (e.g., type 2 diabetes), hypertension, dyslipidemia, coronary heart disease, cirrhosis, fatty liver disease, chronic kidney disease, Prader-Willi syndrome (PWS syndrome), fibrosis, diabetic nephropathy, diabetic gastroparesis, tobacco dependence, high cholesterol, and cancer.

[0168] Fourthly, the present invention provides a method for preventing or treating diseases or conditions mediated by cannabinoid receptors (preferably type I cannabinoid receptors (CB1)), comprising administering to a patient a therapeutically effective dose of the compound as described above, its stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the present invention.

[0169] Fifthly, the present invention provides compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof as described in the first aspect, or pharmaceutical compositions as described in the second aspect, for the prevention and / or treatment of cannabinoid receptor (preferably type I cannabinoid receptor (CB1)) mediated diseases or conditions.

[0170] In the absence of contradictions and conflicts, the technical solutions or features described in the third aspect are applicable to the fourth and fifth aspects.

[0171] In a sixth aspect, the present invention provides a method for preparing a compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0172] Option 1:

[0173]

[0174] Where: X, Y, R 1 R 2 R 3 R 4 The definitions are as described in this invention;

[0175] M 1 M 2 The leaving group is preferably: hydrogen, halogen, OMs, OTf, OTs, B(OH)2, Bpin, or Bneop; or,

[0176] Option 2:

[0177]

[0178] Where: X, Y, R 1 R 2 R 3 R 4 The definitions are as described in this invention; Z is hydroxyl, chlorine, or bromine;

[0179] M 1 M 2 M 3 The leaving group is preferably: hydrogen, halogen, OMs, OTf, OTs, B(OH)2, Bpin, or Bneop.

[0180] In some implementation schemes, in scheme 1,

[0181] (1) 1A and 1B undergo a cyclization reaction under suitable solvent and heating conditions to generate 1C;

[0182] (2) 1C and 1D or their salts under alkaline conditions undergo a catalytic coupling or substitution reaction to generate 1E;

[0183] (3) 1E and 1F or their salts, under alkaline conditions, undergo catalytic coupling or substitution reactions to produce the compound shown in formula (I);

[0184] Or (4) 1A and 2A undergo a cyclization reaction under suitable solvent and heating conditions to generate 2B;

[0185] (5) 2B reacts with the iodide reagent to produce 2C;

[0186] (6) 2C and 2D, under alkaline conditions, undergo a catalytic coupling reaction to produce 1C.

[0187] In some implementation schemes, in scheme 2,

[0188] (1) 3A and 1D or their salts react under alkaline conditions via condensation, catalytic coupling or substitution to produce 3B;

[0189] (2) 3B and 1B undergo a cyclization reaction under suitable solvent and heating conditions to generate 3C;

[0190] (3) 3C under oxidizing conditions generates 3D;

[0191] (4) 3D and 1F or their salts, under alkaline conditions, undergo catalytic coupling or substitution reactions to produce the compound shown in formula (I);

[0192] Alternatively, (5) 3A and 2A undergo a cyclization reaction under suitable solvent and heating conditions to generate 4A;

[0193] (6) 4A reacts with an iodinated reagent to produce 4B;

[0194] (7) 4B and 2D, under alkaline conditions, undergo a catalytic coupling reaction to produce 4C;

[0195] (8) 4C and 1D or their salts, under alkaline conditions, undergo condensation, catalytic coupling or substitution reactions to produce 3C.

[0196] In some implementation schemes,

[0197] The catalysts used in steps (2), (3) and (6) of Scheme 1 and steps (1), (4), (7) and (8) of Scheme 2 are preferably transition metal catalysts, and more preferably palladium catalysts or nickel catalysts.

[0198] In some embodiments, the preparation method, wherein,

[0199] The bases used in steps (2), (3) and (6) of Scheme 1 and steps (1), (4), (7) and (8) of Scheme 2 are organic or inorganic bases, including but not limited to: lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium fluoride, lithium diisopropylamino, lithium bis(trimethylsilylamino), triethylamine, N,N-diisopropylethylamine or 1,8-diazobis(spirocyclo[5.4.0]undecyl-7-ene.

[0200] In some embodiments, the preparation method includes:

[0201] The iodination reagent in step (5) of scheme 1 and step (6) of scheme 2 is N-iodosuccinimide, iodine chloride, elemental iodine, benzyltrimethyldichloroiodate ammonium, and more preferably N-iodosuccinimide.

[0202] In some implementations, in scheme 2:

[0203] The condensing agent mentioned in steps (1) and (8) is benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate.

[0204] In some implementations, in scheme 2:

[0205] The oxidant mentioned in step (3) is peroxymchlorobenzoic acid, hydrogen peroxide, potassium peroxymonosulfonate, sodium hypochlorite, potassium permanganate, oxygen, etc., and is more preferably peroxymchlorobenzoic acid, hydrogen peroxide, etc.

[0206] In some embodiments, the preparation method, wherein the above reaction can be carried out in a suitable solvent conventionally used in the art, preferably, the solvent used is selected from one or a mixture of several of the following: benzene, toluene, methanol, ethanol, isopropanol, water, N,N-dimethylformamide, dimethyl sulfoxide, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N-methylpyrrolidone, N,N-dimethylacetamide, etc.

[0207] In some embodiments, the preparation method involves carrying out the above-mentioned reaction at a suitable temperature, preferably -20 to 150°C, more preferably -10°C to 120°C.

[0208] In the preparation methods described above, the intermediates or target products obtained from the reaction can be purified as needed using conventional purification methods in the field, such as column chromatography purification, thin-layer chromatography purification, recrystallization, etc.

[0209] definition

[0210] Unless otherwise stated, the following terms as used in this invention have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0211] C in this article m-n This refers to the part having an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0212] When any variable (e.g., R) 6 When a group, a site, or an atom appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group, a site, or an atom is represented by two R... 6 Replaced, then each R 6 Each has its own independent options.

[0213] Unless otherwise specified, D in this invention represents deuterium ( 2 H).

[0214] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group comprising 1-20 carbon atoms, preferably comprising 1-12 carbon atoms (i.e., C12). 1-10 Alkyl groups, preferably containing 1-10 carbon atoms (i.e., C64-C ... 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0215] The term "alkenyl" or "alkenyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group having 2 to 20 carbon atoms (preferably 2-12, 2-10, 2-8, 2-6, 2-4, 2-3) and at least one carbon-carbon double bond, including but not limited to vinyl, propenyl, and butenyl groups. For example, "C 2-6 "Alkenyl" refers to an alkenyl group with 2-6 carbon atoms in its carbon chain. Alkenyl groups can be optionally substituted.

[0216] The term "alkynyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group having 2 to 20 carbon atoms (preferably 2-12, 2-10, 2-8, 2-6, 2-4, 2-3) and at least one carbon-carbon triple bond, including but not limited to ethynyl, propynyl, and butynyl. For example, "C 2-6 "Alynyl" refers to an alkynyl group with 2-6 carbon atoms in the carbon chain. The alkynyl group can be optionally substituted.

[0217] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C12-C12). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkyl groups, more preferably 3-8 carbon atoms (C 3-8 cycloalkyl groups), 3-6 carbon atoms (C 3-6 cycloalkyl groups, 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 (Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0218] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, defined as above, containing 1-20 carbon atoms, preferably 1-12 carbon atoms, more preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc. The term "haloalkoxy" refers to an alkoxy group as defined above where one, several (e.g., 2, 3, 4, 5, 6), or all of the hydrogen atoms are replaced by a halogen; a representative example is CF3CH2O-.

[0219] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHF2, CH2F, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0220] Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having a ring carbon atom and 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) ring heteroatoms, comprising 3 to 12 ring atoms, wherein the heteroatoms are selected from N, O, P, or S, and the remaining ring atoms are C, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., forming an oxo group). Preferably, it comprises 3 to 10 ring atoms (3-10 membered heterocyclic group), more preferably 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), 5 to 8 ring atoms (5-8 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused (or fused), and bridged heterocyclic groups. A “heterocyclic group” can be a monocyclic (“monocyclic heterocyclic group”) or a fused (“fused heterocyclic group” or “heterofused-cyclic group”), bridged (“heterobridged ring group” or “bridged ring heterocyclic group”) or spiro-fused (“heterospirocyclic group” or “spirocyclic heterocyclic group”) ring system, such as a bicyclic system (“bicyclic heterocyclic group”), and can be saturated or partially unsaturated. A bicyclic heterocyclic system can include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or "heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which a cycloalkyl ring as defined above is fused with one or more heteroaryl groups, wherein the attachment point is on the heterocyclic or cycloalkyl ring, and in such cases, the number of members in the heterocyclic ring system is the number of atoms in the fused ring system. In some embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic group") or substituted with one or more substituents (a "substituted heterocyclic group"). Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrocyclobutane, oxocyclobutane, and thiocyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione.Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, dioxolanecyclopentyl, oxathiacyclopentyl, dithiacyclopentyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatomum include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazineyl, morpholinyl, dithiacyclopentyl, and dioxazinanyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0221] Unless otherwise specified, "heterocyclic alkyl" refers to a monocyclic or polycyclic (spirocyclic, bridged, or fused) saturated "heterocyclic group" or "heterocycle" as defined above, with the same definition of ring atoms, i.e., containing 3 to 20 ring atoms ("3-20 membered heterocyclic alkyl"), and the number of heteroatoms is 1 to 4 (1, 2, 3, or 4), preferably 1 to 3 (1, 2, or 3), wherein each heteroatom is independently selected from N, O, or S. One or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and one or more carbocyclic atoms may optionally be oxidized (i.e., forming an oxo group). Preferably, it comprises 3 to 12 ring atoms (“3-12-membered heterocyclic alkyl”), more preferably 3 to 10 ring atoms (“3-10-membered heterocyclic alkyl”), even more preferably 3 to 8 ring atoms (“3-8-membered heterocyclic alkyl”), even more preferably 3 to 6 ring atoms (“3-6-membered heterocyclic alkyl”), and even more preferably 4 to 6 (4, 5, or 6) ring atoms (“4-6-membered heterocyclic alkyl”). In some embodiments, each example of a heterocyclic alkyl group may be optionally substituted independently, for example, unsubstituted (an “unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (an “substituted heterocyclic alkyl”). The “heterocyclic group” or “heterocyclic” section above has given some exemplary “heterocyclic alkyl groups”, which also include, but are not limited to, azirrocyclopropane, oxacyclopropane, thiocyclopropane, azirrocyclobutane, oxacyclobutane, thiocyclobutane, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazineyl, morpholinyl, thiomorpholinyl, oxathiohexyl, oxazolidinyl, dioxane, dithiohexyl, thiazolyl, pyrrolidinyl, pyrazolyl, imidazolinyl, etc.

[0222] Unless otherwise specified, "cycloalkenyl" refers to a system composed of monocyclic, bicyclic, and spirocyclic hydrocarbon rings as daughter groups; however, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. Preferably, it contains 3-12 carbon atoms (i.e., C12-C22). 3-12 Cycloalkenyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 (Cycloalkenyl).

[0223] Unless otherwise specified, “heterocyclic alkenyl” refers to an unsaturated alicyclic (non-aromatic) cyclic group, including monocyclic and bridged, spirocyclic and / or fused ring systems (which may consist of two or three rings; for example, a fused ring system consisting of two or three fused rings), wherein the cyclic group comprises one or more (e.g., one, two, three or four) cyclic heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., form an oxo group), and wherein the cyclic group also contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring included in the unsaturated alicyclic cyclic group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4, and that there is at least one carbocyclic atom in the corresponding heteroatom-containing ring (which may optionally be oxidized). "Heterocyclic alkenyl" can refer to, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolinyl), 3-imidazolinyl or 4-imidazolinyl), tetrahydropyridyl (e.g., 1,2,3,6-tetrahydropyridyl), dihydropyridyl (e.g., 1,2-dihydropyridyl or 2,3-dihydropyridyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiaranyl (e.g., 2H-thiaranyl or 4H-thiaranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocyclic alkenyl" preferably refers to a 3- to 12-membered unsaturated alicyclic group, which is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the cyclic group contains one or more (e.g., one, two, three, or four) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbide ring atoms are optionally oxidized, wherein the cyclic group contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms; more preferably, "heterocyclic alkenyl" refers to a 5- to 7-membered monocyclic unsaturated nonaromatic cyclic group containing one or more (e.g., one, two, or three) cyclic heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbide ring atoms are optionally oxidized, and wherein the cyclic group contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms.

[0224] Unless otherwise specified, the term "aryl" or "aromatic cycloyl" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic cycloyl". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene.

[0225] Unless otherwise specified, the term "heteroaryl" or "heteroary cycloyl" refers to an aromatic monocyclic or polycyclic system containing a 5-14 member structure, or preferably a 5-10 member structure, or preferably a 5-8 member structure, more preferably a 5-6 member structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzo[] Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0226] In this article, -C(O)- represents a carbonyl group, i.e., -C(=O)-; -S(O)- represents a sulfinyl group, i.e., -S(=O)-; -S(O)2- represents a sulfonyl group, i.e., -S(=O)2-; -P(O)- represents a phosphorous acyl group, i.e., -P(=O)-; -B(OR 15 )2 represents a borate ester group.

[0227] The term "oxo group" refers to C=O.

[0228] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by one or more substituents, wherein the oxo group refers to a double bond formed by replacing two H atoms at the same substitution position with the same O atom group. Preferably, the substituents are selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or C 1-4 The alkoxy group is substituted by one or more substituents. Preferably, the substituents are selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaromatic, wherein the C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaromatic rings may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 It is replaced by one or more substituents in the alkoxy group.

[0229] The terms “optional” or “optional” mean that the event or situation described below may, but does not have to, occur, including in cases where the event or situation does not occur.

[0230] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0231] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0232] Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may contain an E or Z configuration of a carbon-carbon double bond or a carbon-nitrogen double bond, wherein the term "E" represents a higher-order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents a higher-order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rule). The compounds of the present invention may also exist in the form of a mixture of "E" and "Z" isomers.

[0233] Unless otherwise indicated, the compounds described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers), tautomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, geometric isomers (or conformational isomers), or tautomers, is within the scope of this invention.

[0234] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0235] The compounds of this invention also include isotopic derivatives thereof. Unless otherwise specified, the term "isotopic derivative" refers to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. The isotopes can be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds. The isotope derivatives are preferably deuterated derivatives.

[0236] The compounds of this invention also include their solvates or solvent compounds. Unless otherwise specified, the terms "solvate" or "solvate" refer to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0237] The compounds of the present invention also include their cocrystals. Unless otherwise specified, the term "cocrystal" is used to describe a situation in which neutral molecular components are present in a definite stoichiometric ratio within a crystalline compound. The preparation of pharmaceutical cocrystals allows for alteration of the crystal form of the active pharmaceutical ingredient, which in turn alters its physicochemical properties without impairing its desired biological activity (see Pharmaceutical Salts and Cocrystals, eds. J. Wouters and L. Quere, RSC Publishing, 2012).

[0238] The compounds of this invention also include their polymorphs. Unless otherwise specified, the term "polymorph" refers to different arrangements of chemical drug molecules, generally manifested as the form in which the drug raw material exists in a solid state. A drug can exist in multiple crystalline states. Different crystalline forms of the same drug may have different solubility and absorption in the body, thus affecting the dissolution and release of the formulation.

[0239] The compounds of this invention also include their metabolites. Unless otherwise specified, the term "metabolite" refers to a product obtained in vivo by the metabolism of a specific compound or its salt. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficient contact of the compounds of this invention with mammals for a period of time.

[0240] The compounds of this invention also include their prodrugs. Unless otherwise specified, the term "prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, can be any compound of this invention administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0241] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0242] The term “subject” can also be referred to as “individual” or “subject”, referring to a cell or animal, including but not limited to mammals such as laboratory animals or humans.

[0243] "Effective amount" means an amount of the compound or pharmaceutical composition described herein sufficient to achieve the intended application, including but not limited to the treatment of a disease or the relief of its symptoms. In some embodiments, for example, the amount may be a dose that can induce a specific response in cells, or a dose that exerts a therapeutic effect on a disease in a model animal. The specific amount will vary depending on, for example, the specific compound selected, the type of subject and their age / pre-existing health condition, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue of administration, and the physical delivery system carrying it.

[0244] Unless otherwise specified, the term “treatment” covers any treatment of a patient’s disease, symptom, and condition, including: (a) suppressing the symptoms of the disease, symptom, and condition, i.e., preventing its development; or (b) alleviating the symptoms of the disease, symptom, and condition, i.e., causing the disease or symptoms to subside; or (c) improving or eliminating the disease, symptom, and condition or one or more symptoms associated with said disease.

[0245] Unless otherwise specified, the term "pharmaceuticalally acceptable carrier," also known as "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable excipient," refers to a generally recognized medium in the field of delivering bioactive agents to animals (specifically, mammals). Pharmaceutically acceptable carriers are formulated based on a number of factors well understood by those skilled in the art. These include (but are not limited to) the type and nature of the formulated active agent, the subject to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. The preparation of pharmaceutical compositions described herein includes, but is not limited to, mixing, for example, the compounds described in the first or second aspect, or their stereoisomers or pharmaceutically acceptable salts, with a pharmaceutically acceptable carrier.

[0246] The above embodiments represent exemplary embodiments of the present invention, but the present invention is not limited to the above embodiments. Furthermore, the various technical features in the above embodiments of the present invention can be combined with each other to constitute one or more new technical solutions, and these new technical solutions also fall within the scope of the present invention, as long as such new technical solutions are technically feasible.

[0247] The compounds of the present invention have one or more of the following beneficial effects:

[0248] This invention provides a novel CB1 antagonist or inverse agonist.

[0249] (1) In vitro experimental results show that the compounds of the present invention have strong CB1 antagonistic activity or reverse agonistic activity;

[0250] (2) In vivo test results show that the compound of the present invention has good pharmacokinetic properties;

[0251] (3) The compound of the present invention has a lower cerebral blood ratio in terms of PK, which can better reduce neurotoxic side effects. Detailed Implementation

[0252] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0253] The structures of the compounds in this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker Avance III 600MHz instrument; the LC-MS measurements were performed using an LCMS Waters ACQUITY UPLC H-Class PLUS and / or SQD2 instrument; and the HPLC measurements were performed using a WaterSe2695_2998 and / or an Agilent 1100 instrument.

[0254] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0255] Explanation of terms or abbreviations:

[0256] OMs: Methylsulfonyl

[0257] OTf: Trifluoromethanesulfonyl

[0258] OTs: p-Toluenesulfonyl group

[0259] B(OH)2: Boric acid group

[0260] Bpin: Pinaryl borate group

[0261] Bneop: Neopentylboronic acid ester group.

[0262] Example 1: Preparation of Compound 1

[0263]

[0264] (1) Preparation of intermediate 1-1

[0265] 2-Bromo-1-(4-chlorophenyl)-2-phenylethyl-1-one (554 mg, 1.79 mmol) and 3-amino-4-bromo-6-chloropyridazine (373 mg) were added to ethanol (20 mL), heated to 80 °C, and stirred for 12 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1, v / v) to give intermediate 1-1 (465 mg).

[0266] (2) Preparation of intermediate 1-2

[0267] Intermediate 1-1 (465 mg, 1.11 mmol), cesium carbonate (723 mg), and 4-methyl-4-piperidinic carboxamide (189 mg) were added to N,N-dimethylformamide (20 mL), heated to 80 °C, and stirred for 3 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 1-2 (400 mg).

[0268] (3) Preparation of compound 1

[0269] Intermediates 1-2 (82 mg, 0.17 mmol) were added to dimethyl sulfoxide (10 mL), followed by L-prolyl (52 mg) and potassium fluoride (49 mg). The mixture was heated to 130 °C and stirred for 12 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 1 (28 mg). ESI-MS (m / z): 545.2 [M+H] + .

[0270] 1 H NMR (600MHz, CDCl3) δ7.61-7.59(m,1H),7.48-7.47(m,1H),7.43-7.41(m,1H),7.39-7.36 (m,1H),7.34-7.32(m,1H),7.28-7.26(m,4H),7.23-7.22(m,1H),5.66-5.60(m,3H),4.37 -4.35(m,1H),4.27-4.25(m,1H),4.05-4.02(m,1H),3.70-3.67(m,2H),3.56-3.46(m,3H) ,3.39-3.35(m,1H),2.22-2.20(m,2H),2.04-1.91(m,3H),1.80-1.70(m,3H),1.33(s,3H).

[0271] Example 2: Preparation of Compound 2

[0272]

[0273] (1) Preparation of intermediate 2-1

[0274] 601 mg (1.79 mmol) of 5-(2-bromo-2-(4-chlorophenyl)acetyl)pyridinium (prepared according to WO2023155004) and 3-amino-4-bromo-6-chloropyridazine (373 mg) were added to 20 mL of ethanol, heated to 80 °C and stirred for 12 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 2-1 (374 mg).

[0275] (2) Preparation of intermediate 2-2

[0276] Intermediate 2-1 (374 mg, 0.84 mmol), cesium carbonate (547 mg), and 4-methyl-4-piperidinic carboxamide (142 mg) were added to N,N-dimethylformamide (20 mL), heated to 80 °C, and stirred for 3 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 2-2 (332 mg).

[0277] (3) Preparation of compound 2

[0278] Intermediate 2-2 (81 mg, 0.16 mmol) was added to dimethyl sulfoxide (10 mL), followed by L-prolyl (48 mg) and potassium fluoride (46 mg). The mixture was heated to 130 °C and stirred for 12 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 2 (10 mg). ESI-MS (m / z): 571.2 [M+H] + .

[0279] 1 HNMR(600MHz,MeOD)δ8.89(d,J=1.7Hz,1H),8.10(dd,J=8.2,2.2Hz,1H),

[0280] 7.79(d,J=8.1Hz,1H),7.57(d,J=8.5Hz,2H),7.51(d,J=8.5Hz,2H),5.97(s,1H),4.32-4.30(m,2H),4.0 1-4.00(m,1H),3.56-3.53(m,4H),2.29-2.26(m,3H),2.09-1.95(m,5H),1.76-1.71(m,2H),1.31(s,3H).

[0281] Example 3: Preparation of Compound 3

[0282]

[0283] Intermediate 2-2 (20 mg, 0.04 mmol) was added to dimethyl sulfoxide (2 mL), followed by N-methyl-2-hydroxyethylamine (9 mg) and potassium fluoride (12 mg). The mixture was heated to 140 °C and stirred for 12 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 3 (10 mg). ESI-MS (m / z): 545.2 [M + H] + .

[0284] 1 HNMR(600MHz,DMSO-d6)δ8.62(d,J=1.5Hz,1H),8.16(dd,J=8.2,2.2Hz,1H),

[0285] 7.79(d,J=8.2Hz,1H),7.58(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,2H),6.99(s,1H),6.95(s,1H),6.02(s,1H),4.66(t,J=5.4Hz,1H),4.60 -4.50(m,2H),4.30-4.28(m,1H),3.73-3.64(m,2H),3.56-3.44(m,3H),2.96(s,3H),2.18-2.13(m,2H),1.54-1.50(m,2H),1.18(s,3H).

[0286] Example 4: Preparation of Compound 4

[0287]

[0288] (1) Preparation of intermediate 4-1

[0289] Thioaminourea (1.00 g, 10.97 mmol) was dissolved in anhydrous ethanol (10 mL), and then iodomethane (1.56 g) was added. The reaction was carried out at 60 °C for 1 h. LCMS monitoring showed no raw material remaining. The solvent was removed by vacuum distillation, and the residue was washed with tert-butyl methyl ether and filtered to give intermediate 4-1 (2.30 g).

[0290] (2) Preparation of intermediate 4-2

[0291] Intermediate 4-1 (2.30 g, 9.87 mmol) and ethyl thiooxazone (1.58 g) were dispersed in anhydrous ethanol (20 mL), and then triethylamine (2.99 g) was added. The reaction was carried out at 100 °C for 5 h. LCMS monitoring showed no starting material remaining. The reaction solution was cooled to room temperature, filtered, and the solid was washed with ethanol and dried to obtain intermediate 4-2 (0.80 g).

[0292] (3) Preparation of intermediate 4-3

[0293] Intermediate 4-2 (133 mg, 0.84 mmol), 4-methyl-4-piperidinecarboxamide hydrochloride (150 mg), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (874 mg), and N,N-diisopropylethylamine (326 mg) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 12 h. LCMS monitoring showed no residual starting material. The reaction mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to obtain intermediate 4-3 (150 mg).

[0294] (4) Preparation of intermediate 4-4

[0295] Intermediate 4-3 (150 mg, 0.53 mmol) and 4-(2-bromo-2-(4-chlorophenyl)acetyl)benzylnitrile (177 mg) were dissolved in N,N-dimethylformamide (10 mL), and then N,N-diisopropylethylamine (68 mg) was added. The reaction was carried out at 120 °C for 12 h. LCMS monitoring showed no residual starting material. The reaction mixture was then extracted with water (20 mL), followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then purified by column chromatography (n-hexane:ethyl acetate = 1:1-1:5) to obtain intermediate 4-4 (30 mg).

[0296] (5) Preparation of intermediate 4-5

[0297] Intermediate 4-4 (30 mg, 0.058 mmol) was dissolved in trifluoroacetic acid (2 mL), followed by the addition of hydrogen peroxide (2 mL). The reaction was carried out at room temperature for 1 h, and LCMS monitoring showed no residual starting material. The solvent was removed by vacuum distillation, and the mixture was purified by direct column chromatography (dichloromethane:methanol = 20:1-15:1) to obtain intermediate 4-5 (25 mg).

[0298] (6) Preparation of compound 4

[0299] Intermediate 4-5 (25 mg, 0.045 mmol) was dissolved in N-methylpyrrolidone (1 mL), followed by the addition of L-prolyl (51 mg). The reaction was carried out at 140 °C for 6 h, and LC-MS monitoring showed no starting material remaining. The reaction mixture was then diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with water (10 mL × 3), washed twice with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solution was then purified by column chromatography (dichloromethane:methanol = 20:1-15:1) to give compound 4 (10 mg). ESI-MS (m / z): 571.2 [M+H] + .

[0300] 1 H NMR(600MHz, CDCl3)δ7.71(d,J=7.8Hz,2H),7.58(d,J=8.4Hz,2H),7.49-7.4 6(m,4H),5.73-5.72(m,1H),5.55-5.54(m,2H),4.41-4.40(m,2H),4.17-4.16 (m,1H),3.71-3.70(m,2H),3.62-3.61(m,2H),3.52-3.51(m,1H),2.26-2.24( m,2H),2.10-2.05(m,2H),1.98-1.87(m,3H),1.72-1.70(m,2H),1.36(s,3H).

[0301] Example 5: Preparation of Compound 5

[0302]

[0303] (1) Preparation of intermediate 5-1

[0304] Intermediate 2-1 (151 mg, 0.34 mmol), 2-trifluoromethyl-5-pyridineboronic acid (130 mg), copper 3-methylsalicylate (218 mg), and tetra-triphenylphosphine palladium (20 mg) were added to tetrahydrofuran (10 mL), purged with nitrogen three times, and heated to 60 °C and stirred for 3 h under a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1-3:1) to obtain intermediate 5-1 (102 mg).

[0305] (2) Preparation of compound 5

[0306] Intermediate 5-1 (102 mg, 0.20 mmol) was added to dimethyl sulfoxide (5 mL), followed by 2-methyl-1-(methylamino)prop-2-ol (62 mg) and potassium fluoride (60 mg). The mixture was heated to 140 °C and stirred for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 5 (55 mg). ESI-MS (m / z): 578.2 [M+H] + . 1 HNMR(600MHz,MeOD)δ9.54(d,J=1.5Hz,1H),8.93(d,J=1.2Hz,1H),8.89(dd,J=8.1,1.8Hz,1H),8.19(dd,J=8.2,2.2Hz,1H) ,8.05(d,J=8.2Hz,1H),7.82(d,J=8.2Hz,1H),7.64-7.63(m,2H),7.58-7.56(m,3H),3.63(s,2H),3.24(s,3H),1.23(s,6H).

[0307] Example 6: Preparation of Compound 6

[0308]

[0309] (1) Preparation of intermediate 6-1

[0310] 2-Bromo-1-(2-chlorophenyl)-2-(4-chlorophenyl)ethyl-1-one (616 mg, 1.79 mmol) and 3-amino-4-bromo-6-chloropyridazine (373 mg) were added to ethanol (20 mL), heated to 80 °C, and stirred for 12 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate 6-1 (430 mg).

[0311] (2) Preparation of intermediate 6-2

[0312] Intermediate 6-1 (154 mg, 0.34 mmol), 2-trifluoromethyl-5-pyridineboronic acid (130 mg), 3-methylcopper salicylate (218 mg), and tetra-triphenylphosphine palladium (20 mg) were added to tetrahydrofuran (10 mL), purged with nitrogen three times, and heated to 60 °C and stirred for 3 h under a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to obtain intermediate 6-2 (113 mg).

[0313] (3) Preparation of compound 6

[0314] Intermediate 6-2 (113 mg, 0.22 mmol) was added to dimethyl sulfoxide (5 mL), followed by 2-methyl-1-(methylamino)prop-2-ol (68 mg) and potassium fluoride (66 mg). The mixture was heated to 140 °C and stirred for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 6 (93 mg). ESI-MS (m / z): 586.1 [M+H] + .

[0315] 1 HNMR(600MHz,MeOD)δ9.37(s,1H),8.93(d,J=1.2Hz,1H),8.75(dd,J=8.1,1.6Hz,1H),8.00(d,J=8.2Hz,1H),7.59(d,J=8.6Hz,1H) ,7.54(dd,J=7.2,1.8Hz,1H),7.49(s,1H),7.47(dd,J=7.8,1.3Hz,1H),7.43-7.36(m,4H),3.69(s,2H),3.30(s,3H),1.28(s,6H).

[0316] Example 7: Preparation of Compound 7

[0317]

[0318] Compound 5 (20 mg, 0.04 mmol) and lithium hydroxide (12 mg) were added to tetrahydrofuran (2 mL), heated to 60 °C and stirred for 12 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 7 (10 mg). ESI-MS (m / z): 596.2 [M+H] + .

[0319] 1 HNMR(600MHz,DMSO-d6)δ9.60(d,J=1.2Hz,1H),9.00(dd,J=7.8,1.8Hz,1H),8.67(d,J=1.4Hz,1H),8.21-8.18(m,2H),8.1 0(s,1H),8.05(d,J=8.4Hz,1H),7.68-7.65(m,3H),7.61-7.60(m,3H),4.55(s,1H),3.57(s,2H),3.15(s,3H),1.12(s,6H).

[0320] Example 8: Preparation of Compound 8

[0321]

[0322] (1) Preparation of intermediate 8-1

[0323] α-Bromo-o-chloroacetophenone (1.00 g, 4.28 mmol) and 3-amino-4-bromo-6-chloropyridazine (892 mg) were added to ethanol (50 mL), heated to 80 °C and stirred for 12 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate 8-1 (1.20 g).

[0324] (2) Preparation of intermediate 8-2

[0325] Intermediate 8-1 (1.20 g, 3.50 mmol) and N-iodosuccinimide (1.18 g) were added to N,N-dimethylformamide (30 mL), heated to 100 °C and stirred for 4 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 8-2 (600 mg).

[0326] (3) Preparation of intermediate 8-3

[0327] Intermediate 8-2 (500 mg, 1.07 mmol), 4-ethoxypiperidine-4-carboxamide hydrochloride (prepared according to WO2023155004) (267 mg), and cesium carbonate (695 mg) were added to N,N-dimethylformamide (20 mL), heated to 80 °C, and stirred for 4 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1) to obtain intermediate 8-3 (600 mg).

[0328] (4) Preparation of intermediate 8-4

[0329] Intermediate 8-3 (600 mg, 1.07 mmol), 4-chlorophenylboronic acid (200 mg), potassium carbonate (296 mg), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (87 mg) were added to a dioxane / water mixture (20 mL / 5 mL). The mixture was purged with nitrogen three times, heated to 100 °C under a nitrogen atmosphere, and stirred for 4 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1) to obtain intermediate 8-4 (500 mg).

[0330] (5) Preparation of compound 8

[0331] Intermediate 8-4 (80 mg, 0.147 mmol) was added to dimethyl sulfoxide (2 mL), followed by 2-methyl-1-(methylamino)prop-2-ol (45 mg) and potassium fluoride (43 mg). The mixture was heated to 140 °C and stirred for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 8 (33 mg). ESI-MS (m / z): 611.2 [M+H] + .

[0332] 1 HNMR (600MHz, CDCl3) δ7.51-7.48(m,1H),7.43-7.42(m,2H),7.37-7.36(m,1H),7.28-7.26(m,5H),6.39(s,1H),5.92(s,1H) ),5.38(s,1H),4.62-4.53(m,2H),3.55-3.48(m,6H),3.16(s,3H),2.29-2.25(m,2H),1.97-1.95(m,2H),1.29-1.24(m,9H).

[0333] Example 9: Preparation of Compound 9

[0334]

[0335] 2-Methyl-1,2-propanediol (40 mg) and sodium tert-butoxide (43 mg) were added to N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 8-4 (80 mg, 0.147 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 9 (41 mg). ESI-MS (m / z): 598.2 [M+H] + .

[0336] 1 HNMR(600MHz,DMSO-d6)δ7.51-7.40(m,8H),7.29(s,1H),7.20(s,1H),6.07(s,1H),4.69-4.52(m,2H),4.64(s,1 H),3.96(s,2H),3.47-3.43(m,2H),3.37-3.35(m,2H),1.99-1.92(m,2H),1.86-1.84(m,2H),1.23-1.18(m,9H).

[0337] Example 10: Preparation of Compound 10

[0338]

[0339] Preparation of intermediate 10-1

[0340] α-Bromo-o-chloroacetophenone (1.00 g, 1.79 mmol) and intermediate 4-2 (1.00 g) were added to N,N-dimethylformamide (20 mL), heated to 120 °C and stirred for 3 h. The reaction solution was cooled to room temperature, and water (30 mL) was added to the reaction solution, causing a solid to precipitate. The solid was purified by filtration to obtain intermediate 10-1 (1.10 g).

[0341] (2) Preparation of intermediate 10-2

[0342] Intermediate 10⁻¹ (1.08 g, 3.70 mmol) and N-iodosuccinimide (0.92 g) were added to acetonitrile (20 mL), heated to 85 °C and stirred for 12 h. The reaction solution was cooled to room temperature, filtered and purified to obtain intermediate 10⁻² (1.05 g).

[0343] (3) Preparation of intermediate 10-3

[0344] Intermediate 10⁻² (1.02 g, 2.44 mmol), 4-chlorophenylboronic acid (460 mg), potassium carbonate (1.01 g), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (178 mg) were added to dioxane / water (20 mL / 5 mL), the mixture was purged with nitrogen three times, and the mixture was heated to 100 °C and stirred for 4 h under a nitrogen atmosphere. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1-20:1) to obtain intermediate 10⁻³ (550 mg).

[0345] (4) Preparation of intermediate 10-4

[0346] Intermediate 10⁻³ (330 mg, 0.82 mmol), 4-ethoxypiperidine-4-carboxamide hydrochloride (prepared according to WO2023155004) (188 mg), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (854 mg), and N,N-diisopropylethylamine (318 mg) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 12 h. LCMS monitoring showed no residual starting material. The reaction mixture was then extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 30:1-15:1) to obtain intermediate 10⁻⁴ (190 mg).

[0347] (5) Preparation of intermediate 10-5

[0348] Intermediate 10⁻⁴ (150 mg, 0.27 mmol) was dissolved in trifluoroacetic acid (2 mL), followed by the addition of hydrogen peroxide (2 mL). The reaction was carried out at room temperature for 1 h, and LCMS monitoring showed no residual starting material. The solvent was removed under reduced pressure, and the mixture was purified by direct column chromatography (dichloromethane:methanol = 20:1-15:1) to obtain intermediate 10⁻⁵ (80 mg).

[0349] (6) Preparation of compound 10

[0350] Intermediate 10-5 (80 mg, 0.136 mmol) was added to N-methylpyrrolidone (2 mL), followed by 2-methyl-1-(methylamino)prop-2-ol (70 mg) and potassium fluoride (40 mg). The mixture was heated to 140 °C and stirred for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 10 (39 mg). ESI-MS (m / z): 612.2 [M+H] + . 1 HNMR(600MHz, CDCl3)δ7.47(d,J=8.4Hz,2H),7.44-7.42(m,1H),7.39-7.38(m,1H),7.30-7.27(m,4H),6.38(s,1H),6.05(s,1H),5.43(s,1H),4 .71-4.66(m,1H),3.89-3.79(m,1H),3.61-3.41(m,6H),3.16(s,3H),2. 20-2.16(m,2H),1.99-1.97(m,2H),1.27(t,J=7.2Hz,3H),1.25(s,6H).

[0351] Example 11: Preparation of Compound 11

[0352]

[0353] 2-Methyl-1,2-propanediol (21 mg) and sodium tert-butoxide (33 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 10⁻⁵ (60 mg, 0.102 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 11 (22 mg). ESI-MS (m / z): 599.2 [M + H₂] + . 1HNMR (600MHz, CDCl3) δ7.44-7.39(m,4H),7.30-7.28(m,4H),6.38(s,1H),6.05(s,1H),5.41(s,1H),4.87-4.85(m,1H),4. 16(s,2H),3.92-3.87(m,1H),3.50-3.44(m,4H),2.24-2.16(m,2H),2.09-2.01(m,2H),1.33(s,6H),1.29(t,J=7.2Hz,3H).

[0354] Example 12: Preparation of Compound 12

[0355]

[0356] Intermediate 10-5 (60 mg, 0.102 mmol) was added to N-methylpyrrolidone (2 mL), followed by L-prolyl (52 mg) and potassium fluoride (30 mg). The mixture was heated to 140 °C and stirred for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 12 (27 mg). ESI-MS (m / z): 610.2 [M+H] + .

[0357] 1 HNMR(600MHz, CDCl3)δ7.45(d,J=8.4Hz,2H),7.43-7.41(m,1H),7.39-7.38(m,1H),7 .31-7.28(m,4H),6.41(s,1H),6.05-5.97(m,1H),5.37(s,1H),4.73-4.61(m,1H),4.2 7-4.22(m,1H),3.93-3.83(m,1H),3.76-3.73(m,1H),3.66-3.61(m,2H),3.57-3.47(m ,4H),2.23-2.17(m,2H),2.10-1.89(m,6H),1.76-1.73(m,1H),1.28(t,J=7.2Hz,3H).

[0358] Example 13: Preparation of Compound 13

[0359]

[0360] (1) Preparation of intermediate 13-1

[0361] α-Bromo-o-chloroacetophenone (1.00 g, 4.28 mmol) and 2-amino-3-bromo-5-chloropyrazine (892 mg) were added to ethanol (50 mL), heated to 80 °C and stirred for 12 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate 13-1 (1.00 g).

[0362] (2) Preparation of intermediate 13-2

[0363] Intermediate 13-1 (0.96 g, 2.80 mmol) and N-iodosuccinimide (0.95 g) were added to N,N-dimethylformamide (30 mL), heated to 100 °C and stirred for 4 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 13-2 (490 mg).

[0364] (3) Preparation of intermediate 13-3

[0365] Intermediate 13-2 (490 mg, 1.05 mmol), 4-ethoxypiperidine-4-carboxamide hydrochloride (262 mg), and cesium carbonate (682 mg) were added to N,N-dimethylformamide (20 mL), heated to 80 °C, and stirred for 4 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1) to obtain intermediate 13-3 (400 mg).

[0366] (4) Preparation of intermediate 13-4

[0367] Intermediate 13-3 (400 mg, 0.71 mmol), 4-chlorophenylboronic acid (133 mg), potassium carbonate (197 mg), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (58 mg) were added to dioxane / water (16 mL / 4 mL), the mixture was purged with nitrogen three times, and the mixture was heated to 100 °C and stirred for 4 h under a nitrogen atmosphere. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1) to obtain intermediate 13-4 (350 mg).

[0368] (5) Preparation of compound 13

[0369] Intermediate 13-4 (80 mg, 0.147 mmol) was added to dimethyl sulfoxide (2 mL), followed by L-prolyl (75 mg) and potassium fluoride (43 mg). The mixture was heated to 140 °C and stirred for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 13 (42 mg). ESI-MS (m / z): 609.2 [M+H] + .

[0370] Example 14: Preparation of Compound 67

[0371]

[0372] (1) Preparation of intermediate 67-1

[0373] Intermediate 2-1 (374 mg, 0.84 mmol), cesium carbonate (547 mg), and 3-methyl-3-cyanozyrazine hydrochloride (167 mg) were added to N,N-dimethylformamide (20 mL), heated to 80 °C, and stirred for 3 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 67-1 (315 mg).

[0374] (2) Preparation of compound 67

[0375] 2-Methyl-1,2-propanediol (80 mg) and sodium tert-butoxide (86 mg) were added to N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 67-1 (138 mg, 0.3 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 67 (46 mg). ESI-MS (m / z): 514.2 [M+H] + . 1¹H NMR (600MHz, CDCl₃) δ 8.93 (d, J = 1.4 Hz, 1H), 8.04 (dd, J = 8.1, 2.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.48–7.42 (m, 4H), 7.26 (s, 1H), 5.50 (s, 1H), 4.89–4.77 (m, 2H), 4.46–4.36 (m, 2H), 4.01 (s, 2H), 1.85 (s, 3H), 1.29 (s, 6H). Example 15: Preparation of compound 68

[0376]

[0377] (1) Preparation of intermediate 68-1

[0378] Intermediate 2-1 (200 mg, 0.45 mmol), cesium carbonate (293 mg), and 3-methoxy-3-methylazacyclobutane hydrochloride (93 mg) were added to N,N-dimethylformamide (10 mL), heated to 80 °C, and stirred for 3 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 68-1 (150 mg).

[0379] (2) Preparation of compound 68

[0380] 2-Methyl-1,2-propanediol (80 mg) and sodium tert-butoxide (86 mg) were added to N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 68-1 (140 mg, 0.3 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 68 (47 mg). ESI-MS (m / z): 519.2 [M+H] + .

[0381] Example 16: Preparation of Compound 72

[0382]

[0383] (1) Preparation of intermediate 72-1

[0384] Intermediate 2-1 (374 mg, 0.84 mmol), cesium carbonate (547 mg), and 4-isopropoxypiperidine-4-carboxamide hydrochloride (prepared according to WO2023155004) (188 mg) were added to N,N-dimethylformamide (20 mL), heated to 80 °C, and stirred for 3 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 72-1 (278 mg).

[0385] (2) Preparation of compound 72

[0386] 2-Methyl-1,2-propanediol (80 mg) and sodium tert-butoxide (86 mg) were added to N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 72-1 (165 mg, 0.3 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 72 (57 mg). ESI-MS (m / z): 604.2 [M+H] + . 1 H NMR (600MHz, CDCl3) δ8.97 (d, J=1.4Hz, 1H), 8.04 (dd, J=8.1, 2.0Hz, 1H), 7.60 (d,J=8.1Hz,1H),7.49-7.46(m,4H),7.26(s,1H),6.33(s,1H),5.88(s,1H),5 .42(s,1H),4.57-4.52(m,2H),4.00(s,2H),3.93-3.89(m,1H),3.82-3.78(m, 2H),2.27-2.23(m,2H),2.00-1.97(m,2H),1.29(s,6H),1.27(d,J=6.0Hz,6H).

[0387] Example 17: Preparation of Compound 87

[0388]

[0389] (1) Preparation of intermediate 87-1

[0390] Following the synthesis method of intermediate 10-5, intermediate 87-1 (293 mg) was obtained.

[0391] (2) Preparation of compound 87

[0392] 2-Methyl-1,2-propanediol (21 mg) and sodium tert-butoxide (33 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 87-1 (60 mg, 0.10 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 87 (18 mg). ESI-MS (m / z): 613.2 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ7.51-7.42(m,8H),7.32(s,1H),7.22(s,1H),5.48-5.46(m,1H),4.67-4.63(m,1H),4.46-4.43 (m,1H),4.15-4.09(m,1H),3.98(s,2H),3.78-3.73(m,1H),3.61-3.55(m,1H),2.00-1.88(m,4H),1.18-1.15(m,12H).

[0393] Example 18: Preparation of Compound 48

[0394]

[0395] (1) Preparation of intermediate 48-1

[0396] Intermediate 10-3 (150 mg, 0.37 mmol), 4-methylpiperidin-4-carboxamide hydrochloride (80 mg), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (388 mg), and N,N-diisopropylethylamine (193 mg) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 12 h. LCMS monitoring showed no residual starting material. The reaction mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 30:1-15:1) to give intermediate 48-1 (190 mg).

[0397] (2) Preparation of intermediate 48-2

[0398] Intermediate 48-1 (190 mg, 0.36 mmol) was dissolved in trifluoroacetic acid (5 mL), followed by the addition of hydrogen peroxide (2 mL). The reaction was carried out at room temperature for 1 h, and LCMS monitoring showed no residual starting material. The solvent was removed by vacuum distillation, and the mixture was purified by direct column chromatography (dichloromethane:methanol = 20:1-15:1) to obtain intermediate 48-2 (120 mg).

[0399] (3) Preparation of intermediate 48-3

[0400] N-(tert-Butoxycarbonyl)ethanolamine (97 mg) and sodium tert-butoxide (96 mg) were added to tetrahydrofuran (10 mL) and stirred at room temperature for 0.5 h. Then, intermediate 48-2 (112 mg, 0.20 mmol) was added to the reaction solution and stirred at room temperature for 2 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain intermediate 48-3 (82 mg).

[0401] (4) Preparation of compound 48

[0402] Intermediate 48-3 (82 mg, 0.128 mmol) was dissolved in a 1,4-dioxane hydrochloric acid solution (2 M, 10 mL) and reacted with the solution at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the solution was then dissolved in dichloromethane. Methanesulfonyl chloride (22 mg) and triethylamine (52 mg) were then added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 48 (57 mg), ESI-MS (m / z): 618.1 [M+H]. + .

[0403] 1 HNMR(600MHz,DMSO-d6)δ7.51-7.50(m,2H),7.47-7.42(m,6H),7.29-7.27(m,2H),6.99(s,1H),5.42-5.40(m,1H),4.43-4.39(m,1H),4.27 (t,J=6.0Hz,2H),4.07-4.04(m,1H),3.50-3.45(m,1H),3.36-3.34(m,2H),2.94(s,3H),2.16-2.14(m,2H),1.53-1.43(m,2H),1.16(s,3H).

[0404] Example 22: Preparation of Compound 93

[0405]

[0406] (1) Preparation of intermediate 93-1

[0407] 601 mg (1.79 mmol) of 5-(2-bromo-2-(4-chlorophenyl)acetyl)pyridinemethyl nitrile (prepared according to WO2023155004) and intermediate 4-2 (283 mg) were added to N,N-dimethylformamide (20 mL), heated to 100 °C and stirred for 6 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1-20:1) to give intermediate 93-1 (529 mg).

[0408] (2) Preparation of intermediate 93-2

[0409] Intermediate 93-1 (529 mg, 1.34 mmol), 4-isopropoxypiperidine-4-carboxamide hydrochloride (prepared according to WO2023155004) (358 mg), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1046 mg), and N,N-diisopropylethylamine (520 mg) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 12 h. LCMS monitoring showed no residual starting material. The reaction mixture was then diluted with water (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then purified by column chromatography (dichloromethane:methanol = 30:1-15:1) to obtain intermediate 93-2 (497 mg).

[0410] (3) Preparation of intermediate 93-3

[0411] Intermediate 93-2 (203 mg, 0.36 mmol) was dissolved in trifluoroacetic acid (5 mL), followed by the addition of hydrogen peroxide (2 mL). The reaction was carried out at room temperature for 1 h, and LCMS monitoring showed no residual starting material. The solvent was removed by vacuum distillation, and the mixture was purified by direct column chromatography (dichloromethane:methanol = 20:1-15:1) to obtain intermediate 93-3 (173 mg).

[0412] (4) Preparation of compound 93

[0413] 2-Methyl-1,2-propanediol (9 mg) and sodium tert-butoxide (16 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 93-3 (20 mg, 0.034 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 93 (14 mg). ESI-MS (m / z): 605.2 [M+H] + . 1 HNMR(600MHz,DMSO-d6)δ8.85(d,J=1.4Hz,1H),8.06(dd,J=8.2,1.4Hz,1H),8.02(d,J=8.2Hz ,1H),7.62(d,J=8.6Hz,2H),7.59(d,J=8.6Hz,2H),7.34(s,1H),7.24(s,1H),5.54-5.52(m,1 H),4.64(s,1H),4.43-4.41(m,1H),4.23-4.20(m,1H),3.92-3.88(m,2H),3.81-3.76(m,1H), 3.64-3.59(m,1H),2.06-2.02(m,2H),1.95-1.93(m,2H),1.16(d,J=6.0Hz,6H),1.15(s,6H).

[0414] Example 23: Preparation of Compound 116

[0415]

[0416] 2-Methyl-1,2-propanediol (39 mg) and sodium tert-butoxide (62 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 48-2 (120 mg, 0.215 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 116 (62 mg). ESI-MS (m / z): 569.2 [M+H] + . 1HNMR(600MHz,DMSO-d6)δ7.51-7.49(m,2H),7.47-7.41(m,6H),7.29(s,1H),6.99(s,1H),5.41-5.38(m,1H),4.66(s,1H),4.40- 4.38(m,1H),4.08-4.04(m,1H),3.98(s,2H),3.49-3.46(m,1H),2.16-2.13(m,2H),1.52-1.44(m,2H),1.18(s,6H),1.16(s,3H).

[0417] Example 24: Preparation of compound 117

[0418]

[0419] (1) Preparation of intermediate 117-1

[0420] Intermediate 10-3 (150 mg, 0.37 mmol), 4-(ethylamino)-4-piperidinecarboxamide (77 mg), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (388 mg), and N,N-diisopropylethylamine (144 mg) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 12 h. LCMS monitoring showed no residual starting material. The reaction mixture was then extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then purified by column chromatography (dichloromethane:methanol = 30:1-15:1) to obtain intermediate 117-1 (200 mg).

[0421] (2) Preparation of intermediate 117-2

[0422] Intermediate 117-1 (200 mg, 0.36 mmol) was dissolved in trifluoroacetic acid (5 mL), followed by the addition of hydrogen peroxide (2 mL). The reaction was carried out at room temperature for 1 h, and LCMS monitoring showed no residual starting material. The solvent was removed under reduced pressure, and the mixture was purified by direct column chromatography (dichloromethane:methanol = 20:1-15:1) to obtain intermediate 117-2 (116 mg).

[0423] (3) Preparation of compound 117

[0424] 2-Methyl-1,2-propanediol (36 mg) and sodium tert-butoxide (57 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 117-2 (116 mg, 0.198 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 117 (57 mg). ESI-MS (m / z): 598.2 [M+H] + . 1 HNMR(600MHz,DMSO-d6)δ7.51-7.49(m,2H),7.46-7.41(m,6H),7.33(s,1H) ,7.04(s,1H),5.39-5.37(m,1H),4.66(s,1H),4.38-4.36(m,1H),4.25-4.22 (m,1H),3.98(s,2H),3.71-3.68(m,1H),2.40-2.39(m,2H),2.20-2.07(m,1H ),1.94-1.92(m,2H),1.73-1.71(m,2H),1.18(s,6H),1.16(t,J=6.6Hz,3H).

[0425] Example 25: Preparation of Compound 118

[0426]

[0427] 2-Hydroxyacetamide (15 mg) and sodium tert-butoxide (29 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 87-1 (60 mg, 0.10 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 118 (23 mg). ESI-MS (m / z): 598.2 [M+H] + . 1HNMR(600MHz,DMSO-d6)δ7.53-7.50(m,2H),7.49-7.42(m,6H),7.33(s,1H),7.26(s,1H),7.22(s,1H),7.15(s,1H),5.46-5.43(m,1H ),4.59(s,2H),4.44-4.42(m,1H),4.16-4.12(m,1H),3.78-3.75(m,1H),3.62-3.58(m,1H),1.99-1.95(m,4H),1.15(d,J=4.8Hz,6H).

[0428] Example 26: Preparation of compound 119

[0429]

[0430] (1) Preparation of intermediate 119-2

[0431] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 4-methylpiperidine-4-carboxylic acid hydrochloride to obtain intermediate 119-2 (129 mg).

[0432] (2) Preparation of compound 119

[0433] 2-Methyl-1,2-propanediol (9 mg) and sodium tert-butoxide (16 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 119-2 (19 mg, 0.034 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 119 (10 mg). ESI-MS (m / z): 570.2 [M+H] + . 1 HNMR(600MHz,DMSO-d6)δ12.51(s,1H),7.51-7.49(m,2H),7.47-7.41(m,6H),5.54-5.46(m,1H),4.66(s,1H),4.52- 4.45(m,1H),4.04-3.98(m,3H),3.47-3.40(m,1H),2.13-2.09(m,2H),1.60-1.49(m,2H),1.20(s,3H),1.18(s,6H).

[0434] Example 27: Preparation of Compound 120

[0435]

[0436] (1) Preparation of intermediate 120-1

[0437] N-(tert-Butoxycarbonyl)ethanolamine (97 mg) and sodium tert-butoxide (96 mg) were added to tetrahydrofuran (10 mL) and stirred at room temperature for 0.5 h. Then, intermediate 87-1 (120 mg, 0.20 mmol) was added to the reaction solution and stirred at room temperature for 2 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain intermediate 120-1 (91 mg).

[0438] (2) Preparation of compound 120

[0439] Intermediate 120-1 (91 mg, 0.13 mmol) was dissolved in a 1,4-dioxane hydrochloric acid solution (2 M, 10 mL) and stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the solution was then dissolved in dichloromethane. Methanesulfonyl chloride (22 mg) and triethylamine (40 mg) were then added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 120 (64 mg). ESI-MS (m / z): 662.2 [M+H] + .

[0440] 1 HNMR(600MHz,DMSO-d6)δ7.53-7.43(m,8H),7.33(s,1H),7.29(t,J=6.0Hz,1 H),7.23(s,1H),5.48-5.46(m,1H),4.45-4.43(m,1H),4.28(t,J=6.0Hz,2H),

[0441] 4.16-4.14(m,1H),3.78-3.74(m,1H),3.61-3.57(m,1H),3.36-3.34(m,2H),2.95(s,3H),1.99-1.91(m,4H),1.16(d,J=6.0Hz,6H).

[0442] Example 28: Preparation of Compound 121

[0443]

[0444] 2,2-Dimethyl-3-hydroxypropionic acid (47 mg) and sodium tert-butoxide (96 mg) were added to tetrahydrofuran (10 mL) and stirred at room temperature for 0.5 h. Then, intermediate 87-1 (120 mg, 0.20 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound 121 (43 mg). ESI-MS (m / z): 641.2 [M+H] + .

[0445] 1 HNMR(600MHz,DMSO-d6)δ12.40(brs,1H),7.50-7.43(m,8H),7.32(s,1H),7.21(s,1H),5.48-5.46(m,1H),4.45-4.43(m,1H), 4.21(s,2H),4.13-4.08(m,1H),3.79-3.73(m,1H),3.62-3.55(m,1H),2.03-1.88(m,4H),1.20(s,6H),1.16(d,J=4.2Hz,6H).

[0446] Example 29: Preparation of Compound 122

[0447]

[0448] Compound 121 (32 mg, 0.05 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (29 mg), ammonium chloride (6 mg), and triethylamine (15 mg) were dissolved in dichloromethane (5 mL) and stirred overnight at room temperature. The solvent was removed by concentration under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 122 (24 mg), ESI-MS (m / z): 640.2 [M+H]. + . 1HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.46-7.41(m,6H),7.32(s,1H),7.21(s,1H),7.18(s,1H),6.91(s,1H),5.48-5.46(m,1H),4.45 -4.43(m,1H),4.19(s,2H),4.13-4.06(m,1H),3.78-3.73(m,1H),3.59-3.55(m,1H),2.03-1.90(m,4H),1.17(s,6H),1.15(d,J=5.4Hz,6H).

[0449] Example 30: Preparation of Compound 123

[0450]

[0451] (1) Preparation of intermediate 123-1

[0452] Intermediate 87-1 (48 mg, 0.08 mmol), 4-methoxybenzylamine (114 mg), and N,N-diisopropylethylamine (107 mg) were added to N-methylpyrrolidone (2 mL). The mixture was stirred at 120 °C for 12 h. The mixture was then cooled to room temperature, and water (5 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 123-1 (32 mg).

[0453] (2) Preparation of intermediate 123-2

[0454] Intermediate 123-1 (32 mg, 0.048 mmol) was dissolved in trifluoroacetic acid (2 mL), stirred at room temperature for 2 h, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 123-2 (18 mg).

[0455] (3) Preparation of compound 123

[0456] Intermediate 123-2 (18 mg, 0.033 mmol) was dissolved in acetic anhydride (2 mL), and the mixture was stirred at 80 °C for 1 h. The solvent was removed by concentration under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 123 (10 mg). ESI-MS (m / z): 582.2 [M+H] + .

[0457] 1HNMR(600MHz,DMSO-d6)δ10.11(s,1H),7.54-7.51(m,4H),7.48-7.42(m,4H),7.32(s,1H),7.22(s,1H),5.44-5.41(m,1H),4.4 9-4.47(m,1H),4.17-4.13(m,1H),3.79-3.74(m,1H),3.64-3.60(m,1H),2.13(s,3H),1.99-1.93(m,4H),1.15(d,J=6.0Hz,6H).

[0458] Example 31: Preparation of Compound 124

[0459]

[0460] (1) Preparation of intermediate 124-1

[0461] D-methyl lactate (9 mg) and sodium tert-butoxide (12 mg) were added to tetrahydrofuran (2 mL) and stirred at room temperature for 0.5 h. Then, intermediate 87-1 (48 mg, 0.08 mmol) was added to the reaction solution and stirred at room temperature for 2 h. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 124-1 (31 mg).

[0462] (2) Preparation of compound 124

[0463] Intermediate 124-1 (31 mg, 0.05 mmol) was dissolved in ammonia-methanol solution (2 M, 5 mL), stirred at 100 °C for 6 h, and the solvent was removed under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 124 (20 mg), ESI-MS (m / z): 612.2 [M+H]. + .

[0464] 1HNMR(600MHz,DMSO-d6)δ7.53-7.50(m,3H),7.48-7.42(m,6H),7.33(s,1H),7.22(s,1H),7.17(s,1H),5.46-5.41(m,1H),4.94(q,J=6.7Hz,1H ),4.48-4.43(m,1H),4.18-4.11(m,1H),3.80-3.74(m,1H),3.65-3.56( m,1H),2.02-1.90(m,4H),1.44(d,J=6.0Hz,3H),1.16(d,J=6.0Hz,6H).

[0465] Example 32: Preparation of Compound 125

[0466]

[0467] Intermediate 120-1 (59 mg, 0.086 mmol) was dissolved in a 1,4-dioxane hydrochloric acid solution (2 M, 10 mL) and stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the mixture was then dissolved in dichloromethane. Acetyl chloride (13 mg) and triethylamine (18 mg) were added immediately, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 125 (28 mg), ESI-MS (m / z): 626.2 [M+H]. + .

[0468] 1 HNMR(600MHz,DMSO-d6)δ8.12(t,J=6.0Hz,1H),7.52-7.50(m,2H),7.47-7. 41(m,6H),7.32(s,1H),7.22(s,1H),5.47-5.45(m,1H),4.44-4.42(m,1H),4 .21(t,J=6.0Hz,2H),4.15-4.12(m,1H),3.78-3.73(m,1H),3.61-3.57(m,1H ),3.43-3.40(m,2H),1.99-1.92(m,4H),1.81(s,3H),1.15(d,J=6.0Hz,6H).

[0469] Example 33: Preparation of Compound 126

[0470]

[0471] Intermediate 123-2 (18 mg, 0.033 mmol), methanesulfonyl chloride (8 mg), and triethylamine (10 mg) were dissolved in dichloromethane (2 mL). The mixture was stirred at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 126 (8 mg), ESI-MS (m / z): 618.2 [M+H]. + .

[0472] 1 HNMR(600MHz,DMSO-d6)δ10.65(s,1H),7.56-7.53(m,4H),7.50-7.44(m,4H),7.32(s,1H),7.22(s,1H),5.44-5.41(m,1H),4.4 9-4.47(m,1H),4.17-4.13(m,1H),3.79-3.74(m,1H),3.64-3.60(m,1H),2.95(s,3H),1.99-1.93(m,4H),1.15(d,J=6.0Hz,6H).

[0473] Example 34: Preparation of Compound 127

[0474] (1) Preparation of intermediate 127-1

[0475] N-(tert-Butoxycarbonyl)ethanolamine (97 mg) and sodium tert-butoxide (96 mg) were added to tetrahydrofuran (10 mL) and stirred at room temperature for 0.5 h. Then, intermediate 117-2 (118 mg, 0.20 mmol) was added to the reaction solution and stirred at room temperature for 2 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain intermediate 127-1 (78 mg).

[0476] (2) Preparation of compound 127

[0477] Intermediate 127-1 (78 mg, 0.116 mmol) was dissolved in a 1,4-dioxane hydrochloric acid solution (2 M, 10 mL) and stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the solution was then dissolved in dichloromethane. Methanesulfonyl chloride (20 mg) and triethylamine (47 mg) were then added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 127 (53 mg). ESI-MS (m / z): 647.2 [M+H]+ .

[0478] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.46-7.41(m,6H),7.33(s,1H),7.28(t, J=6.0Hz,1H),7.04(s,1H),5.39-5.37(m,1H),4.38-4.36(m,1H),4.27(t,J=6.0Hz,2H ),4.26-4.23(m,1H),3.71-3.68(m,1H),3.36-3.34(m,2H),2.94(s,3H),2.41-2.39(m ,2H),2.20-2.08(m,1H),1.97-1.90(m,2H),1.73-1.71(m,2H),1.04(t,J=6.9Hz,3H).

[0479] Example 36: Preparation of Compound 128

[0480]

[0481] (1) Preparation of intermediate 128-2

[0482] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 1-trifluoromethanesulfonylpiperazine hydrochloride to obtain intermediate 128-2 (100 mg).

[0483] (2) Preparation of compound 128

[0484] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 128-2 to obtain compound 128 (47 mg), ESI-MS (m / z): 694.1 [M+H] + .

[0485] 1HNMR(600MHz,DMSO-d6)δ7.54-7.44(m,8H),7.31(t,J=6.0Hz,1H),5.45-4.67(m,2H),4. 30(t,J=5.6Hz,2H),4.22-4.02(m,2H),3.76-3.71(m,4H),3.37-3.34(m,2H),2.94(s,3H).

[0486] Example 37: Preparation of Compound 129

[0487]

[0488] Intermediate 123-2 (20 mg, 0.037 mmol) and sodium cyanate (18 mg) were dissolved in acetic acid / water solution (1 mL / 1 mL). The mixture was stirred at 100 °C for 8 h, and the solvent was removed by concentration under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound 129 (12 mg), ESI-MS (m / z): 583.2 [M+H]. + .

[0489] 1 HNMR(600MHz,DMSO-d6)δ9.03(s,1H),7.52-7.49(m,2H),7.47-7.40(m,6H),7.33(s,1H),7.23(s,1H),7.01-6.86(brs,2H),5.41- 5.39(m,1H),4.43-4.41(m,1H),4.18-4.14(m,1H),3.78-3.74(m,1H),3.64-3.59(m,1H),2.01-1.91(m,4H),1.15(d,J=6.0Hz,6H).

[0490] Example 38: Preparation of Compound 130

[0491]

[0492] (1) Preparation of intermediate 130-1

[0493] N-(tert-Butoxycarbonyl)ethanolamine (97 mg) and sodium tert-butoxide (96 mg) were added to tetrahydrofuran (10 mL) and stirred at room temperature for 0.5 h. Then, intermediate 93-3 (119 mg, 0.20 mmol) was added to the reaction solution and stirred at room temperature for 2 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain intermediate 130-1 (77 mg).

[0494] (2) Preparation of compound 130

[0495] Intermediate 130-1 (77 mg, 0.114 mmol) was dissolved in a 1,4-dioxane hydrochloric acid solution (2 M, 10 mL) and reacted with the solution at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the solution was then dissolved in dichloromethane. Methanesulfonyl chloride (20 mg) and triethylamine (46 mg) were then added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 130 (42 mg). ESI-MS (m / z): 654.2 [M+H] + .

[0496] 1 HNMR(600MHz,DMSO-d6)δ8.87(d,J=1.4Hz,1H),8.08(dd,J=8.2,1.4Hz,1H),8.03(d,J=8.2Hz,1H ),7.62(d,J=8.6Hz,2H),7.59(d,J=8.6Hz,2H),7.34(s,1H),7.26-7.24(m,2H),5.54-5.48(m,1H ),4.43-4.39(m,1H),4.27-4.24(m,1H),4.20(t,J=6.0Hz,2H),3.80-3.72(m,1H),3.65-3.59(m, 1H),3.39-3.30(m,2H),2.92(s,3H),2.06-2.04(m,2H),1.96-1.94(m,2H),1.16(d,J=6.0Hz,6H).

[0497] Example 39: Preparation of Compound 131

[0498]

[0499] (1) Preparation of intermediate 131-1

[0500] Intermediate 10-3 (150 mg, 0.37 mmol), 1,3,8-triazaspiro[4.5]decane-2,4-dione (75 mg), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (388 mg), and N,N-diisopropylethylamine (144 mg) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 12 h. LCMS monitoring showed no residual starting material. The reaction mixture was then extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 30:1-20:1) to obtain intermediate 131-1 (183 mg).

[0501] (2) Preparation of intermediate 131-2

[0502] Intermediate 131-1 (183 mg, 0.33 mmol) was dissolved in trifluoroacetic acid (5 mL), followed by the addition of hydrogen peroxide (2 mL). The reaction was carried out at room temperature for 1 h, and LCMS monitoring showed no residual starting material. The solvent was removed under reduced pressure, and the mixture was purified by direct column chromatography (dichloromethane:methanol = 20:1-15:1) to obtain intermediate 131-2 (122 mg).

[0503] (3) Preparation of compound 131

[0504] 2-Methyl-1,2-propanediol (32 mg) and sodium tert-butoxide (50 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 131-2 (103 mg, 0.175 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 131 (52 mg). ESI-MS (m / z): 596.2 [M+H] + .

[0505] 1 HNMR(600MHz,DMSO-d6)δ10.78(s,1H),8.67(s,1H),7.52-7.42(m,8H),5.74-5.72(m,1H),4.76-4.70(m,1H),4. 67(s,1H),4.14-4.10(m,1H),3.99(s,2H),3.61-3.57(m,1H),1.99-1.93(m,2H),1.81-1.77(m,2H),1.18(s,6H).

[0506] Example 40: Preparation of Compound 132

[0507]

[0508] Intermediate 87-1 (139 mg, 0.23 mmol) and sodium cyanide (227 mg) were dissolved in dimethyl sulfoxide (10 mL). The reaction solution was reacted at 100 °C for 16 h. After cooling to room temperature, an aqueous solution was added, and a solid precipitated. The mixture was filtered, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 132 (30 mg). ESI-MS (m / z): 550.2 [M+H] + .

[0509] 1 H NMR (600MHz, DMSO-d6) δ7.54-7.44(m,6H),7.43-7.39(m,2H),7.35(s,1H),7.24(s,1H),5.51-5.47(m,1H),4.51 -4.46(m,1H),4.25-4.18(m,1H),3.86-3.70(m,1H),3.66-3.62(m,1H),2.01-1.91(m,4H),1.16(d,J=6.0Hz,6H).

[0510] Example 41: Preparation of compound 133

[0511]

[0512] Compound 132 (20 mg, 0.036 mmol) and sodium hydroxide (0.36 mg) were dissolved in N-methylpyrrolidone / water (2 mL / 0.4 mL). The reaction solution was reacted at 75 °C for 2 h. After cooling to room temperature, an aqueous solution was added, and a solid precipitated. The mixture was filtered, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 133 (14 mg). ESI-MS (m / z): 568.2 [M+H] + .

[0513] 1 H NMR(600MHz, DMSO-d6)δ8.08(s,1H),7.81(s,1H),7.53-7.42(m,8H),7.36(s,1H),7.23(s,1H),5.51-5.47 (m,1H),4.51-4.46(m,1H),4.19-4.16(m,1H),3.79-3.65(m,2H),2.03-1.95(m,4H),1.16(d,J=6.0Hz,6H).

[0514] Example 42: Preparation of compound 134

[0515]

[0516] 1-(hydroxymethyl)cyclopropyl-1-ol (26 mg) and sodium tert-butoxide (48 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 87-1 (60 mg, 0.10 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 134 (28 mg). ESI-MS (m / z): 611.2 [M+H] + . 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.47-7.41(m,6H),7.32(s,1H),7.22(s,1H),5.63(s,1H),5.46-5.44(m,1H),4.44-4.42(m, 1H),4.21(s,2H),4.15-4.12(m,1H),3.79-3.73(m,1H),3.63-3.58(m,1H),2.00-1.92(m,4H),1.16(d,J=6.0Hz,6H),0.69-0.63(m,4H).

[0517] Example 43: Preparation of Compound 135

[0518]

[0519] Intermediate 120-1 (89 mg, 0.13 mmol) was dissolved in a 1,4-dioxane hydrochloric acid solution (2 M, 10 mL) and reacted with the solution at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the solution was then dissolved in dichloromethane. Ethylsulfonyl chloride (25 mg) and triethylamine (40 mg) were then added, and the mixture was reacted with the solution at room temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 135 (67 mg), ESI-MS (m / z): 676.2 [M+H]. + .

[0520] 1HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.47-7.42(m,6H),7.32(s,1H),7.31(t, J=6.0Hz,1H),7.22(s,1H),5.47-5.45(m,1H),4.44-4.42(m,1H),4.25(t,J=6.0Hz,2 H),4.16-4.12(m,1H),3.78-3.74(m,1H),3.62-3.57(m,1H),3.34(t,J=6.0Hz,2H),3 .04(q,J=7.2Hz,2H),1.98-1.91(m,4H),1.19(t,J=7.2Hz,3H),1.15(d,J=6.0Hz,6H).

[0521] Example 44: Preparation of compound 136

[0522]

[0523] Intermediate 120-1 (89 mg, 0.13 mmol) was dissolved in a 1,4-dioxane hydrochloric acid solution (2 M, 10 mL) and stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and the solution was then dissolved in dichloromethane. Cyclopropanesulfonyl chloride (28 mg) and triethylamine (40 mg) were then added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 136 (67 mg), ESI-MS (m / z): 688.2 [M+H]. + .

[0524] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.47-7.41(m,6H),7.35(t,J=6.0Hz,1H),7 .32(s,1H),7.22(s,1H),5.47-5.45(m,1H),4.44-4.42(m,1H),4.28(t,J=6.0Hz,2H),4 .15-4.12(m,1H),3.78-3.74(m,1H),3.61-3.57(m,1H),3.39-3.36(m,2H),2.62-2.58( m,1H),1.98-1.91(m,4H),1.15(d,J=6.0Hz,6H),0.92-0.90(m,2H),0.86-0.84(m,2H).

[0525] Example 45: Preparation of Compound 137

[0526]

[0527] Intermediate 87-1 (48 mg, 0.08 mmol), potassium fluoride (24 mg), and 3-(methylamino)propionamide (20 mg) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was reacted at 140 °C for 16 h, cooled to room temperature, and water (5 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 137 (20 mg). ESI-MS (m / z): 625.2 [M+H] + .

[0528] 1 H NMR (600MHz, DMSO-d6) δ7.53-7.49(m,4H),7.46-7.40(m,4H),7.34(s,1H),7.31(s,1H),7.20(s,1H),6.80(s,1H),5.40-5.38(m,1H),4.43-4.4 1(m,1H),4.11-4.05(m,1H),3.77-3.69(m,3H),3.58-3.55(m,1H),3.02 (s,3H),2.38(t,J=6.0Hz,2H),1.95-1.89(m,4H),1.15(d,J=6.0Hz,6H).

[0529] Example 46: Preparation of Compound 138

[0530]

[0531] 2-Hydroxyethanesulfonamide (38 mg) and sodium tert-butoxide (48 mg) were added to tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 87-1 (60 mg, 0.10 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound 138 (25 mg). ESI-MS (m / z): 648.2

[0532] [M+H] + . 1H NMR (600MHz, DMSO-d6) δ7.52-7.42(m,8H),7.33(s,1H),7.22(s,1H),7.00(s,2H),5.48-5.46(m,1H),4.57(t,J=6.6Hz,2H),4.45-4. 43(m,1H),4.19-4.11(m,1H),3.79-3.74(m,1H),3.65-3.57(m,1H),3.51(t,J=6.6Hz,2H),2.01-1.89(m,4H),1.15(d,J=6.0Hz,6H).

[0533] Example 47: Preparation of Compound 139

[0534]

[0535] Intermediate 87-1 (48 mg, 0.08 mmol), potassium fluoride (24 mg), and 2-aminoethylsulfonamide (21 mg) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was reacted at 140 °C for 16 h, cooled to room temperature, and water (5 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound 139 (25 mg). ESI-MS (m / z): 647.2 [M+H] + .

[0536] 1 H NMR (600MHz, DMSO-d6) δ7.51-7.50(m,4H),7.45-7.40(m,4H),7.31(s,1H),7.21(s,1H),6.90(s,2H),6.63(t,J=6.0Hz,1H),5.43-5.34(m,1H) ,4.44-4.38(m,1H),4.15-4.06(m,1H),3.77-3.72(m,1H),3.60-3.57( m,3H),3.27(t,J=7.2Hz,2H),1.98-1.85(m,4H),1.15(d,J=6.0Hz,6H).

[0537] Example 48: Preparation of Compound 140

[0538]

[0539] Following the synthetic method of Example 27, N-(tert-butyloxycarbonyl)ethanolamine was replaced with (1-hydroxy-2-methylpropyl-2-yl)tert-butyl carbamate to obtain compound 140 (44 mg), ESI-MS (m / z): 690.2 [M+H] + .

[0540] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.41(m,8H),7.32(s,1H),7.22(s,1H),7.10(s,1H),5.49-5.46(m,1H),4.46-4.44(m,1H),4.24-4.19 (m,2H),4.14-4.11(m,1H),3.78-3.74(m,1H),3.60-3.58(m,1H),2.98(s,3H),1.99-1.91(m,4H),1.34(s,6H),1.16(d,J=6.0Hz,6H).

[0541] Example 49: Preparation of Compound 141

[0542]

[0543] Following the synthetic method of Example 27, N-(tert-butyloxycarbonyl)ethanolamine was replaced with N-(3-hydroxypropyl)carbamate tert-butyl ester to obtain compound 141 (40 mg), ESI-MS (m / z): 676.2 [M+H]. + .

[0544] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.48-7.41(m,6H),7.32(s,1H) ,7.22(s,1H),7.07(t,J=6.0Hz,1H),5.47-5.45(m,1H),4.45-4.42(m,1H),4 .27(t,J=6.0Hz,2H),4.14-4.10(m,1H),3.77-3.73(m,1H),3.60-3.56(m,1H ),3.11-3.07(m,2H),2.90(s,3H),1.99-1.89(m,6H),1.16(d,J=6.0Hz,6H).

[0545] Example 50: Preparation of Compound 142

[0546]

[0547] Following the synthetic method of Example 27, N-(tert-butoxycarbonyl)ethanolamine was replaced with N-tert-butoxycarbonyl-D-propanoamino alcohol to obtain compound 142 (45 mg), ESI-MS (m / z): 676.2 [M+H]. + .

[0548] 1 HNMR(600MHz,DMSO-d6)δ7.53-7.51(m,2H),7.48-7.42(m,6H),7.33(s,1H),7.27(d,J=7.8Hz,1H),7.23(s,1H),5.51-5.46(m,1H),4.48-4.42 (m,1H),4.23-4.18(m,3H),3.81-3.73(m,2H),3.64-3.56(m,1H),2.95( s,3H),1.99-1.92(m,4H),1.19(d,J=6.6Hz,3H),1.16(d,J=6.0Hz,6H).

[0549] Example 51: Preparation of compound 143

[0550]

[0551] Following the synthetic method of Example 27, N-(tert-butoxycarbonyl)ethanolamine was replaced with N-tert-butoxycarbonyl-L-propanoamino alcohol to obtain compound 143 (45 mg), ESI-MS (m / z): 676.2 [M+H]. + .

[0552] 1 HNMR(600MHz,DMSO-d6)δ7.53-7.51(m,2H),7.48-7.42(m,6H),7.32(s,1H),7.25(d,J=7.8Hz,1H),7.22(s,1H),5.50-5.43(m,1H),4.47-4.41 (m,1H),4.21-4.17(m,3H),3.78-3.73(m,2H),3.64-3.56(m,1H),2.95( s,3H),1.96-1.93(m,4H),1.19(d,J=6.6Hz,3H),1.16(d,J=6.0Hz,6H).

[0553] Example 52: Preparation of Compound 144

[0554]

[0555] (1) Preparation of intermediate 144-2

[0556] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with thiomorpholine-1,1-dioxide to obtain intermediate 144-2 (95 mg).

[0557] (2) Preparation of compound 144

[0558] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 144-2 to obtain compound 144 (59 mg), ESI-MS (m / z): 611.1 [M+H]. + .

[0559] 1 HNMR(600MHz,DMSO-d6)δ7.53-7.43(m,8H),7.32(t,J=7.8Hz,1H),5.24-5.13(m,2H),4.4 4-4.36(m,2H),4.31(t,J=6.0Hz,2H),3.46-3.39(m,2H),3.37-3.34(m,4H),2.96(s,3H).

[0560] Example 53: Preparation of Compound 145

[0561]

[0562] (1) Preparation of intermediate 145-2

[0563] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with morpholine to obtain intermediate 145-2 (87 mg).

[0564] (2) Preparation of compound 145

[0565] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 145-2 to obtain compound 145 (47 mg), ESI-MS (m / z): 563.1 [M+H]. + .

[0566] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.49(m,2H),7.46-7.41(m,6H),7.29(t,J=7.8Hz,1H),4.85-4.78(m ,2H),4.28(t,J=5.4Hz,2H),4.00-3.95(m,2H),3.78-3.76(m,2H),3.36-3.34(m,4H),2.94(s,3H).

[0567] Example 54: Preparation of Compound 146

[0568]

[0569] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 10-5 to obtain compound 146 (35 mg), ESI-MS (m / z): 648.2 [M+H]. + .

[0570] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.46-7.41(m,6H),7.31(s,1H),

[0571] 7.28(t,J=6.0Hz,1H),7.22(s,1H),5.78-5.75(m,1H),4.65-4.63(m,1H),4.27(t,J

[0572] =6.0Hz,2H),3.84-3.80(m,1H),3.42-3.34(m,5H),2.94(s,3H),1.98-1.88(m,

[0573] 4H), 1.21(t, J = 6.6 Hz, 3H).

[0574] Example 55: Preparation of Compound 147

[0575]

[0576] Following the synthetic method of Example 27, N-(tert-butyloxycarbonyl)ethanolamine was replaced with (1-hydroxymethylcyclopropyl)-tert-butyloxycarbonylamino to obtain compound 147 (39 mg), ESI-MS (m / z): 688.2 [M+H]. + .

[0577] 1 HNMR(600MHz,DMSO-d6)δ7.80(s,1H),7.52-7.50(m,2H),7.47-7.41(m,6H),7 .32(s,1H),7.22(s,1H),5.47-5.45(m,1H),4.45-4.43(m,1H),4.26-4.25(m, 2H),4.15-4.11(m,1H),3.78-3.74(m,1H),3.62-3.57(m,1H),2.95(s,3H),1. 96-1.93(m,4H),1.16(d,J=6.0Hz,6H),0.98-0.96(m,2H),0.87-0.85(m,2H).

[0578] Example 56: Preparation of Compound 148

[0579]

[0580] Following the synthetic method of Example 27, N-(tert-butoxycarbonyl)ethanolamine was replaced with N-tert-butoxycarbonyl-(R)-1-amino-2-propanol to obtain compound 148 (38 mg), ESI-MS (m / z): 676.2 [M+H]. + .

[0581] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.47-7.41(m,6H),7.32(s,1H),7.2 5(t,J=6.0Hz,1H),7.22(s,1H),5.49-5.42(m,1H),5.02-4.96(m,1H),4.46-4.41 (m,1H),4.17-4.09(m,1H),3.78-3.72(m,1H),3.64-3.55(m,1H),3.27-3.17(m,2 H), 2.92 (s, 3H), 1.99-1.92 (m, 4H), 1.31 (d, J = 8.7Hz, 3H), 1.15 (d, J = 5.5Hz, 6H).

[0582] Example 57: Preparation of Compound 149

[0583]

[0584] Following the synthetic method of Example 27, N-(tert-butoxycarbonyl)ethanolamine was replaced with N-tert-butoxycarbonyl-(S)-1-amino-2-propanol to obtain compound 149 (39 mg), ESI-MS (m / z): 676.2 [M+H]. + .

[0585] 1HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.47-7.41(m,6H),7.32(s,1H),7.2 5(t,J=6.0Hz,1H),7.22(s,1H),5.49-5.42(m,1H),5.03-4.98(m,1H),4.46-4.41 (m,1H),4.17-4.09(m,1H),3.79-3.72(m,1H),3.64-3.55(m,1H),3.27-3.17(m,2 H),2.91(s,3H),1.99-1.90(m,4H),1.31(d,J=8.7Hz,3H),1.15(d,J=5.5Hz,6H).

[0586] Example 58: Preparation of Compound 150

[0587]

[0588] (1) Preparation of intermediate 150-2

[0589] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 3-methoxy-3-methylazacyclobutane hydrochloride to obtain intermediate 150-2 (80 mg).

[0590] (2) Preparation of compound 150

[0591] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 150-2 to obtain compound 150 (41 mg), ESI-MS (m / z): 577.1 [M+H] + .

[0592] 1 HNMR(600MHz,DMSO-d6)δ7.53-7.49(m,2H),7.48-7.42(m,6H),7.29(t,J=6.0Hz,1H),4.61-4.54(m,2H),4.27(t ,J=5.6Hz,2H),4.21-4.19(m,1H),4.12-4.10(m,1H),3.36-3.31(m,2H),3.24(s,3H),2.94(s,3H),1.51(s,3H).

[0593] Example 59: Preparation of Compound 151

[0594]

[0595] (1) Preparation of intermediate 151-2

[0596] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 4-(trifluoromethyl)piperidine to obtain intermediate 151-2 (75 mg).

[0597] (2) Preparation of compound 151

[0598] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 151-2 to obtain compound 151 (44 mg), ESI-MS (m / z): 629.1 [M+H] + .

[0599] 1 HNMR (600MHz, DMSO-d6) δ7.53-7.50(m,2H),7.47-7.42(m,6H),7.28(t,J=6.0Hz,1H),6.35-6.24(m,1H),5.11-5.00(m,1H),4.28(t,J=6. 0Hz,2H),3.47-3.39(m,1H),3.09-3.02(m,1H),2.94(s,3H),2.82-2.76(m,1H),2.03-2.00(m,2H),1.63-1.49(m,2H),1.28-1.16(m,2H).

[0600] Example 60: Preparation of Compound 152

[0601]

[0602] (1) Preparation of intermediate 152-2

[0603] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with N-(4-methylpiperidine-4-yl)acetamide to obtain intermediate 152-2 (73 mg).

[0604] (2) Preparation of compound 152

[0605] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 152-2 to obtain compound 152 (51 mg), ESI-MS (m / z): 632.2 [M+H]. + .

[0606] 1HNMR(600MHz,DMSO-d6)δ7.55(s,1H),7.51-7.49(m,2H),7.47-7.41(m,6H),7 .28(t,J=6.0Hz,1H),5.53-5.51(m,1H),4.45-4.43(m,1H),4.27(t,J=5.6Hz,2 H),4.05-3.98(m,1H),3.47-3.43(m,1H),3.35-3.32(m,2H),2.94(s,3H),2.32 -2.30(m,1H),2.23-2.20(m,1H),1.85(s,3H),1.61-1.52(m,2H),1.31(s,3H).

[0607] Example 61: Preparation of Compound 153

[0608]

[0609] (1) Preparation of intermediate 153-2

[0610] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 4,4-difluoropiperidine to obtain intermediate 153-2 (69 mg).

[0611] (2) Preparation of compound 153

[0612] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 153-2 to obtain compound 153 (41 mg), ESI-MS (m / z): 597.1 [M+H]. + .

[0613] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.43(m,8H),7.30(t,J=6.0Hz,1H),4.97-4.83(m,2H),4.2 7(t,J=5.6Hz,2H),4.14-4.05(m,2H),2.95(s,3H),2.24-2.13(m,4H),1.30-1.20(m,2H).

[0614] Example 62: Preparation of Compound 154

[0615]

[0616] (1) Preparation of intermediate 154-2

[0617] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 3-methyl-3-cyanozaziridine hydrochloride to obtain intermediate 154-2 (47 mg).

[0618] (2) Preparation of compound 154

[0619] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 154-2 to obtain compound 154 (29 mg), ESI-MS (m / z): 572.1 [M+H] + .

[0620] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.44(m,8H),7.30(t,J=6.0Hz,1H),

[0621] 5.00(d,J=10.3Hz,1H),4.69(d,J=10.3Hz,1H),4.60(d,J=10.3Hz,1H),

[0622] 4.27(t,J=5.6Hz,2H),4.26(d,J=10.3Hz,1H),3.36-3.33(m,2H),2.94(s,3H),1.72(s,3H).

[0623] Example 63: Preparation of Compound 155

[0624]

[0625] (1) Preparation of intermediate 155-1

[0626] Compound 133 (23 mg, 0.04 mmol) and nickel chloride hexahydrate (1 mg) were dissolved in methanol (2 mL). Sodium borohydride (8 mg) was slowly added at 0 °C. The reaction mixture was reacted at room temperature for 4 h. The solvent was removed by concentration under reduced pressure. Water (5 mL) was added to the mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 155-1 (15 mg).

[0627] (2) Preparation of compound 155

[0628] Intermediate 155-1 (15 mg, 0.027 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of methanesulfonyl chloride (6 mg) and triethylamine (8 mg). The mixture was stirred at room temperature for 2 h, and the solvent was removed under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 155 (12 mg), ESI-MS (m / z): 632.2 [M+H]. + .

[0629] 1 HNMR(600MHz,DMSO-d6)δ7.61(t,J=6.0Hz,1H),7.57-7.42(m,8H),7.34(s,1H),7.22(s,1H),5.48-5.46(m,1H),4.60-4.58(m,1H),4 .18-4.16(m,1H),4.15(d,J=6.0Hz,2H),3.78-3.74(m,1H),3.67-3.59(m,1H),2.90(s,3H),1.99-1.93(m,4H),1.16(d,J=6.0Hz,6H).

[0630] Example 64: Preparation of Compound 156

[0631]

[0632] (1) Preparation of intermediate 156-2

[0633] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 4-methyl-4-hydroxypiperidine to obtain intermediate 156-2 (68 mg).

[0634] (2) Preparation of compound 156

[0635] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 156-2 to obtain compound 156 (33 mg), ESI-MS (m / z): 591.1 [M+H] + .

[0636] 1 HNMR(600MHz, CDCl3)δ7.46-7.38(m,4H),7.34-7.28(m,4H),6.02-5.90(m,1H),4.98-4.90(m,1H),4.77-4.69 (m,1H),4.47-4.38(m,2H),4.02-3.93(m,1H),3.60-3.49(m,3H),2.99(s,3H),1.85-1.71(m,5H),1.26(s,3H).

[0637] Example 65: Preparation of Compound 157

[0638]

[0639] (1) Preparation of intermediate 157-2

[0640] Following the synthetic method of intermediate 10-5, 4-ethoxypiperidine-4-carboxamide hydrochloride was replaced with 4-aminotetrahydropyran to obtain intermediate 157-2 (45 mg).

[0641] (2) Preparation of compound 157

[0642] Following the synthetic method of Example 27, intermediate 87-1 was replaced with 157-2 to obtain compound 157 (21 mg), ESI-MS (m / z): 577.1 [M+H]. + .

[0643] 1 HNMR(600MHz,DMSO-d6)δ9.05(d,J=6.0Hz,1H),7.55-7.42(m,8H),7.30(t,J=6.0Hz,1H),4.39-4.32(m,1H),4 .29(t,J=5.6Hz,2H),3.92-3.90(m,2H),3.44-3.40(m,2H),3.37-3.35(m,2H),2.95(s,3H),1.82-1.73(m,4H).

[0644] Example 66: Preparation of Compound 158

[0645]

[0646] 2-Hydroxy-N-methylacetamide (18 mg) and sodium tert-butoxide (29 mg) were added to tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 0.5 h. Then, intermediate 87-1 (60 mg, 0.10 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 158 (32 mg). ESI-MS (m / z): 612.2 [M+H] + .

[0647] 1HNMR(600MHz, CDCl3)δ7.43-7.40(m,4H),7.34-7.29(m,4H),6.60-6.55(m ,1H),6.34(s,1H),5.75-5.72(m,1H),5.41(s,1H),4.79(s,2H),4.66-4.63 (m,1H),4.30-4.25(m,1H),3.90-3.86(m,1H),3.72-3.69(m,1H),2.90(d, J=4.9Hz,3H),2.25-2.14(m,2H),2.03-1.97(m,2H),1.25(d,J=6.0Hz,6H).

[0648] Example 67: Preparation of Compound 159

[0649]

[0650] (R)-2-hydroxypropionamide (21 mg) and sodium tert-butoxide (38 mg) were added to tetrahydrofuran (5 mL) and stirred at room temperature for 0.5 h. Then, intermediate 117-2 (47 mg, 0.08 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 159 (25 mg). ESI-MS (m / z): 597.2 [M+H] + .

[0651] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,3H),7.47-7.42(m,6H),7.34(s,1H),7.1 7(s,1H),7.04(s,1H),5.39-5.33(m,1H),4.94(q,J=6.8Hz,1H),4.39-4.35(m,1H ),4.27-4.21(m,1H),3.74-3.66(m,1H),2.42-2.37(m,2H),2.25-2.09(m,1H),1. 99-1.88(m,2H),1.76-1.71(m,2H),1.44(d,J=6.0Hz,3H),1.04(d,J=6.0Hz,3H).

[0652] Example 68: Preparation of Compound 160

[0653]

[0654] (1) Preparation of intermediate 160-1

[0655] Methyl glycolate (22 mg) and sodium tert-butoxide (38 mg) were added to tetrahydrofuran (5 mL) and stirred at room temperature for 0.5 h. Then, intermediate 87-1 (48 mg, 0.08 mmol) was added to the reaction solution and stirred at room temperature for 2 h. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 160-1 (24 mg).

[0656] (2) Preparation of compound 160

[0657] Intermediate 160-1 (24 mg, 0.039 mmol) and lithium hydroxide (2 mg) were dissolved in tetrahydrofuran / water solution (2 mL / 0.5 mL). The mixture was stirred at room temperature for 4 h, the solvent was removed under reduced pressure, and the solution was directly dissolved in N,N-dimethylformamide (2 mL). Then, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (23 mg), 3-oxacyclobutylamine (6 mg), and triethylamine (12 mg) were added. The mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give compound 160 (15 mg). ESI-MS (m / z): 654.2 [M+H] + .

[0658] 1 HNMR(600MHz,DMSO-d6)δ8.80(d,J=6.0Hz,1H),7.52-7.50(m,2H),7.47-7.42(m,6H),7.34(s,1H),7.23(s,1H),5.46-5.43(m,1H),4.79-4.74( m,1H),4.66-4.64(m,4H),4.43-4.37(m,3H),4.18-4.10(m,1H),3.79-3 .74(m,1H),3.63-3.55(m,1H),1.96-1.91(m,4H),1.15(d,J=6.0Hz,6H).

[0659] Example 69: Preparation of Compound 161

[0660]

[0661] (1) Preparation of intermediate 161-1

[0662] Intermediate 10-3 (330 mg, 0.82 mmol) and phosphorus tribromooxy (353 mg) were dissolved in acetonitrile (10 mL) and reacted at 100 °C for 4 h. LCMS monitoring showed no residual starting material. The reaction mixture was then extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then purified by column chromatography (dichloromethane:methanol = 100:1-50:1) to obtain intermediate 161-1 (100 mg).

[0663] (2) Preparation of intermediate 161-2

[0664] Following the synthesis method of intermediate 5-1, intermediate 2-1 was replaced with intermediate 161-1 to obtain intermediate 161-2 (57 mg).

[0665] (3) Preparation of compound 161

[0666] Following the synthetic method of Example 48, intermediate 48-1 was replaced with 161-2 to obtain compound 161 (35 mg), ESI-MS (m / z): 623.1 [M+H] + .

[0667] 1 HNMR(600MHz,DMSO-d6)δ10.00(s,1H),9.43(d,J=6.0Hz,1H),8.23(d,J=6.0Hz,1H) ,7.62-7.48(m,8H),7.38(t,J=6.0Hz,1H),4.49(t,J=6.0Hz,2H),3.47-3.44(m,2H).

[0668] Example 70: Preparation of Compound 162

[0669]

[0670] Following the synthetic method of Example 34, N-(tert-butoxycarbonyl)ethanolamine was replaced with N-Boc-L-propanol to obtain compound 162 (35 mg), ESI-MS (m / z): 661.2 [M+H]. + .

[0671] 1HNMR (600MHz, DMSO-d6) δ7.53-7.50(m,2H),7.48-7.42(m,6H),7.34(s,1H),7.26(d,J=7. 8Hz,1H),7.04(s,1H),5.44-5.37(m,1H),4.38-4.36(m,1H),4.28-4.16(m,2H),4.13-4.09 (m,1H),3.79-3.74(m,1H),3.73-3.66(m,1H),2.96(s,3H),2.42-2.39(m,2H),2.20-2.10( m,1H),1.95-1.90(m,2H),1.73-1.71(m,2H),1.20(d,J=6.6Hz,3H),1.05(t,J=6.9Hz,3H).

[0672] Example 71: Preparation of Compound 163

[0673]

[0674] (1) Preparation of intermediate 163-1

[0675] Following the synthesis method of intermediate 10-5, intermediate 163-1 (291 mg) was obtained.

[0676] (2) Preparation of compound 163

[0677] Following the synthetic method of Example 51, intermediate 87-1 was replaced with intermediate 163-1 to obtain compound 163 (47 mg), ESI-MS (m / z): 698.2 [M+H] + .

[0678] 1 HNMR(600MHz,DMSO-d6)δ7.49-7.47(m,2H),7.44-7.39(m,6H),7.34(s,1H),7.33 (s,1H),7.23(d,J=7.8Hz,1H),6.23(tt,J=54,3.6Hz,1H),5.79-5.75(m,1H),4.64 -4.60(m,1H),4.17-4.13(m,1H),4.10-4.05(m,1H),3.79-3.70(m,2H),3.68-3.62 (m,2H),3.35-3.31(m,1H),2.92(s,3H),1.99-1.95(m,4H),1.17(d,J=6.6Hz,3H).

[0679] Example 72: Preparation of Compound 164

[0680]

[0681] Preparation of compound 164

[0682] Following the synthesis method of Example 31, D-methyl lactate was replaced with (S)-3-hydroxyisobutyrate methyl ester to obtain compound 164 (67 mg), ESI-MS (m / z): 626.2 [M+H] + .

[0683] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.50(m,2H),7.47-7.42(m,7H),7.32(s,1H) ,7.22(s,1H),6.88(s,1H),5.47-5.45(m,1H),4.43-4.41(m,1H),4.30-4.2 6(m,1H),4.15-4.10(m,2H),3.77-3.73(m,1H),3.60-3.58(m,1H),2.81-2. 75(m,1H),1.96-1.92(m,4H),1.15(d,J=6.0Hz,6H),1.06(d,J=6.0Hz,3H).

[0684] Example 73: Preparation of Compound 165

[0685]

[0686] (1) Preparation of intermediate 165-1

[0687] Following the synthetic method of intermediate 117-2, 4-(ethylamino)-4-piperidinecarboxamide was replaced with 4-[(3,3,3-trifluoropropyl)amino]piperidine-4-carboxamide (prepared according to the synthetic method of patent US2011183960) to obtain intermediate 165-1 (125 mg).

[0688] (2) Preparation of compound 165

[0689] Following the synthetic method of Example 67, intermediate 117-2 was replaced with 165-1 to obtain compound 165 (54 mg), ESI-MS (m / z): 665.2 [M+H]. + .

[0690] 1HNMR(600MHz,DMSO-d6)δ7.53-7.7.42(m,9H),7.34(s,1H),7.17(s,1H),7.12(s,1H),5.43-5.36(m,1H),4.94(q,J=6.8Hz,1H),4.41-4.37(m, 1H),4.25-4.17(m,1H),3.71-3.63(m,1H),2.62-2.59(m,2H),2.48-2. 42(m,3H),1.99-1.92(m,2H),1.74-1.69(m,2H),1.44(d,J=6.0Hz,3H).

[0691] Example 74: Preparation of Compound 166

[0692]

[0693] (1) Preparation of intermediate 166-1

[0694] Following the synthetic method of intermediate 117-2, 4-(ethylamino)-4-piperidinecarboxamide was replaced with 4-(cyclopropylamino)piperidine-4-carboxamide (prepared according to the synthetic method of patent US2011183960) to obtain intermediate 166-1 (114 mg).

[0695] (2) Preparation of compound 166

[0696] Following the synthetic method of Example 67, intermediate 117-2 was replaced with 166-1 to obtain compound 166 (42 mg), ESI-MS (m / z): 609.2 [M+H] + .

[0697] 1 HNMR(600MHz,DMSO-d6)δ7.53-7.42(m,9H),7.37(s,1H),7.16(s,1H),7.08(s,1H),5.41-5.36(m,1H),4.93(q,J=6.8Hz,1H),4.39-4.36(m,1 H),4.18-4.11(m,1H),3.65-3.58(m,1H),2.89-2.87(m,1H),1.97-1.7 8(m,5H),1.44(d,J=6.0Hz,3H),0.39-0.38(m,2H),0.31-0.30(m,2H).

[0698] Example 75: Preparation of Compound 167

[0699]

[0700] (1) Preparation of intermediate 167-1

[0701] Following the synthetic method of intermediate 117-2, 4-(ethylamino)-4-piperidinecarboxamide was replaced with 4-(isopropylamino)piperidine-4-carboxamide (prepared according to the synthetic method of patent US2011183960) to obtain intermediate 167-1 (118 mg).

[0702] (2) Preparation of compound 167

[0703] Following the synthetic method of Example 67, intermediate 117-2 was replaced with 167-1 to obtain compound 167 (47 mg), ESI-MS (m / z): 611.2 [M+H]. + .

[0704] 1 HNMR(600MHz,DMSO-d6)δ7.52-7.42(m,9H),7.34(s,1H),7.17(s,1H),7.04(s,1H),5.23-5.19(m,1H),4.93(q,J=6.8Hz,1H),4.36-4 .28(m,3H),3.82-3.77(m,1H),2.85-2.75(m,1H),2.01-1.90(m,2H),1.77-1.70(m,2H),1.44(d,J=6.0Hz,3H),1.02(d,J=4.2Hz,6H).

[0705] Example 76: Preparation of Compound 168

[0706]

[0707] (2) Preparation of intermediate 168-1

[0708] Following the synthetic method of intermediate 127-1, N-(tert-butoxycarbonyl)ethanolamine was replaced with N-BOC-N-methylaminoethanol to obtain intermediate 168-1 (81 mg).

[0709] (2) Preparation of compound 168

[0710] Following the synthetic method of Example 34, intermediate 127-1 was replaced with 168-1 to obtain compound 168 (56 mg), ESI-MS (m / z): 661.2 [M+H] + .

[0711] 1HNMR(600MHz,DMSO-d6)δ7.52-7.42(m,8H),7.33(s,1H),7.04(s,1H),5. 43-5.34(m,1H),4.44-4.31(m,3H),4.28-4.18(m,1H),3.74-3.64(m,1H), 3.49(t,J=6.0Hz,2H),2.94(s,3H),2.83(s,3H),2.44-2.36(m,2H),2.22- 2.05(m,1H),2.01-1.83(m,2H),1.80-1.67(m,2H),1.04(t,J=6.9Hz,3H).

[0712] Other embodiments:

[0713] Following the above methods for synthesizing compounds, the following compounds were prepared.

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721] Test Example 1: Experiment on the human CB1R cAMP generation function of the compound

[0722] Human CB1R-CHO cells (provided by Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. 2500 cells / 5 μL / well were seeded into 384-well plates. The test compound was serially diluted 10 times (10×) with 1× Stimulation Buffer. 1 μL of the diluted 10× test compound was added to the corresponding well and incubated at 37°C for 10 minutes. A 2.5 μM Forskolin & 2.5 nM CP55940 agonist solution was prepared with 1× Stimulation Buffer, and 4 μL / well was added to the corresponding well and incubated for 30 minutes to induce cAMP production. Eu-cAMP was diluted to the working concentration with Detection buffer, and 5 μL / well was added to the corresponding well. TM The anti-cAMP antibody was diluted to the working concentration with detection buffer, and 5 μL / well was added to the corresponding experimental well. After centrifugation, the mixture was incubated at room temperature for 1 hour. TM The anti-cAMP antibody was diluted to the working concentration with detection buffer, and 5 μL / well was added to the corresponding experimental wells. After centrifugation, the mixture was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader under excitation at 330 nm. The dose-response curves of the compounds were generated using a nonlinear four-parameter equation in GraphPadPrism software, and the corresponding IC50 values ​​were calculated. 50 value.

[0723] The compounds of the present invention and control compounds were tested using the methods described above, and it was found that the compounds of the present invention have strong blocking activity against the human CB1 receptor. Activity data of exemplary compounds are shown in the table below.

[0724]

[0725]

[0726] Note: 1nM <A≤10nM;A+≤1nM。

[0727] Test Example 2: Pharmacokinetic Study in Mice

[0728] This study investigated the pharmacokinetic behavior of the test compounds in ICR mice after single-dose, single intravenous injection, or gavage administration. Test animals: Six male ICR mice were used for each compound test, divided into two groups of three mice each, purchased from Beijing Vital River Pharmaceutical Co., Ltd. Drug solvent:

[0729] Intravenous solvent: 5% DMSO + 50% PEG400 + 45% normal saline;

[0730] Gavage solvent: 5% DMSO + 5% Solutol + 15% PEG400 + 75% HP-β-CD (0.2g / mL).

[0731] Sampling method: In the intravenous injection group, 100 μL of blood was collected from the orbital vein of mice at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration; in the gavage group, 100 μL of blood was collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration and placed in EDTA-K2 anticoagulant tubes. The collected mouse venous blood was centrifuged at 8000 rpm for 10 minutes within 2 h to separate plasma. The plasma was transferred and aliquoted into 1.5 mL centrifuge tubes and stored at -80℃ for LC-MS / MS analysis.

[0732] The compounds of this invention possess favorable pharmacokinetic properties. The pharmacokinetic parameters of the exemplary compounds in mice are shown in the table below:

[0733]

[0734] Test Example 3: Study on plasma and tissue concentrations and brain / blood ratio in mouse brain

[0735] This study investigated the concentration of the test compound in the brain tissue and plasma of ICR mice and the brain / blood ratio after a single dose was administered by gavage.

[0736] Test animals: For each compound test: 6 male ICR mice, divided into 2 groups of 3 mice each, purchased from Beijing Vital River Pharmaceutical Co., Ltd. Drug solvent: Oral solvent: 5% DMSO + 5% Solutol + 15% PEG400 + 75% HP-β-CD (0.2 g / mL).

[0737] Dosage: 10 mg / kg.

[0738] Sampling method: 1 h and 8 h after drug administration, 100 μL of blood was collected from the orbital vein of mice and placed in EDTA-K2 anticoagulant tubes. Within 2 h of collection, the mouse venous blood was centrifuged at 8000 rpm for 10 minutes to separate plasma. The plasma was aliquoted into 1.5 mL centrifuge tubes and stored at -80°C for LC-MS / MS analysis. At the corresponding time points, brain tissue was collected, washed with physiological saline, dried, and stored at -80°C for LC-MS / MS analysis.

[0739] The compounds of this invention exhibit very low exposure in mouse brain tissue and a very low brain / blood ratio. The brain / blood ratio parameters calculated from the plasma concentrations (ng / mL) and brain tissue concentrations (ng / g) of the exemplary compounds at 1 h and 8 h in mice are shown in the table below:

[0740]

Claims

1. A compound, its stereoisomers, or pharmaceutically acceptable salts, wherein, The compound is shown in formula (I): in, X and Y are each independently selected from N or CR 5 ; R 5 The group independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, -C(O)OH, -C(O)NH2, or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups, halogen groups or methyl groups; R 1 R 2 Each is independently selected from the arbitrarily substituted: C 6-10 Aryl or 5-14 heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different R 6 replace; R 6 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, nitro, halogen, and -OR. 7 -SR 7 -NR 7 R 7 -C(O)R 7 -C(O)OR 7 -C(O)NR 7 R 7 -OC(O)R 7 -C(=NR) 7 )R 7 ,-S(O) 1-2 R 7 -OS(O) 1-2 R 7 -S(O)2NR 7 R 7 -NR 7 S(O)2R 7 -NR 7 C(O)R 7 -NR 7 C(O)NR 7 R 7 -NR 7 S(O)2NR 7 R 7 -P(O)R 7 R 7 -P(O)(OR) 7 2. -B(OR) 7 2. Or optionally substituted with the following groups: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R groups. 7 replace; R 7 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different hydrogens, deuterium, cyano, nitro, halogen, -R 8 -OR 8 -SR 8 -NR 8 R 8 -C(O)R 8 -C(O)OR 8 -C(O)NR 8 R 8 -OC(O)R 8 -C(=NR) 8 )R 8 ,-S(O) 1-2 R 8 -S(O)2NR 8 R 8 -NR 8 S(O)2R 8 -NR 8 C(O)R 8 -NR 8 C(O)NR 8 R 8 -NR 8 S(O)2NR 8 R 8 -P(O)R 8 R 8 -P(O)(OR) 8 )2 or -B(OR 8 )2 replaces; R 8 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or 3-12 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups or halogens. R 3 Independently selected from -OR 9 -NR 9 R 9 -NR 9 S(O)2R 9 -NR 9 C(O)R 9 -NR 9 C(O)NR 9 R 9 -NR 9 S(O)2NR 9 R 9 The following groups, or optionally substituted groups: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R groups. 10 replace; R 9 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; or, two R 9 Together with the N atom to which they are attached, they form an optionally substituted 4-11 membered heterocyclic group, which, in addition to the already included N atom, contains 0-2 (0, 1, or 2) heteroatoms selected from N, O, or S; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R atoms. 10 replace; R 10 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, nitro, halogen, oxo group, and -OR. 11 -SR 11 -SF5, -NR 11 R 11 -C(O)R 11 -C(O)OR 11 -C(O)NR 11 R 11 -OC(O)R 11 -C(=NR) 11 )R 11 ,-S(O) 1-2 R 11 -S(O)2NR 11 R 11 -NR 11 S(O)2R 11 -NR 11 C(O)R 11 -NR 11 C(O)NR 11 R 11 -NR 11 S(O)2NR 11 R 11 -P(O)R 11 R 11 -P(O)(OR) 11 2. -B(OR) 11 2. Or optionally substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; or, when two R atoms are simultaneously attached to the same carbon atom. 10 At that time, two R 10 The carbon atoms connected thereto form optionally substituted 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl groups; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups, halogen groups, oxo groups, -C(O)OH groups, -CONH2 groups, C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-C(O)NHC 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2、-NHC(O)C 1-6 Alkyl, -NC 1-6 Alkyl C(O)C 1-6 Alkyl, -P(O)(C 1-6 Alkyl)2, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The C-terminals of halogenated alkoxy and hydroxyl groups (1 or 2) are... 1-6 Alkyl or hydroxyl-substituted (1 or 2) C 1-6 Alkyl substitution; R 11 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g. 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuterium, cyano, nitro, halogen, -R 12 -OR 12 -SR 12 -NR 12 R 12 -C(O)R 12 -C(O)OR 12 -C(O)NR 12 R 12 -OC(O)R 12 -C(=NR) 12 )R 12 ,-S(O) 1-2 R 12 -S(O)2NR 12 R 12 -NR 12 S(O)2R 12 -NR 12 C(O)R 12 -NR 12 C(O)NR 12 R 12 -NR 12 S(O)2NR 12 R 12 -P(O)R 12 R 12 -P(O)(OR) 12 )2 or -B(OR 12 )2 replaces; R 12 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl or 3-12 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups or halogens. R 4 Selected from amino, halogen, cyano, carboxyl, -OR 13 -NR 13 R 13 -NR 13 S(O)2R 13 -NR 13 C(O)R 13 -COOR 13 -NR 13 C(O)NR 13 R 13 -NR 13 S(O)2NR 13 R 13 -NHC(=NH)NHC(O)R 13 -NHC(=NH)NHR 13 -NHC(=NH)R 13 -C(O)NR 13 R 13 -C(O)NR 13 S(O)2R 13 The following groups, or optionally substituted groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g. 0, 1, 2, 3, 4, 5 or 6) identical or different R groups. 14 replace; R 13 Each time it appears, it is independently selected from hydrogen, deuterium, hydroxyl, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic or 5-10 membered heteroaryl; or, two R 13 Together with the N atom to which they are attached, they form an optionally substituted 4-6 membered heterocyclic group, which, in addition to the already included N atom, contains 0-2 (0, 1, or 2) heteroatoms selected from N, O, or S; wherein the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6) identical or different R atoms. 14 replace; R 14 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, halogen, and -OR. 15 -SR 15 -NR 15 R 15 -C(O)R 15 -C(O)OR 15 -C(O)NR 15 R 15 -OC(O)R 15 -C(=NR) 15 )R 15 ,-S(O) 1-2 R 15 -NR 15 S(O) 1-2 R 15 -S(O)2NR 15 R 15 -NR 15 C(O)R 15 -NR 15 C(O)NR 15 R 15 -NR 15 S(O)2NR 15 R 15 -P(O)R 15 R 15 -P(O)(OR) 15 2. -B(OR) 15 2. Or optionally substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 aryl, 3-12 membered heterocyclic, or 5-10 membered heteroaryl; or, when two R atoms are present on the same carbon atom. 14 At that time, two R 14 The carbon atoms connected thereto form optionally substituted 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl groups; wherein the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, cyano groups, nitro groups, halogens, -OR groups. 16 , Oxide group, -SR 16 -NR 16 R 16 -C(O)R 16 -C(O)OR 16 -C(O)NR 16 R 16 -OC(O)R 16 -C(=NR) 16 )R 16 ,-S(O) 1-2 R 16 -S(O)2NR 16 R 16 -NR 16 S(O)2R 16 -NR 16 C(O)R 16 -NR 16 C(O)NR 16 R 16 -NR 16 S(O)2NR 16 R 16 -P(O)R 16 R 16 -P(O)(OR) 16 2. -B(OR) 16 2. C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The C-terminals of halogenated alkoxy and hydroxyl groups (1 or 2) are... 1-6 Alkyl or hydroxyl-substituted (1 or 2) C 1-6 Alkyl substitution; R 15 and R 16 Each time it appears, it is independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups; wherein the optional substitution means unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6) identical or different hydrogens, deuteriums, hydroxyl groups, amino groups, mercapto groups, cyano groups, nitro groups or halogens; The condition is that it does not contain the following compounds:

2. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to claim 1, wherein, R 1 and R 2 Each is independently selected from optionally substituted: phenyl or 5-6 heteroaryl; wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different R 6 replace.

3. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-2, wherein, R 6 Each time it appears, it is independently selected from hydrogen, deuterium, cyano, halogen, and -OR. 7 -NR 7 R 7 -C(O)R 7 -C(O)NR 7 R 7 -C(=NR) 7 )R 7 ,-S(O) 1-2 R 7 -OS(O) 1-2 R 7 -S(O)2NR 7 R 7 -NR 7 S(O)2R 7 -NR 7 C(O)R 7 -NR 7 C(O)NR 7 R 7 -NR 7 S(O)2NR 7 R 7 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-10 Aryl, 3-6 membered heterocyclic or 5-10 membered heteroaryl; Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different R 7 replace.

4. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-3, wherein, R 3 Independently selected from -OR 9 -NR 9 R 9 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic, or 5-10 membered heteroaryl; wherein, the optional substitution refers to unsubstituted or optionally substituted with 0-6 (e.g., 0, 1, 2, 3, 4, 5, or 6; preferably 0, 1, or 2; more preferably 0 or 1) identical or different R 10 replace.

5. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-4, wherein, R 9 Each time it appears, it is independently selected from hydrogen, or optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic or 5-10 heteroaryl; Or, two Rs 9 Together with the N atom to which they are connected, they form optional substituted 4-10 member heterocyclic groups (e.g., 4, 5, 6, 7, 8, 9, 10 members), which, in addition to the 1 N atom already contained, contain 0-2 (0, 1 or 2) heteroatoms selected from N, O or S. Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different R 10 replace.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-5, wherein, R 4 Selected from amino, cyano, carboxyl, -OR 13 -NR 13 R 13 -NR 13 C(O)R 13 -COOR 13 -NHC(=NH)NHC(O)R 13 -NHC(=NH)NHR 13 -NHC(=NH)R 13 -C(O)NR 13 R 13 The following groups, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, aryl, 3-10 membered heterocyclic or 5-6 membered heteroaryl; Wherein, the optional substitution refers to unsubstituted or optionally substituted by 0-6 (e.g., 0, 1, 2, 3, 4, 5 or 6; preferably 0, 1 or 2; more preferably 0 or 1) identical or different R 14 replace.

7. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-6, wherein, The compound is a compound represented by the following formula: Where Z represents CH or N.

8. The compound, its stereoisomer, or a pharmaceutically acceptable salt according to any one of claims 1-7, wherein, The compounds mentioned are those described on pages 16 to 21 of the specification.

9. A pharmaceutical composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt as described in any one of claims 1-8, optionally further comprising a pharmaceutically acceptable carrier.

10. The compound, its stereoisomer, or a pharmaceutically acceptable salt, or the pharmaceutical composition of claim 9, as a medicament or for use in the preparation of a medicament; preferably, the medicament is a medicament for the prevention, relief, or treatment of cannabinoid receptor-mediated diseases or conditions; more preferably, the cannabinoid receptor is a type I cannabinoid receptor (CB1); preferably, the medicament is a medicament for the prevention, relief, or treatment of metabolic diseases, metabolic disorders, or metabolic conditions.

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