GLP-1 receptor agonist and use thereof

Abstract

Provided are a GLP-1 receptor agonist and the use thereof. Specifically provided is a compound as represented by formula (I-1). The compound exhibits excellent GLP-1 receptor agonist activity and pharmacokinetic properties, and can be used for treating GLP-1 receptor-mediated diseases, including diabetes, obesity, and non-alcoholic fatty liver.

Description

GLP-1 receptor agonists and their applications Technical Field

[0001] This invention relates to the field of innovative medicinal chemistry, specifically to a novel oral non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist compound, or its available salts, hydrates, isotopic variants, tautomers, stereoisomers, or prodrugs, and their medicinal uses. This compound may be used to treat obesity and type 2 diabetes, and non-alcoholic fatty liver disease. Background Technology

[0002] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose levels, with high morbidity and mortality. In 2023, the number of people with diabetes worldwide reached 537 million, including 141 million in China, primarily suffering from T2DM. Type 2 diabetes is often associated with obesity, and weight loss is a crucial aspect of its treatment.

[0003] Currently, the mainstream method of medication is subcutaneous injection. Compared to injectable formulations, oral medications offer greater convenience and accessibility, and can also alleviate some patients' fear of injections. Semaglutide is an oral medication that has been developed; because it is a peptide, its absorption rate is relatively low, with a bioavailability of only 1%. Small molecules that act on GLP-1 receptors, being non-proteins, are not degraded by enzymes, making them easier to produce and less expensive, thus offering a price advantage. Developing non-peptide GLP-1 receptor small molecule agonists is of great significance for improving patient adherence and has become one of the hot research topics in the field of diabetes. LY3502970 is a GLP-1 receptor agonist currently in Phase III clinical trials.

[0004] Therefore, there is an urgent need for novel GLP-1 receptor agonists with at least one favorable property selected from ease of administration, solubility, drug interactions, potency, stability, selectivity, toxicity, drug resistance, pharmacokinetic and pharmacodynamic properties, as alternative drugs for the treatment of metabolic disorders and related diseases (including but not limited to T2DM, obesity and NASH). Summary of the Invention

[0005] The purpose of this invention is to provide a class of GLP-1 receptor agonists.

[0006] In a first aspect, the present invention provides a compound of general formula (I-1), or a pharmaceutically acceptable salt, solvate, hydrate, isotopic variant, prodrug, stereoisomer, or tautomer thereof.

[0007] In the formula, X1 is N, C, or CH; X2 is C or N; X3 is CH, S, or N;

[0008] Ring D is a 5-membered heteroaromatic ring; ring E is a benzene ring or a 6-membered heteroaromatic ring;

[0009] R is one or more, and each is independently selected from: halogen, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, cyano, carboxyl; the above groups are optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, carboxyl;

[0010] R4 and R5 are each independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; or C3-C6 cycloalkyl or C3-C6 heterocyclic group formed by R4 and R5 together;

[0011] Ring B is a 5-12 membered heterocycle, a C3-C10 carbon ring, a C6-C10 aromatic ring, or a 5-12 membered heteroaromatic ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, C1-C6 alkyl, halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl.

[0012] The ring C is a C3-C10 carbon ring or a 5-12 membered heterocycle; the above groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylene-O-C0-C6 alkylene-C3-C10 carbon ring, (C1-C6) alkylene-O-C1-C6 alkyl, C1-C6 alkoxy; or two substituents together with the intercalary atom form a C3-C6 carbon ring; the above substituents are optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C6 cycloalkoxy substituted or unsubstituted by C1-C6 alkyl, C1-C6 deuterated alkyl or halogen, -O-(CH2). 1-2 -C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl substituted or unsubstituted with C1-C6 deuterated alkoxy, CN or halogen;

[0013] Ring A is a C6-C10 aromatic ring, a 5-12 membered heteroaromatic ring, a C3-C10 carbon ring, a benzo5-10 membered heteroaromatic ring, a benzo5-10 membered heterocyclic ring, or a 5-12 membered heterocyclic ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C3-C6 cycloalkyl, 5-8 membered heterocyclic group, C1-C6 deuterated alkyl, NRaRb, PO(C1-C6 alkyl), =S, =O, hydroxyl, C1-C6 alkyl, SF5, 5-8 membered heteroaryl, benzo5-8 membered heteroaryl, N=S(C1-C =6alkyl)2(=O), SO(=NH)(C3-C6 cycloalkyl), C1-C6 alkoxy, cyano, carboxyl, C2-C6 alkenyl, C2-C6 alkynyl; or two substituents together with the intercalary atom to form a C5-C8 carbon ring or a 5-8 membered heterocycle; the above substituents may be optionally replaced by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, =O, =S, C3-C6 cycloalkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, carboxyl;

[0014] Ra and Rb are each independently selected from H and C1-C6 alkyl groups.

[0015] In another preferred embodiment, the compound has the structure shown in formula (I-2).

[0016] In the formula, X1 is N, C, or CH; X2 is C or N; X3 is CH, S, or N;

[0017] Ring D is a 5-membered heteroaromatic ring; ring E is a benzene ring or a 6-membered heteroaromatic ring;

[0018] R1, R2, and R3 are each independently selected from: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, cyano, and carboxyl; the above groups may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, and carboxyl;

[0019] R4 and R5 are each independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; or C3-C6 cycloalkyl or C3-C6 heterocyclic group formed by R4 and R5 together;

[0020] Ring B is a 5-12 membered heterocycle, a C3-C10 carbon ring, a C6-C10 aromatic ring, or a 5-12 membered heteroaromatic ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, C1-C6 alkyl, halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl.

[0021] The ring C is a C3-C10 carbon ring or a 5-12 membered heterocycle; the above groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylene-O-C0-C6 alkylene-C3-C10 carbon ring, (C1-C6) alkylene-O-C1-C6 alkyl, C1-C6 alkoxy; or two substituents together with the intercalary atom form a C3-C6 carbon ring; the above substituents are optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C6 cycloalkoxy substituted or unsubstituted by C1-C6 alkyl, C1-C6 deuterated alkyl or halogen, -O-(CH2). 1-2 -C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl substituted or unsubstituted with C1-C6 deuterated alkoxy, CN or halogen;

[0022] Ring A is a C6-C10 aromatic ring, a 5-12 membered heteroaromatic ring, a C3-C10 carbon ring, a benzo5-10 membered heteroaromatic ring, a benzo5-10 membered heterocyclic ring, or a 5-12 membered heterocyclic ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C3-C6 cycloalkyl, 5-8 membered heterocyclic group, C1-C6 deuterated alkyl, NRaRb, PO(C1-C6 alkyl), =S, =O, hydroxyl, C1-C6 alkyl, SF5, 5-8 membered heteroaryl, benzo5-8 membered heteroaryl, N=S(C1-C =6alkyl)2(=O), SO(=NH)(C3-C6 cycloalkyl), C1-C6 alkoxy, cyano, carboxyl, C2-C6 alkenyl, C2-C6 alkynyl; or two substituents together with the intercalary atom to form a C5-C8 carbon ring or a 5-8 membered heterocycle; the above substituents may be optionally replaced by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, =O, =S, C3-C6 cycloalkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, carboxyl;

[0023] Ra and Rb are each independently selected from H and C1-C6 alkyl groups.

[0024] In another preferred embodiment, the compound has the structure shown in formula (I).

[0025] In the formula, X1 is N, C, or CH; X2 is C or N; X3 is CH, S, or N;

[0026] Ring D is a 5-membered heteroaromatic ring; ring E is a benzene ring or a 6-membered heteroaromatic ring;

[0027] R1, R2, and R3 are each independently selected from: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, cyano, and carboxyl; the above groups may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, and carboxyl;

[0028] Ring B is a 5-12 membered heterocycle, a C3-C10 carbon ring, a C6-C10 aromatic ring, or a 5-12 membered heteroaromatic ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, C1-C6 alkyl, halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl.

[0029] The ring C is a C3-C10 carbon ring or a 5-12 membered heterocycle; the above groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylene-O-C3-C10 carbon ring, C1-C6 alkoxy; or two substituents together with the intercalary atom form a C3-C6 carbon ring; the above substituents are optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C6 cycloalkoxy substituted or unsubstituted by C1-C6 alkyl, C1-C6 deuterated alkyl or halogen, -O-(CH2). 1-2 -C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl substituted or unsubstituted with C1-C6 deuterated alkoxy, CN or halogen;

[0030] Ring A is a C6-C10 aromatic ring, a 5-12 membered heteroaromatic ring, a C3-C10 carbon ring, a benzo5-10 membered heteroaromatic ring, a benzo5-10 membered heterocyclic ring, or a 5-12 membered heterocyclic ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C3-C6 cycloalkyl, 5-8 membered heterocyclic group, C1-C6 deuterated alkyl, NRaRb, PO(C1-C6 alkyl), =S, =O, hydroxyl, C1-C6 alkyl, SF5, 5-8 membered heteroaryl, benzo5-8 membered heteroaryl, N=S(C1-C =6alkyl)2(=O), SO(=NH)(C3-C6 cycloalkyl), C1-C6 alkoxy, cyano, carboxyl, C2-C6 alkenyl, C2-C6 alkynyl; or two substituents together with the intercalary atom to form a C5-C8 carbon ring or a 5-8 membered heterocycle; the above substituents may be optionally replaced by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, =O, =S, C3-C6 cycloalkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, carboxyl;

[0031] Ra and Rb are each independently selected from H and C1-C6 alkyl groups.

[0032] In another preferred embodiment, the compound has the structure shown in Formula II:

[0033] In the formula, each group is defined as described in this invention.

[0034] In another preferred embodiment, the C atom connected to ring B and ring E has an S-type configuration.

[0035] In another preferred embodiment, ring B is selected from: 5-12 membered heterocyclic alkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, or C3-C10 cycloalkyl groups, wherein the heterocyclic alkyl group or cycloalkyl group is optionally substituted with 1, 2 or 3 C1-C6 alkyl groups.

[0036] In another preferred embodiment, ring B is selected from: 5-7 membered heterocyclic alkyl groups or C5-C7 cycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the heterocyclic alkyl group or cycloalkyl group is optionally substituted with 1, 2 or 3 C1-C3 alkyl groups.

[0037] In another preferred embodiment, ring B is selected from:

[0038] In another preferred embodiment, ring B is selected from:

[0039] In another preferred embodiment, ring B is

[0040] In another preferred embodiment, the compound has the structure shown in Formula III:

[0041] In the formula, X4 and X6 are each independently selected from O and CH2; X5 is CH2, CH(C1-C6 alkyl), C(C1-C6 alkyl)(C1-C6 alkyl) or Si(C1-C6 alkyl)(C1-C6 alkyl);

[0042] Other functional groups are defined as described in this invention.

[0043] In another preferred embodiment, the compound has the structure shown in Formula IV:

[0044] In the formula, each group is defined as described in this invention.

[0045] In another preferred embodiment, X4 and X6 are each independently selected from O and CH2; X5 is CH2, CH(C1-C6 alkyl), C(C1-C6 alkyl)(C1-C6 alkyl) or Si(C1-C6 alkyl)(C1-C6 alkyl).

[0046] In another preferred example, X2 is C.

[0047] In another preferred embodiment, X4 is O, X6 is CH2, and X5 is CH2, CH(C1-C3 alkyl) or C(C1-C3 alkyl)(C1-C3 alkyl).

[0048] In another preferred embodiment, ring D is a 5-membered heteroaromatic ring containing one heteroatom selected from N, O, or S.

[0049] In another preferred embodiment, ring E is selected from the group consisting of: benzene rings, 6-membered heteroaromatic rings containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0050] In another preferred embodiment, ring E is selected from the group consisting of benzene rings and six-membered heteroaromatic rings containing one nitrogen atom.

[0051] In another preferred embodiment, Selected independently from:

[0052] In another preferred embodiment, for

[0053] In another preferred embodiment, ring A is selected from the group consisting of: benzene rings, The above groups may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, cyano, SF5, PO (C1-C4 alkyl), NH2, NH (C1-C4 alkyl), N (C1-C4 alkyl), C1-C4 deuterated alkyl, C3-C6 cycloalkyl, =S, =O, 5-8 membered heterocyclic group, hydroxyl, 5-8 membered heteroaryl. Alternatively, the two substituents and the intercalary atom may together form a C5-C8 carbon ring or a 5-8 membered heterocycle; the above substituents may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C4 alkyl, C1-C4 deuterated alkyl, =O, =S, C3-C6 cycloalkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, carboxyl.

[0054] In another preferred embodiment, ring A is selected from the following group: Furthermore, the H atom on the NH group is substituted with a group selected from the following group: C3-C6 cycloalkyl, 5-8 membered heterocyclic group, The group is unsubstituted or one or more hydrogen atoms on the group are optionally substituted independently by a group selected from the group consisting of: deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy.

[0055] In another preferred embodiment, ring A is selected from the following group: Furthermore, the H atom on the NH group is substituted with a group selected from the following group: C3-C5 cycloalkyl, The group is either unsubstituted or one or more hydrogen atoms on the group are optionally substituted independently by groups selected from the group consisting of: deuterium, halogen, trifluoromethyl, methoxy, and deuterated methoxy.

[0056] In another preferred embodiment, ring A is Where R d Selected from: C3-C6 cycloalkyl groups, 5-8 membered heterocyclic groups, And the group is unsubstituted or one or more hydrogens on the group are optionally substituted independently by a group selected from the group consisting of: deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy.

[0057] R c Selected from: H, D, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, cyano, SF5, PO (C1-C4 alkyl)(C1-C4 alkyl).

[0058] In another preferred embodiment, R d Selected from: cyclopropyl, More preferably

[0059] In another preferred embodiment, for

[0060] In another preferred embodiment, R c Selected from: halogens, SF5, C1-C4 haloalkyl; preferably F or CF3; more preferably F.

[0061] In another preferred embodiment, ring A is selected from the following group: The above-mentioned groups may optionally be substituted by one or more groups selected from the group consisting of: D, halogen, C1-C4 haloalkyl and SF5; preferably, the above-mentioned groups may optionally be substituted by one or more groups selected from the group consisting of: halogen and C1-C4 haloalkyl.

[0062] In another preferred embodiment, ring A is selected from the following group:

[0063] In another preferred embodiment, ring A is selected from the following group:

[0064] In another preferred embodiment, ring A is:

[0065] In another preferred embodiment, ring A is: Preferably

[0066] In another preferred embodiment, ring A is: like

[0067] In another preferred embodiment, the additional condition is: when ring A is The ring C is a C3-C8 monocyclic carbon ring, and the C3-C8 monocyclic carbon ring is substituted by one or more groups selected from the group consisting of: C1-C4 alkylene-O-C3-C6 monocyclic carbon ring, C1-C4 alkylene-O-C3-C6 bridged ring carbon ring, and C1-C4 alkylene-O-C3-C6 spirocyclic carbon ring.

[0068] In another preferred embodiment, the ring C is a C3-C8 carbon ring or a 5-8 membered heterocycle; the above-mentioned groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylene-O-C3-C6 carbon ring, C1-C4 alkoxy; or two substituents together with the intercalary atom form a C3-C6 carbon ring; the above-mentioned substituents are optionally substituted by one or more groups selected from the group consisting of: halogen, D, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 deuterated alkoxy, C3-C6 cycloalkoxy substituted or unsubstituted by C1-C4 alkyl, C1-C4 deuterated alkyl or halogen, -O-(CH2). 1-2 -C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl substituted or unsubstituted with C1-C4 deuterated alkoxy, CN or halogen.

[0069] In another preferred embodiment, ring C is a C3-C8 monocyclic carbon ring, a C3-C8 bridged carbon ring, or a 5-8 membered heterocycle; the above group is optionally substituted by one or more groups selected from the group consisting of: halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C1-C4 alkylene-O-C3-C6 monocyclic carbon ring, C1-C4 alkylene-O-C3-C6 bridged carbon ring, C1-C4 alkylene-O-C3-C6 spirocyclic carbon ring, C1- C4 alkoxy; or two substituents together with the intercalary atom to form a C3-C6 carbon ring; the above substituents may optionally be substituted by one or more groups selected from the group consisting of: halogen, D, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 deuterated alkoxy, C3-C6 cycloalkoxy substituted or unsubstituted by C1-C4 alkyl, C1-C4 deuterated alkyl or halogen, -O-(CH2) 1-2 -C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl substituted or unsubstituted with C1-C4 deuterated alkoxy, CN or halogen.

[0070] In another preferred embodiment, Selected from the following group of groups, whether substituted or unsubstituted:

[0071] The substitution is by being substituted by one or more groups selected from the group consisting of: D, halogen, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 deuterated alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C1-C4 deuterated alkyl, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl.

[0072] In another preferred embodiment, for Where Re The substituents are selected from C1-C4 alkyl, C1-C4 alkylene-O-C3-C6 carbocyclic, C1-C4 alkoxy, and C1-C4 alkylene-O-C1-C4 alkyl, and the above substituents may be optionally replaced by one or more groups selected from the group consisting of: halogen, D.

[0073] In another preferred embodiment, R e The substituent is selected from C1 alkylene-O-C3-C4 carbon ring and C1 alkylene-O-C1-C2 alkyl, and the above substituent is optionally replaced by one or more groups selected from the group consisting of: halogen, D; more preferably C1 alkylene-O-deuterated C1-C2 alkyl.

[0074] In another preferred embodiment, for Where R e As defined in this invention. In another preferred embodiment, for In another preferred embodiment, for

[0075] In another preferred embodiment, for In another preferred embodiment, for

[0076] In another preferred embodiment, X1 is N, X2 is C, ring D is a 5-membered heteroaromatic ring, and ring E is a benzene ring; or

[0077] X1 is C, X2 is N, ring D is a 5-membered heteroaryl ring, and ring E is a 6-membered heteroaryl ring.

[0078] In another preferred embodiment, R1 is a C1-C4 alkyl group.

[0079] In another preferred embodiment, R2 is a halogen, a C2-C4 haloalkenyl group, or SF5.

[0080] In another preferred embodiment, R3 is a C1-C4 alkyl, SF5, or C2-C4 haloalkenyl.

[0081] In another preferred embodiment, for R1, R2 and R3 are as defined in this invention.

[0082] In another preferred embodiment, for R1, R2 and R3 are as defined in this invention.

[0083] In another preferred embodiment, for R1, R2 and R3 are as defined in this invention.

[0084] In another preferred embodiment, Selected from the following group: Preferred

[0085] In another preferred embodiment, the isomorph is a deuterated compound.

[0086] In another preferred embodiment, the deuterated compound is a compound in which one or more C atoms are substituted with deuterium. This substitution can be 1, 2, 3, 4, 5, or 6 deuterated, but is preferably 2 or 3 deuterated.

[0087] In another preferred embodiment, for

[0088] In another preferred embodiment, for

[0089] In another preferred embodiment, Selected from the following group:

[0090] In another preferred embodiment, the compounds are selected from compounds A1-A32, compounds B11-B17, B19-B20, B22-B25, B29-B30, B38-B92, B101-B104, compounds C1-C45-2, and compounds D1-D13.

[0091] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0092] The compound described in the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate, isotope variant, prodrug, stereoisomer or tautomer thereof; and a pharmaceutically acceptable carrier.

[0093] The compounds provided by this invention can be used alone or mixed with pharmaceutically acceptable excipients (such as excipients, diluents, etc.) to formulate oral tablets, capsules, granules, or syrups. The pharmaceutical composition can be prepared according to conventional pharmaceutical methods.

[0094] A third aspect of the invention provides the use of the compound described in the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic variant, prodrug, stereoisomer, or tautomer thereof, or the pharmaceutical composition described in the second aspect, in the preparation of a GLP-1 receptor agonist.

[0095] A fourth aspect of the invention provides the use of the compound described in the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic variant, prodrug, stereoisomer or tautomer thereof, or a pharmaceutical composition described in the second aspect, for the preparation of a medicament for the prevention and / or treatment of GLP-1 receptor-mediated diseases.

[0096] In another preferred embodiment, the disease is selected from: diabetes (such as type 2 diabetes), obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, diabetic nephropathy, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

[0097] A fifth aspect of the invention provides the use of the compound of the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate, isotope variant, prodrug, stereoisomer or tautomer thereof, or the pharmaceutical composition of the second aspect, in the preparation of a medicament for reducing body weight.

[0098] In another preferred embodiment, the drug can be used for long-term weight management and is suitable for obese or non-obese subjects, especially those with a BMI ≥ 27 kg / m². 2 The crowd.

[0099] In another preferred embodiment, the weight loss includes reducing fat accumulation.

[0100] The compounds of this invention have novel structures, excellent GLP-1 receptor agonist activity, and superior pharmacokinetic properties and safety. Furthermore, these compounds can be administered orally as small molecule drugs, offering greater convenience and accessibility, and alleviating some patients' fear of injectable medications.

[0101] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0102] Through long-term and in-depth research, the inventors unexpectedly prepared a compound with a novel structure, excellent GLP-1R agonist activity, and superior pharmacokinetic properties. Based on this, the inventors completed this invention.

[0103] the term

[0104] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0105] In this invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5, or 6 carbon atoms, and so on. "3-8" refers to having 3, 4, 5, 6, 7, or 8 ring atoms, and so on.

[0106] In this invention, the halogen is F, Cl, Br or I.

[0107] In this invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon group. For example, the term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0108] "Alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having a specified number of carbon atoms and being attached to at least two other groups. The two groups attached to the alkylene can be the same or different atoms on the alkylene. For example, a straight-chain alkylene can be -(CH2). n - A divalent group, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. Alkylenes can be substituted or unsubstituted.

[0109] In this invention, the term "alkoxy" refers to an -O-(alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, and butoxy groups.

[0110] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one double bond. For example, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0111] In this invention, the term "alkynyl" refers to a straight-chain or branched alkynyl group containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0112] In this invention, the term "carbocyclic ring" refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group, wherein the ring atom is carbon and does not contain heteroatoms. The carbocyclic ring can be a monocyclic, bridged, fused, or spirocyclic ring.

[0113] In this invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, such as the term "C3-C". 10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. The cycloalkyl group can be monocyclic, bridged, fused, or spirocyclic. The terms "C3-C8 cycloalkyl," "C3-C7 cycloalkyl," and "C3-C6 cycloalkyl" have similar meanings.

[0114] In this invention, the term "aryl or aromatic ring" refers to a hydrocarbon group comprising one or more aromatic rings. For example, the term "C6-C..." 12 "Aryl" refers to an aromatic cyclic group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl.

[0115] In this invention, the term "heterocyclic group" refers to a saturated or unsaturated, non-aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., N, O, or S), such as tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothiophenyl, or morpholinyl. The heterocyclic group can be monocyclic, bridged, fused, or spirocyclic.

[0116] In this invention, the term "heteroaryl or heteroaryl ring" refers to an aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., N, O, or S), which is a monocyclic or fused ring structure, such as furanyl, pyrroleyl, thiopheneyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, indolyl, pyrimidinyl, or pyranyl.

[0117] Unless otherwise stated, the alkyl, alkoxy, cycloalkyl, heteroaryl, heterocyclic, and aryl groups mentioned herein are substituted and unsubstituted groups. Possible substituents on the alkyl, alkoxy, cycloalkyl, heterocyclic, and aryl groups include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocyclic alkyl, C1-C20 heterocyclic alkenyl, C1-C6 alkoxy, C6-C10 aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, C6- C10 arylamino, diC6-C10 arylamino, C1-C10 alkylaminosulfonyl, C6-C10 arylaminosulfonyl, C1-C10 alkylimino, C1-C10 alkylsulfonylimino, C6-C10 arylsulfonylimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidine, urea, cyano, acyl, thioacyl, acyloxy, carboxyl, and carboxylic acid ester groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused together.

[0118] In this invention, the substitution can be monosubstituted or polysubstituted, and the polysubstituted can be disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted. Disubstituted means having two substituents, and so on.

[0119] The term "multiple" refers to 2 to 6, such as 2, 3, 4, 5, or 6.

[0120] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent of each other; they can be the same or different. That is, the term "selected from:" and the term "each independently selected from:" have the same meaning.

[0121] compound

[0122] This invention provides compounds of general formula (I-1), or pharmaceutically acceptable salts, solvates, hydrates, isotopic variants, prodrugs, stereoisomers, or tautomers thereof.

[0123] In the formula, each group is defined as above.

[0124] In another preferred embodiment, the compound is a compound represented by formula (I-2), formula (I), formula (II) or formula (III).

[0125] In another preferred embodiment, in the compound, any one of R, R1, R2, R3, R4, R5, ring A, X1, X2, X3, ring B, ring C, ring D, and ring E is independently the corresponding group in the specific compound of the present invention.

[0126] The pharmaceutically acceptable salts described in this invention can be salts formed by anion and a positively charged group on the compound of this invention. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, or maleate. Similarly, salts can be formed by cations and negatively charged groups on the compound of formula O. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium ions.

[0127] In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid; or a sodium salt, potassium salt, calcium salt, aluminum salt, or ammonium salt formed by the compound of the present invention with an inorganic base; or a methylamine salt, ethylamine salt, or ethanolamine salt formed by the compound of the present invention with an organic base.

[0128] The term "solvent" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0129] Furthermore, the compounds of the present invention also include prodrugs of the compounds of the present invention. The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, when taken by an appropriate method, are metabolized or chemically reacted in the human body to become compounds of the present invention, or salts or solutions composed of compounds of the present invention. The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc., of the compounds.

[0130] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, transisomers, racemic mixtures thereof, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0131] The term "isotope variant" refers to a compound of the present invention containing atomic isotopes in a non-natural proportion on one or more atoms constituting the compound. For example, the compound may be labeled with radioactive isotopes such as deuterium (₂H) or C-14 (₂H). 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention. Preferably, the isotopic variants are deuterated compounds obtained by substituting one or more H atoms (especially H atoms bonded to C atoms) with deuterium.

[0132] Pharmaceutical Composition

[0133] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective range, and a pharmaceutically acceptable carrier.

[0134] The "active ingredient" as described in this invention refers to the compound described in this invention, or its pharmaceutically acceptable salt, solvate, hydrate, isotope variant, prodrug, stereoisomer, or tautomer.

[0135] The "active ingredient" and pharmaceutical composition described in this invention are used to prepare remedies for treating diseases or conditions mediated by GLP-1 receptors. The "active ingredient" and pharmaceutical composition described in this invention can be used as GLP-1 receptor agonists. The diseases or conditions mediated by GLP-1 receptors are selected from: diabetes (such as type 2 diabetes), obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, diabetic nephropathy, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

[0136] The compounds or pharmaceutical compositions of the present invention can also be used for weight loss, especially for long-term weight management, and are suitable for obese or non-obese subjects, particularly those with a BMI ≥ 27 kg / m². 2 Even BMI ≥ 30 kg / m 2The target population. In another preferred embodiment, the weight loss includes reducing fat accumulation.

[0137] "Safe and effective dose" refers to an amount of active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg of active ingredient per dose. Preferably, "one dose" refers to one tablet.

[0138] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0139] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous, intramuscular, or subcutaneous), etc.

[0140] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0141] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0142] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0143] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0144] The compounds of this invention can be administered alone or in combination with other therapeutic agents (such as antihypertensive drugs).

[0145] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0146] Compared with the prior art, the present invention has the following main advantages:

[0147] (1) The compound has a novel structure and excellent GLP-1R agonist activity;

[0148] (2) The compound has excellent pharmacokinetic properties;

[0149] (3) The compound has excellent ease of administration;

[0150] (4) The compound has excellent safety;

[0151] (5) The compound is beneficial for drug preparation and easy to make into a drug.

[0152] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions (such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0153] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0154] The embodiments of this invention specifically describe methods for preparing the compounds of this invention, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0155] Typically, the raw materials and reagents used in the preparation process of the compounds of this invention can be purchased commercially unless otherwise specified.

[0156] Example A1

[0157] Step 1: (4S)-3-(3-(3-bromo-4-(hydroxymethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-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

[0158] To a solution of (2-bromo-4-iodophenyl)methanol (300 mg, 0.96 mmol) in 5 mL of N-methylpyrrolidone, (4S)-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 (423 mg, 0.96 mmol), potassium carbonate (398 mg, 2.89 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (68 mg, 0.5 mmol), and cuprous iodide (37 mg, 0.2 mmol) were added sequentially. The reaction mixture was incubated at 100°C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the target compound (180 mg, 0.29 mmol, yield: 30.0%) as a white solid. LCMS (ESI) m / z = 626.2 [M+H] + .

[0159] Step 2: (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborphane-6-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 is converted to (4S)-3-(3-(3-bromo-4-(hydroxymethyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- To a 2 mL ethanol solution of 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (180 mg, 0.29 mmol), tetrahydroxydiboron (52 mg, 0.58 mmol), potassium acetate (56 mg, 0.58 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (24 mg, 0.03 mmol) were added. The reaction mixture was stirred at 80 °C for 0.75 hours under nitrogen protection. After the reaction was complete, the reaction mixture was poured into 50 mL of water, extracted with ethyl acetate (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0-10% anhydrous methanol) to give the target compound (80 mg, 0.14 mmol, yield: 48.6%) as a white solid. LCMS (ESI) m / z = 574.3 [M+H] + .

[0160] Step 3: 1-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabor-6-yl)-1,3-dihydroxy-2H-imidazol-2-one

[0161] A solution of 4M dioxane hydrochloride (2 mL) was added to a solution of (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborphane-6-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 (80 mg, 0.14 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude (70 mg) yellow solid. LCMS (ESI) m / z = 474.2 [M+H]+ .

[0162] Step 4: 3-[(1S,2S)-1-{5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-hydroxy-1,3-dihydrobenzo[2,1-c][1,2]oxazol-6-yl)-2-oxoimidazol-1-yl]-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]carbonyl}indol-1-yl}-2-methylcyclopropyl]-4H,5H-1,2,4-oxadiazol-5-one

[0163] Add 5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabor-6-yl)-1,3-dihydroxy-2H-imidazol-2-one (70 mg, crude) to N,N-dimethylformamide (2 mL). The reaction mixture consisted of [(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (58 mg, 0.14 mmol), N,N-diisopropylethylamine (36 mg, 0.28 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (80 mg, 0.21 mmol). The reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was purified by reverse-phase synthesis to obtain the target compound (50 mg, 0.06 mmol, two-step yield: 41.3%). LCMS (ESI) m / z = 867.4 [M+H] + . 1H NMR (400MHz, DMSO) δ11.74(s,1H),9.35(s,1H),8.00(s,1H),7.73–7.65(m,1H),7.54(d,J=7.6Hz,2H),7.4 0(d,J=8.6Hz,1H),7.31–7.24(m,2H),7.16(d,J=6.2Hz,2H),6.96(d,J=9.9Hz,2H),5.67–5.51(m,1H),5.02 (s,2H),4.44–4.31(m,1H),3.73–3.60(m,3H),3.25–3.12(m,1H),3.07–3.00(m,1H),2.92–2.85(m,1H),2.2 0(d,J=12.9Hz,7H),1.80–1.63(m,5H),1.62–1.47(m,2H),1.40(d,J=6.6Hz,2H),1.27(s,3H),1.18(s,6H).

[0164] Referring to Example A1, the following compounds were synthesized.

[0165] Example A6

[0166] Step 1: (4S)-3-(3-(3-bromo-4-(methoxycarbonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-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

[0167] To a solution of methyl 2-bromo-4-iodobenzoate (300 mg, 0.88 mmol) in N-methylpyrrolidone (5 mL), (4S)-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 (389 mg, 0.88 mmol), potassium carbonate (365 mg, 2.64 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (63 mg, 0.44 mmol), and cuprous iodide (17 mg, 0.09 mmol) were added sequentially. The reaction solution was reacted at 100°C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the target compound (400 mg, 0.61 mmol, yield: 69.5%) as a yellow solid. LCMS (ESI) m / z = 654.2 [M+H] + .

[0168] Step 2: (4S)-3-(3-(3-bromo-4-(2-hydroxypropyl-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-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

[0169] Under nitrogen protection at 0°C, methyl magnesium bromide (0.62 mL, 1.83 mmol, 3 M) was added to an anhydrous tetrahydrofuran (3 mL) solution of (4S)-3-(3-(3-bromo-4-(methoxycarbonyl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-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 (400 mg, 0.61 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the target compound (200 mg, 0.31 mmol, yield: 50.0%). LCMS (ESI) m / z = 654.2 [M+H] + .

[0170] Step 3: (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-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 to (4S)-3-(3-(3-bromo-4-(2-hydroxypropyl-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H- To a 4 mL ethanol solution of H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (200 mg, 0.31 mmol), tetrahydroxydiboron (83 mg, 0.92 mmol), potassium acetate (90 mg, 0.92 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (15 mg, 0.03 mmol), and chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (49 mg, 0.06 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-5% anhydrous methanol) to give the crude target compound (140 mg, 0.23 mmol), a yellow solid. LCMS (ESI) m / z = 602.3 [M+H] + .

[0171] Step 4: 1-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxorbollol-6-yl)-1,3-dihydro-2H-imidazol-2-one to (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy) A solution of 3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-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 (140 mg, 0.23 mmol) in dichloromethane (2 mL) was added to a 4M dioxane hydrochloride solution (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain the target crude product (120 mg, crude), a yellow solid. LCMS (ESI) m / z = 502.3 [M+H] + .

[0172] Step 5: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxazol-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-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

[0173] Add 5-((S)-2,2-dimethyltetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxorbodanol-6-yl)-1,3-dihydro-2H-imidazol-2-one (120 mg, crude) to N,N-dimethylformamide (2 mL). The reaction mixture consisted of 1,4-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (99 mg, 0.24 mmol), N,N-diisopropylethylamine (93 mg, 0.72 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (137 mg, 0.36 mmol). The reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was purified by reverse-phase synthesis to obtain the target compound (84 mg, 0.09 mmol, yield: 39.2%). LCMS (ESI) m / z = 895.4 [M+H] + .

[0174] 1 H NMR (400MHz, DMSO) δ11.74(s,1H),9.20(s,1H),7.91(d,J=2.0Hz,1H),7.65(d,J=8.3Hz,1H),7.58–7.52(m,2H), 7.40(d,J=8.6Hz,1H),7.27(t,J=7.3Hz,2H),7.15(d,J=6.3Hz,2H),6.96(d,J=8.2Hz,2H),5.63–5.52(m,1H),4. 38(d,J=14.0Hz,1H),3.71(d,J=8.4Hz,2H),3.62(d,J=11.5Hz,1H),3.24–3.13(m,1H),3.06–3.01(m,1H),2.92– 2.88(m,1H),2.23(s,6H),1.72–1.64(m,4H),1.47(s,6H),1.40(d,J=6.5Hz,3H),1.27(s,6H),1.19–1.13(m,6H).

[0175] Referring to Example A6, the following compounds were synthesized.

[0176] Example A11

[0177] Step 1: (1R,5S)-2,4-dioxa-3-thiabicyclo[3.2.0]heptane 3,3-dioxide

[0178] At room temperature, thionyl chloride (0.8 mL, dissolved in 1 mL of carbon tetrachloride) was slowly added dropwise to a solution of (1R,2S)-cyclobutane-1,2-diol (750 mg, 8.51 mmol) in 10 mL of carbon tetrachloride, and the mixture was then heated under reflux for 30 minutes. Acetonitrile (6 mL), ruthenium trichloride hydrate (5 mg), sodium periodate (2.75 g, 12.8 mmol), and water (9 mL) were added sequentially, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, isopropyl ether (50 mL) was added, and the organic phase was separated. The organic phase was washed sequentially with water, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the target compound (950 mg, 6.3 mmol, yield: 74.3%).

[0179] Step 2: 1-(5-cyanobicyclo[2.1.0]pentan-5-yl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0180] Under nitrogen protection, at 0°C, a 2M solution of lithium tert-butoxide in tetrahydrofuran (6 mL, 13.4 mmol) was slowly added dropwise to a tetrahydrofuran solution (10 mL) of (1R,5S)-2,4-dioxa-3-thiabicyclo[3.2.0]heptane 3,3-dioxide (500 mg, 3.33 mmol) and (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (668 mg, 1.67 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was quenched with 50% acetic acid aqueous solution, extracted with ethyl acetate (3 x 10 mL), the organic phase was separated, the aqueous organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the target compound (400 mg, 0.89 mmol, yield: 53%), LCMS (ESI) m / z = 454.3 [M+H). + .

[0181] Step 3: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(5-((Z)-N'-hydroxycarbamoyl)bicyclo[2.1.0]pentan-5-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0182] To a tetrahydrofuran (5 mL) solution of 1-(5-cyanobicyclo[2.1.0]pentan-5-yl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (400 mg, 0.89 mmol), a 50% aqueous solution of hydroxylamine (117 mg, 1.76 mmol) was slowly added. The reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to 5°C, filtered, the filter cake was washed with water, and dried to give the crude compound (387 mg, 0.80 mmol), LCMS (ESI) m / z = 487.3 [M+H]. + .

[0183] Step 4: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)bicyclo[2.1.0]pentan-5-yl)-N-phenyl-1H-indole-2-carboxamide

[0184] To a solution of compound 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(5-((Z)-N'-hydroxycarbamoyl)bicyclo[2.1.0]pentan-5-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (387 mg, 0.80 mmol) in tetrahydrofuran (5 mL), N,N'-carbonyldiimidazole (259 mg, 1.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (365 mg, 2.4 mmol) were added. The reaction was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched with 2M hydrochloric acid aqueous solution, extracted with ethyl acetate (3 x 10 mL), and the organic phase was separated. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-5% anhydrous methanol) and reversed-phase chromatography to obtain the target compound (40 mg, 0.08 mmol, yield: 9.8%). LCMS (ESI) m / z = 513.3 [M+H] + .

[0185] Step 5: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)bicyclo[2.1.0]pentan-5-yl)-1H-indole-2-carboxylic acid

[0186] Potassium hydroxide (120 mg, 2.14 mmol) was added to a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)bicyclo[2.1.0]pentan-5-yl)-N-phenyl-1H-indole-2-carboxamide (40 mg, 0.08 mmol) in n-butanol (2 mL). The reaction mixture was reacted in a microwave oven at 125 °C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative chromatography to obtain the target compound (15 mg, 0.04 mmol, yield: 45.4%). LCMS (ESI) m / z = 424.2 [M+H] + .

[0187] Step 6, referring to step 4 of Example A1, to obtain the target product. LC-MS (ESI+) m / z: 879.1 [M+H] +

[0188] Example A16

[0189] Step 1: 1-(2-bromo-5-iodophenyl)ethyl ketone

[0190] To a solution of 1-(5-amino-2-bromophenyl)ethyl ketone (300 mg, 1.4 mmol) in acetonitrile (30 mL), p-toluenesulfonic acid (722 mg, 4.2 mmol) was added. Then, potassium iodide (580 mg, 3.5 mmol) and sodium nitrite (194 mg, 2.8 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed successively with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the target product (300 mg, 0.92 mmol, yield: 65.9%). LCMS (ESI) m / z = 325.1 [M+H] + .

[0191] Step 2: ((1-(2-bromo-5-iodophenyl)vinyl)oxy)trimethylsilane

[0192] Sodium iodide (417 mg, 2.78 mmol) was added to a solution of 1-(2-bromo-5-iodophenyl)ethyl ketone (300 mg, 0.92 mmol), trimethylchlorosilane (201 mg, 1.85 mmol), and triethylamine (187 mg, 1.85 mmol) in acetonitrile (5 mL). After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed successively with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-15% ethyl acetate) to give the target product (300 mg, 0.76 mmol, yield: 81.8%). LCMS (ESI) m / z = 397.2 [M+H] + .

[0193] Step 3: (1-(2-bromo-5-iodophenyl)cyclopropoxy)trimethylsilane

[0194] Under nitrogen protection, diiodomethane (322 mg, 1.2 mmol) was added to a solution of ((1-(2-bromo-5-iodophenyl)vinyl)oxy)trimethylsilane (300 mg, 0.76 mmol) and diethylzinc (1.2 mL, 1.2 mmol, 1 M) in diethyl ether (5 mL). The reaction mixture was refluxed for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and pyridine was added to quench the reaction. Water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed successively with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-15% ethyl acetate) to give the target product (100 mg, 0.24 mmol, yield: 32.2%). LCMS (ESI) m / z = 411.2 [M+H] + .

[0195] Steps 4-7 refer to steps 1-4 of Example A1 to obtain the target product.

[0196] LCMS(ESI)m / z = 893.4 [M+H] + .

[0197] Example A17

[0198] Reaction route:

[0199] Operating steps:

[0200] Starting with 1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-yl)pyrrolo[3,2-b]pyridine-2-carboxylic acid, the target compound was obtained with an LCMS (ESI) m / z of 840.4 [M+H], following Example A1. + .

[0201] Example A20

[0202] Reaction route:

[0203] Operating steps:

[0204] Step 1: 2-[(4-bromophenyl)amino]-2-methylpropionic acid

[0205] To a solution of p-bromoaniline (5 g, 29.1 mmol) in isopropanol (50 mL), 2-bromo-2-methylpropionic acid (4.85 g, 29.1 mmol) and triethylamine (8.1 mL, 58.1 mmol) were added. The reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction mixture was distilled under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give the target compound (3 g, 11.6 mmol, yield: 40.0%) as a white solid. LCMS (ESI) m / z = 258.1 [M+H] + .

[0206] Step 2: Methane isothiocyanate-d3

[0207] N,N-diisopropylethylamine (3.66 g, 28.4 mmol) and cesium carbonate (9.24 g, 28.4 mmol) were added to a solution of methylamine-d3 hydrochloride (1 g, 14.2 mmol) in dichloromethane (30 mL). Then, phosgene (1.96 g, 17.0 mmol) was dissolved in dichloromethane (10 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the mixture was filtered, and the reaction solution was concentrated under reduced pressure to obtain the target crude compound (2 g), a yellow solid.

[0208] Step 3: 1-(4-bromophenyl)-5,5-dimethyl-3-(methyl-d3)-2-thioimidazolidine-4-one

[0209] Triethylamine (1.8 mL, 13.2 mmol) and methane isothiocyanate-d3 (2 g, 26.3 mmol) were added to a 20 mL ethanol solution of 2-[(4-bromophenyl)amino]-2-methylpropionic acid (1 g, 3.87 mmol). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the target compound (200 mg, 0.63 mmol, yield: 16.3%) as a white solid. LCMS (ESI) m / z = 316.1 [M+H] + .

[0210] Step 4: (4S)-3-(3-(4-(5,5-dimethyl-3-(methyl-d3)-4-oxo-2-thioimidazolidine-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-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

[0211] To a solution of 1-(4-bromophenyl)-5,5-dimethyl-3-(methyl-d3)-2-thioimidazolidine-4-one (200 mg, 0.63 mmol) in N-methylpyrrolidone (3 mL), add sequentially (4S)-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 (279 mg, 0.63 mmol), potassium carbonate (262 mg, 1.90 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (45.0 mg, 0.32 mmol), and cuprous iodide (24.0 mg, 0.13 mmol) were added. The reaction mixture was subjected to nitrogen protection at 130°C for 3 hours. After the reaction was complete, the reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the target compound (327 mg, 0.48 mmol, yield: 76.4%) as a white solid. LCMS (ESI) m / z = 677.3 [M+H] + .

[0212] Step 5: 1-(4-(5,5-dimethyl-3-(methyl-d3)-4-oxo-2-thioimidazolidine-1-yl)phenyl)-3-((4S)-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

[0213] To a solution of (4S)-3-(3-(4-(5,5-dimethyl-3-(methyl-d3)-4-oxo-2-thioimidazolidine-1-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-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 (327 mg, 0.483 mmol) in dichloromethane (3 mL), 4 M dioxane hydrochloride solution (3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain the target crude product (280 mg, crude), a yellow solid. LCMS (ESI) m / z = 577.3 (M+H).

[0214] Step 6: 3-((1S,2S)-1-(3-((4S)-3-(3-(4-(5,5-dimethyl-3-(methyl-d3)-4-oxo-2-thioimidazolidine-1-yl)phenyl)-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-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0215] Add 5-((S)-2,2-dimethyltetrahydro-1-yl)phenyl)-3-((4S)-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 (280 mg, 0.49 mmol) to a solution of 1-(4,5-dimethylformamide (5 mL))-3-((4S)-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 (280 mg, 0.49 mmol) in N,N-dimethylformamide (5 mL) sequentially. The reaction mixture consisted of 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 (200 mg, 0.49 mmol), N,N-diisopropylethylamine (126 mg, 0.97 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (277 mg, 0.73 mmol). The reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was purified by reverse-phase preparation (eluent: acetonitrile / 0.5% formic acid water, gradient: 0–100% acetonitrile) to give the target compound (221 mg, 0.23 mmol, yield: 46.9%) as a white solid. LCMS(ESI)m / z = 970.4 [M+H] + .

[0216] 1 H NMR (400MHz, DMSO) δ11.74(s,1H),7.86(d,J=8.4Hz,2H),7.53(s,1H),7.45(d,J=8.1Hz,3H),7.40(d,J =8.5Hz,1H),7.26(d,J=8.7Hz,1H),7.17(d,J=6.2Hz,2H),7.05(s,1H),6.95(s,1H),5.69–5.48(m,1H) ,4.45–4.30(m,1H),3.75–3.58(m,3H),3.19(s,1H),3.07–2.98(m,1H),2.95–2.85(m,1H),2.23(s,7H) ,1.79–1.61(m,5H),1.53(d,J=13.0Hz,2H),1.37(s,6H),1.27(s,3H),1.25–1.22(m,2H),1.18(s,6H).

[0217] Example A21

[0218] Operating steps:

[0219] Step 1: 6-Bromo-7-fluoro-1-(methyl-d3)-1H-benzo[d]imidazole

[0220] Sodium hydride (82 mg, 2.05 mmol, 60% purity) was added to a solution of 6-bromo-7-fluoro-1H-benzo[d]imidazole (220 mg, 1.02 mmol) in N,N-dimethylformamide (3 mL) at 0°C. The mixture was stirred for 10 minutes, followed by the addition of deuterated iodomethane (297 mg, 2.05 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%–10% anhydrous methanol) to give the target compound (230 mg, 1.0 mmol, yield: 96.9%). LCMS (ESI) m / z = 232.1 [M+H] + .

[0221] Step 2: 5-Bromo-4-fluoro-1,3-bis(methyl-d3)-1,3-dihydro-2H-benzo[d]imidazol-2-thione

[0222] At 0°C, deuterated iodomethane (360 mg, 2.48 mmol) was added to a ethyl acetate (3 mL) solution of 6-bromo-7-fluoro-1-(methyl-d3)-1H-benzo[d]imidazole (230 mg, 1.0 mmol). The reaction mixture was stirred at 0°C for 48 hours. A solid precipitated, which was filtered. The solid was dissolved in anhydrous methanol (3 mL), and cyclooctasulfide (254 mg, 1.0 mmol) was added. The mixture was heated under reflux for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the target compound (30 mg, 0.11 mmol, yield: 10.8%). LCMS (ESI) m / z = 281.1 [M+H] + .

[0223] Step 3: (4S)-3-(3-(4-fluoro-1,3-bis(methyl-d3)-2-thio-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydroxy-1H-imidazol-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

[0224] Add (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4 ... Tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (47 mg, 0.11 mmol), potassium carbonate (44 mg, 0.33 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.05 mmol), and cuprous iodide (5 mg, 0.02 mmol). The reaction solution was reacted at 130°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into 20 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the target compound (30 mg, 0.05 mmol, yield: 43.8%) as a white solid. LCMS (ESI) m / z = 642.3 [M+H] + .

[0225] Step 4: 1-(4-fluoro-1,3-bis(methyl-d3)-2-thio-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-((4S)-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

[0226] A solution of 4M dioxane hydrochloride (2 mL) was added to a solution of (4S)-3-(3-(4-fluoro-1,3-bis(methyl-d3)-2-thio-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydroxy-1H-imidazol-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 (30 mg, 0.05 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude target compound (25 mg), a yellow solid. LCMS (ESI) m / z = 542.3 [M+H] + .

[0227] Step 5: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-3-(3-(4-fluoro-1,3-bis(methyl-d3)-2-thio-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydroxy-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)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0228] Add 5-((S)-2,2-dimethyltetrahydro-1H-benzo[d]imidazol-5-yl)-3-((4S)-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 (25 mg, crude) to N,N-dimethylformamide (2 mL). 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 (19 mg, 0.05 mmol), N,N-diisopropylethylamine (13 mg, 0.1 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (28 mg, 0.07 mmol) were reacted and stirred overnight at room temperature. After the reaction was complete, the reaction solution was purified by reverse-phase synthesis to obtain the target compound (13.7 mg, 0.015 mmol, yield: 31.8%). LCMS (ESI) m / z = 935.1 [M+H] + .

[0229] Example A22

[0230] Reaction route:

[0231] Operating steps:

[0232] Step 1: 5-Bromo-1,2,3,4-Tetrahydroquinoline-8-amine

[0233] Platinum dioxide (50 mg, 0.12 mmol) was added to a solution of 5-bromoquinoline-8-amine (500 mg, 2.24 mmol) in acetic acid (5 mL). The reaction mixture was stirred at 50 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the target crude compound (600 mg). LCMS (ESI) m / z = 227.1 [M+H] + .

[0234] Step 2: 7-Bromo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-one

[0235] To a solution of 5-bromo-1,2,3,4-tetrahydroquinoline-8-amine (600 mg, 2.64 mmol) in tetrahydrofuran (10 mL), N,N-carbonyldiimidazole (857 mg, 5.28 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–70% ethyl acetate) to give the crude compound (150 mg). LCMS (ESI) m / z = 253.1 [M+H] + .

[0236] Step 3: 7-Bromo-1-(methyl-d3)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-one

[0237] Under nitrogen protection, sodium hydride (48 mg, 1.12 mmol, 60% purity) was added to a solution of 7-bromo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-one (150 mg, 0.59 mmol) in N,N-dimethylformamide (3 mL) at 0°C. The mixture was stirred for 10 minutes, followed by the addition of deuterated iodomethane (86 mg, 0.59 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the target compound (150 mg, 0.56 mmol, yield: 93.7%). LCMS (ESI) m / z = 270.1 [M+H] + .

[0238] Step 4: 7-Bromo-1-(methyl-d3)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione

[0239] Phosphorus pentasulfide (247 mg, 1.11 mmol) was added to a pyridine (3 mL) solution of 7-bromo-1-(methyl-d3)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-one (150 mg, 0.56 mmol), and the reaction mixture was stirred at 130 °C for 5 hours. After the reaction was complete, the mixture was filtered, water was added, and the extract was obtained with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the compound 7-bromo-1-(trideuterylmethyl)-2,4,5,6-tetrahydro-1H-imidazo[5,4,3-ij]quinoline-2-one (18 mg, 0.06 mmol, yield: 11.3%). LCMS(ESI)m / z = 286.1[M+H] + .

[0240] Step 5: 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one

[0241] A solution of 4M dioxane hydrochloride (4 mL) was added to a solution of (4S)-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 (400 mg, 0.91 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to obtain the crude target compound (300 mg), a yellow solid. LCMS (ESI) m / z = 342.3 [M+H] + .

[0242] Step 6: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-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 to 1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro 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 (362 mg, 0.88 mmol), N,N-diisopropylethylamine (341 mg, 2.64 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (502 mg, 1.32 mmol) were added to N,N-dimethylformamide (2 mL) of 1H-imidazol-2-one (300 mg, crude). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / anhydrous methanol, gradient: 0%-10% anhydrous methanol) to give the target compound (400 mg, 0.54 mmol, yield: 61.9%). LCMS (ESI) m / z = 735.4 [M+H] + .

[0243] Step 7: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-(methyl-d3)-2-thio-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-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

[0244] Add 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-(methyl-d3)-2-thio-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinoline-7-yl) to a solution of 7-bromo-1-(methyl-d3)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-7-yl) in N-methylpyrrolidone (2 mL) sequentially. The reaction mixture consisted of 2-oxo-2,3-dihydro-1H-imidazol-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 (47 mg, 0.06 mmol), potassium carbonate (27 mg, 0.19 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (5 mg, 0.03 mmol), and cuprous iodide (3 mg, 0.01 mmol). The reaction solution was reacted at 130°C for 3 hours under nitrogen protection. After the reaction, the solution was purified by reverse-phase synthesis to obtain the target compound (7.7 mg, 0.008 mmol, yield: 13%). LCMS (ESI) m / z = 940.4 [M+H] + .

[0245] 1 H NMR (400MHz, DMSO) δ11.76(s,1H),7.53(s,1H),7.39(t,J=8.1Hz,2H),7.25(d,J=8.3Hz,1H),7.17(d,J=7.0 Hz,3H),7.00(d,J=12.0Hz,2H),6.93(s,1H),5.59(d,J=6.9Hz,1H),4.44–4.29(m,1H),4.05–3.98(m,2H),3. 71(d,J=8.5Hz,3H),3.24–3.12(m,1H),3.05(d,J=12.5Hz,1H),2.93–2.85(m,1H),2.65–2.54(m,2H),2.24(d ,J=10.4Hz,6H),2.13–2.05(m,2H),1.73–1.63(m,4H),1.43(d,J=6.4Hz,3H),1.28(s,6H),1.21–1.13(m,6H)

[0246] Example B19

[0247] Steps 1-5 refer to steps 2-6 of Example A11.

[0248] Step 6: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoboronyl-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0249] At room temperature, 3-((1S,2S)-2-(benzyloxy)methyl)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabor-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.31 mmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 80°C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the crude target compound (200 mg, 0.23 mmol). LCMS (ESI) m / z = 883.4 [M+H] + .

[0250] Step 7: (1S,2S)-2-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoboronyl-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropane-1-carboxaldehyde

[0251] At room temperature, 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoborhecopenten-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] Pyridine-5-carbonyl)-1H-indol-1-yl)-2-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (200 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), and then Dys-Martin oxidant (195 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 14 hours. The reaction was stopped by LCMS. The reaction solution was diluted with dichloromethane (20 mL), and then washed successively with saturated sodium bicarbonate solution (15 mL x 2) and saturated brine (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography to give the target compound (100 mg, yield 50.1%). LCMS (ESI) m / z = 881.4 [M+H] + .

[0252] Step 8: 3-((1S,2R)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoboronyl-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-ethynylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0253] At room temperature, (1S,2S)-2-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoborhecyclopenten-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indole-1- 100 mg (0.11 mmol) of 2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropane-1-carboxaldehyde was dissolved in methanol (3 mL), followed by the addition of 1-diazo-1-dimethoxyphospho-propane-2-one (44 mg (0.22 mmol)) and potassium carbonate (48 mg (0.33 mmol). The mixture was stirred at room temperature for 5 hours. The reaction was stopped by LC-MS. The reaction solution was quenched with saturated brine (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reversed-phase preparative chromatography to give the target compound (20 mg, 0.02 mmol, yield 20.1%). LC-MS (ESI) m / z = 877.4 [M+H] + .

[0254] Example B38:

[0255] Operating steps:

[0256] Step 1: (R)-4-((methoxy-d3)methyl)-2,2-dimethyl-1,3-dioxolane

[0257] At 0°C, sodium hydride (1.97 g, 49.2 mmol, 60% purity) was added to a solution of (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol (5.0 g, 37.8 mmol) in tetrahydrofuran (100 mL). After stirring for 30 minutes, deuterated iodomethane (8.3 g, 56.8 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and used directly in the next step.

[0258] Step 2: (S)-3-(methoxy-d3)propane-1,2-diol

[0259] At room temperature, acetone (50 mL) was added to the solvent containing (R)-4-((2-methoxyethoxy)methyl)-2,2-dimethyl-1,3-dipentane in the previous step, followed by dilute hydrochloric acid (1.0 M, 49.6 mmol, 49.6 mL). The mixture was stirred at room temperature for 2 hours. The reaction was stopped by TLC. The organic phase was removed by rotary evaporation, and the aqueous phase was lyophilized to give the crude target compound (2.5 g, 22.9 mmol).

[0260] Step 3: (4R)-4-((methoxy-d3)methyl)-1,3,2-dioxothiacyclohexane 2-oxide

[0261] (S)-3-(methoxy-d3)propane-1,2-diol (2.5 g, 22.9 mmol) and triethylamine (11.6 g, 114.5 mmol) were dissolved in dichloromethane (50 mL). Under ice-water bath cooling and nitrogen protection, thionyl chloride (3.27 g, 27.5 mmol) was added. The mixture was stirred at 0 °C for 1 hour. The reaction solution was washed with saturated brine (30 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude target compound (3 g). The crude product was used directly in the next step.

[0262] Step 4: (R)-4-((methoxy-d3)methyl)-1,3,2-dioxothiacyclohexane 2,2-dioxide

[0263] (4R)-4-((methoxy-d3)methyl)-1,3,2-dioxothiacyclohexane 2-oxide (3 g, 19.4 mmol) was dissolved in dichloromethane (9 mL), acetonitrile (9 mL), and water (9 mL). Under ice-water bath cooling and nitrogen protection, sodium periodate (8.3 g, 38.8 mmol) and ruthenium trichloride (200 mg, 0.97 mmol) were added. The mixture was stirred at 0°C for 2 hours. The mixture was filtered, and the solid was washed with dichloromethane (30 mL). The liquid phase was extracted with dichloromethane (30 mL x 2) after adding saturated brine (50 mL). The organic phases were combined and washed successively with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the target compound (1.1 g, 6.4 mmol).

[0264] Step 5: 1-((1S,2S)-1-cyano-2-((methoxy-d3)methyl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0265] At 0°C, a 2.2 M lithium tert-butoxide solution in tetrahydrofuran (7.8 mL, 17.2 mmol) was slowly added dropwise to a tetrahydrofuran solution (20 mL) of (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (866 mg, 2.15 mmol) and (R)-4-(benzyloxy)methyl)-1,3,2-dioxothiacyclohexane 2,2-dioxide (1.1 g, 6.4 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched with 50% acetic acid aqueous solution, extracted with ethyl acetate (3 x 20 mL), and the organic phase was separated. The aqueous organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the target compound (300 mg, 0.63 mmol, yield: 29.5%), LCMS (ESI) m / z = 475.3 [M+H). + .

[0266] Step 6: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(Z)-N'-hydroxyaminocarbamoyl)-2-((methoxy-d3)methyl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0267] To a solution of 1-((1S,2S)-1-cyano-2-((methoxy-d3)methyl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (300 mg, 0.63 mmol) in ethanol (5 mL), hydroxylamine hydrochloride (88 mg, 1.26 mol) and triethylamine (191 mg, 1.89 mmol) were added. The mixture was heated at 80°C for 1 hour under nitrogen protection. After LCMS analysis showed the reaction was complete, ethyl acetate (20 mL), water (10 mL x 2), and saturated brine (10 mL x 2) were added. The mixture was dried and concentrated to give the crude target compound (287 mg). LCMS (ESI) m / z = 508.3 [M+H] + .

[0268] Step 7: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0269] To a THF (5 mL) solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-(Z)-N'-hydroxyaminocarbamoyl)-2-((methoxy-d3)methyl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (287 mg, 0.56 mmol), N,N-carbonyldiimidazole (180 mg, 1.12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (210 mg, 1.4 mmol) were added. The mixture was heated at 55 °C for 1 hour. After the reaction was complete as indicated by LCMS, ethyl acetate (30 mL) was added, followed by washing with water (10 mL x 2) and saturated brine (10 mL x 2). 2) The product was washed, dried, and concentrated to obtain an oily substance. Column chromatography yielded the target compound 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (240 mg, 0.45 mmol, yield 79.6%), LCMS (ESI) m / z = 534.3 [M+H]. + .

[0270] Step 8: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0271] Potassium hydroxide (720 mg, 12.8 mmol) was added to a n-butanol (5 mL) solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (240 mg, 0.45 mmol). The reaction was carried out in a microwave reactor at 120°C for 2 hours. After the reaction was completed, the target compound 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (100 mg, 0.45 mmol, yield 50%) was obtained by reverse-phase preparation and purification. The LCMS (ESI) m / z was 445.3 [M+H]. + .

[0272] Step 9: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0273] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50 mg, 0.23 mmol), 1-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyrazol N,N-diisopropylethylamine (89 mg, 0.69 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethylurea hexafluorophosphate (131 mg, 0.35 mmol) were added to a 2 mL solution of N,N-dimethylformamide containing 53 mg (53 mg, 0.23 mmol) of pyridin-3-yl)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabor-5-yl)-1,3-dihydroxy-2H-imidazol-2-one (2 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, 50 mL of water was added, and the solution was diluted with ethyl acetate (3x) Extracted with 20 mL of solution, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase extraction to give compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxazol-5-yl) -2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 0.33 mmol, yield: 29.7%) LCMS (ESI) m / z = 900.4 [M+H] + .

[0274] 1H NMR(400MHz,DMSO)δ12.02(d,J=177.3Hz,1H),9.24(s,1H),7.88–7.64(m,3H),7.62–7.35 (m,3H),7.29–7.12(m,3H),7.02(t,J=23.4Hz,1H),6.90–6.71(m,1H),5.78–5.55(m,1H), 5.03(s,2H),4.40(d,J=13.7Hz,1H),3.85–3.50(m,4H),3.30–2.71(m,5H),2.37(s,1H),2 .21(s,6H),2.05–1.50(m,7H),1.40(d,J=6.5Hz,1H),1.27(d,J=7.1Hz,3H),1.19(s,3H).

[0275] Referring to Example B38, the following compounds were synthesized.

[0276] Example B40:

[0277] Reaction route:

[0278] Experimental steps:

[0279] Step 1: (allyloxy)cyclopropane

[0280] At 0–5°C, cyclopropanol (2 g, 34.4 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen protection. Sodium hydrogen hydride (2.76 g, 68.9 mmol, 60% purity) was added in portions. After stirring in an ice-water bath for 35 minutes, 3-bromoprop-1-ene (8.3 g, 68.9 mmol) was added dropwise. After stirring for 10 minutes, the ice-water bath was removed, and the mixture was allowed to return to room temperature naturally before being refluxed at 68°C overnight. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with an ice-cold saturated ammonium chloride aqueous solution (40 mL), and extracted to separate the layers. The resulting organic phase was used directly in the next reaction step.

[0281] Step 2: 3-Cyclopropoxypropane-1,2-diol

[0282] Add water (50 mL), potassium osmium tetroxide dihydrate (1.26 g, 3.44 mmol), potassium ferricyanide (33.6 g, 10.3 mmol), and potassium carbonate (14 g, 10.3 mmol) to the organic phase from the previous step, and stir overnight at room temperature. After the reaction is complete, add sodium sulfite (5.3 g, 4.30 mmol) to the reaction solution, extract with ethyl acetate (20 x 3), wash with a small amount of saturated ammonium chloride aqueous solution, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the target product (1.2 g, 9.1 mmol, yield: 26.4%).

[0283] Steps 3-9: Following steps 3-9 of Example B38, the target compound was obtained, with LCMS (ESI) m / z = 923.4 [M+H]. + . 1 H NMR (400MHz, DMSO) δ12.14(s,1H),9.24(s,1H),7.91–7.58(m,4H),7.42(d,J=40.8Hz,2H),7.26–7.00 (m,4H),6.82(s,1H),5.48(d,J=6.9Hz,1H),5.03(s,2H),4.33(d,J=13.1Hz,1H),3.95(d,J=6.9Hz,1H) ,3.77–3.66(m,2H),3.62–3.40(m,2H),3.23–2.76(m,4H),2.33(t,J=1.8Hz,1H),2.20(s,6H),1.84–1. 43(m,7H),1.32(d,J=6.7Hz,2H),1.28(s,3H),1.19(s,3H),0.46(d,J=23.2Hz,3H),0.33–0.25(m,1H).

[0284] Referring to Example B40, the following compounds were synthesized.

[0285] Example B43

[0286] Step 1: Ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid

[0287] Ethyl 5-bromo-1H-indole-3-carboxylic acid (10.00 g, 37.30 mmol) was added to 1,4-dioxane (250 mL) and water (25 mL), followed by 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentane (10.19 g, 48.49 mmol), potassium carbonate (15.46 g, 111.89 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.73 g, 3.73 mmol). The reaction mixture was stirred at 90 °C for 20 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (500 mL) was added. Extraction was performed with ethyl acetate (3 x 200 mL). The organic phases were combined, washed with saturated sodium chloride (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (8.00 g, 29.49 mmol, 79.0%). LC / MS (ESI) M / Z: 272.1 [M+H] + .

[0288] Step 2: Ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid

[0289] Ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid (8.00 g, 29.49 mmol) was added to a mixed solution of methanol (50 mL) and tetrahydrofuran (50 mL), followed by the addition of palladium on carbon (3.14 g, wt: 10%). The mixture was reacted overnight at room temperature under a hydrogen atmosphere with three purging cycles. The reaction solution was filtered and slurried with methanol to give the title compound (7.00 g, 25.61 mmol, 86.9%). LC / MS (ESI) M / Z: 274.1 [M+H] + .

[0290] Step 3: Ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid

[0291] Ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid (7.00 g, 25.61 mmol) was dissolved in dry N,N-dimethylformamide (100 mL) under nitrogen protection. Sodium hydride (1.54 g, 38.42 mmol, 60%) was slowly added at 0 °C, and the mixture was stirred at this temperature for 1 hour. Then, chloroacetonitrile (3.87 g, 51.22 mmol) was added, and the reaction was continued at room temperature for 5 hours. After the reaction was completed, the reaction was quenched by adding ammonium chloride solution (10 mL) at 0 °C, and water (300 mL) was added. The mixture was extracted with ethyl acetate (3 x 100 mL), the organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid column chromatography to give the title compound (7.50 g, 24.09 mmol, 94.1%). LC / MS(ESI)M / Z:313.2[M+H] + .

[0292] Step 4: 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid

[0293] Ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid (7.50 g, 24.09 mmol) was dissolved in a mixture of water (60 mL) and tetrahydrofuran (120 mL). A solution of lithium hydroxide monohydrate (1.51 g, 36.01 mmol) in water (10 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was stopped by LC-MS. The pH was adjusted to 4 with 1 mol / L hydrochloric acid, and water (100 mL) was added to the reaction solution. The precipitated solid was filtered to give the title compound (6.00 g, 21.10 mmol, 87.9%). LC / MS (ESI) M / Z: 285.2 [M+H] + .

[0294] Step 5: 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxamide

[0295] 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxylic acid (6.00 g, 21.10 mmol) was dissolved in N,N-dimethylformamide (100 mL), followed by N,N-diisopropylethylamine (8.18 g, 63.31 mmol), then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (12.03 g, 31.65 mmol). After 15 minutes at room temperature, N-methylaniline (3.39 g, 31.66 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was then analyzed by LCMS to confirm its completion. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (3 x 80 mL). The organic phases were combined, washed with saturated sodium chloride (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (5.50 g, 14.73 mmol, 69.8%). LC / MS (ESI) M / Z: 374.1 [M+H] + .

[0296] Step 6: 1-((1S,2S)-1-cyano-2-(cyclopropoxymethyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxamide

[0297] 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carboxamide (2.00 g, 5.36 mmol) was dissolved in tetrahydrofuran (25 mL). Compound (R)-4-(cyclopropoxymethyl)-1,3,2-dioxothiocyclopentane-2,2-dioxide (3.12 g, 16.07 mmol) was added at 0 °C, followed by lithium tert-butoxide (19.47 mL, 2.2 mol / L). The reaction was allowed to proceed overnight at room temperature, and the reaction was confirmed by LC-MS. The reaction was quenched at 0 °C with 50% acetic acid solution. The mixture was extracted with water (100 mL) and ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (1.6 g, 3.41 mmol, 63.6%). LC / MS (ESI) M / Z: 470.1 [M+H] + .

[0298] Steps 7-10 are performed following steps 6-9 of Example B38 to obtain the target product. LCMS(ESI) m / z = 895.4 [M+H] + .

[0299] Referring to Example B43, the following compound was synthesized.

[0300] Example B62

[0301] Step 1: (2-bromo-5-iodophenyl)methane-d2-ol

[0302] Methyl 2-bromo-5-iodobenzoate (340 mg, 1.0 mmol) was dissolved in 10 mL of tetrahydrofuran. Lithium aluminum hydride (42 mg, 1.0 mmol) was added at 0 °C. After reacting for half an hour, the starting material was observed to disappear by TLC. 0.04 mL of water and 0.04 mL of 15% sodium hydroxide solution were added, followed by 0.13 mL of water. After stirring for 10 minutes, the ice bath was removed, and the filtrate was filtered. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-30% ethyl acetate) to obtain the target product (180 mg, 0.57 mmol, yield: 57.1%).

[0303] Steps 2-5 were performed following steps 1-4 of Example A1 to obtain the target compound. LCMS (ESI) m / z = 925.4 [M+H] + .

[0304] Example C1:

[0305] Reaction route:

[0306] Operating steps:

[0307] Step 1: Methyl (1-fluorocyclopropyl) methanesulfonate

[0308] At 0°C, (1-fluorocyclopropyl)methanol (5.0 g, 55.5 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (11.2 g, 111 mmol) was added. After stirring for 10 minutes, methanesulfonyl chloride (7.63 g, 66.6 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-30% ethyl acetate) to give the target product (8.5 g, 50.6 mmol, yield: 91.1%).

[0309] 1 H NMR (400MHz, CDCl3) δ4.51–4.48(m,1H),4.46–4.43(m,1H),3.10(s,3H),1.30–1.17(m,2H),0.92–0.81(m,2H).

[0310] Step 2: (R)-4-(((1-fluorocyclopropyl)methoxy)methyl)-2,2-dimethyl-1,3-dioxolane

[0311] At 0°C, (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol (6.3 g, 47.7 mmol) was dissolved in N,N-dimethylformamide (90 mL), and sodium hydride (3.82 g, 95.34 mmol, 60% wt) was added. After stirring for 30 minutes, methyl (1-fluorocyclopropyl)methanesulfonate (8.5 g, 50.6 mmol) was added, and the reaction mixture was stirred at 75°C for 2 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-30% ethyl acetate) to give the target product (7.0 g, 34.3 mmol, yield: 72.0%).

[0312] 1 H NMR (400MHz, DMSO) δ4.23–4.14(m,1H),4.02–3.96(m,1H),3.74(s,1H),3.68(s,1H),3.65–3. 59(m,1H),3.56–3.47(m,2H),1.32(s,3H),1.27(s,3H),1.04–0.94(m,2H),0.76–0.67(m,2H).

[0313] Step 3: (S)-3-((1-fluorocyclopropyl)methoxy)propane-1,2-diol

[0314] At room temperature, (R)-4-(((1-fluorocyclopropyl)methoxy)methyl)-2,2-dimethyl-1,3-dioxolane (7.0 g, 34.3 mmol) was dissolved in acetone (35 mL), and then dilute hydrochloric acid (1.0 M, 68.6 mmol, 68.6 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was stopped by TLC. The acetone was removed by rotary evaporation, and the crude target compound (5.5 g, 33.5 mmol) was obtained by lyophilization.

[0315] Step 4: (4R)-4-(((1-fluorocyclopropyl)methoxy)methyl)-1,3,2-dioxothiacyclohexane 2-oxide

[0316] (S)-3-((1-fluorocyclopropyl)methoxy)propane-1,2-diol (5.5 g, 33.5 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (16.9 g, 167.5 mmol) was added. Under ice-water bath cooling and nitrogen protection, thionyl chloride (4.79 g, 40.3 mmol) was added. The mixture was stirred at 0°C for half an hour. The reaction solution was washed with saturated brine (30 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude target compound (7.0 g). The crude product was used directly in the next step.

[0317] Step 5: (R)-4-(((1-fluorocyclopropyl)methoxy)methyl)-1,3,2-dioxane-2,2-dioxide

[0318] (4R)-4-(((1-fluorocyclopropyl)methoxy)methyl)-1,3,2-dioxothiacyclohexane 2-oxide (7.0 g, 33.3 mmol) was dissolved in dichloromethane (20 mL), acetonitrile (20 mL), and water (20 mL). Under ice-water bath cooling and nitrogen protection, sodium periodate (14.3 g, 66.7 mmol) and ruthenium trichloride hydrate (345 mg, 1.67 mmol) were added. The mixture was stirred at 0°C for 2 hours. The mixture was filtered, the solid was washed with dichloromethane (30 mL), and the liquid phase was extracted with dichloromethane (30 mL x 2) after adding saturated brine (50 mL). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-30% ethyl acetate) to give the crude target product (6.0 g, 26.5 mmol).

[0319] 1 H NMR (400MHz, DMSO) δ4.23–4.14(m,1H),4.02–3.96(m,1H),3.74(s,1H),3.68(s,1H),3.65–3. 59(m,1H),3.56–3.47(m,2H),1.32(s,3H),1.27(s,3H),1.04–0.94(m,2H),0.76–0.67(m,2H).

[0320] Step 6: 1-((1S,2S)-1-cyano-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0321] Under nitrogen protection at 0°C, 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (1.3 g, 3.49 mmol) and (R)-4-(((1-fluorocyclopropyl)methoxy)methyl)-1,3,2-dioxothiacyclohexane 2,2-dioxide (2.36 g, 10.5 mmol) were dissolved in tetrahydrofuran solution (10 mL), and 2.2 M lithium tert-butoxide tetrahydrofuran solution (12.67 mL, 27.9 mmol) was slowly added dropwise. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched with 50% acetic acid aqueous solution, extracted with ethyl acetate (3 x 20 mL), the organic phase was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the title compound (1.1 g, 2.20 mmol, yield: 63.1%), LCMS (ESI) m / z = 502.3 [M+H). + .

[0322] Step 7:

[0323] 1-((1S,2S)-2-(((1-fluorocyclopropyl)methoxy)methyl)-1-((Z)-N'-hydroxycarbamoyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0324] At room temperature, 1-((1S,2S)-1-cyano-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (1.1 g, 2.20 mmol) was dissolved in ethanol (10 mL), followed by the addition of hydroxylamine hydrochloride (305 mg, 4.40 mmol) and triethylamine (665 mg, 6.60 mmol). The mixture was heated and stirred at 80°C for 1 hour under nitrogen protection. LCMS showed that the reaction was complete. Ethyl acetate (20 mL) was added, followed by washing with water (10 mL x 2) and saturated brine (10 mL x 2) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (1.1 g, 2.06 mmol). LCMS (ESI) m / z = 535.3 [M+H] + .

[0325] Step 8: 1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0326] 1-((1S,2S)-2-(((1-fluorocyclopropyl)methoxy)methyl)-1-((Z)-N'-hydroxycarbamoyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (1.1 g, 2.06 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N-carbonyldiimidazole (667 mg, 4.12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (783 mg, 5.15 mmol) were added. The mixture was heated and stirred at 55°C for 1 hour. After the reaction was complete as indicated by LCMS, ethyl acetate (30 mL) was added, followed by water (10 mL x 2) and saturated brine (10 mL x 2) in sequence. 2) The organic phase was washed, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. Column chromatography yielded the title compound (900 mg, 1.61 mmol, yield 78.1%), LCMS (ESI) m / z = 561.3 [M+H]. + .

[0327] Step 9: 1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0328] 1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (900 mg, 1.61 mmol) was dissolved in n-butanol (18 mL), and potassium hydroxide (1.35 g, 24.1 mmol) was added. The reaction was stirred at 125 °C for 4.5 h. After the reaction was completed, the title compound (400 mg, 0.85 mmol, yield 52.8%) was purified by reverse-phase chromatography, LCMS (ESI) m / z = 472.3 [M+H] + .

[0329] Step 10: 3-((1S,2S)-1-(2-(4S)-3-(3-(1-cyclopropyl-4-fluoro-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-indol-1-yl)-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0330] 1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (90 mg, 0.191 mmol), 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4S)-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 (98 mg, 0.191 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (99 mg, 0.764 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (87 mg, 0.229 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography to give the target compound (108 mg, 0.11 mol, yield: 58.4%). LCMS(ESI)m / z = 969.4 [M+H] + .

[0331] 1H NMR (400MHz, DMSO) δ12.29–11.63(m,1H),8.34–8.13(m,1H),7.73–7.32(m,4H),7.21–6.91(m,5H),6.84 –6.71(m,1H),5.84–5.49(m,1H),4.70–4.35(m,1H),4.00–3.94(m,2H),3.88–3.73(m,2H),3.69–3.58(m, 2H),3.56–3.40(m,4H),2.94–2.68(m,3H),2.26(s,6H),2.13–1.96(m,1H),1.91–1.80(m,1H),1.78–1.6 6(m,5H),1.47–1.42(m,1H),1.38–1.23(m,2H),1.19–1.09(m,4H),1.04–0.92(m,2H),0.75–0.64(m,2H).

[0332] Example C2:

[0333] Reaction route:

[0334] Operating steps:

[0335] Step 1: (E)-1-(bicyclo[1.1.1]pentan-1-yl)-2-(3,6-dibromo-2-fluorobenzyl)hydrazine was dissolved in acetic acid (30 mL) under nitrogen protection. (E)-1-(bicyclo[1.1.1]pentane-1-hydrazine (2 g, 11.7 mmol) was added. After stirring at room temperature for 17 hours overnight, the mixture was diluted with water (30 mL), filtered, and the filter cake was concentrated and dried under reduced pressure to obtain the crude target compound (340 mg). LCMS (ESI) m / z = 361.1, 363.1 [M+H] + .

[0336] Step 2: (E)-1-(bicyclo[1.1.1]pentan-1-yl)-5-bromo-4-fluoro-1H-indazole

[0337] (E)-1-(bicyclo[1.1.1]pent-1-yl)-2-(3,6-dibromo-2-fluorobenzyl)hydrazine (340 mg, 0.94 mmol) was dissolved in 1,3-dimethyl-2-imidazolinone (7 mL), and cuprous chloride (279 mg, 2.82 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (429 mg, 2.82 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was extracted with water (30 mL) and dichloromethane (50 mL), and the organic phase was washed successively with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–8% ethyl acetate) to give the target product (87 mg, 0.31 mmol). LCMS (ESI) m / z = 281.1, 283.1 [M+H] + .

[0338] Step 3: (4S)-3-(3-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-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

[0339] Dissolve (E)-1-(bicyclo[1.1.1]pent-1-yl)-5-bromo-4-fluoro-1H-indazole (72 mg, 0.256 mmol) in N-methylpyrrolidone (3 mL), then add (4S)-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 (113 mg, 0.256 mmol), potassium carbonate (106 mg, 0.768 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (18 mg, 0.128 mmol), and cuprous iodide (10.0 mg, 0.051 mmol) were reacted at 130°C for 3 hours. After the reaction, the solution was poured into 10 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound (50 mg, 0.078 mmol, yield: 30.5%) as a brown solid. LCMS (ESI) m / z = 642.3 [M+H] + .

[0340] Step 4: 1-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-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

[0341] (4S)-3-(3-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-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 (50 mg, 0.078 mmol) was dissolved in dichloromethane (2 mL), and 4M dioxane hydrochloride solution (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to obtain the crude product of the target compound (40 mg, crude), a yellow solid. LCMS (ESI) m / z = 542.3 [M+H] + .

[0342] Step 5: 3-((1S,2S)-1-(2-(4S)-3-(3-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-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-indole-1-yl)-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0343] 1-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-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 (20 mg crude) was dissolved in N,N-dimethylformamide (2 mL), and 1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methoxy The reaction mixture consisted of methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (18 mg, 0.037 mmol), N,N-diisopropylethylamine (19 mg, 0.148 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (17 mg, 0.044 mmol), and was stirred overnight at room temperature. After the reaction was completed, the reaction solution was purified by reverse-phase preparation to obtain compound 3-((1S,2S)-1-(2-(4S)-3-(3-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazole-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-indole-1-yl)-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (4 mg, 0.004 mmol, yield: 10.9%). LCMS(ESI)m / z=995.4[M+H] + .

[0344] Example C3:

[0345] Reaction route:

[0346] Experimental steps:

[0347] Step 1: 1-((1S,2S)-1-cyano-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-5-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0348] Under nitrogen protection at 0°C, (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1.4 g, 3.49 mmol) and (R)-4-(((1-fluorocyclopropyl)methoxy)methyl)-1,3,2-dioxothiacyclohexane 2,2-dioxide (2.36 g, 10.5 mmol) were dissolved in tetrahydrofuran (10 mL), and a 2.2 M solution of lithium tert-butoxide in tetrahydrofuran (12.67 mL, 27.9 mmol) was slowly added dropwise. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched with 50% acetic acid aqueous solution, extracted with ethyl acetate (3 x 20 mL), and the organic phase was separated. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the title compound (1.16 g, 2.20 mmol, yield: 62.8%), LCMS (ESI) m / z = 530.3 [M+H). + .

[0349] Step 2: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-(((1-fluorocyclopropyl)methoxy)methyl)-1-((Z)-N'-hydroxycarbamoyl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0350] 1-((1S,2S)-1-cyano-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-5-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1.16 g, 2.20 mmol) was dissolved in ethanol (10 mL), and hydroxylamine hydrochloride (305 mg, 4.39 mol) and triethylamine (665 mg, 6.59 mmol) were added. The mixture was heated and stirred at 80°C for 1 hour under nitrogen protection. After the reaction was complete as indicated by LCMS, ethyl acetate (20 mL) was added, followed by washing with water (10 mL x 2) and saturated brine (10 mL x 2) successively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (1.16 g, 2.06 mmol). LCMS (ESI) m / z = 563.3 [M+H] + .

[0351] Step 3: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0352] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-(((1-fluorocyclopropyl)methoxy)methyl)-1-((Z)-N'-hydroxycarbamoyl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1.16 g, 2.06 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N-carbonyldiimidazole (667 mg, 4.12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (783 mg, 5.15 mmol) were added. The mixture was heated and stirred at 55 °C for 1 hour. After the reaction was complete as indicated by LCMS, ethyl acetate (30 mL) was added, followed by water (10 mL x 2) and saturated brine (10 mL x 2) in sequence. 2) Wash, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain an oily substance, and column chromatography to give the title compound (947 mg, 1.61 mmol, yield 78.1%), LCMS (ESI) m / z = 589.3 [M+H] + .

[0353] Step 4: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0354] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (947 mg, 1.61 mmol) was dissolved in n-butanol (18 mL), and potassium hydroxide (1.35 g, 24.1 mmol) was added. The reaction mixture was stirred at 125 °C for 4.5 h. After the reaction was completed, the title compound (424 mg, 0.85 mmol, yield 52.8%) was purified by reverse-phase chromatography. LCMS (ESI) m / z = 500.3 [M+H] + .

[0355] Step 5: 3-((1S,2S)-1-(2-(4S)-3-(3-(1-cyclopropyl-4-fluoro-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-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-(((1-fluorocyclopropyl)methoxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0356] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((1-fluorocyclopropyl)methoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (95 mg, 0.191 mmol), 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4S)-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 (98 mg, 0.191 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (99 mg, 0.764 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (87 mg, 0.229 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography to give the target compound (110 mg, 0.11 mol, yield: 58.0%). LCMS(ESI)m / z = 997.4 [M+H] + .

[0357] 1H NMR(400MHz,DMSO)δ12.02(d,J=461.1Hz,1H),8.33–8.19(m,1H),7.71–7.58(m,1H),7.57–7.32(m,3H), 7.22–6.91(m,5H),6.76(s,1H),5.79–5.17(m,1H),4.86–4.36(m,1H),3.92–3.60(m,6H),3.57–3.39(m, 2H),3.10–2.70(m,3H),2.26(s,6H),2.16–1.96(m,1H),1.93–1.80(m,1H),1.79–1.64(m,3H),1.61–1.5 1(m,2H),1.48–1.30(m,3H),1.29–1.18(m,6H),1.17–1.10(m,4H),1.05–0.91(m,2H),0.75–0.62(m,2H).

[0358] Example C4:

[0359] Reaction route:

[0360] Experimental steps:

[0361] Step 1: (S)-1-(((1-cyanopropyl-2-yl)amino)methyl)cyclopropane-1-carboxylic acid methyl ester

[0362] 5 g (39.2 mmol) of methyl 1-formylcyclopropane-1-carboxylate and 4.7 g (39.2 mmol) of (S)-3-aminobutyronitrile hydrochloride were dissolved in 200 mL of dichloromethane. Anhydrous sodium acetate (3.3 g, 39.2 mmol) and sodium triacetoxyborohydride (8.3 g, 39.2 mmol) were then added at 0°C. The reaction was carried out overnight at room temperature under nitrogen protection. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, the pH was adjusted to 8–9, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude target compound (7.7 g). This crude compound was used directly in the next reaction without further purification. LCMS (ESI) m / z = [M + H] + =197.2.

[0363] Step 2: (S)-1-(((tert-Butoxycarbonyl)(1-cyanopropyl-2-yl)amino)methyl)cyclopropane-1-carboxylic acid methyl ester

[0364] Methyl (S)-1-(((1-cyanopropyl-2-yl)amino)methyl)cyclopropane-1-carboxylic acid (7.7 g, 39.2 mmol) was dissolved in dichloromethane (180 mL), followed by the addition of triethylamine (7.9 g, 78.4 mmol) and di-tert-butyl dicarbonate (12.8 g, 58.8 mmol) at room temperature, and the mixture was stirred overnight at room temperature. After the reaction was complete, water (200 mL) was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain the target compound (6.3 g, 21.2 mmol, yield: 54.5%), LCMS (ESI) m / z = 297.2 [M+H). + .

[0365] Step 3: (6S)-7-cyano-6-methyl-8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester

[0366] Methyl (S)-1-(((tert-Butoxycarbonyl)(1-cyanopropyl-2-yl)amino)methyl)cyclopropane-1-carboxylic acid (6.3 g, 21.2 mmol) was dissolved in tetrahydrofuran (130 mL). Under nitrogen protection, sodium bis(trimethylsilyl)amino (2.0 M in THF solution, 21.5 mL, 43 mmol) was added dropwise at -20°C, maintaining the internal temperature below -10°C during the addition. After the addition was complete, the mixture was slowly brought back to room temperature and stirred for 30 min. After the reaction was completed, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-15% ethyl acetate) to obtain the target compound (4.7 g, 17.7 mmol, yield: 83.7%), LCMS (ESI) m / z = 265.2 [M+H). + .

[0367] Step 4: (S)-3'-amino-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-tert-butyl carboxylate

[0368] 4.7 g (17.7 mmol) of (6S)-7-cyano-6-methyl-8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester, 4-fluoro-3,5-dimethylphenylhydrazine hydrochloride (5.1 g (26.6 mmol)), and pyridine hydrochloride (206 mg (1.77 mmol) were dissolved in 100 mL of ethanol and reacted at 80 °C for 5 hours under nitrogen protection. After the reaction was complete, the solvent was concentrated to dryness, and 200 mL of ethyl acetate was added. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain the target compound (2.3 g, 5.7 mmol, yield: 32.3%), LCMS (ESI) m / z = 401.2 [M+H). + .

[0369] Step 5: (S)-3'-(3-(2,2-dimethoxyethyl)ureo)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-tert-butyl carboxylate

[0370] Compound (S)-3'-amino-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (1.22 g, 3.0 mmol) was dissolved in pyridine (120 mL), and 2-isocyano-1,1-dimethoxyethane (2 g, 15 mmol) was added under ice-water bath. The reaction was carried out at room temperature for 5 hours. After the reaction was completed, the solution was directly evaporated to dryness and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-25% ethyl acetate) to obtain the target compound ((1.1 g, 2.1 mmol, yield: 67.9%), LCMS (ESI) m / z = 532.3 [M+H)). +

[0371] Step 6: (4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-tert-butyl carboxylate

[0372] Weigh out 1.1 g (2.1 mmol) of compound (S)-3'-(3-(2,2-dimethoxyethyl)ureo)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester and dissolve it in tetrahydrofuran (40 mL). Under nitrogen protection, add methanesulfonic acid (200 mg, 2.1 mmol) and stir at 60 degrees Celsius for 4 hours. After cooling to room temperature, the pH was adjusted to 8–9 with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–30% ethyl acetate) to give the target compound (700 mg, 1.5 mmol, yield: 72.3%), LCMS (ESI) m / z = 468.2 [M+H). + .

[0373] Steps 7-9 refer to Steps 3-5 of Example C2 to obtain the target compound 3-((1S,2S)-1-(2-((4'S)-3'-(3-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-(methoxy-d-3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one. LCMS(ESI)m / z = 966.4 [M+H] + .

[0374] 1H NMR (400MHz, DMSO) δ12.18(s,1H),8.36–8.27(m,1H),7.79–7.53(m,2H),7.52–7.44(m,1H),7.43–7.30(m,1H),7.29–7.17( m,1H),7.16–7.01(m,3H),7.01–6.87(m,1H),6.84–6.62(m,1H),5.93–5.58(m,1H),4.03–3.90(m,2H),3.82–3.67(m,1H),3. 51–3.40(m,2H),2.96–2.79(m,1H),2.74(s,1H),2.47(s,5H),2.23(s,6H),2.07–1.93(m,1H),1.89–1.58(m,6H),1.55–1.46 (m,1H),1.43(s,1H),1.37(d,J=6.6Hz,3H),1.31–1.20(m,2H),1.16(t,J=7.2Hz,1H),1.09–0.95(m,1H),0.93–0.72(m,2H).

[0375] The following compounds were synthesized according to Example C1.

[0376] Example C12

[0377] Reaction route:

[0378] Operating steps:

[0379] Step 1: (R)-4-((methoxy-d3)methyl)-2,2-dimethyl-1,3-dioxolane

[0380] Sodium hydride (5.2 g, 128.6 mmol, 60% purity) was added to a tetrahydrofuran (100 mL) solution of (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol (8.5 g, 64.3 mmol). After stirring for 30 minutes, deuterated iodomethane (14 g, 96.5 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed successively with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-30% ethyl acetate) to give the crude target product (6.3 g).

[0381] Step 2: (S)-3-(methoxy-d3)propane-1,2-diol

[0382] At room temperature, (R)-4-((methoxy-d3)methyl)-2,2-dimethyl-1,3-dioxolane (6.3 g, 42.2 mmol) was dissolved in acetone (50 mL), and then dilute hydrochloric acid (1.0 M, 84.5 mmol, 84.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was stopped by TLC. The acetone was removed by rotary evaporation, and the aqueous phase was lyophilized to obtain the crude target compound (4.61 g).

[0383] Step 3: (4R)-4-((methoxy-d3)methyl)-1,3,2-dioxothiacyclohexane 2-oxide

[0384] (S)-3-(methoxy-d3)propane-1,2-diol (4.61 g, 42.2 mmol) and triethylamine (17.06 g, 168.9 mmol) were dissolved in dichloromethane (100 mL). Under ice-water bath cooling and nitrogen protection, thionyl chloride (6.03 g, 50.6 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction solution was washed with saturated brine (50 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude target compound (5.2 g). The crude product was used directly in the next step.

[0385] Step 4: (R)-4-((methoxy-d3)methyl)-1,3,2-dioxothiacyclohexane 2,2-dioxide

[0386] (4R)-4-((methoxy-d3)methyl)-1,3,2-dioxothiacyclohexane 2-oxide (5.2 g, 33.3 mmol) was dissolved in dichloromethane (15 mL), acetonitrile (15 mL), and water (15 mL). Under ice-water bath cooling and nitrogen protection, sodium periodate (14.3 g, 66.6 mmol) and ruthenium trichloride hydrate (345 mg, 1.67 mmol) were added. The mixture was stirred at 0°C for 2 hours. The mixture was filtered, the solid was washed with dichloromethane (50 mL), and the liquid phase was extracted with dichloromethane (50 mL x 2) after adding saturated brine (50 mL). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the target product (3.6 g, 21.0 mmol, yield: 62.8%).

[0387] Step 5: 1-((1S,2S)-1-cyano-2-((methoxy-d3)methyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0388] Under nitrogen protection at 0°C, 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (1.96 g, 5.26 mmol) and (R)-4-(methoxy)methyl)-1,3,2-dioxothiacyclohexane 2,2-dioxide (3.6 g, 21.1 mmol) were dissolved in tetrahydrofuran (30 mL), and a 2.2 M solution of lithium tert-butoxide in tetrahydrofuran (19.2 mL, 42.1 mmol) was slowly added dropwise. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched with 50% acetic acid aqueous solution, extracted with ethyl acetate (3 x 50 mL), and the organic phase was separated. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to give the target compound (730 mg, 1.64 mmol, yield: 31.2%), LCMS (ESI) m / z = 447.3 [M+H). + .

[0389] Step 6: 1-((1S,2S)-1-((Z)-N'-hydroxyaminocarbamoyl)-2-((methoxy-d3)methyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0390] 1-((1S,2S)-1-cyano-2-((methoxy-d3)methyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (730 mg, 1.64 mmol) was dissolved in ethanol (7 mL), and hydroxylamine hydrochloride (228 mg, 3.28 mol) and triethylamine (496 mg, 4.91 mmol) were added. The reaction was carried out at 80°C for 1 hour under nitrogen protection. After the reaction was complete as indicated by LCMS, ethyl acetate (30 mL) was added, followed by washing with water (20 mL x 2) and saturated brine (10 mL x 2) successively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude target compound (786 mg). LCMS (ESI) m / z = 480.2 [M+H] + .

[0391] Step 7: 1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0392] Will

[0393] In a THF (5 mL) solution of 1-((1S,2S)-1-((Z)-N'-hydroxyaminocarbamoyl)-2-((methoxy-d3)methyl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (786 mg, 1.64 mmol), N,N-carbonyldiimidazole (532 mg, 3.28 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (624 mg, 4.1 mmol) were added. The mixture was heated at 55°C for 1 hour. After the reaction was complete as indicated by LCMS, ethyl acetate (30 mL) was added, followed by water (20 mL x 2) and saturated saline solution (10 mL x 2). 2) The organic phase was washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily substance. The oil was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-40% ethyl acetate) to obtain the target compound (650 mg, 1.29 mmol, yield 78.5%), LCMS (ESI) m / z = 506.3 [M+H). + .

[0394] Step 8: 1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0395] 1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (650 mg, 1.29 mmol) was dissolved in n-butanol (15 mL), and potassium hydroxide (1.09 g, 19.35 mmol) was added. The reaction was carried out at 125 °C for 5 hours. After the reaction was completed, the target compound (240 mg, 0.58 mmol, yield 44.7%) was obtained by reverse-phase synthesis and purification. LCMS (ESI) m / z = 417.2 [M+H] + .

[0396] Step 9: 3-((1S,2S)-1-(2-((4S)-3-(3-(1-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1H-indol-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-indol-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxazol-5(4H)-one

[0397] 1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (50 mg, 0.12 mmol), 1-(1-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1H-indoleazol-5-yl)-3-((4S)-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 (65 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (47 mg, 0.36 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (69 mg, 0.18 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography to give the target compound (30 mg, 0.032 mol, yield: 26.5%). LCMS(ESI)m / z = 940.4 [M+H] + .

[0398] 1H NMR (400MHz, DMSO) δ12.03(d,J=175.2Hz,1H),8.34(s,1H),7.78–7.70(m,1H),7.56–7.42(m,2H ),7.32–7.15(m,3H),7.02(d,J=49.6Hz,2H),6.84(d,J=65.8Hz,2H),5.67(d,J=60.7Hz,1H),4.4 0(d,J=13.6Hz,1H),4.13–3.72(m,3H),3.70–3.54(m,1H),3.46(s,2H),3.31–3.10(m,2H),3.02– 2.69(m,4H),2.47(s,6H),2.26(s,6H),2.06–1.93(m,1H),1.81–1.68(m,5H),1.48–1.27(m,3H).

[0399] The following compounds were synthesized according to Example C12.

[0400] The following compounds were synthesized according to Example B40.

[0401] Example C13:

[0402] Reaction route:

[0403] Experimental steps:

[0404] Step 1: 3-((1S,2S)-1-(2-((4S)-3-(3-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-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-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0405] At room temperature, 1-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-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 (100 mg, 0.18 mmol) and 5-( (S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (82 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (2 mL), and the reaction mixture was stirred overnight at room temperature. N,N-diisopropylethylamine (70 mg, 0.54 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (103 mg, 0.27 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography to give the target compound (80 mg, 0.08 mmol, yield: 44.8%). LCMS (ESI) m / z = 968.4 [M+H] + .

[0406] 1 H NMR (400MHz, DMSO) δ12.27–11.85(m,1H),8.34(s,1H),7.73(d,J=9.0Hz,1H),7.53–7.43(m,2H),7. 27–7.16(m,3H),7.01(d,J=51.9Hz,2H),6.93–6.83(m,1H),6.81–6.70(m,1H),5.67(d,J=61.1Hz,1 H),4.40(d,J=13.4Hz,1H),3.72(d,J=8.4Hz,3H),3.06–3.00(m,1H),2.74(s,2H),2.48(s,6H),2.2 5(s,6H),1.72–1.64(m,3H),1.59–1.51(m,2H),1.48–1.41(m,2H),1.33–1.23(m,8H),1.18(s,4H).

[0407] Example C18:

[0408] Reaction route:

[0409] Experimental steps:

[0410] Using (3-fluorobicyclo[1.1.1]pentan-1-yl)hydrazine dihydrochloride as the starting material, the target compound C18 was synthesized according to Example C2. LCMS (ESI) m / z = 1013.4 [M+H] + .

[0411] The following compounds were synthesized according to Example C18.

[0412] Example C22

[0413] Reaction route:

[0414] Operating steps:

[0415] Steps 1-2 were performed according to Steps 1-2 of Example C2 to synthesize the target compound 5-bromo-4-fluoro-1-(3-methoxybicyclo[1.1.1]pent-1-yl)-1H-indazole. LCMS (ESI) m / z = 311.3 [M+H] + .

[0416] Step 3: (4S)-3-(3-(4-fluoro-1-(3-methoxybicyclo[1.1.1]pent-1-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-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] 5-Bromo-4-fluoro-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1H-indazole (300 mg, 0.96 mol) was dissolved in N-methylpyrrolidone (5 mL), and (4S)-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 (423 mg, 0.96 mmol), potassium carbonate (398 mg, 2.89 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (68 mg, 0.5 mmol) and cuprous iodide (37 mg, 0.2 mmol) were reacted at 90°C for 3 hours. After the reaction was complete, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the target compound (195 mg, 0.29 mmol, yield: 30.0%) as a white solid. LCMS (ESI) m / z = 672.3 [M+H] + .

[0418] Step 4: 1-(4-fluoro-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1H-indoleazol-5-yl)-3-((4S)-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

[0419] (4S)-3-(3-(4-fluoro-1-(3-methoxybicyclo[1.1.1]pent-1-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-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 (94 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), and 4M dioxane hydrochloride solution (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product (70 mg), a yellow solid. LCMS (ESI) m / z = 572.3 [M+H] + .

[0420] Step 5: 3-((1S,2S)-1-(2-((4S)-3-(3-(4-fluoro-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-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-pyrazol[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0421] Dissolve 70 mg crude of 1-(4-fluoro-1-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1H-indolezol-5-yl)-3-((4S)-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 in N,N-dimethylformamide (2 mL), and add 1-((1S,2S)-2- Methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyridine-4-yl)-1H-indole-2-carboxylic acid (54 mg, 0.14 mmol), N,N-diisopropylethylamine (36 mg, 0.28 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (80 mg, 0.21 mmol) were reacted and stirred overnight at room temperature. After the reaction was complete, the reaction solution was purified by reverse-phase synthesis to obtain the target compound (56 mg, 0.06 mmol, yield: 41.4%). LCMS (ESI) m / z = 937.4 [M+H] + .

[0422] Example C25:

[0423] Reaction route:

[0424] Operating steps:

[0425] The target compound C25 was synthesized from 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide according to the procedure in Example B19. LCMS (ESI) m / z = 947.4 [M+H] +

[0426] Example C26:

[0427] Reaction route:

[0428] Operating steps:

[0429] Step 1: 3-oxabicyclo[3.1.0]hexyl-6-pinacol boronic acid ester

[0430] Chromium dichloride (3.16 g, 25.7 mmol) was dissolved in ultra-dry tetrahydrofuran (20 mL). Under nitrogen protection, tetramethylethylenediamine (2.99 g, 25.7 mmol) was added. After stirring at room temperature for 1 hour, diiodomethylpinacol boronic acid ester (2.53 g, 6.42 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, 2,5-dihydrofuran (300 mg, 4.28 mmol) was added to the reaction mixture, and the mixture was stirred at 50 °C for 18 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, diatomaceous earth was added, the mixture was stirred to precipitate, and the precipitate was filtered. The filtrate was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed successively with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-5% ethyl acetate) to give the target product (810 mg, 3.86 mmol). LCMS(ESI)m / z = 210.9[M+H] + .

[0431] 1 HNMR(400MHz, CDCl3), δ3.82(d,J=8.4Hz,2H),3.70(d,J=8.4Hz,2H),1.73(dt,J=4.8,1.2Hz,2H),1.23(s,12H),0.03-011(m,1H).(Trans:Cis=10:1)

[0432] Step 2: 3-oxabicyclo[3.1.0]hexyl-6-boronic acid

[0433] At room temperature, 3-oxabicyclo[3.1.0]hexyl-6-pinacolborate (810 mg, 3.86 mmol) was dissolved in a mixture of tetrahydrofuran (18 mL) and pure water (4.5 mL). Sodium periodate (2.48 g, 11.6 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. Hydrochloric acid aqueous solution (3 M, 4.5 mL) was then added, and the mixture was stirred at room temperature for 14 hours overnight. After the reaction was complete, the reaction solution was directly filtered. The filter cake was washed with tetrahydrofuran (5 mL x 2), and the filtrate was dried to remove the tetrahydrofuran. The filtrate was then dissolved in ethyl acetate (30 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude target compound (341 mg, 2.66 mmol). LCMS (ESI) m / z = 129.1 [M+H] +

[0434] Step 3: 1-(3-oxabicyclo[3.1.0]hexyl-6-)-5-bromo-4-fluoro-1H-indazole

[0435] 5-Bromo-4-fluoro-1H-indazole (170 mg, 0.79 mmol), 3-oxabicyclo[3.1.0]hexyl-6-boronic acid (200 mg, 1.57 mmol) were dissolved in 1,2-dichloroethane (10 mL), and copper acetate (144 mg, 0.79 mmol), 2,2′-bipyridine (124 mg, 0.79 mmol), and sodium carbonate (168 mg, 1.58 mmol) were added. The mixture was stirred overnight at 70 °C with an open container, and the solvent was replenished as needed to prevent it from drying out. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and extracted with water (20 mL) and dichloromethane (30 mL). The organic phase was washed successively with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-13% ethyl acetate) to give the target product (93 mg, 0.31 mmol) in the Trans configuration. No Cis configuration was detected. LCMS(ESI) m / z = 297.1 [M+H] +

[0436] 1 HNMR(400MHz, CDCl3)7.99(s,1H),7.48(dd,J=8.8,6.1Hz,1H),7.19(dd,J=8.8,0.8Hz, 1H),4.23(d,J=8.8Hz,2H),3.90(d,J=8.8Hz,2H),3.45-3.50(m,1H),2.44-2.48(m,2H).

[0437] Step 4: (4'S)-3'-(3-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazole[4,3-c]pyridine]-5'(6'H)-tert-butyl carboxylate

[0438] 1-(3-oxabicyclo[3.1.0]hexyl-6-)-5-bromo-4-fluoro-1H-indazole (30 mg, 0.101 mmol) was dissolved in N-methylpyrrolidone (2 mL), and (4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-di Hydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-tert-butyl carboxylate (47 mg, 0.101 mmol), potassium carbonate (45 mg, 0.303 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (7 mg, 0.051 mmol), and cuprous iodide (4 mg, 0.020 mmol). The reaction mixture was reacted at 130°C for 3 hours. After the reaction was complete, the reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound (35 mg, 0.051 mmol, yield: 50.5%) as a brown solid. LCMS(ESI)m / z = 684.4[M+H] + .

[0439] Step 5: 1-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-3-((4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0440] (4'S)-3'-(3-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazole[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (35 mg, 0.051 mmol) was dissolved in dichloromethane (2 mL), and 4 M dioxane hydrochloride solution (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product (25 mg), a yellow solid. LCMS (ESI) m / z = 584.3 [M+H] + .

[0441] Step 6: 3-((1S,2S)-1-(2-((4'S)-3'-(3-(1-(1R,5R)-3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0442] Dissolve 1-(1-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-fluoro-1H-indazol-5-yl)-3-((4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (25 mg, crude) in N,N-dimethylformamide (2 mL), and add 1-((1S, 2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (16 mg, 0.043 mmol), N,N-diisopropylethylamine (22 mg, 0.171 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (20 mg, 0.051 mmol) were reacted and stirred overnight at room temperature. After the reaction was complete, the reaction solution was purified by reverse-phase synthesis to obtain the target compound in the Trans configuration, i.e., C26-P1 (2.5 mg, 0.003 mmol, yield: 6.2%). LCMS (ESI) m / z = 949.4 [M+H] + .

[0443] 1H NMR (400MHz, DMSO) δ11.69(s,1H),8.31(s,1H),7.70(d,J=8.8Hz,1H),7.59(s,1H),7.49(d,J=8.3Hz,1H),7 .39(d,J=9.0Hz,1H),7.26(d,J=8.6Hz,1H),7.13(s,2H),7.06(s,1H),6.96(d,J=34.4Hz,2H),5.63(s,1H),4 .15(d,J=8.5Hz,2H),3.96(d,J=10.8Hz,2H),3.77(d,J=8.6Hz,2H),3.58(s,1H),3.46(s,2H),2.84(s,1H),2 .47(s,1H),2.24(s,7H),1.68(d,J=28.8Hz,9H),1.51(s,2H),1.37(d,J=8.9Hz,4H),1.13(d,J=29.0Hz,4H).

[0444] In this invention, there is The compounds in the examples of the group were all prepared into the corresponding intermediates through steps 1-3 of this example, and therefore all have the Trans configuration. This method is applicable to compounds of C27, C28, C30, C39, D2, D3, D4, D5, D7, and D10. Refer to Example C26 for the synthesis of the compound.

[0445] The compound was synthesized according to Example C25.

[0446] Example C34

[0447] Reaction route:

[0448] Operating steps:

[0449] Steps 1-4 were performed using (2-bromo-5-iodophenyl)methanol as the starting material, following steps 1-4 of Example A1, to synthesize the target compound C34. LCMS (ESI) m / z = 893.4 [M+H] +

[0450] 1H NMR (400MHz, DMSO) δ11.70(s,1H),9.24(s,1H),7.78(dd,J=36.3,25.1Hz,2H),7.63(d,J=23.9Hz,1H),7 .49(s,1H),7.38(d,J=8.8Hz,2H),7.25(d,J=9.1Hz,1H),7.12(d,J=5.5Hz,2H),6.88(s,1H),6.71(d,J= 32.2Hz,1H),5.45(d,J=143.9Hz,1H),5.07–4.87(m,2H),4.27–3.92(m,1H),3.89–3.63(m,3H),3.02(s, 1H),2.25–1.96(m,7H),1.76–1.43(m,9H),1.38–1.25(m,6H),1.16(d,J=19.6Hz,4H),1.12–0.73(m,3H)

[0451] The compound was synthesized according to Example C34.

[0452] Example C39

[0453] Reaction route:

[0454] Operating steps:

[0455] The target compound C39 was synthesized using 1,2-propanediol-D8 as the starting material, following steps 4-10 of Example C1. LCMS (ESI) m / z = 955.4 [M+H] +

[0456] Example C42

[0457] Reaction route:

[0458] Experimental steps:

[0459] Steps 1-9, referring to Example C12, yielded the target compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-3-(3-(4-fluoro-1-((R)-spiro[2.2]pentan-1-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-4H). - Ketones and 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(4S)-3-(3-(4-fluoro-1-(S)-spiro[2.2]pentan-1-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-4H)-ketones. LCMS(ESI) m / z=968.5[M+H] + .

[0460] Example D2

[0461] Reaction route:

[0462] Operating steps:

[0463] Steps 1-3, using 1-(3-oxabicyclo[3.1.0]hexane-6-yl)-5-bromo-4-fluoro-1H-indazole as the starting material, followed steps 4-6 of Example C26 to obtain the target product 3-((1S,2S)-1-(2-(4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazole-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-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one. LCMS(ESI) m / z = 951.4 [M+H] +

[0464] 1H NMR (400MHz, DMSO) δ11.75(s,1H),8.31(s,1H),7.70(d,J=8.8Hz,1H),7.58–7.44(m,2H),7.40(d,J=8.2Hz,1H),7.26(d,J=8.5Hz,1H) ,7.18(d,J=6.2Hz,2H),7.12–7.03(m,1H),6.95(s,1H),6.73(s,1H),5.58(d,J=7.0Hz,1H),4.38(d,J=10.3Hz,1H),4.15(d,J=8.5Hz,2 H),3.77(d,J=8.2Hz,2H),3.71(d,J=7.8Hz,2H),3.59(s,1H),3.24–3.12(m,1H),3.08–2.99(m,1H),2.89(d,J=15.4Hz,1H),2.47(s,1H ),2.26(s,6H),1.81–1.57(m,6H),1.56–1.47(m,2H),1.44(d,J=5.8Hz,2H),1.35–1.30(m,1H),1.27(s,4H),1.18(s,5H),1.05(s,1H).

[0465] Referring to Example D2, the compound was synthesized.

[0466] Example D4

[0467] Reaction route:

[0468] Operating steps:

[0469] Step 1: 3-((1S,2S)-1-(2-((4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-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-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0470] At room temperature, 1-(1-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-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 (100 mg, 0.18 mmol) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (82 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (2 mL), and the reaction mixture was stirred overnight at room temperature. N,N-diisopropylethylamine (70 mg, 0.54 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (103 mg, 0.27 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography to give the target compound (100 mg, 0.1 mmol, yield: 56.5%). LCMS (ESI) m / z = 984.5 [M+H] + . 1 H NMR(400MHz,DMSO)δ11.81(s,1H),8.31(s,1H),7.89–7.33(m,4H),7.31–7.10(m ,3H),7.10–6.92(m,2H),6.74(s,1H),5.84–5.51(m,1H),4.51–4.03(m,3H),3.87 –3.34(m,7H),3.07–2.98(m,1H),2.95–2.61(m,2H),2.47(s,4H),2.25(s,6H),2. 12–1.93(m,1H),1.91–1.49(m,6H),1.45(m,1H),1.31(m,1H),1.30–1.13(m,6H).

[0471] Example D5

[0472] Reaction route:

[0473] Operating steps:

[0474] Step 1: 2-Bromo-4-fluoro-3,5-dimethylaniline

[0475] 4-Fluoro-3,5-dimethylaniline (10 g, 72 mmol) was dissolved in tetrahydrofuran (100 mL), and bromosuccinimide (12.8 g, 72 mmol) was added at 0°C. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–20% ethyl acetate) to give the title compound (14.2 g, 65.1 mmol, yield: 90.6%) as a yellow solid. LCMS (ESI) m / z = 218.0 [M+H] + .

[0476] Step 2: 4-Fluoro-3,5-Dimethylphenyl-2-d-amine

[0477] 2-Bromo-4-fluoro-3,5-dimethylaniline (14.2 g, 65.1 mmol) was dissolved in 1,4-dioxane (150 mL) and water (15 mL). N,N,N',N'-tetramethylethylenediamine (11.2 g, 96.8 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (5.3 g, 6.45 mmol), and sodium borodeuteride (5.4 g, 129 mmol) were added. The reaction mixture was stirred at 85°C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the title compound (5.7 g, 40.4 mmol, yield: 62.4%), a brown oil, LCMS (ESI) m / z = 141.1 [M+H]. + .

[0478] Step 3: 4-Fluoro-3,5-Dimethylphenyl-2-d-amine hydrochloride

[0479] 4-Fluoro-3,5-dimethylphenyl-2-d-amine (5.7 g, 40.4 mmol) was added to a mixture of concentrated hydrochloric acid (50 mL) and water (50 mL) at room temperature, stirred for 1 hour, then filtered, and the filter cake was collected and dried. The resulting solid was dissolved in methoxycyclopentane (50 mL), stirred at 50 °C for 1 hour, followed by stirring at room temperature for 1.5 hours. The precipitate was collected by filtration and washed with methoxycyclopentane (20 mL). The resulting solid was dried under reduced pressure to give the title compound (7.89 g, crude), a yellow solid. The compound was used directly in the next step.

[0480] Step 4: (4-Fluoro-3,5-dimethylphenyl-2-d)hydrazine hydrochloride

[0481] 4-Fluoro-3,5-dimethylphenyl-2-d-amine hydrochloride (7.89 g, crude) was dissolved in concentrated hydrochloric acid (500 mL) at 0°C. A 20 mL aqueous solution of sodium nitrite (4 g, 57.9 mmol) was added in portions with vigorous stirring, and the mixture was stirred at 0°C for 30 minutes. Then, a 20 mL aqueous solution of stannous chloride (17.8 g, 93.6 mmol) was added in portions. Next, 10 mL of water was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filter cake was washed with water (10 mL), and dried to give the title compound (6.3 g, crude). LCMS (ESI) m / z = 156.1 [M+H] + .

[0482] Step 5: (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0483] 5.22 g (21.91 mmol) of (6S)-7-cyano-6-methyl-8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester, (4-fluoro-3,5-dimethylphenyl-2-d)hydrazine hydrochloride (6.3 g (32.87 mmol)) and pyridine hydrochloride (380 mg (3.29 mmol) were dissolved in 120 mL of ethanol and reacted at 80 °C for 5 hours under nitrogen protection. After the reaction was completed, the solvent was concentrated to dryness, and 200 mL of ethyl acetate was added. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain the target compound (3 g (7.99 mmol, yield: 36.5%), LCMS (ESI) m / z = 376.2 [M+H). + .

[0484] Step 6: (S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0485] (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (3 g, 7.99 mmol) was dissolved in pyridine (60 mL), and 2-isocyano-1,1-dimethoxyethane (4.19 g, 32 mmol) was added under ice-water bath. The reaction was carried out at room temperature for 5 hours. After the reaction was completed, the solution was directly evaporated to dryness and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-25% ethyl acetate) to obtain the target compound (1.35 g, 2.67 mmol, yield: 33.35%), LCMS (ESI) m / z = 507.3 [M+H]. + .

[0486] Step 7: (4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-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

[0487] Compound (S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.35 g, 2.67 mmol) was dissolved in tetrahydrofuran (15 mL). Methanesulfonic acid (512 mg, 5.34 mmol) was added under nitrogen protection, and the mixture was stirred at 60°C for 4 hours. After cooling to room temperature, the pH was adjusted to 8–9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–30% ethyl acetate) to give the target compound (1 g, 2.26 mmol, yield: 84.7%), LCMS (ESI) m / z = 443.2 [M+H). + .

[0488] Step 8: (4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0489] 1-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-bromo-4-fluoro-1H-indazole (250 mg, 0.84 mmol) was dissolved in N-methylpyrrolidone (3 mL), and (4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-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 (372 mg, 0.84 mmol), potassium carbonate (349 mg, 2.53 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (60 mg, 0.42 mmol) and cuprous iodide (33 mg, 0.17 mmol) were added sequentially. The reaction mixture was reacted at 130°C for 3 hours. After the reaction was complete, the mixture was poured into 10 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound (350 mg, 0.53 mmol, yield: 63.2%) as a brown solid. LCMS (ESI) m / z = 659.3 [M+H] + .

[0490] Step 9: 1-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0491] (4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (350 mg, 0.53 mmol) was dissolved in dichloromethane (4 mL), and 4M dioxane hydrochloride solution (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product (280 mg), a yellow solid. LCMS (ESI) m / z = 559.1 [M+H] + .

[0492] Step 10: 3-((1S,2S)-1-(2-(4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0493] Dissolve 1-(1-(3-oxabicyclo[3.1.0]hexan-6-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (280 mg, crude) in N,N-dimethylformamide (3 mL), and add 5-((S)-2,2-dimethyltetrahydro-2H-pyran -4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (223 mg, 0.5 mmol), N,N-diisopropylethylamine (194 mg, 1.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (285 mg, 0.75 mmol) were reacted and stirred overnight at room temperature. After the reaction was completed, the reaction solution was purified by reverse-phase synthesis to obtain the target compound (110 mg, 0.1 mmol, yield: 22.2%). LCMS (ESI) m / z = 985.4 [M+H] +. 1H NMR (400MHz, DMSO) δ12.39–11.57(m,1H),8.31(s,1H),7.81–7.33(m,4H),7.27(d,J=8.4Hz,1H ),7.20–7.04(m,2H),6.98–6.73(m,2H),5.86–5.15(m,1H),4.86–4.36(m,1H),4.15(d,J=8.5Hz ,2H),3.85–3.46(m,7H),3.10–3.00(m,1H),2.94–2.61(m,2H),2.49–2.42(m,4H),2.26(s,6H), 2.16–1.89(m,1H),1.88–1.50(m,6H),1.49–1.43(m,1H),1.35–1.29(m,1H),1.30–1.15(m,6H).

[0494] Example D6

[0495] Reaction route:

[0496] Operating steps:

[0497] Step 1: 1-(diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl)hydrazine

[0498] Add distilled tert-amyl alcohol (1.5 L), water (200 mL), 5-bromo-2-fluoro-1,3-dimethylbenzene (500 g, 2.46 mol), (diphenylmethylene)hydrazine (507 g, 2.59 mol), and sodium hydroxide (394 g, 9.85 mol) to the reaction vessel. Degas the mixture under nitrogen bubbling for 30 minutes, then add palladium acetate (0.55 g, 24.62 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (1.4 g, 24.62 mmol). After degassing again under nitrogen for 30 minutes, heat the mixture to 100–106 °C and react for 1 hour. After the reaction is complete, cool the system to 85–95 °C and slowly add water (500 mL) dropwise over 1 hour. Continue stirring at 85-95°C for 1-2 hours, cool to 65-75°C and stir for 1-2 hours, then continue cooling to 15-25°C and stirring for 2-4 hours. The resulting filter cake is filtered and washed with tert-amyl alcohol (500 mL) and water (1 L). Transfer water (2.5 L) and the wet filter cake to a reaction vessel, slurry at 15-30°C for 2-4 hours, filter, and wash the filter cake with water (1 L). The resulting solid is heated under nitrogen protection at temperatures below 60°C to obtain the target compound (715 g, 2.24 mol, yield 90%). LCMS (ESI) m / z = 319.3 [M+H]+ .

[0499] Step 2: 1-(2-bromo-4-fluoro-3,5-dimethylphenyl)-2-(diphenylmethylene)hydrazine

[0500] 1-(diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl)hydrazine (61.4 g, 193 mmol) and dichloromethane (307 mL) were added to a reaction flask and kept in an ice bath at 0–5°C. Bromosuccinimide (34.3 g, 193 mmol) was dissolved in acetonitrile (307 mL) and added dropwise to the reaction flask, maintaining the internal temperature below 10°C during the addition. After the addition was complete, LC-MS analysis showed incomplete reaction, with approximately 3.5% of the starting material remaining unreacted. The mixture was then brought to room temperature (20–30°C) and stirred overnight. After reacting at room temperature for 17 hours, LC-MS analysis showed no further reaction. The reaction was complete, with approximately 3.5% of the starting material remaining unreacted. 3.5% of the feed amount of bromosuccinimide (0.035 eq) was added, and the reaction was continued for 0.5 hours. Sampling and analysis showed complete reaction. The reaction solution was washed with saturated sodium thiosulfate solution (300 mL), back-extracted with dichloromethane (120 mL), and the organic phases were combined. The organic phase was washed with water (300 mL), then with saturated brine (300 mL), and dried over anhydrous sodium sulfate. The dried organic phase was concentrated under reduced pressure at a temperature not exceeding 40°C to obtain the target product as a red solid (76.55 g, 192.8 mmol, yield 99.92%). LCMS (ESI) m / z = 397.3 [M+H] + .

[0501] Step 3: 2-Bromo-4-fluoro-3,5-dimethylphenylhydrazine hydrochloride

[0502] Add 241 mL of 4M hydrochloric acid-1,4-dioxane solution and 8.7 mL of water to a reaction flask, heat to 35–45°C, and add 76.55 g (193 mmol) of 1-(2-bromo-4-fluoro-3,5-dimethylphenyl)-2-(diphenylmethylene)hydrazine (partially) to the reaction flask. After the addition is complete, react overnight at 35–45°C. The reaction is incomplete, so cool to 15–25°C and stir for 2–4 hours. Filter, wash the filter cake with methyl tert-butyl ether, and then dry at 30°C to obtain the target compound (47.4 g, 203.4 mmol, yield 80.4%). LCMS (ESI) m / z = 233.1 [M+H] + .

[0503] Step 4: (S)-3-amino-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0504] 2-Bromo-4-fluoro-3,5-dimethylphenylhydrazine hydrochloride (7.65 g, 25.1 mmol) was dissolved in anhydrous tetrahydrofuran (80 mL), followed by three nitrogen purgings. The mixture was then refluxed for 1 hour until the reaction was complete. After cooling to room temperature, a saturated ammonium chloride solution (100 mL) was added, and the mixture was stirred. The organic phase was separated, and ethyl acetate (100 mL x 2) was added to the aqueous phase. The mixture was stirred, extracted, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure with n-heptane to obtain the crude target compound (14.5 g). LCMS (ESI) m / z = 453.1 [M+H] + .

[0505] Step 5: (S)-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-3-[3-(2,2-dimethoxyethyl)ureo]-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0506] Triphosgene (20 g, 67.4 mmol) was dissolved in dichloromethane (300 mL). Under ice-water bath, a solution of triethylamine (40.92 g, 404.4 mmol) and 2,2-dimethoxyethane-1-amine (21.3 g, 202.2 mmol) in dichloromethane (200 mL) was slowly added dropwise to the mixture. After the addition was complete, the mixture was allowed to warm naturally to room temperature and stirred for 20 minutes. Then, it was refluxed for 20 minutes and stirred at room temperature for 1–3 hours. Water (100 mL) was slowly added dropwise to separate the organic phase. The aqueous phase was extracted with dichloromethane (30 mL). The organic phases were combined, washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target crude compound (25.27 g, oily).

[0507] Add pyridine (100 mL) and (S)-3-amino-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (20.35 g, 44.9 mmol) to the above oily substance, and stir overnight at room temperature. To check for complete reaction, slowly add the material dropwise to water (700 mL), stir for 1–2 hours, filter, dissolve the filter cake in dichloromethane (400 mL), wash with saturated sodium chloride, concentrate under reduced pressure, add tetrahydrofuran (30 mL), concentrate under reduced pressure, and use the crude product directly for the next step. LCMS (ESI) m / z = 584.2 [M+H] + .

[0508] Step 6: (4S)-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-3-[3-(tert-butoxycarbonyl)-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

[0509] Dissolve the crude product from the previous step in tetrahydrofuran (100 mL), add methanesulfonic acid (4.36 g, 45.5 mmol), adjust the pH to between 1 and 2, and heat under reflux for 2–6 hours until the reaction is complete. Cool to 50°C and add di-tert-butyl dicarbonate (12.9 g, 59.2 mmol), triethylamine (40 g, 396 mmol), and 4-dimethylaminopyridine (0.64 g, 5.24 mmol). Stir overnight at room temperature, then slowly add water (1000 mL) dropwise, stirring for 1–2 hours. Filter, dissolve in dichloromethane (200 mL), separate the liquids, and add anhydrous sulfuric acid to the organic phase. Sodium was dried, filtered, and the filter cake was washed with dichloromethane (30 mL). The mixture was concentrated under reduced pressure to obtain 16.9 g of an oily substance. 7.0 mL of dichloromethane and 16.4 mL of n-heptane were added, and the mixture was thoroughly mixed. The mixture was filtered through a 30 g (100-200 mesh) silica gel pad, then washed with 49 mL of n-heptane and 490 mL of a mixture of ethyl acetate and n-heptane (1:5). The mixture was concentrated under reduced pressure, and 3.5 mL of ethyl acetate and 35 mL of n-heptane were added. The mixture was stirred overnight, filtered, washed with 7 mL of n-heptane, concentrated under reduced pressure, and dried to obtain 11.7 g (18.9 mmol, two-step yield 41.99%). LCMS (ESI) m / z = 620.2 [M+H] + .

[0510] Step 7: (4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-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

[0511] (4S)-2-(2-bromo-4-fluoro-3,5-dimethylphenyl)-3-[3-(tert-butoxycarbonyl)-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 (3.65 g, 5.88 mmol) was dissolved in a mixture of 1,4-dioxane (25 mL) and deuterium water (2.5 mL). In the solution, N,N,N',N'-tetramethylethylenediamine (TMEDA) (1.03 g, 8.82 mmol) was added, and the mixture was purged with nitrogen three times. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (390 mg, 47 mmol) and sodium borodeuteride (740 mg, 17.6 mmol) were added, and the mixture was purged with nitrogen three times. The mixture was heated to 85 degrees Celsius and reacted for 2–3 hours. The reaction was then tested to ensure complete reaction. Cool the mixture and control the temperature at 15±5°C. Add the mixture dropwise to a saturated ammonium chloride solution (500 mL). Stir at 15±5°C for 1–2 hours. Filter the mixture. Wash the filter cake with dichloromethane (100 mL). Add hydrochloric acid-methanol solution (4 M). Reflux overnight (outer temperature 45°C). Concentrate the solvent under reduced pressure until dry. Add 200 mL of DCM and 10 mL of triethylamine. Add di-tert-butyl dicarbonate (2.5 g) (dissolved in 20 mL of dichloromethane) in portions, about one-tenth of the amount added each time. React for 30 minutes and monitor until no protected product disappears and no double-protected product is observed. Add 6 g of silica gel. Concentrate the mixture under reduced pressure until dry. Purify by column chromatography. Concentrate the mixture under reduced pressure until dry to obtain the target compound (1.15 g, 2.6 mmol, white foamy solid, yield 44.3%). LCMS (ESI) m / z = 443.3 [M+H] + .

[0512] Step 8: 1-(1-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0513] 1-(bicyclo[1.1.1]pentan-1-yl)-5-bromo-4-fluoro-1H-indazole (5.95 g, 21.2 mmol), (4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-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 The ester (9.37 g, 21.2 mmol) was dissolved in N-methylpyrrolidone (150 mL), and potassium carbonate (8.77 g, 63.5 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (114 mg, 0.8 mmol), and cuprous iodide (800 mg, 4.2 mmol) were added. The reaction mixture was reacted at 130 °C for 8 hours under nitrogen protection. After the reaction was complete, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (3 x 200 mL), washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-70% ethyl acetate) to give the target compound (10.9 g, 17.0 mmol, 80.13%) as a white solid. LCMS(ESI)m / z = 643.2[M+H] + .

[0514] The above-mentioned white solid (10.9 g, 17.0 mmol) was dissolved in dichloromethane (30 mL) at an internal temperature of 15 ± 5 °C. A solution of 1,4-dioxane hydrogen chloride (30 mL) was added dropwise. After the addition was complete, the mixture was stirred at 25 ± 5 °C for 1–2 hours, then concentrated under reduced pressure to obtain the crude target compound (9.4 g), a yellow solid. LCMS (ESI) m / z = 543.3 [M+H] + .

[0515] Step 9: 3-((1S,2S)-1-(2-((4S)-3-(1-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazol[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0516] 1-(1-(bicyclo[1.1.1]pentan-1-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (2.53 g, 4.66 mmol) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) Cyclopropyl)-1H-indole-2-carboxylic acid (2.07 g, 4.66 mmol) was dissolved in N,N-dimethylformamide (40 mL), and N,N-diisopropylethylamine (2.4 g, 18.7 mmol) was added. The reaction mixture was stirred at 25 ± 5 °C for 1 hour. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.13 g, 5.6 mmol) was added in portions while maintaining the internal temperature at 25 ± 5 °C, and the mixture was stirred for 12–16 hours. After the reaction was complete, the reaction mixture was purified by reverse-phase chromatography to obtain the target compound (2.67 g, 2.76 mmol, 59.11%). LCMS (ESI) m / z = 969.5 [M+H] + .

[0517] 1 H NMR (400MHz, DMSO) δ12.30–11.78(m,1H),8.34(s,1H),7.73(d,J=8.9Hz,1H),7.69–7.31(m,3H),7 .30–7.13(m,2H),7.12–6.93(m,2H),6.94–6.73(m,1H),5.83–5.53(m,1H),5.27–4.76(m,1H),4.4 1(s,1H),3.87–3.45(m,4H),3.18(s,1H),3.08–2.84(m,2H),2.74(s,2H),2.47(s,6H),2.26(s,6H ),2.11–1.91(m,1H),1.89–1.48(m,6H),1.48–1.41(m,1H),1.35–1.29(m,1H),1.30–1.10(m,6H).

[0518] Example D7

[0519] Reaction route:

[0520] Operating steps:

[0521] Step 1: 2-Bromo-4-fluoro-3,5-dimethylaniline

[0522] 4-Fluoro-3,5-dimethylaniline (10 g, 72 mmol) was dissolved in tetrahydrofuran (100 mL), and bromosuccinimide (12.8 g, 72 mmol) was added at 0°C. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–20% ethyl acetate) to give the title compound (14.2 g, 65.1 mmol, yield: 90.6%) as a yellow solid. LCMS (ESI) m / z = 218.0 [M+H] + .

[0523] Step 2: 4-Fluoro-3,5-Dimethylphenyl-2-d-amine

[0524] 2-Bromo-4-fluoro-3,5-dimethylaniline (14.2 g, 65.1 mmol) was dissolved in 1,4-dioxane (150 mL) and water (15 mL). N,N,N',N'-tetramethylethylenediamine (11.2 g, 96.8 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (5.3 g, 6.45 mmol), and sodium borodeuteride (5.4 g, 129 mmol) were added. The reaction mixture was stirred at 85°C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to give the title compound (5.7 g, 40.4 mmol, yield: 62.4%), a brown oil, LCMS (ESI) m / z = 141.1 [M+H]. + .

[0525] Step 3: 4-Fluoro-3,5-Dimethylphenyl-2-d-amine hydrochloride

[0526] 4-Fluoro-3,5-dimethylphenyl-2-d-amine (5.7 g, 40.4 mmol) was added to a mixture of concentrated hydrochloric acid (50 mL) and water (50 mL) at room temperature, stirred for 1 hour, then filtered, and the filter cake was collected and dried. The resulting solid was dissolved in methoxycyclopentane (50 mL), stirred at 50 °C for 1 hour, followed by stirring at room temperature for 1.5 hours. The precipitate was collected by filtration and washed with methoxycyclopentane (20 mL). The resulting solid was dried under reduced pressure to give the title compound (7.89 g, crude), a yellow solid. The compound was used directly in the next step.

[0527] Step 4: (4-Fluoro-3,5-dimethylphenyl-2-d)hydrazine hydrochloride

[0528] 4-Fluoro-3,5-dimethylphenyl-2-d-amine hydrochloride (7.89 g, crude) was dissolved in concentrated hydrochloric acid (500 mL) at 0°C. A 20 mL aqueous solution of sodium nitrite (4 g, 57.9 mmol) was added in portions with vigorous stirring, and the mixture was stirred at 0°C for 30 minutes. Then, a 20 mL aqueous solution of stannous chloride (17.8 g, 93.6 mmol) was added in portions. Next, 10 mL of water was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filter cake was washed with water (10 mL), and dried to give the title compound (6.3 g, crude). LCMS (ESI) m / z = 156.1 [M+H] + .

[0529] Step 5: (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0530] 5.22 g (21.91 mmol) of (6S)-7-cyano-6-methyl-8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester, (4-fluoro-3,5-dimethylphenyl-2-d)hydrazine hydrochloride (6.3 g (32.87 mmol)) and pyridine hydrochloride (380 mg (3.29 mmol) were dissolved in 120 mL of ethanol and reacted at 80 °C for 5 hours under nitrogen protection. After the reaction was completed, the solvent was concentrated to dryness, and 200 mL of ethyl acetate was added. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-20% ethyl acetate) to obtain the target compound (3 g (7.99 mmol, yield: 36.5%), LCMS (ESI) m / z = 376.2 [M+H). + .

[0531] Step 6: (S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0532] (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (3 g, 7.99 mmol) was dissolved in pyridine (60 mL), and 2-isocyano-1,1-dimethoxyethane (4.19 g, 32 mmol) was added under ice-water bath. The reaction was carried out at room temperature for 5 hours. After the reaction was completed, the solution was directly evaporated to dryness and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-25% ethyl acetate) to obtain the target compound (1.35 g, 2.67 mmol, yield: 33.35%), LCMS (ESI) m / z = 507.3 [M+H]. + .

[0533] Step 7: (4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-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

[0534] Compound (S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.35 g, 2.67 mmol) was dissolved in tetrahydrofuran (15 mL). Methanesulfonic acid (512 mg, 5.34 mmol) was added under nitrogen protection, and the mixture was stirred at 60°C for 4 hours. After cooling to room temperature, the pH was adjusted to 8–9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–30% ethyl acetate) to give the target compound (1 g, 2.26 mmol, yield: 84.7%), LCMS (ESI) m / z = 443.2 [M+H). + .

[0535] Step 8: (4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0536] 1-(3-oxabicyclo[3.1.0]hexan-6-yl)-5-bromo-4-fluoro-1H-indazole (320 mg, 1.08 mmol) was dissolved in N-methylpyrrolidone (3 mL), and (4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-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 (476 mg, 1.08 mmol), potassium carbonate (447 mg, 3.24 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (77 mg, 0.54 mmol), and cuprous iodide (42 mg, 0.22 mmol). The reaction mixture was reacted at 130°C for 3 hours. After the reaction was complete, the reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%-50% ethyl acetate) to give the title compound (400 mg, 0.61 mmol, yield: 56.4%) as a brown solid. LCMS (ESI) m / z = 659.3 [M+H] + .

[0537] Step 9: 1-(1-(3-oxadicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0538] (4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (400 mg, 0.61 mmol) was dissolved in dichloromethane (4 mL), and 4M dioxane hydrochloride solution (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to obtain a crude product (330 mg, crude), a yellow solid. LCMS (ESI) m / z = 559.1 [M+H] + .

[0539] Step 10: 3-((1S,2S)-1-(2-((4S)-3-(3-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazol[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0540] Dissolve 1-(1-(3-oxadicyclo[3.1.0]hexan-6-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl-2-d)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (140 mg crude) in N,N-dimethylformamide (3 mL), and add 5-((S)-2,2-dimethyltetrahydro-2-yl)-2-yl)-3-dihydro-2H-imidazol-2-one. H-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 (103 mg, 0.25 mmol), N,N-diisopropylethylamine (97 mg, 0.75 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (143 mg, 0.38 mmol) were reacted and stirred overnight at room temperature. After the reaction was complete, the reaction solution was purified by reverse-phase synthesis to obtain the target compound (80 mg, 0.08 mmol, yield: 33.5%). LCMS (ESI) m / z = 952.4 [M+H] + .

[0541] 1H NMR (400MHz, DMSO) δ12.41–11.55(m,1H),8.34–8.18(m,1H),7.80–7.61(m,1H),7.59–7.44(m,2H),7.43–7 .36(m,1H),7.26(d,J=8.5Hz,1H),7.18(d,J=6.3Hz,1H),7.10–6.94(m,2H),6.91–6.67(m,1H),5.70–5.14( m,1H),4.71–4.31(m,1H),4.15(d,J=8.6Hz,2H),3.79–3.52(m,6H),3.28–3.11(m,1H),3.09–2.85(m,2H),2 .48–2.43(m,2H),2.26(s,6H),1.80–1.50(m,7H),1.46–1.40(m,2H),1.36–1.30(m,1H),1.29–1.12(m,9H).

[0542] Example D8

[0543] Reaction route:

[0544] Operating steps:

[0545] Step 1: 2,6-Dibromo-4-fluoro-3,5-dimethylaniline

[0546] 4-Fluoro-3,5-dimethylaniline (500 mg, 3.6 mmol) was dissolved in tetrahydrofuran (5 mL), and bromosuccinimide (1.27 g, 7.2 mmol) was added at 0°C. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0%–20% ethyl acetate) to give the title compound (220 mg, 0.74 mmol, yield: 20.6%) as a yellow solid. LCMS (ESI) m / z = 296.0 [M+H] + .

[0547] Step 2-10, referring to Step 2-10 of Example D4, yielded the target compound 3-((1S,2S)-1-(2-(4S)-3-(3-(1-(3-oxabicyclo[3.1.0]hexane-6-yl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl-2,6-d2)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,2,4-oxadiazol-5(4H)-one. LCMS(ESI)m / z = 986.5[M+H] + .

[0548] Referring to Example D8, the compound was synthesized.

[0549] Example E1

[0550] Reaction route:

[0551] Operating steps:

[0552] Step 1: 3-((1S,2S)-1-(2-(4S)-3-(3-(1-cyclopropyl-4-fluoro-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-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-((methoxy-d3)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0553] Dissolve 1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-((4S)-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 (580 mg, crude) in N,N-dimethylformamide (6 mL), then add 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S) The reaction mixture consisted of 2S)-2-((methoxy-d3)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (500 mg, 1.12 mmol), N,N-diisopropylethylamine (433 mg, 3.36 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (638 mg, 1.68 mmol). The reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was purified by reverse-phase synthesis to obtain the target compound (650 mg, 0.69 mmol, yield: 61.3%). LCMS (ESI) m / z = 942.4 [M+H] + .

[0554] Test Example 1: In vitro GLP-1R agonist activity assay of the compound

[0555] The agonistic activity of the compound or positive compound Orforglipron (purchased from a commercial supplier, hereinafter the same) on GLP-1R in this embodiment was determined by detecting changes in intracellular cAMP levels in HEK293 cells that stably express human GLP-1R.

[0556] Orforglipron:

[0557] Cells and reagents:

[0558] Cell line: hGLP-R / HEK293 stable transgenic cells

[0559] Culture medium: DMEM + 10% fetal bovine serum + 1% penicillin-streptomycin

[0560] Experimental buffer: DPBS containing 0.1% BSA and 250 μM IBMX

[0561] Test kit: cAMP HTRF test kit.

[0562] Experimental steps:

[0563] 1) HEK293 cells stably expressing human GLP-1R were digested with 0.05% trypsin and resuspended in DMED medium (containing 10% fetal bovine serum and 1% penicillin-streptomycin).

[0564] 2) After centrifuging the cells, wash them twice with DPBS, and resuspend them in experimental buffer (DPBS containing 0.1% BSA and 250 μM IBMX) to a concentration of 1 × 10⁻⁶ cells / mL. 5 cells / mL.

[0565] 3) Prepare working solutions of different concentrations by serially diluting the compound or positive compound Orforglipron in this embodiment with DMSO, and add the compound working solutions to 384-well plates using Echo.

[0566] 4) Add resuspended cells at a rate of 1000 cells / well and continue incubation at room temperature for 30 minutes.

[0567] 5) After incubation, the intracellular cAMP level was detected using a cAMP HTRF assay kit, and the agonistic activity of the compound on GLP-1R was calculated.

[0568] Data Calculation: The signal-to-weight ratio (665nm / 620nm) was calculated. The activation of GLP-1R by the compound was calculated using the following formula:

[0569] The activation (%) was nonlinearly fitted to the sample concentration using a four-parameter equation using software to obtain the EC50 value.

[0570] The results of the agonistic activity of the compounds or positive compound Orforglipron in this embodiment for GLP-1R are shown in Table 1. As can be seen from the experimental results, most of the compounds provided by this invention have good agonistic activity for GLP-1R.

[0571] Table 1. Agonistaltic activity of compounds against GLP-1R

[0572] Test Example 2: In vitro GLP-1R agonist activity test of the compound

[0573] In this embodiment, the agonistic activity of the compound on GLP-1R was determined by detecting changes in intracellular cAMP levels in HEK293 cells that stably express human GLP-1R.

[0574] Cells and reagents:

[0575] 1) Cell line: hGLP-R / HEK293 stable transgenic cells

[0576] 2) Culture medium: DMEM + 10% fetal bovine serum + 1% penicillin-streptomycin

[0577] 3) Experimental buffer: DPBS containing 0.1% BSA and 250 μM IBMX

[0578] 4) Detection kit: cAMP HTRF detection kit

[0579] Experimental steps:

[0580] 1) HEK293 cells stably expressing human GLP-1R were digested with 0.05% trypsin and resuspended in DMED medium (containing 10% fetal bovine serum and 1% penicillin-streptomycin).

[0581] 2) After centrifuging the cells, wash them twice with DPBS, and resuspend them in experimental buffer (DPBS containing 0.1% BSA and 250 μM IBMX) to a concentration of 1 × 10⁻⁶ cells / mL. 5 cells / mL.

[0582] 3) The compound in this embodiment was serially diluted with DMSO to prepare working solutions of different concentrations, and the compound working solutions were added to 384-well plates using Echo.

[0583] 4) Add resuspended cells at 1000 cells / well and incubate at 37°C for 2 hours.

[0584] 5) After incubation, the intracellular cAMP level was detected using a cAMP HTRF assay kit, and the agonistic activity of the test compound on GLP-1R was calculated.

[0585] Data Calculation: The signal-to-weight ratio (665nm / 620nm) was calculated. The activation of GLP-1R by the tested compound was calculated using the following formula:

[0586] The activation (%) was nonlinearly fitted to the sample concentration using a four-parameter equation using software to obtain EC. 50 value.

[0587] The agonistic activity results of the compounds in this embodiment for GLP-1R are shown in Table 2. The experimental results show that the compounds provided by this invention have good agonistic activity for GLP-1R.

[0588] Table 2 shows the agonistic activity of the tested compounds against GLP-1R.

[0589] Test Example 3: Pharmacokinetic Evaluation of Compounds in Mice

[0590] ICR mice were used as test animals to investigate the in vivo pharmacokinetic characteristics of the compound of this embodiment after a single oral dose of 5 mg / kg and a single intravenous injection of 1 mg / kg.

[0591] 1) Laboratory animals:

[0592] ICR mice, 3 mice per group, male, from Spifor (Suzhou) Biotechnology Co., Ltd., Hunan Hengxing.

[0593] 2) Preparation of drug delivery formulations:

[0594] Preparation of solvent for oral administration: The solvent is a 10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64mM NaOH, pH=9) solution. Measure 10mL of PEG400, 10mL of PG, and 80mL of glycine buffer (100mM glycine, 64mM NaOH, pH=9) and add them to a 100mL volumetric flask. Stir, mix, and sonicate to obtain a clear solution. The solution can be scaled up proportionally according to the required amount of solvent.

[0595] Preparation of oral administration formulation: Weigh an appropriate amount of the compound from the example and place it in a suitable container. Add the solution and sonicate for 10 minutes to obtain a colorless and clear solution, which is the administration formulation with a concentration of 0.5 mg / mL.

[0596] Preparation of the intravenous administration formulation: The solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh an appropriate amount of the compound from the examples, and add 5% DMSO according to the total volume ratio of the dosage. Vortex and sonicate for 2 minutes to completely dissolve it. Then add 10% Solutol HS15, vortex and sonicate for 2 minutes to completely dissolve it. Finally, add 85% PBS, vortex and sonicate for 5 minutes, and filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution, which is the dosage formulation with a concentration of 0.2 mg / mL.

[0597] 3) Administration:

[0598] Male ICR mice aged 6-8 weeks were housed in an SPF-protected environment. Throughout the experiment, the temperature and relative humidity of the animal room were controlled at 23±2℃ and 50±10%, respectively, with a constant 12-hour light / dark cycle. All mice were acclimatized for 3 days before the start of the experiment. Mice were randomly divided into groups of 3 mice each according to their body weight. The gavage group was fasted overnight before administration of 5 mg / kg at a dose of 10 mL / kg, and fed 4 hours after administration. The intravenous group was fasted overnight before administration of 1 mg / kg at a dose of 5 mL / kg, and fed 4 hours after administration.

[0599] 4) Sample collection and biological analysis:

[0600] Plasma samples were collected from mice before administration and at 0.083 (IV group), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentrations of the compounds were determined using a chromatography-tandem triple quadrupole mass spectrometer.

[0601] 5) Data Analysis:

[0602] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method.

[0603] The results of the mouse pharmacokinetic experiments of the compounds in this example are shown in Tables 3-1 and 3-2. The compounds in this test example showed good PK characteristics, and the exposure AUC and C2 were [data missing]. max All performed well.

[0604] Table 3-1 Pharmacokinetic parameters of the compounds in this embodiment after oral administration to mice

[0605] Table 3-2 Pharmacokinetic parameters of the compounds in this example administered intravenously to mice.

[0606] Test Example 4: Pharmacokinetic Evaluation of Compounds in Rats

[0607] Using SD rats as test animals, the in vivo pharmacokinetic characteristics of the compound of this embodiment or the positive compound Orforglipron (purchased from a commercial supplier) were investigated after a single oral administration of 5 mg / kg and a single intravenous injection of 1 mg / kg.

[0608] 1) Laboratory animals:

[0609] SD rats, 3 males per group, from Spifor (Suzhou) Biotechnology Co., Ltd.

[0610] 2) Preparation of drug delivery formulations:

[0611] Preparation of solvent for oral administration: The solvent is a 10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64mM NaOH, pH=9) solution. Measure 10mL of PEG400, 10mL of PG, and 80mL of glycine buffer (100mM glycine, 64mM NaOH, pH=9) and add them to a 100mL volumetric flask. Stir, mix, and sonicate to obtain a clear solution. The solution can be scaled up proportionally according to the required amount of solvent.

[0612] Preparation of oral administration formulation: Weigh an appropriate amount of the example compound or positive control compound Orforglipron into a suitable container, add the solution, and if it is a colorless and clear solution with a pH of 9.0-9.5, sonicate for 10 minutes. This is the administration formulation with a concentration of 0.5 mg / mL. If it is not a colorless and clear solution, first adjust the pH to 9.0-9.5 with 1M NaOH, then adjust it back to pH 9.0-9.5 with 1M HCl, sonicate for 10 minutes to obtain a colorless and clear solution, which is the administration formulation with a concentration of 0.5 mg / mL.

[0613] Preparation of the intravenous administration formulation: The solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh an appropriate amount of the compound from the examples or the positive control compound Orforglipron, and add 5% DMSO according to the total volume ratio of the administration solution. Vortex and sonicate for 2 minutes to completely dissolve it. Then add 10% Solutol HS15, vortex and sonicate for 2 minutes to completely dissolve it. Finally, add 85% PBS, vortex and sonicate for 5 minutes, and filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution, which is the administration formulation with a concentration of 0.2 mg / mL.

[0614] 3) Administration:

[0615] Six- to eight-week-old male SD rats were housed in an SPF-protected environment. Throughout the experiment, the temperature and relative humidity of the animal room were controlled at 23±2℃ and 50±10%, respectively, with a constant 12-hour light / dark cycle. All rats were acclimatized for 3 days before the start of the experiment. Rats were randomly divided into groups of three according to body weight. The gavage group was fasted overnight before administration of 5 mg / kg at a volume of 10 mL / kg, and fed 4 hours after administration. The intravenous group was fasted overnight before administration of 1 mg / kg at a volume of 5 mL / kg, and fed 4 hours after administration.

[0616] 4) Sample collection and biological analysis:

[0617] Plasma samples were collected from rats before administration and at 0.083 (IV group), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentrations of the compounds were determined using a chromatography-tandem triple quadrupole mass spectrometer.

[0618] 5) Data Analysis:

[0619] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method.

[0620] The results of the pharmacokinetic studies of the compounds in the examples or positive control compounds, Orforglipron, in rats are shown in Tables 4-1 and 4-2. Most of the compounds in the examples showed good PK characteristics, with low exposure AUC and C.max Both were significantly superior to the positive compound Orforglipron.

[0621] Table 4-1 Pharmacokinetic parameters of the compounds in this embodiment after oral administration to rats

[0622] Table 4-2 Pharmacokinetic parameters of the compounds in this example administered intravenously to rats.

[0623] Test Example 5: Pharmacokinetic Evaluation of Compound in Beagle Dogs

[0624] Using beagle dogs as test animals, the in vivo pharmacokinetic characteristics of the compound of this embodiment or the positive compound Orforglipron were investigated after a single oral dose of 2 mg / kg and a single intravenous injection of 0.5 mg / kg.

[0625] 1) Laboratory animals:

[0626] Beagles, 3 per group, male, shorn dogs, Beijing Mas Biotechnology Co., Ltd. / Jiangsu Mas Biotechnology Co., Ltd. / Jiangsu Yadong Experimental Animal Research Institute Co., Ltd., Hunan Hengxing.

[0627] 2) Preparation of drug delivery formulations:

[0628] Preparation of solvent for oral administration: The solvent is a 10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64mM NaOH, pH=9) solution. Measure 10 mL of PEG400, 10 mL of PG, and 80 mL of glycine buffer (100 mM glycine, 64 mM NaOH, pH=9) and add them to a 100 mL volumetric flask. Turbinate, mix, and sonicate to obtain a clear solution. The solution can be scaled up proportionally according to the required amount of solvent.

[0629] Preparation of oral administration formulation: Weigh an appropriate amount of the example compound or positive control compound Orforglipron into a suitable container, add the solution, and if it is a colorless and clear solution with a pH of 9.0-9.5, sonicate for 10 minutes. This is the administration formulation with a concentration of 0.4 mg / mL. If it is not a colorless and clear solution, first adjust the pH to 9.0-9.5 with 1M NaOH, then adjust it back to pH 9.0-9.5 with 1M HCl, sonicate for 10 minutes to obtain a colorless and clear solution, which is the administration formulation with a concentration of 0.4 mg / mL.

[0630] Preparation of the intravenous administration formulation: The solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh an appropriate amount of the example compound or positive control compound Orforglipron, and add 5% DMSO according to the total volume ratio of the administration solution. Vortex and sonicate for 2 minutes to completely dissolve it. Then add 10% Solutol HS15, vortex and sonicate for 2 minutes to completely dissolve it. Finally, add 85% PBS, vortex and sonicate for 5 minutes, and filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution, which is the administration formulation with a concentration of 0.5 mg / mL.

[0631] 3) Administration:

[0632] Throughout the beagle experiment, the temperature and relative humidity in the animal room were controlled at 18-26℃ and 40-70%, respectively, with a constant 12-hour light / dark cycle. Beagles were randomly assigned to groups of three based on body weight. The gavage group was fasted overnight before administration, with a dose of 2 mg / kg administered in a volume of 5 mL / kg, and fed 4 hours after administration. The intravenous group was fasted overnight before administration, with a dose of 0.5 mg / kg administered in a volume of 1 mL / kg, and fed 4 hours after administration.

[0633] 4) Sample collection and biological analysis:

[0634] Plasma samples were collected from dogs before administration and at 0.083 (IV group), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentrations of the compounds were determined using a tandem triple quadrupole mass spectrometer.

[0635] 5) Data Analysis:

[0636] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method.

[0637] The results of canine pharmacokinetic studies of the example compounds or positive control compounds Orforglipron are shown in Tables 5-1 and 5-2. The example compounds exhibited good PK characteristics, with low exposure AUC and C. max It is significantly superior to the positive compound Orforglipron.

[0638] Table 5-1 Pharmacokinetic parameters of the compound administered orally to dogs in this embodiment.

[0639] Table 5-2 Pharmacokinetic parameters of the compound administered intravenously to dogs in this embodiment.

[0640] The oral administration solvent for the compounds in Table 5-3 was 5% DMSO + 95% (10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64 mM NaOH, pH=9)). The animal source was Hunan Hengxing. Other experimental materials and test methods were the same as above. The experimental results are shown in Table 5-3.

[0641] Table 5-3 Pharmacokinetic parameters of the tested compounds after oral administration to beagle dogs

[0642] The results show that the compounds of this invention exhibit good metabolic properties, and the exposure levels (AUC and Cmax) of the compounds are superior to those of the positive compound Orforglipron.

[0643] Test Example 6: In vivo efficacy evaluation of compound hGLP-1R in mice

[0644] 1. Experimental Objective

[0645] The effects of long-term administration of the compounds in the evaluation examples on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high-fat diet were investigated.

[0646] 2. Test System

[0647] C57BL / 6_hGLP-1R mice, male, from Shanghai Southern Model Biotechnology Co., Ltd. Mice were 6 weeks old when the high-fat diet was initiated. The mice used in the following three rounds of experiments were independent.

[0648] 60% high-fat diet (HFD), Research Diet (D12492i).

[0649] Electronic balance, Shanghai Jingtian Electronic Instruments Co., Ltd.

[0650] 3. Test methods

[0651] 3.1 First round of experiment (mice were induced with a 60% high-fat diet for 6 weeks before drug administration)

[0652] 1) C57BL / 6_hGLP-1R mice were fed a 60% high-fat diet until they were 6 weeks old, and this continued until the end of the experiment.

[0653] 2) During week 6 of HFD feeding, the model group animals were randomly divided into groups of 6 based on body weight. The first group was the solvent group, which received the solvent (solvent: 10% PEG400 + 10% propylene glycol + 80% glycine-64mM NaOH buffer (pH=9)). The remaining groups were the drug administration groups, which received oral administration once daily at a dose of 1.5 mg / kg, a volume of 10 mL / kg, for a period of 14 days.

[0654] 3) Define the day of administration as Day 0. Animals were weighed and data recorded three times a week, and administration was based on body weight.

[0655] 4) Starting from day 0 of the experiment, the food intake of mice in each group was measured and recorded 3 times a week. Specifically, the feed was changed after each administration of medication, and the amount added and the amount remaining were recorded.

[0656] 5) On Day 14, the endpoint of the experiment, plasma samples were collected from mice in each group before the last dose, and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after the last dose for PK testing.

[0657] 3.2 Second round of experiment (mice were induced with a 60% high-fat diet for 7 weeks before administration)

[0658] 1) C57BL / 6_hGLP-1R mice were fed a 60% high-fat diet until they were 6 weeks old, and this continued until the end of the experiment.

[0659] 2) During week 7 of HFD feeding, the model group animals were randomly divided into groups of 6 based on body weight. The first group was the solvent group, which received the solvent (solvent: 10% PEG400 + 10% propylene glycol + 80% glycine-64mM NaOH buffer (pH=9)). The remaining groups were the drug administration groups, which received oral administration once daily at a dose of 0.3 or 0.1 mg / kg, with an administration volume of 10 mL / kg, for a period of 14 days.

[0660] 3) Define the day of administration as Day 0. Animals were weighed and data recorded three times a week, and administration was based on body weight.

[0661] 4) Starting from day 0 of the experiment, the food intake of mice in each group was measured and recorded 3 times a week. Specifically, the feed was changed after each administration of medication, and the amount added and the amount remaining were recorded.

[0662] 5) On Day 14, the endpoint of the experiment, plasma samples were collected from mice in some groups before the last dose, and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after the last dose for PK testing.

[0663] 3.3 Third round of experiment (mice were induced with a 60% high-fat diet for 15 weeks before administration)

[0664] 1) C57BL / 6_hGLP-1R mice were fed a 60% high-fat diet until they were 6 weeks old, and this continued until the end of the experiment.

[0665] 2) During week 15 of HFD feeding, the model group animals were randomly divided into groups of 6 based on body weight. The first group was the solvent group, which received the solvent (solvent: 10% PEG400 + 10% propylene glycol + 80% glycine-64mM NaOH buffer (pH=9)). The remaining groups were the drug administration groups, which received oral administration once daily at a dose of 0.3, 0.03, 0.05, or 0.1 mg / kg, with a volume of 10 mL / kg, for a period of 21 days.

[0666] 3) Define the day of administration as Day 0. Animals were weighed and data recorded three times a week, and administration was based on body weight.

[0667] 4) Starting from day 0 of the experiment, the food intake of mice in each group was measured and recorded 3 times a week. Specifically, the feed was changed after each administration of medication, and the amount added and the amount remaining were recorded.

[0668] 4. Experimental data processing and statistical analysis

[0669] The body weight and body weight change rate of mice after drug administration were summarized and statistically analyzed.

[0670] The rate of change in body weight is calculated as: (BWt-BW0) / BW0×100%, where BWt represents the body weight of the mouse on day t of the experiment, and BW0 represents the body weight of the mouse on day 0 of the experiment.

[0671] The cumulative food intake of mice after drug administration was summarized and statistically analyzed.

[0672] Cumulative food intake calculation: (addition amount (g) - remaining amount (g)) / number of animals per cage. Cumulative food intake is the total amount of food consumed by each animal per day during the drug administration period.

[0673] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method.

[0674] 5. Test Results

[0675] 5.1 Results of the first round of experiments (mice were induced with a 60% high-fat diet for 6 weeks before administration)

[0676] Table 6-1 Efficacy results of compound hGLP-1R in mouse DIO model

[0677] According to the experimental results, long-term administration of the compound of the present invention has excellent effects on reducing body weight and inhibiting food intake in GLP-1R humanized C57BL / 6 mice fed with a high-fat diet, and is significantly better than the positive compound.

[0678] Table 6-2 Pharmacokinetic parameters of the hGLP-1R compound in mouse DIO models after the last dose.

[0679] Based on pharmacokinetic results, the exposure of the compounds in the embodiments of the present invention after multiple administrations was significantly better than that of the positive control compound, supporting the interpretation of the efficacy results.

[0680] 5.2 Results of the second round of experiments (mice were induced with a 60% high-fat diet for 7 weeks before administration)

[0681] Table 6-3 Efficacy results of compound hGLP-1R in mouse DIO model.

[0682] According to the experimental results, long-term administration of the compound of the present invention has excellent effects on reducing body weight and inhibiting food intake in GLP-1R humanized C57BL / 6 mice fed with a high-fat diet, and is significantly better than the positive compound.

[0683] Table 6-4 Pharmacokinetic parameters of the tested compound hGLP-1R in mouse DIO models after the last dose

[0684] NA: Parameters cannot be calculated using a non-compartmental model.

[0685] Based on pharmacokinetic results, the exposure of the compounds in the embodiments of the present invention after multiple administrations was significantly better than that of the positive control compound, supporting the interpretation of the efficacy results.

[0686] 5.3 Results of the third round of experiments (mice were induced with a 60% high-fat diet for 15 weeks before administration)

[0687] Table 6-5 Efficacy results of the tested compound hGLP-1R in a mouse DIO model

[0688] According to the experimental results, long-term administration of the compound of the present invention has excellent effects on reducing body weight and inhibiting food intake in GLP-1R humanized C57BL / 6 mice fed with a high-fat diet, and the effect on reducing body weight is still significantly better than that of the positive compound at a 10-fold lower dose.

[0689] Test Example 7: Pharmacokinetic Evaluation of Compounds in Cynomolgus Monkeys

[0690] 1. Experimental Objective

[0691] Using cynomolgus monkeys as test animals, the pharmacokinetic characteristics of the compound of the present invention were studied in cynomolgus monkeys after oral administration at a dose of 2 mg / kg.

[0692] 2. Test System

[0693] Crab-eating macaques, 3 in each group, male, from Xiongsen, Guangxi.

[0694] 3. Preparation of drug delivery formulations

[0695] The oral administration solvent is 5% DMSO + 95% (10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64mM NaOH, pH=9)).

[0696] Preparation of the drug formulation: Accurately weigh an appropriate amount of the compound of this invention and place it in a suitable container. According to the total volume ratio of the formulation, first add 5% DMSO, vortex and sonicate for 2 minutes to completely dissolve it. Then add 95% (10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64mM NaOH, pH=9)), vortex and sonicate for 10 minutes to obtain the desired formulation.

[0697] 4. Administration

[0698] Three cynomolgus monkeys were used in each group. They were fasted overnight before administration and then administered the drug by gavage at a dose of 2 mg / kg in a volume of 5 mL / kg. They were fed again 4 hours after administration.

[0699] 5. Sample collection and biological analysis

[0700] Plasma samples were collected from cynomolgus monkeys before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The concentrations of the test compounds were detected using a chromatography-tandem triple quadrupole mass spectrometer.

[0701] 6. Data Analysis

[0702] Pharmacokinetic parameters were calculated using a non-compartmental model.

[0703] Table 7-1 Pharmacokinetic parameters of the tested compounds after oral administration to cynomolgus monkeys

[0704] Table 7-2 Pharmacokinetic parameters of the tested compounds administered intravenously to cynomolgus monkeys

[0705] The results show that the compounds of this invention exhibit good metabolic properties, with exposure AUC and Cmax being superior to those of the positive compound Orforglipron.

[0706] Example 8: In vivo pharmacodynamic assay of the compound in hGLP1R humanized mice using ipGTT

[0707] 1. Experimental Objective

[0708] Using hGLP1R humanized mice, the ability of the compounds in the embodiments of the present invention to regulate blood glucose was evaluated by ipGTT assay.

[0709] 2. Test System

[0710] C57BL / 6_hGLP-1R mice, male, Shanghai Southern Model Biotechnology Co., Ltd.

[0711] 3. Test methods

[0712] 1) Six- to eight-week-old C57BL / 6_hGLP-1R mice were introduced to the animal facility and acclimatized for at least 7 days, including 3 days of grasping acclimatization training. On the day of the experiment, mice were randomly assigned to groups based on body weight and fasting blood glucose. The grouping day was defined as Day 0, and a single intravenous injection was administered. The vehicle group received the administration solvent (vehicle: 5% DMSO + 10% Solutol HS15 in PBS solution (v:w)) at a volume of 5 mL / kg. The dosage group received 0.01, 0.025, or 0.05 mg / kg at a volume of 5 mL / kg.

[0713] 2) On the day of the glucose tolerance test: at 9:00 am, the animals were weighed, changed to cages, and fasted. Blood glucose was measured after 5 hours of fasting (14:00). Glucose was administered 10 minutes before administration (14:50). After 6 hours of fasting (15:00), a single intraperitoneal injection of 2 g / kg glucose solution (injection volume of 10 mL / kg) was given. The time of glucose administration was recorded as 0:00. Blood glucose was measured at 0 min after glucose administration, and at 15 min, 30 min, 60 min, 90 min, and 120 min after glucose administration.

[0714] 4. Experimental data processing and statistical analysis

[0715] Plot a glucose tolerance curve based on blood glucose data over time and calculate the area under the curve (AUC). 0-120 min ).

[0716] 5. Test Results

[0717] Table 8. Results of ipGTT in mice using compound hGLP-1R.

[0718] According to the experimental results, the compounds in the embodiments of the present invention can downregulate the IPGTT blood glucose level in hGLP1R mice and reduce the area under the blood glucose curve, demonstrating good blood glucose regulation ability.

[0719] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of general formula (I-1), or a pharmaceutically acceptable salt, solvate, hydrate, isotopic variant, prodrug, stereoisomer, or tautomer thereof, In the formula, X1 is N, C, or CH; X2 is C or N; X3 is CH, S, or N; Ring D is a 5-membered heteroaromatic ring; ring E is a benzene ring or a 6-membered heteroaromatic ring; R is one or more, and each is independently selected from: D, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl, cyano, carboxyl; the above groups are optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, carboxyl; R4 and R5 are each independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl; or C3-C6 cycloalkyl or C3-C6 heterocyclic group formed by R4 and R5 together; Ring B is a 5-12 membered heterocycle, a C3-C10 carbon ring, a C6-C10 aromatic ring, or a 5-12 membered heteroaromatic ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, C1-C6 alkyl, halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl. The ring C is a C3-C10 carbon ring or a 5-12 membered heterocycle; the above groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylene-O-C0-C6 alkylene-C3-C10 carbon ring, (C1-C6) alkylene-O-C1-C6 alkyl, C1-C6 alkoxy; or two substituents together with the intercalary atom form a C3-C6 carbon ring; the above substituents are optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C6 cycloalkoxy substituted or unsubstituted by C1-C6 alkyl, C1-C6 deuterated alkyl or halogen, -O-(CH2). 1-2 -C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl substituted or unsubstituted with C1-C6 deuterated alkoxy, CN or halogen; Ring A is a 5-12 membered heteroaryl ring, a C6-C10 aromatic ring, a C3-C10 carbon ring, a benzo5-10 membered heteroaryl ring, a benzo5-10 membered heteroaryl ring, or a 5-12 membered heteroaryl ring; the above group may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C3-C6 cycloalkyl, 5-8 membered heterocyclic group, C1-C6 deuterated alkyl, NRaRb, PO(C1-C6 alkyl), =S, =O, hydroxyl, C1-C6 alkyl, SF5, 5-8 membered heteroaryl, benzo5-8 membered heteroaryl, N=S(C1-C =6alkyl)2(=O), SO(=NH)(C3-C6 cycloalkyl), C1-C6 alkoxy, cyano, carboxyl, C2-C6 alkenyl, C2-C6 alkynyl; or two substituents together with the intercalary atom to form a C5-C8 carbon ring or a 5-8 membered heterocycle; the above substituents may be optionally replaced by one or more groups selected from the group consisting of: D, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, =O, =S, C3-C6 cycloalkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, carboxyl; in, Ra and Rb are each independently selected from: H and C1-C6 alkyl groups.

2. The compound according to claim 1, characterized in that, The compound has the structure shown in Formula IV: In the formula, X4 and X6 are each independently selected from O and CH2; X5 is CH2, CH(C1-C6 alkyl), C(C1-C6 alkyl)(C1-C6 alkyl) or Si(C1-C6 alkyl)(C1-C6 alkyl); Other groups are defined as described in claim 1.

3. The compound according to claim 1 or 2, characterized in that, Selected independently from:

4. The compound according to claim 1, characterized in that, Ring A is selected from the following group: Benzene ring; the above groups may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, cyano, SF5, PO (C1-C4 alkyl), NH2, NH (C1-C4 alkyl), N (C1-C4 alkyl), C1-C4 deuterated alkyl, C3-C6 cycloalkyl, =S, =O, 5-8 membered heterocyclic group, hydroxyl, 5-8 membered heteroaryl, Alternatively, the two substituents and the intercalary atom may together form a C5-C8 carbon ring or a 5-8 membered heterocycle; the above substituents may be optionally substituted by one or more groups selected from the group consisting of: D, halogen, C1-C4 alkyl, C1-C4 deuterated alkyl, =O, =S, C3-C6 cycloalkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, carboxyl.

5. The compound according to claim 1, characterized in that, Ring A is Where R d Selected from: C3-C6 cycloalkyl groups, 5-8 membered heterocyclic groups, And the group is unsubstituted or one or more hydrogens on the group are optionally substituted independently by a group selected from the group consisting of: deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy. R c Selected from: H, D, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, cyano, SF5, PO (C1-C4 alkyl)(C1-C4 alkyl).

6. The compound according to claim 1, characterized in that, The ring C is a C3-C8 carbon ring or a 5-8 membered heterocycle; the above groups are optionally substituted by one or more groups selected from the group consisting of: C1-C4 alkylene-O-C1-C4 alkyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylene-O-C3-C6 carbon ring, C1-C4 alkoxy; or two substituents together with the intercalary atom form a C3-C6 carbon ring; the above substituents are optionally substituted by one or more groups selected from the group consisting of: halogen, D, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 deuterated alkoxy, C3-C6 cycloalkoxy substituted or unsubstituted by C1-C4 alkyl, C1-C4 deuterated alkyl or halogen, -O-(CH2). 1-2 -C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl substituted or unsubstituted with C1-C4 deuterated alkoxy, CN or halogen.

7. The compound according to claim 1, characterized in that, for Where R e The substituents are selected from C1-C4 alkyl, C1-C4 alkylene-O-C3-C6 carbocyclic, C1-C4 alkoxy, and C1-C4 alkylene-O-C1-C4 alkyl, and the above substituents may be optionally replaced by one or more groups selected from the group consisting of: halogen, D.

8. The compound according to claim 1, characterized in that, Ring A is selected from the following group: Selected from the following group: Selected from the following group of groups, whether substituted or unsubstituted: The substitution is by being substituted by one or more groups selected from the group consisting of: D, halogen, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 deuterated alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C1-C4 deuterated alkyl, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl.

9. The compound according to claim 1, characterized in that, The compound is:

10. A pharmaceutical composition, characterized in that, Include: The compound as described in any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic variant, prodrug, stereoisomer, or tautomer thereof; and Pharmaceutically acceptable carrier.

11. Use of the compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic variant, prodrug, stereoisomer, or tautomer, or the pharmaceutical composition of claim 10, characterized in that, Used to prepare drugs for the prevention and / or treatment of GLP-1 receptor-mediated diseases.

12. The use as described in claim 11, characterized in that, The diseases mentioned are selected from: diabetes (such as type 2 diabetes), obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, diabetic nephropathy, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

13. Use of the compound of any one of claims 1-9 or the pharmaceutical composition of claim 10, or a pharmaceutically acceptable salt, solvate, hydrate, isotope variant, prodrug, stereoisomer or tautomer thereof, in the preparation of a medicament for reducing body weight.

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