Heterocyclic compound, pharmaceutical composition, and use thereof

Abstract

The present application relates to a compound represented by formula (I) that modulates GLP-1 receptor activity, or a stereoisomer, a mixture of stereoisomers, a tautomer, a geometric isomer, a solvate, a pharmaceutically acceptable salt, a deuterated compound, or an ester thereof, or a prodrug thereof; a pharmaceutical composition comprising the compound represented by formula (I); and a method for treating or preventing a disease, disorder, or symptom in which the GLP-1 receptor has an effect.

Description

Heterocyclic compounds, pharmaceutical compositions and their applications

[0001] This application claims the following priority:

[0002] Application number: 202410930378.5, application date: July 11, 2024;

[0003] Application number: 202411588592.3, application date: November 7, 2024;

[0004] Application number: 202510366291.4, application date: March 26, 2025. Technical Field

[0005] This invention belongs to the field of medicine, specifically relating to compounds that regulate the activity of GLP-1 receptors, pharmaceutical compositions comprising said compounds, and methods for treating or preventing diseases, conditions, or symptoms in which GLP-1 receptors function. Background Technology

[0006] Glucagon-like peptide-1 (GLP-1) is a hormone primarily produced by L cells in the intestine and belongs to the incretin class. GLP-1 analogues can lower blood sugar and promote weight loss by regulating GLP-1 receptor activity.

[0007] The known progress in the development of small molecule GLP-1 receptor agonists is as follows: WO2009111700A2 discloses a series of oxadiathracene compounds as GLP-1 receptor agonists. WO2010114824A1 discloses substituted azoanthracene derivatives as GLP-1 receptor agonists. WO2017078352A1 discloses a series of cyclohexene derivatives as GLP-1 receptor agonists. KR1020180101671A discloses a series of heteroaryl-substituted pyridine [1,2-a]imidazole derivatives as GLP-1 receptor agonists. WO2018056453A1 discloses a series of pyrazolopyridine derivatives as GLP-1 receptor agonists.

[0008] There is still a need for small molecule GLP-1 receptor agonists, and this invention addresses that need. Summary of the Invention

[0009] This disclosure relates to compounds of formula (I) or stereoisomers thereof, mixtures of stereoisomers, tautomers, geometric isomers, solvates, pharmaceutically acceptable salts, deuterated compounds, esters or prodrugs thereof that modulate the activity of GLP-1 receptors; pharmaceutical compositions comprising compounds of formula (I); and methods for treating or preventing diseases in which GLP-1 receptors function.

[0010] Therefore, this disclosure provides a compound of formula (I) or a stereoisomer thereof, a mixture of stereoisomers, a tautomer, a geometric isomer, a solvate, a pharmaceutically acceptable salt, a deuterated compound, an ester, or a prodrug thereof:

[0011] Among them, ring A is selected from:

[0012] Where aa represents the connection point with C=O;

[0013] X is independently selected from N and C, and when X is N, R 4 R 5 R 6 Accordingly, it does not exist;

[0014] Y is C(R) 13 )2, where R 13 Independently, they are hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl or hydroxyl, or both R 13 It can form a carbonyl group (C=O) together with the carbon atoms it is attached to;

[0015] Ring B is C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1-6 (The alkyl group is optionally substituted with one or more halogens) and C 1-6 Alkyl group, wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group;

[0016] B 2 It is C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0017] Q 1 yes C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0018] Where bb represents the junction with pyrazole; R Q1 R Q2 R Q3 R Q4 R Q5 R Q6 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups), CN and NO2;

[0019] Q 2 Selected from C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl and 5 to 10-membered heteroaryl groups, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1- 6-alkyl)2, CN, NO2, S(=O)(NH)R 10 B(OR) 11 (OR) 12 ), and the substituents are optionally linked to each other to form a 3- to 7-membered carbon ring or a 3- to 7-membered heterocycle, wherein the cycloalkyl group is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl, R 10 R 11 R 12 Independently selected from hydrogen atoms, C 1-6Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens;

[0020] R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens;

[0021] L 1 yes

[0022] Z 1 It is halogen, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1- 6. Substituents of alkoxy and hydroxyl groups), C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1- 6-alkyl), N(C) 1-6 Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl;

[0023] R 8a and R 8b It is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally selected independently from halogens and C. 3-10 Cycloalkyl substituents, or R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-10 Cycloalkanes, wherein R 8a and R8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally selected independently from one or more halogens, hydroxyl groups, and -NR groups. 8c R 8d C 1-6 Substitution with alkoxy groups and 3 to 12-membered heterocyclic groups, and R 8c and R 8d Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0024] n1 is an integer from 0 to 3;

[0025] n2 is an integer from 0 to 5;

[0026] n3 is an integer from 0 to 5;

[0027] R 9 Selected from S(=O)2NR 10 R 10 C(=O)NR 10 R 10 Or CN, and R 9a and R 9b Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0028] R 14 Selected from hydrogen atoms, deuterium atoms, or C atoms 1-6 alkyl;

[0029] The conditions are:

[0030] (a) When ring A is At that time, Q 1 no and / or

[0031] (b) When ring A is At that time, R 9 no and / or

[0032] (c) When ring A is At that time, Q 1 no

[0033] In some embodiments, the compound of formula (I) is a compound of formula (I-1):

[0034] Among them, ring A is selected from:

[0035] Where aa represents the connection point with C=O;

[0036] X is independently selected from N and C, and when X is N, R 4 R 5 R 6 Accordingly, it does not exist;

[0037] Y is C(R) 13 )2, where R 13 Independently, they are hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl or hydroxyl, or both R 13 It can form a carbonyl group (C=O) together with the carbon atoms it is attached to;

[0038] Ring B is C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1-6 (The alkyl group is optionally substituted with one or more halogens) and C 1-6 Alkyl group, wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group;

[0039] B 2 It is C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0040] Q 1 yes C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C1-6 Substitution of alkoxy groups;

[0041] Where bb represents the junction with pyrazole; R Q1 R Q2 R Q3 R Q4 R Q5 R Q6 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups), CN and NO2;

[0042] Q 2 Selected from C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl and 5 to 10-membered heteroaryl groups, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1- 6-alkyl)2, CN, NO2, S(=O)(NH)R 10 B(OR) 11 (OR) 12 ), and the substituents are optionally linked to each other to form a 3- to 7-membered carbon ring or a 3- to 7-membered heterocycle, wherein the cycloalkyl group is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl, R 10 R 11 R 12 Independently selected from hydrogen atoms, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens;

[0043] R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens;

[0044] L 1 yes

[0045] Z 1 It is halogen, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1- 6. Substituents of alkoxy and hydroxyl groups), C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1- 6-alkyl), N(C) 1-6 Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl;

[0046] R 8a and R 8b It is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally selected independently from halogens and C. 3-10 Cycloalkyl substituents, or R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-10 Cycloalkanes, wherein R 8a and R 8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally selected independently from one or more halogens, hydroxyl groups, and -NR groups. 8c R 8d C 1-6 Substitution with alkoxy groups and 3 to 12-membered heterocyclic groups, and R 8c and R 8d Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0047] n1 is an integer from 0 to 3;

[0048] n2 is an integer from 0 to 5;

[0049] n3 is an integer from 0 to 5;

[0050] R 9 Selected from S(=O)2NR 10 R 10 C(=O)NR 10 R 10 Or CN, and R 9a and R 9b Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0051] R 14 Selected from hydrogen atoms, deuterium atoms, or C atoms 1-6 alkyl;

[0052] The conditions are:

[0053] (a) When ring A is At that time, Q 1 no and / or

[0054] (b) When ring A is At that time, R 9 no and / or

[0055] (c) When ring A is At that time, Q 1 no

[0056] In some embodiments, the compound of formula (I) is a compound of formula (I-2):

[0057] Among them, ring A is selected from:

[0058] Where aa represents the connection point with C=O;

[0059] X is independently selected from N and C, and when X is N, R 4 R 5 R 6 Accordingly, it does not exist;

[0060] Y is C(R) 13 )2, where R 13 Independently, they are hydrogen atoms, deuterium atoms, halogens, and carbon atoms.1-6 Alkyl or hydroxyl, or both R 13 It can form a carbonyl group (C=O) together with the carbon atoms it is attached to;

[0061] Ring B is C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1-6 (The alkyl group is optionally substituted with one or more halogens) and C 1-6 Alkyl group, wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group;

[0062] B 2 It is C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0063] Q 1 yes C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0064] Where bb represents the connection point with pyrazole;

[0065] Q 2 Selected from C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl and 5 to 10-membered heteroaryl groups, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from the following: C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1-6 Alkyl)2, CN, NO2, S(=O)(NH)R 10 B(OR) 11 (OR) 12 ), wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group, R 10 R 11 R 12 Independently selected from hydrogen atoms, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens;

[0066] R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens;

[0067] L 1 yes

[0068] Z 1 It is halogen, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substitution of alkoxy and hydroxyl groups), C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1- 6-alkyl), N(C) 1-6Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl;

[0069] R 8a and R 8b It is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally selected independently from halogens and C. 3-10 Cycloalkyl substituents, or R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-10 Cycloalkanes, wherein R 8a and R 8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally selected independently from one or more halogens, hydroxyl groups, and -NR groups. 8c R 8d C 1-6 Substitution with alkoxy groups and 3 to 12-membered heterocyclic groups, and R 8c and R 8d Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0070] n1 is an integer from 0 to 3;

[0071] n2 is an integer from 0 to 5;

[0072] n3 is an integer from 0 to 5;

[0073] R 9 Selected from And R 9a and R 9b Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl;

[0074] R 14 Selected from hydrogen atoms, deuterium atoms, or C atoms 1-6 alkyl;

[0075] The conditions are:

[0076] (a) When ring A is At that time, Q 1 no and / or

[0077] (b) When ring A is At that time, R 9no

[0078] In some embodiments, the compound of formula (I) is a compound of formula (Ia), which is a sulfonamide compound:

[0079] In some embodiments, the compound of formula (I) is a compound of formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), or (Ia-10), which are sulfonyl compounds.

[0080] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0081] The conditions are:

[0082] (a)Q 1 no and / or

[0083] (b)R 9 no

[0084] In some embodiments, the compound of formula (I) is a compound of formula (Ib-1) or (Ib-2):

[0085] In some embodiments, the compound of formula (I) is a compound of formula (Ib-3) or (Ib-4):

[0086] Among them, B 2 It is a phenyl group, wherein the phenyl group is optionally composed of two to four independently selected elements selected from halogens, C, and D. 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Alkoxy (where C 1-6 The alkoxy group is optionally substituted with one or more halogens; Q 2 Selected from 5- to 10-membered heteroaryl groups, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1-6alkyl group 2, CN, NO2, and the substituents are optionally linked together to form a 3- to 7-membered carbon ring or a 3- to 7-membered heterocycle; R Q1 R Q2 R Q3 R Q4 and R Q5 The definition is as described above.

[0087] In some embodiments, the heteroaryl group is indazole-5-yl, which is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1-6 Alkyl group)2, CN, NO2, and the substituents are optionally connected to each other to form a 3- to 7-membered carbon ring or a 3- to 7-membered heterocycle.

[0088] In some embodiments, the compound of formula (I) is a compound of formula (Ib-5) or (Ib-6):

[0089] Among them, R 15 R 16 R 17 R 18 and R 19 Each substituent is independently selected from the following: halogen, C 1- 6-alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, and R 16 R 17 The carbon atoms to which it is attached can be chosen to form 5- to 7-membered heterocycles; R Q1 R Q2 R Q3 R Q4 and R Q5 The definition is as described above.

[0090] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0091] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0092] In some implementations, ring B is C 1-6 Alkyl, C 3-10Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6- 10 Aryl or 5 to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1-6 (The alkyl group is optionally substituted with one or more halogens) and C 1-6 Alkoxy, wherein the cycloalkyl group is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl.

[0093] In some embodiments, ring B is a 3- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1-6 (The alkyl group is optionally substituted with one or more halogens) and C 1-6 Alkyl group.

[0094] In some embodiments, the 3- to 12-membered heterocyclic group is a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

[0095] In some embodiments, the 3- to 12-membered heterocyclic group is a 5- to 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

[0096] In some embodiments, the 3 to 12-membered heterocyclic group is tetrahydropyranyl, morpholinyl, 4-thiomorpholine 1,1-dioxide, 3-thiazolyl 1,1-dioxide, or 3-thioheterocyclic butane-1,1-dioxide, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

[0097] In some embodiments, the 3- to 12-membered heterocyclic group is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

[0098] In some embodiments, the 3- to 12-membered heterocyclic group is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally substituted by one to four independent substituents selected from the following: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

[0099] In some embodiments, the 3 to 12-membered heterocyclic group is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally substituted by one to four substituents independently selected from the following: fluorine atom, methyl and methoxy.

[0100] In some embodiments, the 3 to 12-membered heterocyclic group is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally substituted by one, two, three or four substituents independently selected from the group consisting of fluorine, methyl and methoxy.

[0101] In some embodiments, the 3 to 12-membered heterocyclic group is a morpholino group, wherein the morpholino group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

[0102] In some embodiments, the 3- to 12-membered heterocyclic group is a morpholino group, wherein the morpholino group is optionally substituted by one to four independent substituents selected from the following: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

[0103] In some embodiments, the 3 to 12-membered heterocyclic group is a morpholino group, wherein the morpholino group is optionally substituted by one to four substituents independently selected from the group consisting of fluorine, methyl, and methoxy.

[0104] In some embodiments, the 3 to 12-membered heterocyclic group is a morpholino group, wherein the morpholino group is optionally substituted by one, two, three or four substituents independently selected from the group consisting of fluorine, methyl and methoxy.

[0105] In some implementations, B2 is C 6-10 Aryl, the C 6-10 Aryl groups are optionally selected from one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

[0106] In some embodiments, B2 is phenyl or pyridyl, said phenyl or pyridyl group optionally being composed of two to four independently selected from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3- 10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

[0107] In some embodiments, B2 is a phenyl group, which is optionally composed of two to four independently selected elements, C, and D. 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Substitution of alkoxy groups.

[0108] In some embodiments, B2 is a phenyl group, which is optionally substituted with two to three substituents independently selected from fluorine atoms, methyl groups, and cyclopropyl groups.

[0109] In some implementation schemes, Q 1 yes C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

[0110] In some implementation schemes, Q1 is C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

[0111] In some implementations, the C 6-10 The aryl group is a phenyl group, wherein the phenyl group is optionally composed of one to four radicals independently selected from halogens, C, and D. 1-6 Alkyl, C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

[0112] In some embodiments, the phenyl group is optionally substituted with one to four substituents independently selected from fluorine atoms, methyl, ethyl, propyl, cyclopropyl, and methoxy groups.

[0113] In some implementations, the 5- to 10-membered heteroaryl group is The 5- to 10-membered heteroaryl group is optionally composed of one to four independently selected from halogens, C 1-6 Alkyl, C 3-10cycloalkyl and C 1-6 Substituents of alkoxy groups; where bb represents the linking point with pyrazole.

[0114] In some embodiments, the 5 to 10 heteroaryl group is optionally substituted with one to four substituents independently selected from fluorine atoms, methyl, ethyl, propyl, cyclopropyl, and methoxy.

[0115] In some embodiments, Q2 is a 5- to 10-membered heteroaryl group, which is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1-6 Alkyl)2, CN, NO2, S(=O)(NH)R 10 B(OR) 11 (OR) 12 ), and the substituents are optionally linked together to form 3 to 7-membered carbon rings or 3 to 7-membered heterocycles, wherein R 10 R 11 R 12 Independently selected from hydrogen atoms, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups) and halogens.

[0116] In some embodiments, Q2 is a 5- to 10-membered heteroaryl group, which is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1-6 Alkyl)2, CN, NO2, S(=O)(NH)R 10 B(OR) 11 (OR) 12 ), where R 10 R 11 R 12 Independently selected from hydrogen atoms, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups) and halogens.

[0117] In some embodiments, the 5- to 10-membered heteroaryl group is optionally composed of one or more independently selected from C 1-6 Alkyl and halogen substituents.

[0118] In some implementations, the 5- to 10-membered heteroaryl group is The 5- to 10-membered heteroaryl group is optionally composed of one or more independently selected from C 1-6 Alkyl and halogen substituents; where cc indicates the connection point with Q1.

[0119] In some implementations, the 5- to 10-membered heteroaryl group is The 5- to 10-membered heteroaryl group is optionally composed of one or more independently selected from C 1-6 Alkyl and halogen substituents; where dd represents the connection point with Q1.

[0120] In some embodiments, the 5 to 10 heteroaryl group is optionally substituted by one to four substituents independently selected from methyl and fluorine atoms.

[0121] In some implementation schemes, R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups) and halogens.

[0122] In some implementation schemes, R 1 It is C 1-6 alkyl.

[0123] In some implementation schemes, R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups and halogens.

[0124] In some implementation schemes, R 2 R 3 R 4 R 5 R 6 R 7 Each is an independent hydrogen atom.

[0125] In some implementation schemes, R 4 R 5 R 6 Each is an independent hydrogen atom or does not exist (when X is N).

[0126] In some implementations, L 1 yes Where n3 is an integer from 0 to 5, such as 1, 2, 3, 4 or 5.

[0127] In some implementations, L 1 yes

[0128] In some implementations, L 1 yes

[0129] In some implementation schemes, Z 1 It is halogen, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substitution of alkoxy and hydroxyl groups), C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1-6 Alkyl), N(C) 1-6 Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl.

[0130] In some implementation schemes, Z 1 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1-6 Alkyl), N(C) 1-6 Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl.

[0131] In some implementation schemes, Z 1 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, or heteroaryl groups comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, phenyl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The cycloalkyl group is a halogenated alkoxy group, an OH group, a carbonyl group (C=O), or a halogen, wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group.

[0132] In some implementation schemes, Z 1 It is methyl, ethyl, or cyclopropyl.

[0133] In some implementation schemes, Z 1 yes And R 7a Independently selected from hydrogen atoms and C atoms 1-6 alkyl.

[0134] In some implementation schemes, R 8a and R 8b It is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally selected independently from halogens and C. 3-10 Cycloalkyl substituents, or R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-10 Cycloalkanes, wherein R 8a and R 8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally selected independently from one or more halogens, hydroxyl groups, and -NR groups. 8c R 8d C 1-6 Substitution with alkoxy groups and 3 to 12-membered heterocyclic groups, and R 8c and R 8d Independently selected from hydrogen atoms, C1-6 Alkyl and (C 1-6 Alkyl)carbonyl.

[0135] In some implementation schemes, R 8a and R 8b It is a hydrogen atom on its own.

[0136] In some implementation schemes, R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-4 Cycloalkanes, wherein R 8a and R 8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution.

[0137] In some implementation schemes, R 8a and R 8b Together with the carbon atoms they are attached to, they can form: Where ee represents -(CH2) n1 - Connection point.

[0138] In some implementations, n1 is 0, 1, 2, or 3; n2 is 0, 1, 2, 3, 4, or 5.

[0139] In some implementations, n1 is 0; and / or n2 is 0.

[0140] In some implementation schemes, R 9 Selected from Or CN, and R 9a and R 9b Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl.

[0141] In some implementation schemes, R 9a and R 9b Independently selected from hydrogen atoms and C atoms 1-6 alkyl.

[0142] In some embodiments, non-limiting examples of compounds of formula (I) include the following compounds:

[0143] This disclosure also provides a pharmaceutical composition comprising the compound described herein or a stereoisomer thereof, a mixture of stereoisomers, a tautomer, a geometric isomer, a solvate, a pharmaceutically acceptable salt, a deuterated compound, an ester or a prodrug thereof, and a pharmaceutically acceptable excipient.

[0144] This disclosure also provides the use of the compounds described herein, or stereoisomers thereof, mixtures of stereoisomers, tautomers, geometric isomers, solvates, pharmaceutically acceptable salts, deuterated compounds, esters, or prodrugs thereof, in the preparation of medicaments for the treatment or prevention of diseases, conditions, or symptoms in which GLP-1 receptors function.

[0145] In some implementations, the diseases, conditions, or symptoms in which the GLP-1 receptor functions include diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, overweight, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, hyperinsulinemia, and non-alcoholic fatty liver disease.

[0146] This invention also provides compounds and pharmaceutical compositions that have improved therapeutic profiles (e.g., potency, pharmacodynamics, safety) and significant structural differences compared to known small-molecule GLP-1 receptor agonists. The compounds of this invention also possess favorable pharmacokinetic properties.

[0147] Detailed Terminology

[0148] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0149] The term "alkyl" refers to a saturated, straight-chain, or branched hydrocarbon group. The term "C"... 1-6 "Alkyl" refers to a saturated, straight-chain or branched hydrocarbon group containing 1 to 6 carbon atoms. 1-6 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted.

[0150] The term "cycloalkyl" refers to a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic compound (spirocyclic, fused, and bridged rings). Cycloalkyl groups can be spirocyclic, bridged, or monocyclic. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. The cycloalkyl ring includes cycloalkyl groups (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring connected to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, phenylcyclopentyl, and benzocycloheptyl, etc.; preferably phenylcyclopentyl and tetrahydronaphthyl. Cycloalkyl groups can be substituted or unsubstituted.

[0151] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Alkoxy groups can be substituted or unsubstituted.

[0152] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, preferably 3 to 12 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O), and S(O)2, but excluding the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. Heterocyclic rings include heterocyclic groups (including monocyclic, spirocyclic, fused-ring, and bridged-ring) fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group. Heterocyclic groups can be substituted or unsubstituted.

[0153] The term "aryl" refers to a 6- to 14-membered, preferably 6- to 10-membered, all-carbon monocyclic or fused polycyclic (fused polycyclic) group (a ring sharing adjacent carbon atom pairs) having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring. The aryl group can be substituted or unsubstituted.

[0154] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, and 10), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be substituted or unsubstituted.

[0155] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0156] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0157] The compounds disclosed herein can exist as tautomers. For the purposes of this disclosure, references to compounds of formula (I) refer to the compound itself, any one of its tautomers, or a mixture of two or more tautomers. For example, a reference to a pyrazolyl group should be understood to include any one or a mixture of two of the following structures.

[0158] In the compounds disclosed herein, hydrogen atoms (H) can be replaced by deuterium atoms (D) to form "deuterated compounds". In this disclosure, reference to "hydrogen" includes both hydrogen (H) and deuterium (D); reference to "methyl" includes methyl and its deuterated forms (including cases with one, two, or three deuterium atoms). This rule also applies to other substituents and compounds. Therefore, all possible substitutions of hydrogen and deuterium in the compounds of this disclosure are covered within the scope of this invention.

[0159] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the case where the event or environment occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0160] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms that are independently substituted by the corresponding number of substituents.

[0161] "Pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0162] "Pharmaceutically acceptable salt" means a salt of the compounds disclosed herein that is safe and effective when used in mammals and has the intended biological activity. Detailed Implementation

[0163] The invention is described in detail below with reference to embodiments, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0164] Unless otherwise stated, the proportions of mixed solvents are volume ratios. For example, "petroleum ether / ethyl acetate = 60 / 1" means that the volume ratio of petroleum ether to ethyl acetate is 60:1.

[0165] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0166] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift was measured in units of 10⁻⁶ ppm. The solvents used for NMR measurements included deuterated dimethyl sulfoxide, deuterated chloroform, and deuterated methanol, with tetramethylsilane (TMS) as the internal standard.

[0167] The following abbreviations are used in this disclosure: NaH represents sodium hydride; RT represents retention time; TLC represents thin-layer chromatography.

[0168] Intermediate 1-1: Synthesis of ((2S)-3-cyano-2-methyl-4-oxoperidin-1-carboxylic acid tert-butyl ester)

[0169] Step 1: Synthesis of (S)-(4-amino-4-oxobutyl-2-yl)carbamate tert-butyl ester

[0170] Compound 1a (3.5 g, 17.22 mmol) and CDI (2.972 g, 18.32 mmol) were dissolved in 20 mL of THF and heated under reflux for 30 min. The reaction mixture was cooled to room temperature, and 20 mL of ammonia (25%) was added. The mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and 40 mL of ethyl acetate was added. The mixture was washed with NaOH aqueous solution at pH 9 (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the residue. The residue was purified by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give compound 1b (2.59 g, yield 74.36%) as a white solid. LC-MS (ESI): m / z = 203.13 [M+H] + .

[0171] Step 2: Synthesis of (S)-(1-cyanopropane-2-yl)carbamate tert-butyl ester

[0172] Triethylamine (5 g, 49.41 mmol) was added to an anhydrous DCM (20 mL) solution of compound 1b (5 g, 24.72 mmol), followed by slow dropwise addition of TFAA (6.22 g, 29.61 mmol) at 0 °C and stirring at room temperature for 5 h. The reaction was extinguished by slow addition of H₂O (50 mL) at 0 °C, followed by concentration under reduced pressure. The residual liquid was extracted with EA (40 mL × 3). The organic layer was dried over Na₂SO₄ and concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give compound 1c (2.96 g, yield 65%) as a colorless solid. LC-MS (ESI): m / z = 184.12 [M+H] + .

[0173] Step 3: Synthesis of (S)-3-aminobutyronitrile

[0174] Compound 1c (1 g, 5.42 mmol) was stirred in a 4N dioxane hydrochloride solution (5 mL) for 4 h. The compound was concentrated under vacuum, and a NaOH aqueous solution (pH = 10) (10 mL) was added. Extraction was performed with dichloromethane (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give compound 1d (454 mg, 99% yield), a pale yellow liquid. LC-MS (ESI): m / z = 85.07 [M + H] + .

[0175] Step 4: Synthesis of ethyl (S)-3-((tert-butoxycarbonyl)(1-cyanopropane-2-yl)amino)propionate

[0176] A solution of compound 1d (1.21 g, 6.56 mmol) in EtOH (10 mL) containing triethylamine (796 mg, 7.87 mmol) and ethyl acrylate (790 mg, 7.89 mmol) was heated at 70 °C for 3 h, cooled to room temperature, and then di-tert-butyl dicarbonate (1.72 g, 7.88 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 1e (1.16 g, 62% yield) as a pale yellow viscous solid. LC-MS (ESI): m / z = 285.17 [M+H] + .

[0177] Step 5: Synthesis of tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate

[0178] t-BuOK (1.59 g, 14.1 mmol) was added to 15 mL of THF containing compound 1e (4 g, 14.06 mmol), and the mixture was stirred at room temperature for 1 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated, then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to give intermediate 1-1 (2.68 g, 79% yield) as a pale yellow solid. LC-MS (ESI): m / z = 239.13 [M + H] + .

[0179] Synthesis of N-(2,2-dimethoxyethyl)-1H-imidazol-1-carboxamide

[0180] N,N'-carbonyldiimidazole (2.44 g, 15.0 mmol) was dissolved in acetonitrile (20 mL), and N,N-dimethylformamide (2 mL) was added. Under stirring at room temperature, aminoacetaldehyde dimethyl acetal (1.05 g, 10.0 mmol) was slowly added dropwise, and stirring was continued for 4 h. Then, water (100 mL) was added to the reaction solution and extracted with ethyl acetate (40 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (methanol / dichloromethane = 1:100) to give N-(2,2-dimethoxyethyl)-1H-imidazolium-1-carboxamide (1.65 g, yield 83%) as a white solid.

[0181] Synthesis of 5-bromo-4-fluoro-1-methyl-1H-indazole

[0182] 5-Bromo-4-fluoroindazole (2.14 g, 10.0 mmol) was dissolved in anhydrous DMF. The mixture was placed in an ice bath and cooled to 0 °C. 60% sodium hydride (0.48 g, 12.0 mmol) was added, and the mixture was stirred for 0.5 h. Iodomethane (1.70 g, 12.0 mmol) was then slowly added dropwise. The mixture was then slowly heated to room temperature and stirred for 3 h. After the reaction was monitored by TLC until it was complete, saturated sodium thiosulfate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 30) to give 5-bromo-4-fluoro-1-methyl-1H-indazole (1.53 g, yield 67%) as a white solid.

[0183] Intermediates 1-2: Synthesis of ((S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one)

[0184] Step 1: Synthesis of di-tert-butyl 1-(4-fluoro-3,5-dimethylphenyl)hydrazine-1,2-dicarboxylate

[0185] Magnesium shavings (3.59 g, 147.73 mmol) were added to a 500 mL double-necked flask. Under nitrogen protection, a solution of compound 2a (25 g, 123.12 mmol) in anhydrous tetrahydrofuran (50 mL) and 1,2-dibromoethane (0.1 mL) were injected. The mixture was heated to reflux for 1 h. After the initial initiation stopped, reflux was continued for another 1 h. The mixture was cooled to room temperature, and after the reaction mixture was cooled to 0 °C, a solution of di-tert-butyl azodicarbonate (31.18 g, 135.43 mmol) in THF (100 mL) was slowly added dropwise. The mixture was stirred at room temperature for 5 h. A saturated solution of ammonium chloride (20 mL) was added, and the mixture was filtered through diatomaceous earth. The residue was washed with ethyl acetate (40 mL), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50 / 1 to 10 / 1) to give compound 2b (38.40 g, yield 88%) as a white solid. LC-MS (ESI): m / z = 355.20 [M+H] + .

[0186] Step 2: Synthesis of di-tert-butyl 1-(4-fluoro-3,5-dimethylphenyl)hydrazine-1,2-dicarboxylate

[0187] Add 10 mL of 4N dioxane hydrochloride to a 15 mL solution of compound 2b (5 g, 14.10 mmol) of dioxane, stir at room temperature for 6 h, and concentrate under reduced pressure to obtain the hydrochloride salt of compound 2c, which can be used directly in the next reaction.

[0188] Step 3: Synthesis of (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0189] The crude hydrochloride salt of compound 2c was dissolved in ethanol (20 mL), and Py·HCl (193 mg, 1.41 mol) and intermediate 1 (2.8 g, 11.75 mol) were added. The mixture was stirred at 85 °C for 2 h, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 2c (3.01 g, yield 57%) as a pale yellow foamy solid. LC-MS (ESI): m / z = 375.21 [M+H] + .

[0190] Step 4: Synthesis of (S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0191] Compound 2c (1.56 g, 4.16 mmol) and N-(2,2-dimethoxyethyl)-1H-imidazolium-1-carboxamide (1.24 g, 6.22 mmol) were dissolved in anhydrous DMA (20 mL). Potassium tert-butoxide (920 mg, 4.61 mmol) was added with stirring at room temperature, and the mixture was stirred overnight at room temperature. Water (200 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5:1 to 2:1) to give compound 2d (1.67 g, 79% yield) as a pale yellow solid. LC-MS (ESI): m / z = 506.27 [M+H] + .

[0192] Step 5: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0193] Methylsulfonic acid (1.27 mg, 13.21 mmol) was added to a 20 mL THF solution of compound 2d (3.33 g, 6.58 mmol), and the mixture was heated under reflux for 1.5 h. After cooling to room temperature, a saturated aqueous solution of potassium carbonate was added dropwise to adjust the pH to 10. Ethyl acetate (30 mL × 2) was added for extraction, and the ethyl acetate layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5:1 to 1:2) to give compound 2e (2.58 g, yield 88%) as a yellow solid. LC-MS (ESI): m / z = 442.22 [M+H] + .

[0194] Step 6: Synthesis of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid

[0195] Cuprous iodide (22.56 mg, 0.12 mmol) was added to an NMP solution of compound 2e (523 mg, 1.18 mmol), 5-bromo-4-fluoro-1-methyl-1-H-indazole (407 mg, 1.78 mmol), potassium carbonate (491.14 mg, 3.55 mmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (50.55 mg, 0.36 mmol). The mixture was refluxed overnight at 130 °C under nitrogen with stirring. Water (60 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic layer was washed with brine (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5:1 to 1:1) to give compound 2f (367 mg, yield 67%) as a light brown solid. LC-MS (ESI): m / z = 590.26 [M+H] + .

[0196] Step 7: Synthesis of 1-[2-(4-fluoro-3,5-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-methylindazole-5-yl)imidazol-2-one

[0197] To a solution of compound 2f (100 mg, 0.16 mmol) in dioxane (1.5 mL), 0.5 mL of 4N dioxane hydrochloride was added, and the mixture was stirred at room temperature for 4 h. A saturated solution of sodium carbonate (10 mL) was added dropwise, followed by extraction with dichloromethane (10 mL × 2). The mixture was then concentrated under reduced pressure to give intermediate 1-2 (78 mg, 99% yield) as a pale yellow viscous solid. LC-MS (ESI): m / z = 490.21 [M + H] +.

[0198] Intermediate 1-3: Synthesis of ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0199] Step 1: Synthesis of ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0200] To a mixed solution of compound 3a (3 g, 11.18 mmol) in dioxane (20 mL) and water (4 mL), 3,6-dihydro-2H-pyran-4-boronate pinacol ester (3 g, 14.28 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (251 mg, 0.34 mmol), and potassium carbonate (3.86 g, 27.92 mmol) were added, and the reaction was carried out overnight at 90 °C under nitrogen. The reaction solution was concentrated under reduced pressure, 35 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5:1) to give compound 3b (2.19 g, 72% yield) as a pale yellow solid. LC-MS (ESI): m / z = 272.12 [M+H] + .

[0201] Step 2: Synthesis of ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0202] Palladium on carbon (0.3 g) was added to a THF (30 mL) solution of compound 3b (2 g, 7.37 mmol), and the mixture was heated and stirred overnight at 40 °C under hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate 1-3 (1.82 g, 90% yield) as a white solid. LC-MS (ESI): m / z = 274.14 [M+H] + .

[0203] Intermediates 1-4: Synthesis of ethyl (S)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0204] Step 1: Synthesis of 4-iodo-2,2-dimethyltetrahydro-2H-pyran

[0205] Sodium iodide (22.5 g, 150.0 mmol) and acetone (8.7 g, 150.0 mmol) were added to a solution of compound 4a (10.8 g, 150.0 mmol) in acetonitrile (100 mL). Trimethylchlorosilane (16.3 g, 150.0 mmol) was slowly added dropwise with stirring at room temperature. After the addition was complete, the reaction was allowed to proceed for 6 h. The reaction was confirmed to be complete by TLC. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give compound 4b (11.6 g, yield 32.2%) as a reddish-brown liquid. LC-MS (ESI): m / z = 241.00 [M+H] + .

[0206] Step 2: Synthesis of (2,2-dimethyltetrahydro-2H-pyran-4-yl)zinc iodide

[0207] Zinc powder (1.28 g, 20.0 mmol) was added to a 50 mL double-necked flask. Under a nitrogen atmosphere, 15 mL of N,N-dimethylformamide, 1,2-dibromoethane (279 mg, 1.5 mmol), trimethylchlorosilane (163 mg, 1.5 mmol), and compound 4b (1.2 g, 5.0 mmol) were added. The mixture was stirred at room temperature for 20 min to obtain compound 4c, which was used directly in the next reaction.

[0208] Step 3: Synthesis of ethyl 6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0209] To the reaction solution of compound 4c, a DMF solution of ethyl 5-bromoindole-2-carboxylate (1.33 g, 5.00 mmol), palladium acetate (34 mg, 0.15 mmol), and (4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine (80 mg, 0.30 mmol) was added, and the mixture was stirred in an oil bath at 50 °C for 2 h. The reaction was confirmed to be complete by TLC. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 4d (1.26 g, yield 83.6%) as a white solid. LC-MS (ESI): m / z = 302.17 [M+H] + .

[0210] Step 4: Synthesis of ethyl (S)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0211] Compound 4d (800 mg) was resolved by supercritical fluid chromatography to give intermediate 1-4 (353 mg, 44% yield). X-ray crystallography of intermediate 1-4 determined that the title compound was the S-isomer.

[0212] Intermediates 1-5: Synthesis of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0213] Step 1: Synthesis of ethyl (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0214] Intermediate 1-4 (1.20 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (10 mL). 60% sodium hydride (240 mg, 6.0 mmol) was added with stirring in an ice bath. After 30 min, bromoacetonitrile (960 mg, 8.0 mmol) and potassium iodide (664 mg, 4.0 mmol) were added, and the mixture was stirred in an ice bath for 6 h. The reaction was confirmed to be complete by TLC. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 5a (1.5 g, yield 97.8%) as a colorless viscous liquid. LC-MS (ESI): m / z = 341.18 [M+H] + .

[0215] Step 2: Synthesis of (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0216] Compound 5a (1.02 g, 3.0 mmol) and 1,5,7-triazabicyclo[4.4.0]-5-decene (626 mg, 4.5 mmol) were dissolved in 20 mL of acetonitrile and 4 mL of water, and reacted at room temperature for 4 h. The reaction was confirmed to be complete by TLC. 2 M dilute hydrochloric acid was added dropwise to adjust the acidity to pH 1, and a white precipitate was observed. The precipitate was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 5b (909 mg, yield 97.1%), a pale yellow solid. No purification was required, and the crude product was used directly in the next reaction.

[0217] Step 3: Synthesis of (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0218] To a solution of compound 5b (624 mg, 2.0 mmol) in acetonitrile (15 mL), tripyrrolidinylphosphonium hexafluorophosphate (1.40 g, 3.0 mmol), N-methylaniline (428 mg, 4.0 mmol), and N,N-diisopropylethylamine (775 mg, 6.0 mmol) were added, and the mixture was stirred at room temperature for 8 h. The reaction was monitored by TLC until complete. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 5c (502 mg, yield 62.6%) as a white solid. LC-MS (ESI): m / z = 402.21 [M+H] + .

[0219] Step 4: Synthesis of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0220] Compound 5c (401 mg, 1.0 mmol) was dissolved in 8 mL of anhydrous N,N-dimethylpropenylurea. A solution of (4R)-4-methyl-1,3,2-dioxathiapentane (276 mg, 2.0 mmol) in N,N-dimethylpropenylurea (2 mL) and bis(trimethylsilyl)aminopotassium (798 mg, 4.0 mmol) were injected under nitrogen atmosphere and stirring in an ice bath. The mixture was stirred in an ice bath for 3 h. The reaction was confirmed to be complete by TLC. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with a 3:1 mixture of ethyl acetate and petroleum ether (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 20:1 to 4:1) to give compound 5d (323 mg, yield 73.2%) as a white solid. LC-MS (ESI): m / z = 442.24 [M+H] + .

[0221] Step 5: Synthesis of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(Z)-N'-hydroxycarbamoimido)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0222] Compound 5d (265 mg, 0.6 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 50% hydroxylamine aqueous solution (396 mg, 6.0 mmol) was added dropwise. The mixture was refluxed and stirred in an oil bath at 50 °C for 6 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 5e as a white solid. The crude product was used directly in the next reaction step.

[0223] Step 6: Synthesis of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

[0224] The crude compound 5e was dissolved in 5 mL of anhydrous dimethyl sulfoxide in N,N'-carbonyldiimidazole (130 mg, 0.8 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (152 mg, 1.0 mmol), and stirred in an oil bath at 80 °C for 5 h. The reaction was confirmed to be complete by TLC. The reaction solution was adjusted to neutral pH by adding dilute hydrochloric acid dropwise, and extracted with ethyl acetate (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 40 / 1 to 30 / 1). The crude product was dissolved in a small amount of dichloromethane, and a large amount of n-hexane was added. The precipitated solid was filtered to give compound 5f (155 mg, yield 77.6%) as a white solid.

[0225] Step 7: Synthesis of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0226] Compound 5f (150 mg, 0.3 mmol) was dissolved in n-butanol (8 mL), and potassium hydroxide (168 mg, 3.0 mmol) was added. The mixture was stirred in an oil bath at 100 °C for 12 h. The reaction was confirmed to be complete by TLC. After cooling to room temperature, 15 mL of water was added to the reaction mixture, and the mixture was separated using a separatory funnel. The aqueous phase was adjusted to pH 1 with 6N hydrochloric acid, and a white precipitate was observed. The precipitate was filtered, and the solid was dried under an infrared lamp to give intermediate 1-5 (65 mg, yield 79.8%).

[0227] Intermediates 1-6: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0228] Step 1: Synthesis of 3-cyclopropyl-4-fluoroaniline

[0229] 3-Bromo-4-fluoroaniline (5 g, 26.31 mmol), cyclopropylboronic acid (4.52 g, 52.6 mmol), palladium acetate (267 mg, 1.18 mmol), tricyclohexylphosphine (670 mg, 2.38 mmol), and potassium phosphate (11.17 g, 52.6 mmol) were added to a 250 mL two-necked flask. After purging with nitrogen three times, 63 mL of solvent (dioxane / water = 20 / 1) was added, and the mixture was stirred at 100 °C for 16 h. The mixture was concentrated to obtain a residue, which was then extracted with water (40 mL) and dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1 to 5:1) to give compound 6b (3.96 g, 99.6% yield) as a light brown liquid.

[0230] Step 2: Synthesis of 3-cyclopropyl-4-fluoroaniline hydrochloride

[0231] Compound 6b (4.29 g, 28.20 mmol) was suspended in 15% HCl (30 mL), and a solution of sodium nitrite (2.04 g, 29.65 mmol) in water (3 mL) was slowly added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. A solution of stannous chloride (10.70 g, 56.4 mmol) in concentrated hydrochloric acid (5 mL) was added dropwise to the mixture at 0 °C, and the mixture was stirred for another 2 h at 0 °C, resulting in the precipitation of a grayish-brown solid. The reaction mixture was filtered to obtain compound 6c (6.58 g, crude product), a grayish-brown solid, which was used directly in the next step.

[0232] Step 3: Synthesis of (S)-3-amino-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0233] Triethylamine was added to an ethanol (20 mL) solution of compound 6c (6.5 g, crude) to adjust the pH to neutral. Intermediate 1-1 (4.5 g, 18.88 mmol) and pyridine hydrochloride (60 mg, 0.51 mmol) were then added. The mixture was stirred at 70 °C for 6 h. The mixture was concentrated to obtain a residue, which was then added to a potassium carbonate (30 mL) solution at pH 10 and extracted with dichloromethane (40 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1 to 5:1) to give compound 6d (4.76 g, yield 65.2%) as a light orange foamy solid.

[0234] Step 4: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(2-((dimethoxymethyl)amino)acetamido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0235] To a DMA (4 mL) solution of compound 6d (300 mg, 0.77 mmol), N-(2,2-dimethoxyethyl)-1H-imidazolium-1-carboxamide (309 mg, 1.55 mmol) and potassium tert-butoxide (174 mg, 1.55 mmol) were added. The mixture was stirred overnight at room temperature. Water (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1) to give compound 6e (241 mg, yield 60.4%) as a colorless, foamy solid.

[0236] Step 5: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0237] Methanesulfonic acid (343 mg, 3.57 mmol) was added to an 8 mL solution of tetrahydrofuran containing compound 6e (924 mg, 1.78 mmol). The mixture was refluxed for 0.5 h and then concentrated. The solution was purified by silica gel column chromatography to give compound 6f (454 mg, 56% yield) as a colorless, foamy solid.

[0238] Step 6: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0239] To an anhydrous NMP (4 mL) solution of compound 6f (450 mg, 0.99 mmol), 5-bromo-4-fluoro-1-methyl-1H-indazole (454 mg, 1.98 mmol), cuprous iodide (47 mg, 0.24 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (35 mg, 0.24 mmol), and potassium carbonate (410 mg, 2.96 mmol) were added. The mixture was reacted overnight at 120 °C under nitrogen stirring. Water (25 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (6 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 3:2) to give compound 6 g (542 mg, 91.9% yield) as a pale yellow foamy solid.

[0240] Step 7: Synthesis of (S)-1-(2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0241] To a solution of 6 g (100 mg, 0.16 mmol) of compound in dioxane (1.5 mL), 0.5 mL of 4N dioxane hydrochloride was added and stirred at room temperature for 4 h. A saturated solution of sodium carbonate (10 mL) was added dropwise, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phase was concentrated under reduced pressure to give intermediate 1-6 (81 mg, yield 97%) as a pale yellow solid.

[0242] Example 1: Synthesis of (S)-1-(5-(1-(cyclopropylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0243] Step 1: Synthesis of ethyl 1-(cyclopropylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0244] NaH (60% dispersion in mineral oil, 44 mg, 1.1 mmol) was added to an anhydrous THF (4 mL) solution of intermediate 1-3 (151 mg, 0.55 mmol) at 0 °C. After reacting for 15 min at 0 °C, an anhydrous THF (2 mL) solution of cyclopropylsulfonyl chloride (155 mg, 1.1 mmol) was slowly added dropwise. 5 mg of DMAP was added to the mixture, and the mixture was heated to room temperature for 4 h. The mixture was concentrated under reduced pressure, and water (10 mL) was added to the mixture, followed by extraction with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 1-A (195 mg, 94% yield) as a pale yellow solid. LC-MS (ESI): m / z = 377.14 [M+H] + .

[0245] Step 2: Synthesis of 1-(cyclopropylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0246] 1,5,7-triazabicyclo[4.4.0]dec-5-ene (120 mg, 0.85 mmol) was added to a tetrahydrofuran / water mixture (3 mL, volume ratio 1:1) containing compound 1-A (150 mg, 0.42 mmol). The mixture was stirred at room temperature for 6 h. 3 mL of 1 M hydrochloric acid aqueous solution was added to the reaction mixture. The precipitated white solid was filtered off, and the filter cake was washed with 1 M hydrochloric acid and dried to obtain compound 1-B, a white solid, which was used directly in the next step. LC-MS (ESI): m / z = 349.10 [M+H] + .

[0247] Step 3: Synthesis of (S)-1-(5-(1-(cyclopropylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0248] Intermediate 1-2 (82 mg, 0.16 mmol), triethylamine (51 mg, 0.50 mmol), and PyBroP (157.6 mg, 0.338 mmol) were added to a THF (5 mL) solution of compound 1-B (58 mg, 0.16 mmol), and the mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:2) to give compound 1 (119 mg, yield 85%) as a pale yellow solid. LC-MS (ESI): m / z = 821.30 [M+H]+ . 1 H NMR (400MHz, chloroform-d) δ8.09(m,1H),7.87(m,1H),7.49–7.31(m,2H),7.27(m,1H) ,7.25(m,1H),7.17(m,1H),7.12(m,1H),6.71(m,1H),6.50(m,1H),6.24(m,1H) ,5.80(m,1H),4.16–4.02(m,6H),3.57(m,3H),3.25(m,1H),2.86(m,3H),2.26 (m,6H),1.94–1.75(m,4H),1.53(m,3H),1.52–1.41(m,2H),1.13–1.00(m,2H).

[0249] Example 2: Synthesis of (S)-1-(5-(1-(cyclopropylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0250] Following the synthetic route of Example 1, the only difference was that intermediates 1-3 in step 1 were replaced with intermediate 4d, yielding compound 2, a white solid. LC-MS (ESI): m / z = 849.33 [M+H] + . 1 ¹H NMR (300MHz, chloroform-d) δ 8.13–8.03 (m, 1H), 7.92–7.81 (m, 1H), 7.55–7.40 (m, 2H), 7.27 (s, 1H), 7.25–7.19 (m, 1H), 7.17–7.07 (m, 2H), 6.71–6.65 (m, 1H), 6.61–6.40 (m, 1H), 6.36–6.13 (m, 1H), 5.86–5.72 (m, 1H), 4.15–4. 00(m,4H),3.90–3.77(m,2H),3.64–3.49(m,1H),3.27–3.18(m,1H),3.10–2.99(m,1H),2.96–2.72(m,2H),2 .32–2.22(m,6H),1.79–1.63(m,4H),1.54(m,5H),1.36–1.31(m,3H),1.30–1.25(m,3H),1.12–1.01(m,2H).

[0251] Example 3: Synthesis of (S)-1-(5-(1-(ethylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0252] Following the synthetic route of Example 1, except that cyclopropylsulfonyl chloride in step 1 was replaced with ethylsulfonyl chloride, compound 3 was obtained, which was a white solid. LC-MS (ESI): m / z = 809.30 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.32(s,1H),7.86(s,1H),7.65(s,1H),7.55(s,1H),7. 50–7.47(m,1H),7.36(m,2H),7.30(s,1H),7.18(s,1H),7.07(s,1H),6.97–6.8 8(m,1H),5.65–5.56(m,1H),4.12(s,3H),4.01–3.92(m,4H),3.80(m,2H),3.57 (m,1H),3.46(m,4H),3.37(s,3H),2.96–2.75(m,4H),2.30(s,3H),2.26(m,6H).

[0253] Example 4: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-1-(thiophen-2-ylsulfonyl)-1H-indole-2-carbonyl)-4,5,6,7-tetrahydro-2Hpyrazolo[4,3]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0254] Following the synthetic route of Example 1, except that cyclopropylsulfonyl chloride in step 1 was replaced with 2-thiophenesulfonyl chloride, compound 4 was obtained, which was a pale yellow solid. LC-MS (ESI): m / z = 863.25 [M+H] + . 1¹H NMR (300 MHz, chloroform-d) δ 8.18–8.09 (s, ¹H), 8.08–7.95 (m, 2H), 7.60–7.53 (m, ¹H), 7.47 (t, J = 7.9 Hz, ¹H), 7.41 (s, ¹H), 7.32–7.26 (m, 2H), 7.14 (d, J = 6.1 Hz, 2H), 7.05 (m, ¹H), 6.69 (m, ¹H) ,6.59(m,1H),6.47–6.29(m,1H),5.86(s,1H),4.11(s,3H),4.07(m,2H),3.98(m,1H),3.5 8–3.48(m,2H),3.39(m,2H),2.84(m,2H),2.25(m,6H),1.83(m,4H),1.58(d,J=6.8Hz,3H).

[0255] Example 5: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-(5-(tetrahydro-2H-pyran-4-yl)-1-toluenesulfonyl-1H-indole-2-carbonyl)-4,5,6,7-tetrahydro-2Hpyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0256] Following the synthetic route of Example 1, except that cyclopropylsulfonyl chloride in step 1 was replaced with p-toluenesulfonyl chloride, compound 5 was obtained as a white solid. LC-MS (ESI): m / z = 871.31 [M+H] + . 1 H NMR (300MHz, chloroform-d) δ8.12(s,1H),8.06(m,2H),7.99(m,1H),7.47(m,1H) ,7.39(m,1H),7.28(m,2H),7.25(m,2H),7.15(m,2H),6.71–6.55(m,2H), 6.40(m,1H),5.88(s,1H),4.11(m,4H),4.07(m,2H),3.96(m,1H),3.55( m,3H),2.82(m,2H),2.35(m,3H),2.26(m,6H),1.82(m,4H),1.60(m,3H).

[0257] Example 6: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-4,5,6,7-tetrahydro-2Hpyrazolo[4,3]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0258] Following the synthetic route of Example 1, the only difference being that cyclopropylsulfonyl chloride in step 1 was replaced with 1-methyl-1H-imidazol-4-sulfonyl chloride, yielding compound 6, a white solid. LC-MS (ESI): m / z = 861.31 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ8.36–8.22(m,1H),8.09(s,1H),7.92(d,J=8.6Hz,1H),7.80–7.69(m,1H),7. 67–7.59(m,1H),7.54–7.41(m,2H),7.30(d,J=9.2Hz,1H),7.20–7.12(d,J=6.4Hz,2H),7.08(d,J=3.2 Hz,1H),6.99–6.86(m,2H),5.70–5.48(s,1H),4.14–4.06(m,3H),4.04–3.85(m,3H),3.73–3.63(m,3H ),3.51–3.38(m,2H),3.06-2.65(m,4H),2.29–2.19(m,6H),1.77-1.63(m,4H),1.38(d,J=6.4Hz,3H).

[0259] Example 7: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0260] Following the synthetic route of Example 2, the only difference being that cyclopropylsulfonyl chloride in step 1 was replaced with 1-methyl-1H-imidazol-4-sulfonyl chloride, yielding compound 7, a white solid. LC-MS (ESI): m / z = 889.33 [M+H] + .1 H NMR(300MHz,DMSO-d6)δ8.33(s,1H),8.14–8.08(m,1H),7.92(m,1H),7.76(s,1H),7.65 (m,1H),7.48(m,2H),7.40–7.26(m,2H),7.18(s,1H),7.10(s,1H),7.03–6.86(m,2H),5 .60(s,1H),4.12(s,3H),3.72(s,1H),3.69(s,3H),3.65(s,1H),3.54(m,1H),3.10–2.6 7(m,4H),2.26(m,6H),1.74–1.52(m,4H),1.42(m,3H),1.28–1.25(s,3H),1.18(s,3H).

[0261] Example 8: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0262] Following the synthetic route of Example 6, the only difference was that intermediates 1-3 in step 1 were replaced with ethyl 5-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)1H-indole-2-carboxylate, yielding compound 8, a white solid. LC-MS (ESI): m / z = 917.37 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.34–8.24(s,1H),8.11(s,1H),7.92(s,1H),7.80–7.73(m,1H),7. 73–7.62(m,1H),7.55–7.46(m,2H),7.41–7.25(m,2H),7.18(m,1H),7.10(m,1H),6.96(s,2H ),5.55(m,1H),4.11(s,3H),3.69(s,3H),3.54(m,1H),3.30–3.09(m,2H),2.93–2.62(m,2H) ,2.32–2.21(m,6H),1.71(m,2H),1.50–1.43(m,2H),1.40(s,3H),1.31(s,6H),1.16(s,6H).

[0263] Example 9: Synthesis of 1-((4S)-2-(3-cyclopropyl-4-fluorophenyl)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0264] Referring to the synthetic route of Example 2, the difference is that cyclopropylsulfonyl chloride in step 1 is replaced with 1-methyl-1H-imidazol-4-sulfonyl chloride, and intermediates 1-2 in step 3 are replaced with intermediates 1-6, yielding compound 9, a white solid. LC-MS (ESI): m / z = 901.33 [M+H] + . 1 ¹H NMR (300MHz, chloroform-d) δ 8.19 (d, J = 8.6 Hz, 1H), 8.14–8.03 (m, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.54–7.43 (m, 1H), 7.42–7.32 (m, 2H), 7.30–7.21 (m, 3H), 7.11–6.95 (m, 2H), 6.67–6.54 (m, 2H), 6.47–6.28 (m, 1H), 5.96–5.71 (m, 1H), 4.18–4.05 (m, 3H) ,4.05–3.96(m,1H),3.90–3.74(m,2H),3.72–3.64(m,3H),3.63–3.51(s,1H),3.08–2.94(m,1H),2.91–2.69(s,2H),2. 14–2.02(m,1H),1.83–1.63(m,4H),1.61–1.45(m,3H),1.31(m,3H),1.26(m,3H),1.01–0.92(m,2H),0.76–0.64(m,2H).

[0265] Example 10: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(pyridin-3-ylsulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0266] Following the synthetic route of Example 2, the only difference being that cyclopropylsulfonyl chloride in step 1 was replaced with pyridine-3-sulfonyl chloride, yielding compound 10, a white solid. LC-MS (ESI): m / z = 886.32 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.34–9.27(s,1H),8.88(s,1H),8.60–8.53(s,1H),8.34–8.21(s,1H),8.0 1(s,1H),7.74–7.63(m,2H),7.55–7.47(m,2H),7.37(m,1H),7.33–7.27(s,1H),7.19(m,1H),7.10 (m,1H),7.08(s,1H),6.95(s,1H),5.67(m,1H),4.14–4.04(s,3H),3.74–3.66(m,2H),3.62(m,1H) ,3.12–2.60(m,4H),2.32–2.22(m,6H),1.70–1.50(m,4H),1.45(m,3H),1.25(s,3H),1.17(m,3H).

[0267] Example 11: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((3-methoxyphenyl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0268] Following the synthetic route of Example 2, the only difference being that cyclopropylsulfonyl chloride in step 1 was replaced with 3-methoxybenzenesulfonyl chloride, yielding compound 11, a white solid. LC-MS (ESI): m / z = 915.34 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.30(m,1H),7.91(m,1H),7.74(m,2H),7.65(m,1H),7.51( m,2H),7.36–7.24(m,3H),7.18(m,2H),7.10(m,1H),7.00(m,2H),5.69(s,1H),4.1 1(s,3H),3.80(s,3H),3.69(m,2H),3.19–3.10(m,1H),3.08–2.70(m,4H),2.33–2. 24(m,6H),1.65(m,2H),1.52(m,2H),1.46–1.39(m,3H),1.25(s,3H),1.16(s,3H).

[0269] Example 12: Synthesis of 1-((4S)-5-(1-((1H-pyrazol-4-yl)sulfonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0270] Following the synthetic route of Example 2, the only difference being that cyclopropylsulfonyl chloride in step 1 was replaced with 1H-pyrazole-4-sulfonyl chloride, yielding compound 12, a white solid. LC-MS (ESI): m / z = 875.32 [M+H] + . 1 HNMR(300MHz,DMSO-d6)δ13.06(s,1H),8.64–8.30(m,1H),7.61(m,1H),7.42(s, 1H),7.07(m,1H),6.87–6.70(m,2H),6.60(m,2H),6.46–6.38(m,1H),6.26(m,2H) ,6.21–6.16(m,1H),6.06(s,1H),4.66(m,1H),3.31(m,1H),3.19(m,3H),3.09–2. 66(m,4H),2.29–1.80(m,4H),1.41–1.30(m,6H),0.88–0.73(m,4H),0.50(m,3H).

[0271] Example 13: Synthesis of 1-((4S)-5-(1-((1H-1,2,4-triazol-5-yl)sulfonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0272] Following the synthetic route of Example 2, the only difference being that the cyclopropylsulfonyl chloride in step 1 was replaced with 1H-1,2,4-triazol-5-sulfonyl chloride, compound 13 was obtained as a white solid. LC-MS (ESI): m / z = 876.31 [M+H] + . 1 H NMR (300MHz, chloroform-d) δ8.14–8.06(m,1H),7.72(m,3H),7.55(m,3H),7.43(s,1H) ,7.13(m,2H),6.65–6.54(m,1H),6.30(m,1H),5.95–5.52(m,1H),4.23(m,2H) ,4.12–4.07(m,3H),3.88(m,1H),3.19–2.85(m,4H),2.81(m,1H),2.39–2.21( m,6H),1.73–1.65(m,4H),1.37–1.35(m,3H),1.30–1.28(m,3H),1.27(m,3H).

[0273] Example 14: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0274] Following the synthetic route of Example 2, the only difference being that cyclopropylsulfonyl chloride in step 1 was replaced with 1-methyl-1H-pyrazole-4-sulfonyl chloride, yielded compound 14, a white solid. LC-MS (ESI): m / z = 889.33 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.60(s,1H),8.33(s,1H),8.08(s,1H),7.94(m,1H),7.66(m ,1H),7.55–7.46(m,2H),7.37–7.28(m,2H),7.19(s,1H),7.10(s,1H),6.96(m,2H), 5.65(s,1H),4.11(s,3H),3.88–3.85(m,3H),3.71(m,2H),3.64–3.53(m,1H),3.11– 2.69(m,4H),2.26(m,6H),1.73–1.52(m,4H),1.41(m,3H),1.26(s,3H),1.18(s,3H).

[0275] Example 15: Synthesis of 1-((4S)-2-(3-cyclopropyl-4-fluorophenyl)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0276] Referring to the synthetic route of Example 9, replacing 1-methyl-1H-pyrazole-4-sulfonyl chloride in step 1 with 1-methyl-1H-imidazolium-4-sulfonyl chloride yielded compound 15, a white solid. LC-MS (ESI): m / z = 901.33 [M+H] + . 1¹H NMR (300 MHz, chloroform-d) δ 8.22 (s, ¹H), 8.12 (s, ¹H), 8.07–7.88 (m, 2H), 7.55–7.45 (m, ¹H), 7.42 (s, ¹H), 7.36–7.21 (m, 3H), 7.12–6.96 (m, 2H), 6.82–6.58 (m, 2H), 6.47–6.29 (m, ¹H), 6.24–5.73 (m, ¹H), 4.31–4.05 (m, 3H), 4.04 –3.93(m,1H),3.92–3.72(m,5H),3.68–3.50(m,1H),3.08–2,92(m,1H),2.82(m,2H),2.14–2.02(m,1H),1.80 –1.59(m,4H),1.51–1.38(m,3H),1.35–1.29(m,3H),1.29–1.24(m,3H),1.02–0.91(m,2H),0.76–0.65(m,2H).

[0277] Example 16: Synthesis of 1-((S)-5-(5-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0278] Following the synthetic route of Example 14, the only difference being that intermediate 4d in step 1 was replaced with intermediate 1-4-R, yielding compound 16, a white solid. LC-MS (ESI): m / z = 889.33 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.60(s,1H),8.35–8.22(m,1H),8.08(s,1H),7.93(m,1H),7.70– 7.58(m,1H),7.49(m,2H),7.39–7.27(m,2H),7.19(m,1H),7.16–7.06(m,1H),6.97(s,2H ),5.74–5.46(m,1H),4.11(m,3H),3.86(s,3H),3.74–3.68(m,2H),3.59(m,1H),3.09–2. 68(m,4H),2.32–2.24(m,6H),1.75–1.53(m,4H),1.42(m,3H),1.26(s,3H),1.18(s,3H).

[0279] Example 17: Synthesis of 1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2Hpyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0280] Following the synthetic route of Example 14, the only difference being that intermediate 4d in step 1 was replaced with intermediate 1-4-S, compound 17 was obtained, which was a white solid. LC-MS (ESI): m / z = 889.33 [M+H] + . 1¹H NMR (300 MHz, chloroform-d) δ 8.22 (s, 1H), 8.12 (s, 1H), 8.06–7.89 (m, 2H), 7.55–7.44 (m, 1H), 7.41 (s, 1H), 7.36–7.20 (m, 3H), 7.20–6.96 (m, 2H), 6.71–6.57 (m, 2H), 6.48–6.28 (m, 1H), 6.00–5.74 (m 1H),4.15–4.05(m,3H),4.04–3.93(m,1H),3.91–3.75(m,5H),3.60–3.50(m,1H),3.10–2.92(m,1H),2.82(s,1H),2.90–2.73(m,2H), 2.16–2.00(m,1H),1.79–1.59(m,4H),1.51–1.38(m,3H),1.35–1.29(m,3H),1.28–1.24(m,3H),1.02–0.91(m,2H),0.75–0.66(m,2H).

[0281] Example 18: Synthesis of 1-((S)-2-(3-cyclopropyl-4-fluorophenyl)-5-(5-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0282] Following the synthetic route of Example 15, the only difference being that intermediate 4d in step 1 was replaced with intermediate 1-4-R, compound 18 was obtained, which was a white solid. LC-MS (ESI): m / z = 901.33 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ8.60(s,1H),8.34–8.19(m,1H),8.08(s,1H),7.94(m,1H),7.69–7.58(m,1H),7.5 4–7.43(m,2H),7.42–7.30(m,3H),7.30–7.21(m,1H),7.18–7.04(m,1H),7.02–6.94(m,2H),5.76–5.39(m ,1H),4.16–4.05(m,3H),3.86(s,3H),3.74–3.67(m,2H),3.58(m,1H),3.11–2.66(m,4H),2.17–2.04(m,1 H),1.74–1.50(m,4H),1.48–1.38(m,3H),1.26(s,3H),1.18(s,3H),1.08–0.96(m,2H),0.81–0.61(m,2H).

[0283] Example 19: Synthesis of 1-((S)-2-(3-cyclopropyl-4-fluorophenyl)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0284] Following the synthetic route of Example 15, the only difference being that intermediate 4d in step 1 was replaced with intermediate 1-4-S, yielded compound 19, a white solid. LC-MS (ESI): m / z = 901.33 [M+H] + . 1¹H NMR (300MHz, chloroform-d) δ 8.22 (s, ¹H), 8.14–8.03 (m, ¹H), 8.02–7.07 (m, 2H), 7.54–7.37 (m, 2H), 7.36–7.26 (m, ¹H), 7.25–7.22 (m, ¹H), 7.20–7.07 (m, 2H), 6.73–6.61 (m, ¹H), 6.61–6.53 (m, ¹H), 6.47–6.29 (m, ¹H), 6.24–5.75 ( m,1H),4.17–4.06(m,3H),4.04–3.94(m,1H),3.92–3.73(m,5H),3.71–3.48(m,1H),3.09–2.91(m,1H),2.91– 2.74(s,2H),2.33–2.17(m,6H),1.83–1.67(m,4H),1.61–1.50(m,3H),1.36–1.29(m,3H),1.29–1.23(m,3H).

[0285] Example 20: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-((4-fluoro-1-methyl-1H-indazol-5-yl)ethynyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0286] Step 1: Synthesis of 4-fluoro-5-iodo-1-methyl-1H-indazole

[0287] NaH (60% dispersion in mineral oil, 230 mg, 5.72 mmol) was added in portions to an anhydrous tetrahydrofuran (15 mL) solution of compound 20-1 (1.0 g, 3.8 mmol) at 0 °C. The reaction mixture was reacted at 0 °C for 30 min, and iodomethane (812 mg, 5.71 mmol) was added dropwise, followed by reaction at room temperature for 4 h. Water (20 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to give compound 20-2 (592 mg, 56% yield) as a pale yellow solid. LC-MS (ESI): m / z = 276.96 [M+H] + .

[0288] Step 2: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0289] To anhydrous acetonitrile (42 mL) of compound 2c (3.5 g, 9.34 mmol), diiodomethane (12.5 g, 46.6 mmol) and tert-butyl nitrite (1.9 g, 18.4 mmol) were added, and the mixture was reacted at 50 °C for 3 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 20-3 (1.28 g, yield 25.4%) as a pale orange solid. LC-MS (ESI): m / z = 486.10 [M+H] + .

[0290] Step 3: Synthesis of (S)-3-ethynyl-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0291] To an anhydrous N,N-dimethylformamide (5 mL) solution of compound 20-3 (495 mg, 1.01 mmol), cuprous iodide (20 mg, 0.10 mmol), bis(triphenylphosphine)palladium dichloride (72 mg, 0.10 mmol), trimethylsilylacetylene (212 mg, 2.15 mmol), and anhydrous triethylamine (312 mg, 3.08 mmol) were added. The mixture was bubbled under nitrogen and reacted overnight at 80 °C. The reaction mixture was cooled to room temperature, and 1 M TBAF tetrahydrofuran solution (1.15 mL) was added. The mixture was stirred at room temperature for 1 h, and water (25 mL) was added. The mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15:1) to give compound 20-4 (292 mg, 74% yield) as a colorless, foamy solid. LC-MS (ESI): m / z = 384.20 [M+H] + .

[0292] Step 4: Synthesis of (S)-3-((4-fluoro-1-methyl-1H-indazol-5-yl)ethynyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0293] To an anhydrous N,N-dimethylformamide (7 mL) solution of compounds 20-4 (417 mg, 1.09 mmol), bis(triphenylphosphine)palladium dichloride (72 mg, 0.1 mmol), and anhydrous triethylamine (332 mg, 3.28 mmol) were added to the mixture. The mixture was bubbled under nitrogen and reacted overnight at 90 °C. Water (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 4:1) to give compound 20-5 (449 mg, 77% yield) as a pale yellow solid. LC-MS (ESI): m / z = 532.24 [M+H] + .

[0294] Step 5: Synthesis of (S)-3-((4-fluoro-1-methyl-1H-indazol-5-yl)ethynyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

[0295] To a solution of compound 20-5 (160 mg, 0.30 mmol) in dioxane (1.5 mL), 0.5 mL of 4 M dioxane hydrochloride was added. After stirring at room temperature for 4 h, a saturated solution of sodium carbonate (6 mL) was added dropwise to the reaction, and the mixture was extracted with dichloromethane (10 mL × 2). The solution was then concentrated under reduced pressure to obtain compound 20-6 (122 mg, 94% yield), which was a white solid and was used directly in the next step.

[0296] Step 6: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-((4-fluoro-1-methyl-1H-indazol-5-yl)ethynyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0297] Triethylamine (61 mg, 0.6 mmol), PyBroP (124 mg, 0.26 mmol), and intermediate 1-5 (100 mg, 0.24 mmol) were added to a THF solution of compound 20-6 (122 mg, 0.28 mmol). The mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1) to give compound 20 (32 mg, yield 16%) as a white solid. LC-MS (ESI): m / z = 825.36 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 11.47–11.28 (m, 1H), 8.14–8.02 (m, 1H), 7.64–7.37 (m, 5H), 7.29–7.23 (m, 1H), 7.22–7.08 (m, 1H), 6.82–6.66 (m, 1H), 5.94–5.30 (m, 1H), 4.93–4.39 (m, 1H), 4.15–4.03 (m, 3H) ),4.03–3.93(m,1H)3.90–3.76(m,2H),3.66–3.26(m,1H),3.08–2.92(m,2H),2.42–2.26(m,6H) ,1.96–1.82(m,2H),1.80–1.72(m,4H),1.45–1.40(m,1H),1.36–1.31(m,3H),1.30–1.22(m,9H).

[0298] Example 21: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)-4,5,6,7-tetrahydro-2Hpyrazolo[4,3]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0299] Step 1: Synthesis of 5-azido-1-methyl-1H-indazole

[0300] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)-1H-indazole (516 mg, 2.0 mmol) was dissolved in methanol (10 mL), and then azidotrimethylsilane (345 mg, 3.0 mmol), cuprous chloride (20 mg, 0.2 mmol), and tetrabutylammonium fluoride solution (3 mL, 1 mmol / L THF solution) were added. The mixture was stirred in an oil bath at 65 °C for 8 h. The reaction was confirmed to be complete by TLC. After concentration under reduced pressure and purification by column chromatography (petroleum ether / ethyl acetate = 20:1), compound 21-1 (322 mg, yield 92.5%) was given as a yellow solid. LC-MS (ESI): m / z = 174.07 [M+H] + .

[0301] Step 2: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0302] Compound 21-1 (261 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL), and intermediate 20-4 (3.65 g, 12 mmol), cuprous iodide (95 mg, 0.5 mmol), and triethylamine (303 mg, 3.0 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction was confirmed to be complete by TLC. The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 21-2 (694 mg, yield 83.1%) as a white solid. LC-MS (ESI): m / z = 557.27 [M+H] + .

[0303] Step 3: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

[0304] Compound 21-2 (278 mg, 0.5 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 21-3 (163 mg, yield 72.3%) as a yellow solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 457.22 [M+H] + .

[0305] Step 4: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)-4,5,6,7-tetrahydro-2Hpyrazolo[4,3]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0306] Compound 21-3 (91 mg, 0.2 mmol) was dissolved in acetonitrile (10 mL), and tripyrrolidinyl phosphonium hexafluorophosphate bromide (187 mg, 0.4 mmol), intermediate 1-5 (82 mg, 0.2 mmol), and N,N-diisopropylethylamine (77 mg, 0.6 mmol) were added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. After concentration under reduced pressure and purification by column chromatography (dichloromethane / methanol = 30:1), compound 21 (110 mg, yield 66.3%) was given as a white solid. LC-MS (ESI): m / z = 850.39 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ11.84(s,1H),8.75(s,1H),8.33–8.13(m,2H),7.91(m,2H),7.5 5(s,1H),7.41(m,1H),7.26(m,1H),7.19(m,2H),6.97(s,1H),5.76(m,1H),4.76–4.29(m ,1H),4.10(m,3H),4.02(m,1H),3.72(m,2H),3.28–2.96(m,2H),2.91(m,1H),2.21(s,6 H),1.99(s,1H),1.84–1.64(m,4H),1.54(m,2H),1.47(m,3H),1.26(m,3H),1.17(m,6H).

[0307] Example 22: Synthesis of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)indololin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0308] Step 1: Synthesis of methyl 1-(cyanomethyl)indoline-2-carboxylate

[0309] Methyl indoline-2-carboxylate (1.20 g, 6.77 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of cesium carbonate (4.41 g, 13.54 mmol), potassium iodide (1.12 g, 6.77 mmol), and bromoacetonitrile (1.62 g, 13.54 mmol). The mixture was heated and stirred overnight at 80 °C. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 22-1 (1.3 g, yield 89.0%) as a white solid. LC-MS (ESI): m / z = 217.09 [M+H] + .

[0310] Step 2: Synthesis of methyl 5-bromo-1-(cyanomethyl)indoline-2-carboxylate

[0311] Compound 22-1 (1.30 g, 6.01 mmol) was dissolved in tetrahydrofuran (10 mL), and NBS (1.28 g, 7.21 mmol) was added. The mixture was stirred at room temperature for 4 h, and the reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 22-2 (1.67 g, yield 94.4%) as a white solid. LC-MS (ESI): m / z = 295.00 [M+H] + .

[0312] Step 3: Synthesis of methyl 1-cyanomethyl-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoline-2-carboxylate

[0313] Following the synthetic method of intermediates 1-4, the only difference was that ethyl 5-bromoindole-2-carboxylate was substituted for compound 22-2 in step 3. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 22-3 (yield 85.6%), a pale yellow oil. LC-MS (ESI): m / z = 329.18 [M+H] + .

[0314] Step 4: Synthesis of 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoline-2-carboxylic acid

[0315] Compound 22-3 (1.3 g, 3.96 mmol) and 1,5,7-triazabicyclo[4.4.0]-5-decene (1.1 g, 7.92 mmol) were dissolved in 20 mL of acetonitrile and 4 mL of water, and reacted at room temperature for 4 h. The reaction was confirmed to be complete by TLC. 2 M dilute hydrochloric acid was added dropwise to adjust the acidity to pH = 1, and a white precipitate was observed. The precipitate was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 22-4 (1.22 g, yield 98.4%) as a pale yellow solid. No purification was required, and the crude product was used directly in the next reaction. LC-MS (ESI): m / z = 315.16 [M+H] + .

[0316] Step 5: Synthesis of 1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoline-2-carboxylic acid

[0317] Compound 22-4 (1.22 g, 3.88 mmol), intermediate 1-2 (1.9 g, 3.88 mmol), and PyBrop (2.72 g, 5.82 mmol) were weighed into a flask, dissolved in anhydrous THF, and then DIPEA (3.01 g, 23.29 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2:1) to give compound 22-5 (3.01 g, yield 98.7%) as a white solid. LC-MS (ESI): m / z = 786.36 [M+H] + .

[0318] Step 6: Synthesis of (2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)indoline-1-yl)-2-methylcyclopropane-1-carboxylonitrile

[0319] Compound 22-5 (2 g, 2.54 mmol) was weighed into a double-necked flask, purged three times with nitrogen, and then dissolved in DMPU. After cooling to below 0°C on ice, a solution of (4R)-4-methyl-1,3,2-dioxathiapentane (703.08 mg, 5.09 mmol) in DMPU was injected, followed by slow injection of KHMDS (4.09 g, 20.36 mmol). The reaction was allowed to proceed overnight. The reaction mixture was extracted (ethyl acetate / petroleum ether = 3:1), the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2:1) to give compound 22-6 (1.6 g, yield 85.7%) as a white solid. LC-MS (ESI): m / z = 826.39 [M+H] + .

[0320] Step 7: Synthesis of (2S,E)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)indoline-1-yl)-N'-hydroxy-2-methylcyclopropane-1-formamidin

[0321] Compound 22-6 (1.6 g, 1.94 mmol) was dissolved in DMSO, and 50% hydroxylamine aqueous solution (1.28 g, 19.37 mmol) was added dropwise. The mixture was heated and stirred at 70 °C for 6 h. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2:1) to give compound 22-7 (1.47 g, yield 88.6%) as a white solid. LC-MS (ESI): m / z = 859.41 [M+H] + .

[0322] Step 8: Synthesis of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)indololin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0323] Compound 22-7 (1.47 g, 1.71 mmol), CDI (554.98 mg, 3.42 mmol), and DBU (651.33 mg, 4.28 mmol) were weighed into a flask, dissolved in anhydrous DMSO, and heated and stirred at 80 °C for 5 h. The reaction mixture was then diluted with water and the pH was adjusted to neutral with 1 M hydrochloric acid. Extraction was performed with ethyl acetate, and the ethyl acetate layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0.025:1 to 0.03:1). The crude product was recrystallized from dichloromethane and n-hexane to give compound 22 (1.49 g, yield 98.7%) as a white solid. LC-MS (ESI): m / z = 885.39 [M+H] + . 1 H NMR (300MHz, chloroform-d) δ11.89–11.27(m,1H),8.21–8.05(m,1H),7.66–7.30(m ,2H),7.28–7.07(m,3H),6.99–6.87(m,1H),6.60(m,1H),6.42–6.01(m,1H) ,5.98–5.46(m,1H),5.05–4.62(m,1H),4.28–3.96(m,4H),3.91–3.47(m,4 H),3.47–2.99(m,4H),2.32(m,6H),1.66(m,3H),1.54–1.41(m,4H),1.29(m 9H),1.10(m,1H),1.05–0.69(m,3H).

[0324] Example 23: Synthesis of 3-((1S,2S)-1-((2S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)indololin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0325] Following the synthetic route of Example 22, the only difference being that methyl indoline-2-carboxylate in step 1 was replaced with (S)-indoline-2-carboxylate, yielding compound 23, a white solid. LC-MS (ESI): m / z = 885.39 [M+H] + . 1¹H NMR (300 MHz, chloroform-d) δ 8.22–8.04 (m, 1H), 7.46 (m, 1H), 7.20–7.09 (m, 2H), 7.05–6.79 (m, 2H), 6.66–6.41 (m, 2H), 6.40–6.28 (m, 1H), 6.26–6.07 (m, 1H), 4.93 (m, 1H), 4.16–4.08 (m ,3H),4.08–3.93(m,1H),3.82–3.45(m,4H),3.15(m,2H),3.09–2.77(m,4H),2.29(m,6H ),1.57(m,4H),1.47(m,3H),1.41–1.35(m,3H),1.32(m,3H),1.27(m,3H),1.22(m,2H).

[0326] Example 24: Synthesis of (S)-2-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-acetonitrile

[0327] Step 1: Synthesis of 2-(4-iodo-2-nitrophenyl)amino)acetonitrile

[0328] 2-Fluoro-5-iodonitrobenzene (2.67 g, 10.0 mmol) was dissolved in 1,4-dioxane (20 mL), and aminoacetonitrile hydrochloride (1.85 g, 20.0 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) were added. The mixture was stirred in an oil bath at 80 °C for 8 h. The reaction was confirmed to be complete by TLC. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / dichloromethane = 1:1 to 1:5) to give compound 24-1 (2.56 g, yield 84.3%) as an orange solid. LC-MS (ESI): m / z = 303.95 [M+H] + .

[0329] Step 2: Synthesis of 2-((2-nitro-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)acetonitrile

[0330] Compound 24-1 (2.43 g, 8.0 mmol) was dissolved in N,N-dimethylformamide (15 mL), and prepared (tetrahydro-2H-pyran-4-yl)zinc iodide (3.31 g, 12 mmol), palladium acetate (104 mg, 0.4 mmol), and (4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine (213 mg, 0.8 mmol) were added. The mixture was stirred for 4 h under nitrogen protection in an oil bath at 75 °C. The reaction was confirmed to be complete by TLC. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 24-2 (1.80 g, yield 85.9%) as an orange solid. LC-MS (ESI): m / z = 262.11 [M+H] + .

[0331] Step 3: Synthesis of 2-((2-amino-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)acetonitrile

[0332] Compound 24-2 (1.31 g, 5.0 mmol) was dissolved in a mixed solution of ethanol (30 mL) and water (15 mL). Iron powder (560 mg, 10 mmol) and ammonium chloride (1.07 g, 100 mmol) were added, and the mixture was stirred in an oil bath at 80 °C for 12 h. The reaction was confirmed to be complete by TLC. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 24-3 (1.08 g, yield 92.7%) as a yellow solid. LC-MS (ESI): m / z = 232.14 [M+H] + .

[0333] Step 4: Synthesis of ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazolium-2-carboxylate

[0334] Compound 24-3 (928 mg, 4.0 mmol) was dissolved in tetrahydrofuran (20 mL), and ethyl glyoxylate (449 mg, 4.4 mmol) and p-toluenesulfonic acid monohydrate (76 mg, 0.4 mmol) were added. The mixture was stirred in an oil bath at 60 °C for 6 h. The reaction was confirmed to be complete by TLC. The solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 24-4 (753 mg, yield 59.9%) as a pale yellow solid. LC-MS (ESI): m / z = 314.14 [M+H] + .

[0335] Step 5: Synthesis of 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-carboxylic acid

[0336] Compound 24-4 (628 mg, 2.0 mmol) was dissolved in a mixture of acetonitrile (20 mL) and water (5 mL), and 1,5,7-triazabicyclo[4.4.0]-5-decene (417 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 8 h. 2 M dilute hydrochloric acid was added dropwise to adjust the acidity to pH 5. The mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 24-5 as a yellow solid. The crude product was used directly in the next reaction step.

[0337] Step 6: Synthesis of (S)-2-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-acetonitrile

[0338] To a 15 mL solution of crude compound 24-5 in acetonitrile, tripyrrolidinylphosphonium hexafluorophosphate (933 mg, 2.0 mmol), intermediate 1-2 (489 mg, 1.0 mmol), and N,N-diisopropylethylamine (385 mg, 3.0 mmol) were added, and the mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 30:1) to give compound 24 (143 mg) as a white solid. LC-MS (ESI): m / z = 757.31 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.30(m,1H),7.76(m,1H),7.67–7.63(m,1H),7.57(m,1H),7.5 3–7.45(m,1H),7.41–7.35(m,1H),7.33–7.29(m,1H),7.16(m,2H),7.09(m,1H),5.66(m ,1H),5.13–4.89(m,2H),4.81–4.57(m,1H),4.10(s,3H),4.04–3.93(m,2H),3.52–3.44 (m,2H),3.02(m,2H),2.90(m,1H),2.80(m,1H),2.24(m,6H),1.75(m,4H),1.43(m,3H).

[0339] Example 25: Synthesis of 2-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)indoline-1-yl)acetonitrile

[0340] Following the synthetic route of Example 22, the only difference being that in step 3, 4-iodo-2,2-dimethyltetrahydro-2H-pyran was replaced with 4-iodotetrahydropyran, yielding compound 25, a white solid. LC-MS (ESI): m / z = 758.33 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ8.36–8.23(s,1H),7.67–7.56(s,1H),7.46(s,1H),7.16(m ,2H),7.10–6.95(m,3H),6.94–6.84(m,1H),6.72–6.63(m,1H),5.62–5.42(m,1H),4 .75–4.56(m,2H),4.21–4.13(m,1H),4.10(m,3H),3.93(m,2H),3.66–3.38(m,4H), 3.01(m,1H),2.94–2.60(m,4H),2.31–2.23(m,6H),1.63(m,4H),1.40–1.19(m,3H).

[0341] Example 26: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)thiourea

[0342] Step 1: Synthesis of tert-butyl (4-fluoro-1-methyl-1H-indolezol-5-yl)carbamate

[0343] 5-Bromo-4-fluoro-1-methyl-1H-indazole (1.00 g, 4.37 mmol), tert-butyl carbamate (613.74 mg, 5.24 mmol), tris(dibenzylacetone)palladium (399.79 mg, 0.436 mmol), Xantphos (505.24 mg, 0.873 mmol), and cesium carbonate (4.27 g, 13.10 mmol) were weighed into a flask, and anhydrous dioxane (20 mL) was added. The mixture was heated overnight at 100 °C under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to give compound 26-1 (800 mg, yield 69.0%) as a yellow solid. LC-MS (ESI): m / z = 266.12 [M+H] + .

[0344] Step 2: Synthesis of 4-fluoro-1-methyl-1H-indolezol-5-amine

[0345] Compound 26-1 (800 mg, 3.02 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 26-2 (483 mg, 97.0% yield) as a brown solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 166.07 [M+H] + .

[0346] Step 3: Synthesis of 4-fluoro-5-isothiocyano-1-methyl-1H-indazole

[0347] Compound 26-2 (483 mg, 2.92 mmol) was dissolved in tetrahydrofuran, followed by the sequential addition of carbon disulfide (2.23 g, 29.24 mmol) and triethylamine (355.10 mg, 3.51 mmol). The mixture was stirred at room temperature for 1–2 h, during which solid precipitation was observed. Then, di-tert-butyl dicarbonate (638.21 mg, 2.92 mmol) and 4-dimethylaminopyridine (35.73 mg, 292.42 μmol) were added, and the mixture was stirred at room temperature for another 4–6 h. The solid gradually dissolved, and bubbles were released. The reaction mixture was directly concentrated under reduced pressure to obtain compound 26-3, which was used in the next reaction. LC-MS (ESI): m / z = 208.03 [M+H] + .

[0348] Step 4: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)thiourea)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0349] Intermediate 2d (725.82 mg, 1.94 mmol) was dissolved in N,N-dimethylacetamide, and potassium tert-butoxide (435.01 mg, 3.88 mmol) and compound 26-3 (482 mg, 2.33 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 26-4 (667 mg, yield 59.1%) as a brown solid. LC-MS (ESI): m / z = 582.24 [M+H] + .

[0350] Step 5: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indoleazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)thiourea

[0351] Compound 26-4 (667 mg, 1.15 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 26-5 (550 mg, 99.8% yield) as a brown solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 482.19 [M+H] + .

[0352] Step 6: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)thiourea

[0353] Compound 26-5 (550 mg, 1.14 mmol), intermediate 1-5 (391.60 mg, 951.75 μmol), and HATU (434.27 mg, 1.14 mmol) were dissolved in tetrahydrofuran (15 mL), and DIPEA (295.23 mg, 2.28 mmol) was added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 26 (645 mg, yield 77.5%) as a white solid. LC-MS (ESI): m / z = 875.35 [M+H] + . 1 H NMR (300MHz, chloroform-d) δ11.50(s,1H),8.05(s,1H),7.93(s 1H),7.73(m,2H),7.55(s,2H),7.20–7.09(m,2H),6.99(s,1H),5.94–5.67(m,1H),4.32(m 3H),4.04(m,3H),3.87(m,2H),3.68–3.26(m,2H),2.99(m,4H),2.31(m,6H ),1.46(m,5H),1.35(s,3H),1.29(s,3H),1.25–1.19(m,3H),0.99(m,3H).

[0354] Example 27: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indoleazol-5-yl)thiourea

[0355] Following the synthetic route of Example 26, the only difference being that 5-bromo-4-fluoro-1-methyl-1H-indazole in step 1 was replaced with 5-bromo-1-methyl-1H-indazole, yielding compound 27, a white solid. LC-MS (ESI): m / z = 857.36 [M+H] + . 1H NMR (300MHz, chloroform-d) δ11.47(m,1H),8.23(m,1H),7.88(m,1H),7.57(m,1H),7.53(m,2H),7.40–7.32(m,1H),7.25(m,2 H),7.22–7.16(m,1H),7.12(m,1H),6.95(m,1H),6.70(m,1H),5.69(m,1H),4.61(m,1H),4.01(m,3H),3.86(m,2H),3 .65–3.26(m,1H),3.16–2.98(m,2H),2.92(m,1H),2.34(m,6H),1.94–1.87(m,1H),1.83–1.77(m,2H),1.75(m,2H),1 .70(m,1H),1.62(m,3H),1.58–1.54(m,1H),1.36(m,3H),1.30(m,3H),1.21(d,J=5.5Hz,2H),1.02(d,J=6.3Hz,1H).

[0356] Example 28: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)guanidine

[0357] Step 1: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)guanidinyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0358] Compound 26-4 (1.00 g, 1.72 mmol) and EDCI (659.13 mg, 3.44 mmol) were dissolved in dichloromethane. DIPEA (888.77 mg, 6.88 mmol) and ammonia-methanol solution (58.56 mg, 3.44 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3:1) to give compound 28-1 (867 mg, yield 87.2%) as a white solid. LC-MS (ESI): m / z = 565.28 [M+H] + .

[0359] Step 2: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)guanidine

[0360] Compound 28-1 (867 mg, 1.54 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 28-2 (710 mg, 99.5% yield) as a brown solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 465.22 [M+H] + .

[0361] Step 3: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)guanidine

[0362] Compound 28-2 (710 mg, 1.47 mmol), intermediate 1-5 (505.53 mg, 1.23 mmol), and HATU (560.6 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (6 mL), and DIPEA (381.11 mg, 2.95 mmol) was added. The mixture was stirred at room temperature for 8 h. The reaction was monitored by TLC until complete. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 28 (875 mg, yield 81.1%) as a white solid. LC-MS (ESI): m / z = 858.39 [M+H] + . 1¹H NMR (300 MHz, chloroform-d) δ 7.99 (s, ¹H), 7.56 (s, ¹H), 7.49 (s, ¹H), 7.43 (s, ¹H), 7.28 (s, ¹H), 7.22 (m, ¹H), 7.14 (m) 1H),6.66(s,1H),5.67(m,1H),4.88(m,2H),4.37(s,1H),4.03(s,3H),3.98(s,1H),3.83(m,2H),3.53(s,1H),3.08–2.84(m ,4H),2.21(m,6H),1.90(s,1H),1.73(s,3H),1.64(m,2H),1.54(m,4H),1.33(s,3H),1.27(m,3H),1.21(s,3H),1.03(m,1H).

[0363] Example 29: Synthesis of (E)-1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-methylguanidine

[0364] Following the synthetic route of Example 28, except that the ammonia-methanol solution in step 1 was replaced with methylamine hydrochloride, compound 29 was obtained as a white solid. LC-MS (ESI): m / z = 872.41 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 11.62 (s, ¹H), 7.89 (s, ¹H), 7.66–7.48 (m, 2H), 7.41 (m, 2H), 7.28 (m, 2H), 6.74 (s, ¹H), 6.59–6.14 (m, ¹H), 5.76 (m, ¹H), 5.35 (m, ¹H), 4.87 (m, ¹H), 4.38 ( m,1H),4.04(s,3H),3.88(m,2H),3.75–3.47(m,1H),3.19–2.99(m,2H),2.86(m,4H), 2.30(m,6H),2.01–1.64(m,6H),1.58(s,3H),1.36(s,3H),1.26(m,6H),1.06(m,1H).

[0365] Example 30: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0366] Step 1: Synthesis of 4-(benzylthio)-1H-1,2,3-triazole

[0367] Benzyl bromide (14.58 g, 85.2 mmol) was slowly added dropwise to a solution of 10 g (79.9 mmol) of 5-mercapto-1,2,3-triazole monosodium salt in 100 mL of ethanol at 0 °C. The reaction mixture was stirred at room temperature for 30 min, concentrated under reduced pressure, and extracted with ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded crude compound 30-2 (17.11 g) as a pale yellow solid, which was used directly in the next step. LC-MS (ESI): m / z = 192.15 [M+H] + .

[0368] Step 2: Synthesis of 4-(benzylthio)-2-methyl-2H-1,2,3-triazole, 5-(benzylthio)-1-methyl-1H-1,2,3-triazole and 4-(benzylthio)-1-methyl-1H-1,2,3-triazole

[0369] The crude compound 30-2 (17.11 g) was dissolved in THF (40 mL), and potassium carbonate (24.7 g, 178.9 mmol) and methyl iodide (178.9 mmol) were added. The mixture was stirred at room temperature for 6 h. The reaction mixture was extracted with water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride solution (40 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:10 to 1:1) to give compound 30-3 (2.91 g, colorless liquid, petroleum ether / ethyl acetate = 1:5), LC-MS (ESI): m / z = 206.07 [M+H]. + Compound 30-4 (4.76 g, colorless liquid, petroleum ether / ethyl acetate = 1:2), LC-MS (ESI): m / z = 206.07 [M+H] +Compound 30-5 (5.63 g, pale yellow liquid, petroleum ether / ethyl acetate = 1:1), LC-MS (ESI): m / z = 206.07 [M+H] + .

[0370] Step 3: Synthesis of 1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride

[0371] N-chlorosuccinimide (11.8 g, 88.36 mmol) was added in portions over 10 min to a mixture of acetic acid / water (20 mL / 10 mL) containing compound 30-5 (4.59 g, 22.35 mmol), and the mixture was stirred at room temperature for 3 h. The reaction mixture was extracted with ethyl acetate (50 mL) and water (50 mL), the organic phase was washed with saturated sodium bicarbonate solution (20 mL) and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:5 to 1:3) to give compound 30-6 (3.36 g, 82% yield) as a white solid. LC-MS (ESI): m / z = 181.97 [M+H] + .

[0372] Step 4: Synthesis of ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carboxylate

[0373] NaH (120 mg, 3 mmol, 60% dispersion in mineral oil) was added to a 7 mL anhydrous THF solution of compound 4d (301 mg, 1 mmol) at 0 °C. After reacting for 15 min at 0 °C, anhydrous pyridine (158.2 mg, 2 mmol) and a 5 mL anhydrous THF solution of compound 30-6 (363 mg, 2 mmol) were added to the reaction mixture. The mixture was then allowed to react at room temperature for 6 h. The reaction mixture was extracted with ethyl acetate (15 mL) and water (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3 to 1:1) to give compound 30-7 (83 mg, yield 18.6%) as a white solid. LC-MS (ESI): m / z = 447.00 [M+H] + .

[0374] Step 5: Synthesis of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carboxylic acid

[0375] Following the synthetic route of Example 1, only compound 1-A in step 2 was replaced with compound 30-7 to obtain compound 30-8 (73 mg), a white solid, which was directly used in the next step. LC-MS (ESI): m / z = 419.13 [M+H] + .

[0376] Step 6: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0377] Following the synthetic route of Example 1, only compound 1-B in step 3 was replaced with compound 30-8, yielding compound 30 (118 mg, yield 75.8%), a white solid. LC-MS (ESI): m / z = 890.30 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 8.46 (s, ¹H), 8.20 (m, ¹H), 8.14–8.05 (m, ¹H), 7.50–7.41 (m, ¹H), 7.41–7.35 (m, ¹H), 7.34–7.24 (m, 2H), 7.20–7.10 (m, 2H), 6.70–6.62 (m, ¹H), 6.60–6.42 (m, ¹H), 6.35–6.19 (m, ¹H) ,5.92–4.88(m,1H),4.19–4.02(m,7H),3.91–3.74(m,2H),3.70–3.53(m,1H),3.14–2.78(m,3H),2. 30–2.23(m,6H),1.77–1.71(m,4H),1.58–1.52(m,3H),1.32(d,J=5.0Hz,3H),1.26(d,J=5.7Hz,3H).

[0378] Example 31: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0379] Step 1: Synthesis of 1-methyl-1H-1,2,3-triazol-5-sulfonyl chloride

[0380] Following the synthesis described in Example 30, only compound 30-5 in step 3 was replaced with compound 30-4 to obtain compound 31-2. LC-MS (ESI): m / z = 181.97 [M+H] + .

[0381] Step 2: Synthesis of ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1H-indole-2-carboxylate

[0382] Following the synthesis described in Example 30, only compound 30-6 in step 4 was replaced with compound 31-2 to obtain compound 31-3 (38 mg), a white solid. LC-MS (ESI): m / z = 447.25 [M+H] + .

[0383] Step 3: Synthesis of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1H-indole-2-carboxylic acid

[0384] Following the synthesis described in Example 30, only compound 30-7 in step 5 was replaced with compound 31-3 to obtain compound 31-4 (34 mg), a white solid, which was used directly in the next step. LC-MS (ESI): m / z = 419.13 [M+H] + .

[0385] Step 4: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0386] Following the synthesis described in Example 30, only compounds 30-8 in step 6 were replaced with compounds 31-4, yielding compound 31 (20 mg, yield 24.7%), a white solid. LC-MS (ESI): m / z = 890.15 [M+H] + . 1¹H NMR (300MHz, chloroform-d) δ 8.21–8.14 (m, 1H), 8.13–8.04 (m, 1H), 7.94–7.81 (m, 1H), 7.54–7.41 (m, 2H), 7.36–7.23 (m, 2H), 7.19–7.09 (m, 2H), 6.84–6.74 (m, 1H), 6.61–6.42 (m, 1H), 6.34–6.18 (m, 1H), 5.87–4.88 ( m,1H),4.33–4.26(m,3H),4.14–4.04(m,3H),3.95–3.78(m,3H),3.68–3.53(m,1H),3.10–2.97(m,1H), 2.94–2.75(m,2H),2.28–2.23(m,6H),1.80–1.69(m,4H),1.56–1.46(m,3H),1.28(m,3H),1.25(m,3H).

[0387] Example 32: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0388] Step 1: Synthesis of 2-methyl-2H-1,2,3-triazol-4-sulfonyl chloride

[0389] Following the synthesis described in Example 30, only compound 30-5 in step 3 was replaced with compound 30-3 to obtain compound 32-2. LC-MS (ESI): m / z = 181.97 [M+H] + .

[0390] Step 2: Synthesis of ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carboxylate

[0391] Following the synthesis described in Example 30, but replacing compound 30-6 in step 4 with compound 32-2, compound 32-3 (103 mg, yield 34.7%) was obtained as a white solid. LC-MS (ESI): m / z = 447.25 [M+H] + .

[0392] Step 3: Synthesis of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carboxylic acid

[0393] Following the synthesis described in Example 30, only compound 30-7 in step 5 was replaced with compound 32-3 to obtain compound 31-4 (92 mg), a white solid, which was used directly in the next step. LC-MS (ESI): m / z = 419.13 [M+H] + .

[0394] Step 4: Synthesis of 1-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0395] Following the synthesis described in Example 30, only compounds 30-8 in step 6 were replaced with compounds 32-4, yielding compound 32 (42 mg, yield 21.4%) as a white solid. LC-MS (ESI): m / z = 890.35 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 8.22 (s, 1H), 8.09 (m, 2H), 7.55–7.39 (m, 2H), 7.36–7.24 (m, 2H), 7.17–7.10 (m, 2H), 6.72–6.64 (m, 1H), 6.62–6.43 (m, 1H), 6.38–6.16 (m, 1H), 5.91–4.91 (m, 1H) H),4.20(m,3H),4.11(s,3H),4.07(s,1H),3.92–3.76(m,2H),3.71–3.54(m,1H),3.16–2 .78(m,3H),2.26(m,6H),1.73–1.64(m,4H),1.60–1.53(m,3H),1.32(m,3H),1.27(m,3H).

[0396] Example 33: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-5-oxo-2-thioimidazolidine-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0397] Step 1: Synthesis of 5-isothiocyano-1-methyl-1H-indazole

[0398] 1-Methyl-1H-indazole-5-amine (735 mg, 5.0 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the sequential addition of carbon disulfide (3.81 g, 50 mmol) and triethylamine (759 mg, 7.5 mmol). The mixture was stirred at room temperature for 2 h, and solid precipitation was observed. Then, di-tert-butyl dicarbonate (1.09 g, 5.0 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for another 6 h. The solid gradually dissolved, and bubbles were released. The reaction solution was concentrated under reduced pressure to give compound 33-1, which was directly used in the next reaction. LC-MS (ESI): m / z = 190.04 [M+H] + .

[0399] Step 2: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)thiourea)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0400] Intermediate 2d (1.5 g, 4.0 mmol) was dissolved in N,N-dimethylacetamide, followed by the addition of potassium tert-butoxide (672 mg, 6.0 mmol) and the unpurified compound 33-1 from the previous step. The mixture was stirred at room temperature for 4 h. Water (100 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (30 × 3 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3 to 1:1) to give compound 33-2 (1.54 g, yield 68.3%) as a yellow solid. LC-MS (ESI): m / z = 564.25 [M+H] + .

[0401] Step 3: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-5-oxo-2-thioimidazolidine-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester and (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-4-oxo-2-thioimidazolidine-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0402] Intermediate 33-2 (845 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of triethylamine (455 mg, 4.5 mmol) and chloroacetyl chloride (226 mg, 2.0 mmol), and the mixture was stirred at room temperature for 6 h. Water (100 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (30 × 3 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2 to 1:1) to give compounds 33-3 (224 mg, 24.7% yield) and 33-4 (248 mg, 27.3% yield) as yellow solids. LC-MS (ESI): m / z = 604.24 [M+H] + .

[0403] Step 4: Synthesis of (S)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(1-methyl-1H-indazol-5-yl)-2-thioimidazolidine-4-one

[0404] Compound 33-3 (151 mg, 0.25 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 7-8 with potassium carbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 33-5 (114 mg, 90.8% yield) as a yellow solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 504.19 [M+H] + .

[0405] Step 5: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-5-oxo-2-thioimidazolidine-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0406] Compound 33-5 (114 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (103 mg, 0.27 mmol), intermediate 1-5 (91 mg, 0.22 mmol), and N,N-diisopropylethylamine (114 mg, 0.88 mmol) were added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:2) to give compound 33 (45 mg, yield 22.8%) as a white solid. LC-MS (ESI): m / z = 897.35 [M+H] + . 1 H NMR (300MHz, chloroform-d) δ11.45(m,1H),8.01(m,1H),7.62(m,1H),7.51(s,1H),7.37(m,1H),7.27–7.25 (m,2H),7.18(m,1H),7.17(m,1H),7.12(m,1H),6.74(m,1H),4.80(m,1H),4.57(m,1H),4.26(m,1H) ,4.07(m,3H),3.86–3.81(m,2H),3.53(s,2H),3.03–2.95(m,2H),2.85(m,1H),2.23(m,6H),1.91( m,1H),1.85(m,2H),1.74(m,2H),1.54(m,3H),1.43(s,2H),1.37(m,3H),1.31(s,3H),1.24(s,3H).

[0407] Example 34: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-4-oxo-2-thioimidazolidine-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0408] Following the synthesis of Example 33, only the compound 33-3 in step 4 was replaced with compound 33-4 to obtain compound 34 (37 mg), which is a white solid. 1 ¹H NMR (300 MHz, chloroform-d) δ 11.69 (m, 1H), 8.11 (m, 1H), 7.60 (m, 1H), 7.53 (m, 1H), 7.40–7.30 (m, 1H), 7.27–7.23 (m, 2H), 7.22 (m, 1H), 7.20–7.16 (m, 1H), 7.13 (m, 1H), 6.73 (m, 1H), 5.87 (m, 1H), 5.45 (m, 1H), 5. 38–5.12(m,1H),4.12(m,3H),3.89(m,2H),3.50(s,2H),3.06(m,2H),2.90(m,1H),2.28(m,6H),1.93 (m,1H),1.81(m,2H),1.74(m,2H),1.57(m,3H),1.44(m,2H),1.36(s,3H),1.30(s,3H),1.25(m,3H).

[0409] Example 35: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-4-oxo-2-thioimidazolidine-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0410] Step 1: Synthesis of 2-isothiocyano-1,1-dimethoxyethane

[0411] 2,2-Dimethoxyethane-1-amine (525 mg, 5.0 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of carbon disulfide (3.81 g, 50 mmol) and triethylamine (759 mg, 7.5 mmol). The mixture was stirred at room temperature for 2 h, and a solid precipitated. Then, di-tert-butyl dicarbonate (1.09 g, 5.0 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for 6 h. The solid gradually dissolved, and bubbles were released. The reaction solution was concentrated under reduced pressure to give compound 35-1, which was used directly in the next reaction. LC-MS (ESI): m / z = 148.03 [M+H] + .

[0412] Step 2: Synthesis of (S)-3-(3-(2,2-dimethoxyethyl)thiourea)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0413] Intermediate 2d (1.5 g, 4.0 mmol) was dissolved in N,N-dimethylacetamide, followed by the addition of potassium tert-butoxide (672 mg, 6.0 mmol) and the unpurified compound 35-1 from the previous step. The mixture was stirred at room temperature for 4 h. Water (100 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (30 × 3 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3 to 1:1) to give compound 35-2 (1.91 g, 91.8% yield) as a yellow solid. LC-MS (ESI): m / z = 522.25 [M+H] + .

[0414] Step 3: Synthesis of (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(5-methoxy-2-thioimidazolidine-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0415] Methylsulfonic acid (662 mg, 6.9 mmol) was added to a THF (20 mL) solution of compound 35-2 (1.8 g, 3.45 mmol), and the mixture was heated under reflux for 4 h. After cooling to room temperature, a saturated aqueous solution of potassium carbonate was added dropwise to adjust the pH to 10. Ethyl acetate (30 mL × 2) was added for extraction, and the ethyl acetate layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5:1 to 1:2) to give compound 35-3 (1.49 g, yield 88.4%) as a pale yellow solid. LC-MS (ESI): m / z = 490.22 [M+H] + .

[0416] Step 4: Synthesis of (4S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methoxy-2-thioimidazolidine-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0417] Cuprous iodide (29 mg, 0.15 mmol) was added to an NMP (8 mL) solution of compound 35-3 (735 mg, 1.5 mmol), 5-bromo-4-fluoro-1-methyl-1-H-indazole (684 mg, 3 mmol), potassium carbonate (621 mg, 4.5 mmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (42.6 mg, 0.3 mmol). The mixture was refluxed at 130 °C under nitrogen for 10 h with stirring. Water (60 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 4 / 1 to 1:1) to give compound 35-4 (663 mg, yield 69.3%) as a light brown solid. LC-MS (ESI): m / z = 638.26 [M+H] + .

[0418] Step 5: Synthesis of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-4-methoxyimidazolidine-2-thione

[0419] Compound 35-4 (191 mg, 0.3 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water (100 mL) was added to the reaction mixture, the pH was adjusted to 7-8 with potassium carbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 35-5 (150 mg, 93.3% yield) as a yellow solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 538.21 [M+H] + .

[0420] Step 6: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-5-oxo-2-thioimidazolidine-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0421] Compound 35-5 (150 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (5 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (129 mg, 0.34 mmol), intermediate 1-5 (115 mg, 0.28 mmol), and N,N-diisopropylethylamine (145 mg, 1.12 mmol) were added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:2) to give compound 35 (88 mg, yield 33.8%) as a white solid. LC-MS (ESI): m / z = 931.38 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 11.56–11.27 (m, 1H), 8.12–7.90 (m, 1H), 7.66–7.52 (m, 3H), 7.52–7.31 (m, 1H), 7.28–7.24 (m, 1H), 7.24–7.18 (m, 1H), 7.17–7.00 (m, 2H), 6.88–6.74 (m, 1H), 6.74–6.32 (m, 1H), 5.89–5.44 (m, 1H), 4.92–4.39 (m, 1H), 4.18–4.09 (m, 3H), 4.04 (m,1H),3.98–3.76(m,3H),3.76–3.59(m,1H),3.54–3.19(m,2H),3.18–3.08(m,1H),3.07–2.86(m,2H),2.38–2.26(m,6H),1.92( m,1H),1.80(m,2H),1.73(m,2H),1.67(m3H),1.60–1.56(m,1H),1.55–1.49(m,1H),1.36(m,3H),1.30(m,3H),1.27–1.07(m,3H).

[0422] Example 36: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)isoxazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0423] Step 1: Synthesis of (E)-1-methyl-1H-indazole-5-carboxaldehyde oxime

[0424] 1-Methyl-1H-indazole-5-carboxaldehyde (800 mg, 5.0 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of hydroxylamine hydrochloride (522 mg, 7.5 mmol) and triethylamine (1.52 g, 15 mmol). The mixture was stirred at room temperature for 4 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 × 3 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to give compound 36-1 (835 mg, 95.4%) as a pale yellow solid. LC-MS (ESI): m / z = 176.07 [M+H] + .

[0425] Step 2: Synthesis of (Z)-N-hydroxy-1-methyl-1H-indazole-5-carbonimide acyl chloride

[0426] Compound 36-1 (352 mg, 2.0 mmol) was dissolved in tetrahydrofuran (10 mL), and N-chlorosuccinimide (320 mg, 2.4 mmol) was added. The mixture was stirred at room temperature for 6 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 × 3 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound 36-2 (398 mg, yield 94.8%), which was used directly in the next reaction. LC-MS (ESI): m / z = 210.03 [M+H] + .

[0427] Step 3: Synthesis of tert-butyl ((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)isoxazol-5-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid)

[0428] Compound 36-2 (209 mg, 1.0 mmol) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and water (5 mL). Intermediate 20-4 (345 mg, 0.9 mmol), copper sulfate (32 mg, 0.2 mmol), and sodium L-ascorbate (80 mg, 0.4 mmol) were added, and the mixture was stirred at room temperature for 8 h. The reaction was monitored by TLC until complete. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to give compound 36-3 (411 mg, yield 73.8%) as a white solid. LC-MS (ESI): m / z = 557.26 [M+H] + .

[0429] Step 4: Synthesis of (S)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(1-methyl-1H-indazol-5-yl)-2-thioimidazolidine-4-one

[0430] Compound 36-3 (206 mg, 0.5 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water (100 mL) was added to the reaction mixture, and the pH was adjusted to 7-8 with potassium carbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 36-4 (162 mg, yield 71.1%) as a yellow solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 457.21 [M+H] + .

[0431] Step 5: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)isoxazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0432] Compound 36-4 (162 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (5 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (160 mg, 0.42 mmol), intermediate 1-5 (144 mg, 0.35 mmol), and N,N-diisopropylethylamine (181 mg, 1.4 mmol) were added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. After concentration under reduced pressure, the mixture was purified by column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1) to give compound 36 (76 mg, yield 25.6%) as a white solid. LC-MS (ESI): m / z = 850.38 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 11.35 (m, ¹H), 8.13 (s, ¹H), 8.06 (m, ¹H), 7.96–7.88 (m, ¹H), 7.78–7.60 (m, ¹H), 7.59–7.53 (m, 2H), 7.52–7.44 (m, ¹H), 7.28–7.23 (m, ¹H), 7.14 (m, 2H), 6.78 (m, ¹H), 6.29 (m, ¹H), 6.18 (m, ¹H), 5.01–4. 45(m,1H),4.13(m,3H),3.88(m,2H),3.69(m,1H),3.06(m,3H),2.34(m,6H),1.97–1.85(m,2H),1.84–1.78(m ,2H),1.75(m,1H),1.69(m,3H),1.60–1.56(m,1H),1.52–1.40(m,1H),1.36(m,3H),1.31(s,3H),1.27(m,3H).

[0433] Example 37: Synthesis of 1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dimethyl-3-(1-methyl-1H-indazol-5-yl)thiourea

[0434] Step 1: Synthesis of 5-isothiocyano-1-methyl-1H-indazole

[0435] 5-Amino-1-methyl-1H-indazole (441 mg, 3.0 mmol) was dissolved in tetrahydrofuran, followed by the sequential addition of carbon disulfide (2.28 g, 30.0 mmol) and triethylamine (455 mg, 4.5 mmol). The mixture was stirred at room temperature for 1–2 h, and solid precipitation was observed. Then, di-tert-butyl dicarbonate (638.21 mg, 2.92 mmol) and 4-dimethylaminopyridine (36.6 mg, 0.3 mmol) were added, and stirring continued at room temperature for 4–6 h. The solid gradually dissolved, and bubbles were released. The reaction solution was directly concentrated under reduced pressure to obtain compound 37-1, which was used in the next reaction. LC-MS (ESI): m / z = 190.04 [M+H] + .

[0436] Step 2: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)thiourea)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0437] Intermediate 2d (748 mg, 2.0 mmol) was dissolved in N,N-dimethylacetamide, and potassium tert-butoxide (336 mg, 3.0 mmol) and crude compound 37-1 were added. The mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 37-2 (884 mg, yield 78.5%) as a brown solid. LC-MS (ESI): m / z = 564.25 [M+H] + .

[0438] Step 3: Synthesis of (S)-3-(1,3-dimethyl-3-(1-methyl-1H-indazol-5-yl)thiourea)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0439] Intermediate 37-2 (846 mg, 1.5 mmol) was dissolved in anhydrous tetrahydrofuran, and sodium hydride (160 mg 60%, 4.0 mmol) was added. The mixture was stirred at room temperature for 15 min, followed by the addition of iodomethane (568 mg, 4.0 mmol). The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2:1) to give compound 37-3 (638 mg, 72% yield) as a yellow solid. LC-MS (ESI): m / z = 592.28 [M+H] + .

[0440] Step 4: Synthesis of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dimethyl-3-(1-methyl-1H-indazol-5-yl)thiourea

[0441] Compound 37-3 (591 mg, 1.0 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water was added to the reaction solution, the pH was adjusted to 9-10 with potassium carbonate, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 37-4 as an orange solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 492.23 [M+H] + .

[0442] Step 5: Synthesis of 1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dimethyl-3-(1-methyl-1H-indazol-5-yl)thiourea

[0443] The crude compound 37-4, intermediate 1-5 (411 mg, 1.0 mmol), and HATU (456 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 mL), and DIPEA (387 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 6 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1 to 1:2) to give compound 37 (564 mg, yield 63.7%) as a white solid. LC-MS (ESI): m / z = 885.40 [M+H] + . 1¹H NMR (300MHz, chloroform-d) δ 11.53 (m, 1H), 7.90 (m, 1H), 7.65–7.55 (m, 1H), 7.52 (m, 1H), 7.47–7.43 (m, 1H), 7.41–7.33 (m, 2H), 7.30 (m, 1H), 7.27–7.20 (m, 1H), 7.20–7.08 (m, 1H), 6.73 (m, 1H), 5.49 (m, 1H), 4.92–4.30 (m, 1H), 4. 08(m,3H),3.88(m,2H),3.49(m,4H),3.31(m,1H),3.13–2.82(m,3H),2.35(m,6H),1.95(m,3H),1.81(m,2H), 1.74(m,2H),1.71–1.65(m,2H),1.61(m,1H),1.57(m,3H),1.37(m,3H),1.31(m,3H),1.26(m,2H),1.10(m,1H)

[0444] Example 38: Synthesis of N-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methyl-1H-indazole-5-carboxamide

[0445] Step 1: Synthesis of 1-methyl-1H-indazole-5-carboxylic acid

[0446] Lithium hydroxide monohydrate (494 mg, 11.7 mmol) was added to a mixed solution of methyl 1-methyl-1H-indazole-5-carboxylate (1.12 g, 5.88 mmol) in acetonitrile / water (5 mL / 10 mL). The reaction was carried out at room temperature for 6 h, and the reaction was confirmed by TLC. The pH was adjusted to 1 with dilute hydrochloric acid, and the insoluble residue was filtered off and dried to give compound 38-2 (1.03 g, 100% yield) as a white solid. LC-MS (ESI): m / z = 175.10 [MH] - .

[0447] Step 2: Synthesis of 1-methyl-1H-indazole-5-carbonyl chloride

[0448] Compound 38-2 (230 mg, 1.30 mmol) was dissolved in thionyl chloride (4 mL), two drops of anhydrous DMF were added, and the mixture was reacted at 80 °C for 2 h. The mixture was then concentrated under reduced pressure to obtain compound 38-3, which was a light yellow solid and was used directly in the next step.

[0449] Step 3: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-methyl-1H-indazole-5-carboxamido)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0450] Compound 38-3 obtained in the previous step was dissolved in anhydrous DMA (5 mL), and compound 2d (486 mg, 1.29 mmol) and potassium tert-butoxide (290 mg, 2.58 mmol) were added. The mixture was reacted at room temperature for 2 h. Water (30 mL) was added to the reaction solution and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1) to give compound 38-4 (207 mg, yield 29.8%) as a white solid. LC-MS (ESI): m / z = 533.05 [M + H] + .

[0451] Step 4: Synthesis of (S)-N-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methyl-1H-indazole-5-carboxamide

[0452] To a solution of compound 38-4 (201 mg, 0.37 mmol) in dioxane (3 mL), 4 M dioxane hydrochloride (2 mL) was added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC to indicate completion. The reaction solution was concentrated under reduced pressure, water was added, and the pH was adjusted to 10 with saturated sodium carbonate solution. Extraction was performed with dichloromethane (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 38-5 (161 mg, 98.6% yield), which was used directly in the next step. LC-MS (ESI): m / z = 433.05 [M + H] + .

[0453] Step 5: Synthesis of N-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methyl-1H-indazole-5-carboxamide

[0454] Intermediate 1-5 (152 mg, 0.37 μmol), HATU (182 mg, 0.48 mmol), and DIPEA (192 μL) were added to a solution of compound 38-5 in N,N-dimethylformamide (160 mg, 0.36 mmol), and the reaction was carried out at room temperature for 6 h. The reaction was confirmed to be complete by TLC. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (8 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (dichloromethane / methanol = 100:1 to 20:1) to give compound 38 (229 mg, 77% yield) as a white solid. LC-MS (ESI): m / z = 826.10 [M + H] + . 1 H NMR(300MHz,DMSO-d6)δ11.80(s,1H),10.48–10.10(m,1H),8.43(s,1H),8.22(m,1H),7.93(m,1H),7.81–7.61(m ,1H),7.50(m,1H),7.39(m,1H),7.34–7.20(m,3H),6.91(m,1H),5.65–5.14(m,1H),4.68–4.27(m,1H),4.14–3.99 (m,3H),3.79–3.67(m,2H),3.66–3.53(m,1H),3.17(m,1H),3.09–2.93(m,1H),2.91–2.77(m,1H),2.25–2.17(m, 6H),1.79–1.47(m,7H),1.41(m,2H),1.32–1.22(m,4H),1.21–1.15(m,3H),1.14–1.10(m,2H),1.06–1.00(m,1H).

[0455] Example 39: Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-(2-(4-ethyl-5-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-(4-fluoro-3,5-dimethylphenyl)-1H-pyrazol-3-yl)ethyl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indol-2-carboxamide

[0456] Step 1: Synthesis of ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carboxylate

[0457] At 0 °C, NaH (60% dispersion in mineral oil, 82 mg, 2.05 mmol) and intermediate 30-6 (246 mg, 1.35 mmol) were added to an anhydrous tetrahydrofuran (7 mL) solution of compound 1-4 (201 mg, 0.66 mmol), and the reaction was carried out at 0 °C for 6 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3:1 to 1:1) to give compound 39-1 (34 mg, 11.5%) as a white solid. LC-MS (ESI): m / z = 447.25 [M+H] + .

[0458] Step 2: Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carboxylic acid

[0459] 1,5,7-triazabicyclo[4.4.0]dec-5-ene (21.1 mg, 0.15 mmol) was added to a tetrahydrofuran / water (4 mL / 2 mL) mixture of compound 39-1 (34 mg, 0.07 mmol), and the reaction was allowed to proceed overnight at room temperature. 1 M dilute hydrochloric acid (3 mL) was added to the reaction mixture, and the precipitated white solid was filtered off. The filter cake was washed with 1 M hydrochloric acid and dried to give compound 39-2 (28 mg, 88% yield) as a white solid, which was used directly in the next step. LC-MS (ESI): m / z = 419.13 [M+H] + .

[0460] Step 3: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0461] Intermediate 1-2 (39 mg, 0.07 mmol), PyBrop (46 mg, 0.09 mmol), and triethylamine (23 mg, 0.228 mmol) were added to a tetrahydrofuran (5 mL) solution of compound 39-2, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 50:1 to 20:1) to give compound 39. LC-MS (ESI): m / z = 890.30 [M+H] + . 1 ¹H NMR (300 MHz, chloroform-d) δ 8.46 (s, ¹H), 8.20 (m, ¹H), 8.14–8.05 (m, ¹H), 7.50–7.42 (m, ¹H), 7.40 (s, ¹H), 7.35–7.27 (m, 2H), 7.21–7.10 (m, 2H), 6.71–6.61 (m, ¹H), 6.61–6.42 (m, ¹H), 6.36–6.19 (m, 2H). 1H),5.80(s,1H),4.19–4.01(m,7H),3.90–3.79(m,2H),3.68–3.54(m,1H),3.12–2.78(m,3H), 2.31–2.21(m,6H),1.90–1.81(m,4H),1.60–1.51(m,3H),1.34–1.29(m,3H),1.28–1.24(m,3H).

[0462] Example 40: Synthesis of 3-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methyl-1-(1-methyl-1H-indoleazol-5-yl)thiourea

[0463] Step 1: Synthesis of tert-butyl(4-fluoro-1-methyl-1H-indoleazol-5-yl)(methyl)carbamate

[0464] Intermediate 26-1 (800 mg, 3.02 mmol) was dissolved in anhydrous DMF (6 mL). The mixture was placed in an ice bath and cooled to 0 °C. 60% sodium hydride (0.24 g, 6.0 mmol) was added, and the mixture was stirred for 0.5 h. Iodomethane (0.85 g, 6.0 mmol) was then slowly added dropwise. The mixture was then slowly brought to room temperature and stirred for 3 h. After the reaction was complete as monitored by TLC, a saturated sodium thiosulfate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 30) to give compound 40-1 (846 mg, yield 92.1%) as a yellow solid. LC-MS (ESI): m / z = 180.09 [M+H] + .

[0465] Step 2: Synthesis of 4-fluoro-N,1-dimethyl-1H-indolezol-5-amine

[0466] Compound 40-1 (846 mg, 3.03 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was confirmed to be complete by TLC. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 8-9 with potassium hydroxide. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 40-2 (540 mg, 99.8% yield) as a yellow solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 180.09 [M+H] + .

[0467] Step 3: Synthesis of o-phenyl (4-fluoro-1-methyl-1H-indoleazol-5-yl)(methyl)carbamate

[0468] Compound 40-2 (540 mg, 3.01 mmol) was dissolved in acetonitrile (10 mL), and phenyl thiochloroformate (624.23 mg, 3.62 mmol) and pyridine (476.74 mg, 6.03 mmol) were added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1:5) to give compound 40-3 (885.3 mg, yield 93.1%) as a white solid. LC-MS (ESI): m / z = 316.08 [M+H] + .

[0469] Step 4: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indoleazol-5-yl)-3-methylthiourea)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0470] Intermediate 2d (725.82 mg, 1.94 mmol) was dissolved in N,N-dimethylacetamide, and potassium tert-butoxide (435.01 mg, 3.88 mmol) and compound 40-3 (532.1 mg, 2.33 mmol) were added. The mixture was heated and stirred overnight at 80 °C. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 40-4 (721.2 mg, yield 68.3%) as a brown solid. LC-MS (ESI): m / z = 596.25 [M+H] + .

[0471] Step 5: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indoleazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methylthiourea

[0472] Compound 40-4 (721.2 mg, 1.21 mmol) was dissolved in acetonitrile (10 mL). The mixture was placed in an ice bath and cooled to 0 °C. Sodium iodide (272.2 mg, 1.82 mmol) and TMSCl (197.29 mg, 1.82 mmol) were added, followed by slow warming to room temperature and stirring overnight. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 40-5 (586.8 mg, yield 97.8%) as a white solid. LC-MS (ESI): m / z = 496.20 [M+H] + .

[0473] Step 6: Synthesis of 3-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methyl-1-(1-methyl-1H-indoleazol-5-yl)thiourea

[0474] Compound 40-5 (586.8 mg, 1.18 mmol), intermediate 1-5 (403.5 mg, 980.64 μmol), and HATU (434.27 mg, 1.14 mmol) were dissolved in tetrahydrofuran (15 mL), and DIPEA (295.23 mg, 2.28 mmol) was added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 40 (621 mg, yield 77.8%) as a white solid. LC-MS (ESI): m / z = 871.38 [M+H] +.1 ¹H NMR (300 MHz, chloroform-d) δ 11.44 (m, 1H), 7.97 (m, 1H), 7.66–7.47 (m, 3H), 7.41 (s, 1H), 7.17 (m, 2H), 7.03 (m 1H),6.67(m,1H),6.43(m,1H),5.79–5.35(m,1H),4.81–4.32(m,1H),4.11(m,3H),3.89(m,2H),3.76(s,2H),3.53(s ,2H),3.44–3.22(m,1H),2.98(m,3H),2.34(m,6H),1.81(m,3H),1.75–1.62(m,4H),1.57(m,2H),1.37(m,3H),1.30(m 3H),1.28–1.22(m,3H),1.05(m,1H).

[0475] Example 41: Synthesis of 3-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)amino)-4-((1-methyl-1H-indazol-5-yl)amino)cyclobut-3-ene-1,2-dione

[0476] Step 1: Synthesis of (S)-3-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0477] Intermediate 2d (748 mg, 2.0 mmol) was dissolved in N,N-dimethylacetamide, and potassium tert-butoxide (336 mg, 3.0 mmol) and 3,4-diethyl-3-cyclobutyl-1,2-ketophenol (510 mg, 3.0 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 41-1 (805 mg, yield 80.8%) as a yellow solid. LC-MS (ESI): m / z = 499.23 [M+H] + .

[0478] Step 2: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-((2-((1-methyl-1H-indazol-5-yl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0479] Intermediate 41-1 (649 mg, 1.3 mmol) was dissolved in a mixed solvent of toluene (10 mL) and N,N-dimethylacetamide (1 mL), and 5-amino-1-methyl-1H-indazole (221 mg, 1.5 mmol) and zinc trifluoromethanesulfonate (73 mg, 0.2 mmol) were added. The reaction mixture was reacted at 110 °C for 12 h. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to give compound 41-2 (461 mg, yield 59.2%) as an orange solid. LC-MS (ESI): m / z = 600.27 [M+H] + .

[0480] Step 3: Synthesis of (S)-3-((2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)amino)-4-((1-methyl-1H-indazol-5-yl)amino)cyclobut-3-ene-1,2-dione

[0481] Compound 41-2 (400 mg, 0.67 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. Water was added to the reaction solution, the pH was adjusted to 9-10 with potassium carbonate, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 41-3 as an orange solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 500.21 [M+H] + .

[0482] Step 4: Synthesis of 3-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)amino)-4-((1-methyl-1H-indazol-5-yl)amino)cyclobut-3-ene-1,2-dione

[0483] The crude compound 41-3, intermediate 1-5 (275 mg, 0.67 mmol), and HATU (380 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (8 mL), and DIPEA (387 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 6 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1 to 1:3) to give compound 41 (205 mg, yield 34.3%) as a yellow solid. LC-MS (ESI): m / z = 893.38 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ11.68(m,1H),10.81(m,1H),9.10(m,1H),7.79(m,1H),7.67(m,1H),7.57(m,1H),7.53(m,1H),7 .50–7.42(m,1H),7.37(m,1H),7.24(m,1H),7.18(m,2H),7.09(m,1H),6.70–6.60(m,1H),6.13–5.71(m,1H),5.65(m, 1H),4.64(m,1H),4.34(m,1H),3.97(m,3H),3.92–3.84(m,2H),3.49–3.37(m,1H),2.19(m,6H),1.78(m,2H),1.75–1 .70(m,2H),1.67(m,1H),1.53(m,2H),1.47(m,2H),1.41(s,1H),1.35(m,3H),1.31(m,3H),1.25(m,2H),1.05(m,1H).

[0484] Example 42: Synthesis of (E)-1-((S)-2-(3-cyclopropyl-4-fluorophenyl)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-methylguanidine

[0485] Following the synthetic route of Example 29, the only difference being that intermediate 2d in step 4 was replaced with intermediate 6d, yielding compound 42, a white solid. LC-MS (ESI): m / z = 884.41 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 11.49 (m, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.62–7.58 (m, 1H), 7.52 (s, 1H), 7.49–7.34 (m, 2H), 7.26 (s, 1H), 7.23–7.19 (m, 1H), 7.14–7.07 (m, 2H), 6.62 (s, 1H), 5.70–5.59 (m, 1H), 4.35 (m, 1H), 4.01 (s, 3H), 3.87 (m, 2H). 3.09–3.02(m,1H),2.94–2.82(m,4H),2.15(m,1H),1.94–1.90(m,1H),1.84(m,1H),1.78(m,2H),1.75–1.70(m,2H),1 .67(m,1H),1.60(m,3H),1.38(s,1H),1.35(s,3H),1.31(s,1H),1.29(s,3H),1.23(dm,3H),1.04(m,3H),0.82(m,2H).

[0486] Example 43: Synthesis of (E)-1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-2-methyl-2H-indazol-5-yl)-2-methylguanidine

[0487] Step 1: Synthesis of 5-bromo-4-fluoro-2-methyl-2H-indazole

[0488] At 0 °C, NaH (60% dispersion in mineral oil, 744 mg, 18.6 mmol) and iodomethane (2.64 g, 18.6 mmol) were added to an anhydrous tetrahydrofuran (20 mL) solution of 5-bromo-4-fluoro-1H-indazole (2.01 g, 9.3 mmol), and the reaction was carried out at 0 °C for 6 h. The reaction was detected by TLC and extinguished by extraction with water (5 mL) at 0 °C. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound 43-2 (915 mg, yield 42.9%) as a pale yellow solid. LC-MS (ESI): m / z = 230.10 [M+H] + .

[0489] Step 2: Synthesis of N-(4-fluoro-2-methyl-2H-indoleazol-5-yl)-1,1-diphenyltoluidine

[0490] Compound 43-2 (614 mg, 2.68 mmol), benzophenone imine (971 mg, 5.36 mmol), tris(dibenzylacetone)dipalladium (245 mg, 0.26 mmol), BINAP (167 mg, 0.26 mmol), sodium tert-butoxide (515 mg, 5.36 mmol), and toluene (12 mL) solution were added to a two-necked flask. After purging with nitrogen three times, the reaction was allowed to proceed overnight at 100 °C. The reaction was monitored by TLC to confirm completion. The mixture was concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give compound 43-3 (759 mg, yield 85.9%) as a yellowish-brown solid. LC-MS (ESI): m / z = 330.23 [M+H] + .

[0491] Step 3: Synthesis of 4-fluoro-2-methyl-2H-indolezol-5-amine

[0492] Sodium acetate (453 mg, 2.4 mmol) and hydroxylamine hydrochloride (288 mg, 4.14 mmol) were added to a methanol solution of compound 43-3 (759 mg, 2.30 mmol), and the reaction was carried out overnight at room temperature. The reaction was detected by TLC to indicate completion. The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 5:1 to 3:2) to give compound 43-4 (314 mg, yield 82.6%) as a brown solid. LC-MS (ESI): m / z = 166.05 [M+H] + .

[0493] Step 4: Synthesis of 4-fluoro-5-isothiocyano-2-methyl-2H-indazole

[0494] Following step 3 of Example 26, compound 43-5 was obtained as a pale yellow solid. LC-MS (ESI): m / z = 208.03 [M+H] + .

[0495] Step 5: Synthesis of (S)-3-(3-(4-fluoro-2-methyl-2H-indazol-5-yl)thiourea)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0496] Following step 4 of Example 26, compound 43-6 was obtained as a yellow solid. LC-MS (ESI): m / z = 582.25 [M+H] + .

[0497] Step 6: Synthesis of (S,E)-3-(3-(4-fluoro-2-methyl-2H-indazol-5-yl)-2-methylguanidinyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0498] To a solution of compound 43-6 (120 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL), methylamine hydrochloride (55.7 mg, 0.82 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (158 mg, 0.82 mmol), and DIPEA (502 μL) were added, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:2) to give compound 43-7 (54 mg, 46.6% yield) as a white solid. LC-MS (ESI): m / z = 578.35 [M+H] + .

[0499] Step 7: Synthesis of (S,E)-1-(4-fluoro-2-methyl-2H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-methylguanidine

[0500] To a methanol (2 mL) solution of compound 43-7 (51 mg, 0.08 mmol), 2 mL of 4 M dioxane hydrochloride was added, and the reaction was carried out at room temperature for 4 h. The solution was concentrated under reduced pressure, water (14 mL) was added, and the pH was adjusted to 10 with saturated sodium carbonate solution. Extraction was performed with dichloromethane (10 mL × 2). The organic phase was concentrated under reduced pressure to give compound 43-8 (42 mg, 100% yield) as a white solid, which was used directly in the next step. LC-MS (ESI): m / z = 479.72 [M + H] + .

[0501] Step 8: Synthesis of (E)-1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-2-methyl-2H-indazol-5-yl)-2-methylguanidine

[0502] Intermediate 1-5 (39 mg, 0.09 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (40 mg, 0.10 mmol), and DIPEA (46 μL) were added to a solution of compound 43-8 (42 mg, 0.08 mmol) in N,N-dimethylformamide (5 mL) to give compound 43 (35 mg, 45.6% yield) as a white solid. LC-MS (ESI): m / z = 872.22 [M+H] + . 1¹H NMR (400MHz, chloroform-d) δ 11.70–11.36 (m, 1H), 8.09 (s, 1H), 7.72–7.53 (m, 2H), 7.51–7.38 (m, 3H), 7.35 (m, 1H), 7.25–7.19 (m, 2H), 7.06–6.84 (m, 1H), 6.78–6.63 (m, 1H), 5.89–5.70 (m, 1H), 5.41–5.30 (m, 1H), 4.44–4.32 (m, 1H), 4.20 (m, 3H) ),3.91–3.77(m,2H),3.57–3.47(m,1H),3.13–2.98(m,2H),2.97–2.83(m,3H),2.38–2.22(m,6H),1.92–1.86(m,1H) ,1.84–1.65(m,6H),1.60–1.52(m,3H),1.37–1.30(m,3H),1.29–1.25(m,3H),1.24–1.19(m,2H),1.06–1.01(m,1H).

[0503] Example 44: Synthesis of (E)-1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-isopropyl-1H-indazol-5-yl)-2-methylguanidine

[0504] Following the synthesis of compound 43, but replacing iodomethane in step 1 with 2-iodopropane, compound 44 was obtained as a white solid. LC-MS (ESI): m / z = 900.35 [M+H] + . 1¹H NMR (400MHz, chloroform-d) δ 11.69–11.29 (m, 1H), 8.25 (m, 1H), 8.05–7.77 (m, 1H), 7.63–7.52 (m, 1H), 7.51–7.40 (m, 1H), 7.36–7.27 (m, 2H), 7.24–6.96 (m, 3H), 6.69–6.54 (m, 1H), 5.76–5.60 (m, 1H), 4.91–4.59 (m, 2H), 4.42–4.27 (m,1H),3.93–3.76(m,2H),3.54–3.43(s,1H),3.14–2.89(m,2H),2.86–2.63(m,3H),2.35–2.24(m,6H),2.01– 1.65(m,6H),1.65–1.38(m,10H),1.37–1.30(m,3H),1.29–1.25(m,3H),1.23–1.20(m,2H),1.06–1.01(m,1H).

[0505] Example 45: Synthesis of (E)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-methylguanidine

[0506] Step 1: Synthesis of 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole

[0507] 5-Bromo-4-fluoroindazole (860 mg, 4.0 mmol) was dissolved in 1,2-dichloroethane (30 mL), followed by the addition of cyclopropylboronic acid (688 mg, 8.0 mmol), acetone (728 mg, 4.0 mmol), 2,2-bipyridine (1.25 g, 8 mmol), and sodium carbonate (848 mg, 8.0 mmol). Oxygen was bubbled through the solution, and the reaction was carried out at 70 °C for 8 h. The reaction was monitored by TLC until complete. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5:1) to give the title product (955 mg, 94% yield) as a yellow solid. LC-MS (ESI): m / z = 254.99 [M+H] + .

[0508] Step 2: Synthesis of (E)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-methylguanidine

[0509] Following the synthesis methods of Examples 26 and 29, compound 45 was obtained as a white solid with LC-MS (ESI) m / z = 898.43 [M+H]. + . 1 ¹H NMR (300 MHz, chloroform-d) δ 11.52 (m, 1H), 8.02 (m, 1H), 7.63–7.58 (m, 1H), 7.54–7.46 (m, 1H), 7.46–7.37 (m, 2H), 7.29–7.24 (m, 2H), 6.74 (m, 1H), 5.93–5.66 (m, 1H), 5.42–4.81 (m, 1H), 4.45–4.17 (m, 1H), 3.93–3.81 (m, 2H), 3.6 5–3.28(m,2H),3.04(m,1H),2.86(m,4H),2.31(m,6H),1.93(m,1H),1.85–1.77(m,2H),1.77–1.70(m,2H),1. 67(m,2H),1.59(m,3H),1.37(m,3H),1.30(m,3H),1.25(m,2H),1.22(m,2H),1.21–1.15(m,2H),1.08(m,1H).

[0510] Example 46: Synthesis of (E)-2-cyclopropyl-1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)guanidine

[0511] Following the synthesis of compound 28, but replacing the ammonia-methanol solution in step 1 with cyclopropylamine, compound 46 was obtained as a white solid. LC-MS (ESI): m / z = 898.43 [M+H]+ . 1 H NMR (300MHz, chloroform-d) δ13.13(m,1H),8.92(m,1H),7.87(m,1H),7.78(m,1H),7.71(m,1H),7.42(m,1H),7 .31(m,1H),7.20(m,1H),7.03(m,2H),6.63(m,1H),5.95(m,1H),4.85(m,1H),4.50(m,1H),3.91(m,2H) ,3.48(m,2H),3.20(m,3H),3.13(m,1H),2.98(m,1H),2.89(m,1H),2.38(m,6H),1.83–1.79(m,2H),1. 76(m,2H),1.71(m,2H),1.66(m,3H),1.38(m,3H),1.33(m,3H),1.07(m,3H),0.90(m,2H),0.79(m,2H).

[0512] Example 47: Synthesis of (E)-1-((S)-2-(3-(difluoromethoxy)-4-fluorophenyl)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-methylguanidine

[0513] Step 1: Synthesis of (5-bromo-2-fluorophenoxy)tert-butyldimethylsilane

[0514] To a solution of 5-bromo-2-fluorophenol (10.0 g, 52.3 mmol) in dichloromethane (25 mL), tert-butyldimethylchlorosilane (9.07 g, 60.2 mmol) and imidazole (4.63 g, 68.06 mmol) were added, and the reaction was carried out at room temperature for 2 h. The reaction was detected by TLC to indicate completion. Water (30 mL) was added to quench the reaction, followed by extraction with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give compound 47-2 (15.9 g, 100% yield) as a pale yellow solid. LC-MS (ESI): m / z = 305.21 [M+H] + .

[0515] Step 2: Synthesis of di-tert-butyl 1-(3-((tert-butyldimethylsilyl)oxy)-4-fluorophenyl)hydrazine-1,2-dicarboxylate

[0516] Compound 47-2 (15.9 g, 52.3 mmol), magnesium shavings (1.51 g, 62.4 mmol), two drops of 1,2-dibromoethane, and anhydrous tetrahydrofuran (50 mL) were added to a 250 mL two-necked flask. The mixture was refluxed for 2 h, and after the initial initiation stopped, reflux was continued for 0.5 h. The mixture was then cooled to room temperature. Di-tert-butyl azodicarbonate (14.36 g, 62.4 mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 1 h. The reaction was quenched by adding water (70 mL) and extracted with dichloromethane (30 mL × 2). The organic phase was concentrated under reduced pressure to obtain the residue. The residue was recrystallized from dichloromethane / petroleum ether to give compound 47-3 (19.6 g, yield 80.9%) as a white solid. LC-MS (ESI): m / z = 479.11 [M + Na] + .

[0517] Step 3: Synthesis of di-tert-butyl 1-(4-fluoro-3-hydroxyphenyl)hydrazine-1,2-dicarboxylate

[0518] A solution of compound 47-3 (6.36 g, 18.6 mmol) in tetrahydrofuran (20 mL) was added to a solution of tetrabutylammonium fluoride (30 mL, 1 mmol / L tetrahydrofuran solution), and the reaction was carried out at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give compound 47-4 (5.54 g, yield 86.9%) as a white solid. LC-MS (ESI): m / z = 343.10 [M+H] + .

[0519] Step 4: Synthesis of di-tert-butyl 1-(3-(difluoromethoxy)-4-fluorophenyl)hydrazine-1,2-dicarboxylate

[0520] To a solution of compound 47-4 (5.54 g, 16.1 mmol) in N,N-dimethylformamide (15 mL), sodium difluorochloroacetate (2.71 g, 17.8 mmol) and cesium carbonate (5.32 g, 16.1 mmol) were added, and the reaction was carried out overnight at 80 °C. The reaction was monitored by TLC until complete. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 15:1 to 5:1) gave compound 47-5 (3.78 g, yield 59.8%) as a colorless, viscous liquid. LC-MS (ESI): m / z = 415.05 [M + Na] + .

[0521] Step 5: Synthesis of (3-(difluoromethoxy)-4-fluorophenyl)hydrazine

[0522] To a 2 mL solution of dioxane (2.63, 6.7 mmol) of compound 47-5, 5 mL of 4 M dioxane hydrochloride was added, and the reaction was carried out at room temperature for 2 h. The solution was then concentrated under reduced pressure to obtain crude compound 47-6, which was used directly in the next step. LC-MS (ESI): m / z = 193.62 [M+H] + .

[0523] Step 6: (S)-3-amino-2-(3-(difluoromethoxy)-4-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0524] The 47-6 obtained in the previous step was dissolved in ethanol (20 mL), and intermediate 1 (1.12 g, 4.7 mmol) was added. The mixture was reacted at 70 °C for 3 h, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1 to 2:1) to give compound 47-7 (1.39 g, yield 50.3%) as a pale yellow solid. LC-MS (ESI): m / z = 413.75 [M+H] + .

[0525] Step 7: Synthesis of (E)-1-((S)-2-(3-(difluoromethoxy)-4-fluorophenyl)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-methylguanidine

[0526] Following steps 4, 5, and 6 of Example 26, compound 47 was obtained as a white solid. LC-MS (ESI): m / z = 910.10 [M+H] + . 1¹H NMR (300 MHz, chloroform-d) δ 11.61–11.31 (m, ¹H), 8.04 (s, ¹H), 7.88–7.74 (m, ¹H), 7.73–7.62 (m, ¹H), 7.60–7.53 (m, ¹H), 7.52–7.36 (m, ¹H), 7.25–7.16 (m, ³H), 6.87–6.54 (m, ²H), 6.53–6.23 (m, ¹H), 5.91–5.68 (m, ¹H), 5.46–5.24 (m, ¹H), 4.46–4.21 (m,1H),4.12–3.96(m,3H),3.95–3.74(m,2H),3.58–3.47(m,1H),3.15–2.99(m,2H),2.98–2.83(m,3H),1.95–1.88(m, 1H),1.86–1.61(m,6H),1.59–1.52(m,3H),1.39–1.31(m,3H),1.30–1.25(m,3H),1.24–1.10(m,2H),1.07–1.02(m,1H).

[0527] Example 48: Synthesis of (E)-2-cyano-1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)guanidine

[0528] Step 1: Synthesis of (S,Z)-3-((cyanoimino)(phenoxy)methyl)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0529] Intermediate 2d (725.82 mg, 1.94 mmol) was dissolved in N,N-dimethylacetamide, and potassium tert-butoxide (435.01 mg, 3.88 mmol) and N-cyanocarbonylimine diphenyl ester (554.15 mg, 2.33 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 48-1 (856.4 mg, yield 85.5%) as a brown solid. LC-MS (ESI): m / z = 519.59 [M+H]+ .

[0530] Step 2: Synthesis of (S,E)-3-(2-cyano-3-(4-fluoro-1-methyl-1H-indazol-5-yl)guanidinyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0531] Intermediate 26-2 (328.87 mg, 1.97 mmol) and compound 48-1 (850 mg, 1.64 mmol) were dissolved in 2-propanol (10 mL), and 4-5 drops of pyridine were added. The tube was sealed and refluxed, and the reaction was carried out for 24 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1:5) to give intermediate 48-2 (457 mg, yield 50.4%) as a yellow solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 590.65 [M+H] + .

[0532] Step 3: Synthesis of (S,E)-2-cyano-1-(4-fluoro-1-methyl-1H-indoleazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)guanidine

[0533] Compound 48-2 (457 mg, 0.78 mmol) was dissolved in 10 mL of dioxane hydrochloride solution and stirred at room temperature for 6 h. The reaction was confirmed to be complete by TLC. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 8-9 with potassium hydroxide. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 48-3 (375 mg, 99.8% yield) as a yellow solid. The crude product was used directly in the next reaction. LC-MS (ESI): m / z = 490.53 [M+H] + .

[0534] Step 4: Synthesis of (E)-2-cyano-1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)guanidine

[0535] Intermediate 48-3 (375 mg, 766.03 μmol), intermediate 1-5 (315.19 mg, 766.03 μmol), and HATU (436.91 mg, 1.15 mmol) were dissolved in tetrahydrofuran (15 mL), and DIPEA (297.02 mg, 2.30 mmol) was added. The mixture was stirred at room temperature for 8 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1:1) to give compound 48 (613 mg, yield 90.7%) as a white solid. LC-MS (ESI): m / z = 883.39 [M+H] + .

[0536] Example 49: Synthesis of (E)-1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-(methyl-d3)guanidine

[0537] Following the synthesis of compound 28, but replacing the ammonia-methanol solution in step 1 with deuterated methylamine hydrochloride, compound 49 was obtained as a white solid. LC-MS (ESI): m / z = 875.43 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 11.51 (m, 1H), 8.17 (m, 1H), 7.82–7.68 (m, 1H), 7.62–7.58 (m, 1H), 7.57–7.50 (m, 1H), 7.36 (m, 2H), 7.28–7.25 (m, 1H), 7.18 (m, 1H), 6.72 (m, 1H), 5.74–5.30 (m, 1H), 4.34 (m, 1H), 4.02 (m, 3H), 3.94 –3.80(m,2H),3.56–3.31(m,1H),3.06(m,1H),2.97–2.83(m,2H),2.32(m,6H),1.95–1.84(m,1H),1.84–1.7 5(m,2H),1.72(m,2H),1.69–1.60(m,2H),1.57(m,3H),1.37(m,3H),1.30(m,3H),1.24(m,2H),1.07(m,1H).

[0538] Example 50: Synthesis of (E)-1-((S)-5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-methylguanidine

[0539] Following the synthesis of compound 43, but replacing iodomethane in step 1 with deuterated iodomethane, compound 50 was obtained as a white solid. LC-MS (ESI): m / z = 875.43 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ12.93(m,1H),8.99(m,1H),7.83(m,1H),7.78(m,1H),7.69(m,1H),7.41(m ,1H),7.34(m,1H),7.14(m,3H),6.34(m,1H),5.89(m,1H),4.91(m,1H),4.49(m,1H),3.96–3.84 (m,2H),3.45(m,2H),3.13(m,4H),2.90(m,1H),2.40(m,6H),1.85(m,1H),1.80(m,2H),1.75(m, 1H),1.74–1.69(m,2H),1.66(m,3H),1.63–1.57(m,1H),1.38(m,3H),1.33(m,3H),1.05(m,3H).

[0540] Experimental Example 1: Compound Activity Test

[0541] 1. Cell Culture

[0542] HEK293T was cultured in DMEM high glucose medium (Keygen) under 5% CO2, 37°C, and humid conditions. This medium contained 10% fetal bovine serum (gibco), 100 units / mL penicillin G, and 100 μg / mL streptomycin sulfate (Keygen), hereinafter referred to as DMEM high glucose complete medium.

[0543] 2. HEK293T cells were transiently transfected with hGLP-1R / pcDNA3.1(+) and CRE / pGL3-basic plasmids.

[0544] HEK293T was inoculated into 6-well plates (6.5 × 10⁻⁶) one day before transfection.5 Cells / well), each well containing 2 mL of DMEM high-glucose complete medium, cultured for 12-24 h to 80-90% cell density. Plasmid (hGLP-1R / pcDNA3.1(+):CRE / pGL3-basic = 1:5) and... Invitrogen 2000 was dissolved separately in Opti-MEM medium (Gibco) and mixed 1:1 by volume to form a DNA-liposome complex. The mixture was incubated at room temperature for 5 min. The original HEK293T medium was then replaced with Opti-MEM medium. Subsequently, 250 μL of the DNA-liposome complex was added dropwise to each well. The final plasmid volume was 2500 ng / well. The final dosage of 2000 was 9 μL / well. After 6 hours, the original medium was replaced with DMEM high-glucose complete medium, and the culture was continued for 12-24 hours.

[0545] 3. Detection of the degree of cAMP signal activation in cells by the compound

[0546] HEK293T cells transiently expressing hGLP-1R and luciferase reporter genes were collected and quantified at 5 × 10⁻⁶. 5 Cells were resuspended at 1 / mL in DMEM high-glucose complete medium. 20 μL of cell suspension and 20 μL of 2× compound were seeded into 384-well white-background cell culture plates and incubated at 37°C under 5% CO2 for 12 h. The plates were then removed and allowed to equilibrate to room temperature for 30 min. 40 μL of the One-Lite assay reagent from the One-Lite Luciferase Assay System (Vazyme) was added to each well. Cells were allowed to lyse at room temperature for at least 3 min. The full-wavelength fluorescence signal was then read using SpectraMax i3X. The EC50 of the tested compound was measured. 50 The values ​​were calculated by fitting the agonist dose-response curve using a 4-parameter nonlinear regression procedure in GraphPad Prism 8.

[0547] As shown in Table 1, the compounds of the present invention have a strong agonistic effect on GLP-1 receptors (“A” indicates ≤20 nM, “B” indicates >20 nM and ≤100 nM, and “C” indicates >100 nM).

[0548] Table 1. The degree of cAMP signal activation in hGLP-1R-HEK293T cells by the tested compounds.

[0549] Experimental Example 2: In vitro liver microsomal stability determination of compounds

[0550] PBS buffer, liver microsome solution, and the test compound were added to a culture plate. The final concentration of the test compound was 1 μM. The mixture was preheated at 37 °C for 5 minutes, the reaction was initiated with NADPH regeneration solution, and incubated in a water bath at 37 °C. The reaction was stopped at 0, 5, 15, 30, and 60 minutes by adding 200 μL of cold methanol:acetonitrile (1:1) internal standard solution. After centrifuging the sample at 4000 rpm for 10 minutes, the supernatant was diluted and used for LC / MS / MS analysis. The in vitro liver microsome stability of some compounds is shown in the table below. The results indicate that the compounds of this application exhibit good liver microsome stability.

[0551] Table 2. In vitro liver microsomal stability assay of compounds

[0552] Reference compounds (hereinafter the same):

[0553] Experimental Example 3: Pharmacokinetic Properties of Compounds in Rats

[0554] The compound of this application was formulated in 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM glycine NaOH pH 10 and administered orally (po) at a dose of 10 mg / kg and intravenously at a dose of 0.15 mg / kg in fasted SD rats. Plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 7, 10, and 24 hours after administration. Compound concentrations were determined by LC / MS / MS, and pharmacokinetic parameters were calculated using WinNonlin 8.2. The experimental results are shown in the table below. The results indicate that the compound of this application exhibits favorable pharmacokinetic properties, with maximum plasma concentration (Cmax), exposure (AUC), absolute bioavailability (F), and half-life (T). 1 / 2 It performed well, with pharmacokinetic properties superior to reference compound 1.

[0555] Table 3. Pharmacokinetic parameters of the compounds orally administered in rats

[0556] Experiment Example 4: Evaluation of the Blood Glucose-Lowering Efficacy of Compounds

[0557] The compounds of this application were formulated in 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Gly-NaOH at pH=10. hGLP1R-KI mice were administered the drug 5 hours prior (by gavage, 10 mg / kg), followed by a single intraperitoneal injection of glucose (2 g / kg). Blood glucose levels were measured at -300, 0, 15, 30, 60, and 120 minutes post-injection, and a blood glucose curve was plotted. The area under the blood glucose-time curve was calculated using the formula: AUC (mmol / L·hr) = (BG0 + BG15) × 0.25 / 2 + (BG15 + BG30) × 0.25 / 2 + (BG30 + BG60) × 0.5 / 2 + (BG60 + BG120) × 1 / 2 (Note: BG0, BG15, BG30, BG60, and BG120 represent the blood glucose values ​​at 0 min before glucose administration and 15, 30, 60, and 120 min after glucose administration, respectively). The rate of decrease in blood glucose was calculated as (1 - AUC of blood glucose in the treated group / AUC of blood glucose in the control group) × 100%. The results showed that the compounds of this application exhibited excellent hypoglycemic effects.

[0558] Table 4. Evaluation of the glycemic efficacy of the compounds.

[0559] The scope of protection of this invention is not limited to the above embodiments. Variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in this invention and are protected by the appended claims.

Claims

1. A compound of formula (I) or a stereoisomer, mixture of stereoisomers, tautomer, geometric isomer, solvate, pharmaceutically acceptable salt, deuterated compound, ester, or prodrug thereof: in, Ring A is selected from: Where aa represents the connection point with C=O; X is independently selected from N and C, and when X is N, R 4 R 5 R 6 Accordingly, it does not exist; Y is C(R) 13 )2, where R 13 Independently, they are hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl or hydroxyl, or both R 13 It can form a carbonyl group (C=O) together with the carbon atoms it is attached to; Ring B is C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1-6 (The alkyl group is optionally substituted with one or more halogens) and C 1-6 Alkyl group, wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group; B 2 It is C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups; Q 1 yes C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups; Where bb represents the junction with pyrazole; R Q1 R Q2 R Q3 R Q4 R Q5 R Q6 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups), CN and NO2; Q 2 Selected from C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl and 5 to 10-membered heteroaryl groups, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1- 6-alkyl)2, CN, NO2, S(=O)(NH)R 10 B(OR) 11 (OR) 12 ), and the substituents are optionally linked to each other to form a 3- to 7-membered carbon ring or a 3- to 7-membered heterocycle, wherein the cycloalkyl group is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl, R 10 R 11 R 12 Independently selected from hydrogen atoms, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens; R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups and halogens; L 1 yes Z 1 It is halogen, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1- 6. Substituents of alkoxy and hydroxyl groups), C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1- 6-alkyl), N(C) 1-6 Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl; R 8a and R 8b It is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally selected independently from halogens and C. 3-10 Cycloalkyl substituents, or R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-10 Cycloalkanes, wherein R 8a and R 8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally selected independently from one or more halogens, hydroxyl groups, and -NR groups. 8c R 8d C 1-6 Substitution with alkoxy groups and 3 to 12-membered heterocyclic groups, and R 8c and R 8d Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; n1 is an integer from 0 to 3; n2 is an integer from 0 to 5; n3 is an integer from 0 to 5; R 9 Selected from S(=O)2NR 10 R 10 C(=O)NR 10 R 10 Or CN, and R 9a and R 9b Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 alkyl)carbonyl; R 14 Selected from hydrogen atoms, deuterium atoms, or C atoms 1-6 alkyl; The conditions are: (a) When ring A is At that time, Q 1 no and / or (b) When ring A is At that time, R 9 no and / or (c) When ring A is At that time, Q 1 no 2. The compound according to claim 1, wherein ring B is C. 1-6 Alkyl, C 3-10 Cycloalkyl, 3 to 12-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1-6 (The alkyl group is optionally substituted with one or more halogens) and C 1-6 Alkoxy, wherein the cycloalkyl group is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl.

3. The compound according to claim 2, wherein ring B is a 3- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl (where C) 1- 6-alkyl groups are optionally substituted with one or more halogens) and C 1-6 Alkyl group.

4. The compound of claim 3, wherein the 3- to 12-membered heterocyclic group is a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

5. The compound according to claim 3, wherein the 3- to 12-membered heterocyclic group is a 5- to 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

6. The compound according to claim 3, wherein the 3- to 12-membered heterocyclic group is tetrahydropyranyl, morpholinyl, 4-thiomorpholine 1,1-dioxide, 3-thiazolyl 1,1-dioxide, or 3-thioheterocyclic butane-1,1-dioxide, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl and C 1-6 Alkyl group.

7. The compound according to claim 1, wherein B 2 It is C 6-10 Aryl, the C 6-10 Aryl groups are optionally selected from one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

8. The compound according to claim 1, wherein B 2 It is phenyl or pyridyl, said phenyl or pyridyl group optionally composed of two to four independently selected from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

9. The compound according to claim 8, wherein B 2 It is a phenyl group, wherein the phenyl group is optionally composed of two to four independently selected elements selected from halogens, C, and D. 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Substitution of alkoxy groups.

10. The compound according to claim 9, wherein B 2 It is a phenyl group, which is optionally substituted by two to three substituents independently selected from fluorine atoms, methyl and cyclopropyl groups.

11. The compound according to claim 1, wherein Q 1 yes C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl and 5 to 10 heteroaryl groups are optionally selected by one to five independently chosen from halogens, C 1-6 Alkyl (where C) 1-6 Alkyl groups may be substituted with one or more halogens), C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

12. The compound according to claim 11, wherein the C 6-10 The aryl group is a phenyl group, wherein the phenyl group is optionally composed of one to four radicals independently selected from halogens, C, and D. 1-6 Alkyl, C 3-10 cycloalkyl and C 1-6 Substitution of alkoxy groups.

13. The compound of claim 12, wherein the phenyl group is optionally substituted with one to four substituents independently selected from fluorine, methyl, ethyl, propyl, cyclopropyl and methoxy.

14. The compound according to claim 11, wherein the 5- to 10-membered heteroaryl group is The 5- to 10-membered heteroaryl group is optionally composed of one to four independently selected halogens, C 1-6 Alkyl, C 3-10 cycloalkyl and C 1-6 Substituents of alkoxy groups; where bb represents the linking point with pyrazole.

15. The compound of claim 14, wherein the 5- to 10-membered heteroaryl group is optionally substituted by one to four substituents independently selected from fluorine, methyl, ethyl, propyl, cyclopropyl, and methoxy.

16. The compound according to claim 1, wherein Q 2 It is a 5- to 10-membered heteroaryl group, said 5- to 10-membered heteroaryl group optionally substituted by one or more substituents independently selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1- 6-alkyl)2, CN, NO2, S(=O)(NH)R 10 B(OR) 11 (OR) 12 ), and the substituents are optionally linked together to form 3 to 7-membered carbon rings or 3 to 7-membered heterocycles, wherein R 10 R 11 R 12 Independently selected from hydrogen atoms, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substituents of alkoxy and hydroxyl groups) and halogens.

17. The compound of claim 16, wherein the 5- to 10-membered heteroaryl group is optionally composed of one or more independently selected from C 1-6 Alkyl and halogen substituents.

18. The compound according to claim 16, wherein the 5- to 10-membered heteroaryl group is The 5- to 10-membered heteroaryl group is optionally composed of one or more independently selected from C 1-6 Alkyl and halogen substituents; where cc indicates substitution with Q. 1 The connection point.

19. The compound according to claim 16, wherein the 5- to 10-membered heteroaryl group is The 5- to 10-membered heteroaryl group is optionally composed of one or more independently selected from C 1-6 Alkyl and halogen substituents; where dd indicates substitution with Q 1 The connection point.

20. The compound according to claim 18 or 19, wherein the 5- to 10-membered heteroaryl group is optionally substituted by one to four substituents independently selected from methyl and fluorine atoms.

21. The compound according to claim 1, wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1- Substituents of 6-alkoxy and hydroxyl groups and halogens.

22. The compound according to claim 21, wherein R 1 It is C 1-6 alkyl.

23. The compound according to claim 21, wherein R 2 R 3 R 4 R 5 R 6 R 7 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups and halogens.

24. The compound according to claim 23, wherein R 2 R 3 R 4 R 5 R 6 R 7 Each is an independent hydrogen atom.

25. The compound according to claim 1, wherein L 1 yes n3 is an integer between 0 and 5.

26. The compound according to claim 25, wherein L 1 yes 27. The compound according to claim 25, wherein L 1 yes 28. The compound according to claim 1, wherein Z 1 It is halogen, C 1-6 Alkyl (where C) 1-6 Alkyl groups are optionally selected independently from halogens, C 1-6 Substitution of alkoxy and hydroxyl groups), C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1-6 Alkyl), N(C) 1-6 Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl.

29. The compound according to claim 28, wherein Z 1 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, heterocyclic group comprising one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl group comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH groups, carbonyl groups (C=O), halogens, NH₂, NH₃ (C) 1-6 Alkyl), N(C) 1-6 Alkyl)2, CN and NO2, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl or a monocycloalkyl.

30. The compound according to claim 29, wherein Z 1 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, or heteroaryl groups comprising one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, phenyl, or heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The cycloalkyl group is a halogenated alkoxy group, an OH group, a carbonyl group (C=O), or a halogen, wherein the cycloalkyl group is a spirocycloalkyl group, a bridged cycloalkyl group, or a monocycloalkyl group.

31. The compound according to claim 30, wherein Z 1 It is methyl, ethyl, or cyclopropyl.

32. The compound according to claim 30, wherein Z 1 yes And R 7a Independently selected from hydrogen atoms and C atoms 1-6 alkyl.

33. The compound according to claim 1, wherein R 8a and R 8b It is independently a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally selected independently from halogens and C. 3-10 Cycloalkyl substituents, or R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-10 Cycloalkanes, wherein R 8a and R 8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution, wherein C 1-6 The alkyl group is optionally selected independently from one or more halogens, hydroxyl groups, and -NR groups. 8c R 8d C 1-6 Substitution with alkoxy groups and 3 to 12-membered heterocyclic groups, and R 8c and R 8d Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl.

34. The compound according to claim 33, wherein R 8a and R 8b It is a hydrogen atom on its own.

35. The compound according to claim 33, wherein R 8a and R 8b Together with the carbon atoms they are attached to, they can form C 3-4 Cycloalkanes, wherein R 8a and R 8b C formed together 3-10 The cycloalkane ring is optionally bounded by one to three Cs. 1-6 Alkyl substitution.

36. The compound according to claim 33, wherein R 8a and R 8b Together with the carbon atoms they are attached to, they can form: Where ee represents -(CH2) n1 - Connection point.

37. The compound according to claim 1, wherein n1 is 0, 1, 2 or 3; n2 is 0, 1, 2, 3, 4 or 5.

38. The compound according to claim 37, wherein n1 is 0; and / or n2 is 0.

39. The compound according to claim 1, wherein R 9 Selected from Or CN, and R 9a and R 9b Independently selected from hydrogen atoms, C 1-6 Alkyl and (C 1-6 Alkyl)carbonyl.

40. The compound according to claim 39, wherein R 9a and R 9b Independently selected from hydrogen atoms and C atoms 1-6 alkyl.

41. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia):

42. The compound according to claim 1 or 41, wherein the compound of formula (I) is a compound of formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), or (Ia-10):

43. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib): The conditions are: (a)Q 1 no and / or (b)R 9 no 44. The compound according to claim 1 or 43, wherein the compound of formula (I) is a compound of formula (Ib-1) or (Ib-2):

45. The compound according to claim 1, 43 or 44, wherein the compound of formula (I) is a compound of formula (Ib-3) or (Ib-4): in, B 2 It is a phenyl group, wherein the phenyl group is optionally composed of two to four independently selected elements selected from halogens, C, and D. 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Alkoxy (where C 1-6 The alkoxy group is optionally substituted with one or more halogens; Q 2 Selected from 5- to 10-membered heteroaryl groups, wherein the heteroaryl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1-6 alkyl group 2, CN, NO2, and the substituents are optionally linked together to form a 3- to 7-membered carbon ring or a 3- to 7-membered heterocycle; R Q1 R Q2 R Q3 R Q4 and R Q5 The definition is the same as in claim 1.

46. ​​The compound according to claim 45, wherein the heteroaryl group is indazole-5-yl, and the indazole-5-yl group is optionally substituted by one or more substituents independently selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, OH, halogens, NH2, NH-(C 1-6 Alkyl), N(C) 1-6 Alkyl group)2, CN, NO2, and the substituents are optionally connected to each other to form a 3- to 7-membered carbon ring or a 3- to 7-membered heterocycle.

47. The compound according to claim 1, 43 or 44, wherein the compound of formula (I) is a compound of formula (Ib-5) or (Ib-6): in, R 15 R 16 R 17 R 18 and R 19 Each substituent is independently selected from the following: halogen, C 1- 6-alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, and R 16 R 17 The carbon atoms to which it is attached can be chosen to form 5- to 7-membered heterocycles; R Q1 R Q2 R Q3 R Q4 and R Q5 The definition is the same as in claim 1.

48. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Ic):

49. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Id):

50. The compound according to claim 1, wherein the compound of formula (I) is a compound of the following:

51. A pharmaceutical composition comprising the compound or stereoisomers thereof, mixtures of stereoisomers, tautomers, geometric isomers, solvates, pharmaceutically acceptable salts, deuterated compounds, esters or prodrugs thereof, and pharmaceutically acceptable excipients according to any one of claims 1-50.

52. Use of any compound or stereoisomer of any one of claims 1-50, a mixture of stereoisomers, tautomers, geometric isomers, solvates, pharmaceutically acceptable salts, deuterated compounds, esters, or prodrugs thereof in the preparation of medicaments for the treatment or prevention of diseases, conditions, or symptoms in which GLP-1 receptors function.

53. The use according to claim 52, wherein the diseases, conditions, or symptoms in which the GLP-1 receptor functions include diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, overweight, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, hyperinsulinemia, and non-alcoholic fatty liver disease.

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