GIPR antagonist, and preparation method therefor and use thereof

Abstract

The present invention relates to a GIPR antagonist, and a preparation method therefor and the use thereof. Specifically, the compound of the present invention has a structure as represented by formula I, wherein the definitions of each group and substituent are as described in the description. Further disclosed in the present invention are a method for preparing the compound and the use thereof in the prevention and / or treatment of obesity and / or diabetes.

Description

GIPR antagonists, their preparation methods and uses Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to GIPR antagonists, their preparation methods, and uses. Background Technology

[0002] Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid peptide secreted by K cells in the small intestine. The glucose-dependent insulinotropic polypeptide receptor (GIPR) belongs to the glucagon subfamily of B1 class G protein-coupled receptors (GPCRs) and is characterized by an extracellular N-terminal domain, seven transmembrane domains, and an intracellular C-terminus. The N-terminal extracellular domain forms the receptor's main peptide recognition and binding site. GIPR is expressed in various tissues, including the pancreas, intestine, adipose tissue, vascular system, heart, and brain.

[0003] GIPR knockout mice resist weight gain induced by a high-fat diet and improve insulin sensitivity and lipid profile. Recent data support that loss of function in the heterozygous form of GIPR leads to a reduction in body mass index and obesity risk in humans. Small molecules with GIPR antagonistic activity have been shown to prevent weight gain and insulin resistance in preclinical obesity models.

[0004] Currently, GIPR only has peptides for combination therapy, and the development of small molecules that can be administered orally is of great significance. Summary of the Invention

[0005] The purpose of this invention is to provide a compound of Formula I, a method for its preparation, and its use in the prevention and / or treatment of obesity and / or type 2 diabetes.

[0006] In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof.

[0007] in,

[0008] Cycle A is selected from the group consisting of: partially unsaturated 3-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 3-4-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 5-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 6-8-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each heterocyclic alkyl group and heteroaryl group is independently and optionally substituted with 1, 2 or 3 R2 groups.

[0009] Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl;

[0010] Alternatively, the two R2s attached to adjacent Cs together with their respective attached Cs form a phenyl, a C3-C6 cycloalkyl, or a C3-C6 spirocycloalkyl;

[0011] Alternatively, two R2s attached to the same C and their common C-attached C together form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S;

[0012] X1 is selected from the following group: N, CH, C;

[0013] X2 is selected from the following group: N, CH, C;

[0014] Y1 is selected from the following groups: -(C=O)-, None, -(C=S)-;

[0015] Y2 is selected from the following group: NR3, None;

[0016] R3 is selected from the following group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0017] Alternatively, R2 located at the position adjacent to ring A and its connected C and R3 together with the connected N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S;

[0018] Y3 is selected from the following groups: -(C=O)-, None, -(C=S)-;

[0019] Y4 is selected from the following group: NR4, -NR4-(CH2)-, none;

[0020] R4 is selected from the following group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0021] Alternatively, R2 located at the position adjacent to ring A and its connected C and R4 together with the connected N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S;

[0022] Ring B is selected from the following group: C6-C10 aryl, 6-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, and C5-C7 bridged cycloalkyl;

[0023] Each R1 is independently selected from the following group: H, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, -NR5R6, -SF5;

[0024] m is selected from the following group: 0, 1, 2, 3, 4;

[0025] Alternatively, the two R1s attached to adjacent Cs together with the Cs they are attached to form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S, wherein each cycloalkyl group or heterocycloalkyl group is independently and optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C=O, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0026] Alternatively, R1 attached to the adjacent position of ring B, together with its attached C, and R3 attached to its attached N, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S;

[0027] R5 and R6 are each independently selected from the following group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0028] The ring C is selected from the group consisting of: C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, C5-C7 bridged cycloalkyl, and 4-7 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, wherein each aryl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2 or 3 R7 atoms independently;

[0029] Each R7 is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

[0030] Alternatively, two R7s located at adjacent Cs together with their respective connected Cs form a saturated or partially unsaturated 4-7 membered heterocyclic alkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0031] Alternatively, R7 located at the aryl ortho position together with its attached C, and R4 together with its attached N, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by 1, 2 or 3 groups selected from the group consisting of: C1-C6 alkyl groups, halogens;

[0032] The ring D is selected from the group consisting of: C6-C10 aryl, none, C5-C7 bridged cycloalkyl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein each of the aryl, cycloalkyl, and heteroaryl groups is independently and optionally substituted by 1, 2 or 3 R8 atoms.

[0033] Each R8 is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and deuterated C1-C6 alkyl.

[0034] Alternatively, the R8 located ortho to the aryl group and its attached C, and the R7 located ortho to the aryl group and its attached C, together form a C5-C7 cycloalkyl group or a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S.

[0035] Alternatively, two R8s located at adjacent Cs together with their respective connected Cs form substituted or unsubstituted saturated or partially unsaturated 4-7 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, or 4-7 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0036] Alternatively, Z is -B(OH)2, and the R8 in the ortho position together with one OH of Z forms a 5-6 membered heterocyclic alkyl group containing B and O;

[0037] Z is selected from the group consisting of: -COOH, -(C1-C6 alkylene)-COOH, -(C2-C6 alkenyl)-COOH, -(C2-C6 alkyne)-COOH, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, and -B(OH)2, wherein the heteroaryl group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: halogen, hydroxyl, cyano, C=O, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkyne.

[0038] In another preferred embodiment, the additional condition is that when ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, the compound has one or more characteristics selected from the group consisting of:

[0039] 1) Two R2s attached to adjacent C atoms, together with their respective attached C atoms, form a phenyl or C3-C6 spirocyclic cycloalkyl group;

[0040] 2) X1 is CH, X2 is N;

[0041] 3) Y1 is zero, Y2 is zero;

[0042] 4) R2 located at the ortho position of ring A and its connected C and R4 together with the connected N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S;

[0043] 5) Y1 is -(C=S)-;

[0044] 6) Two R1s attached to adjacent C and the Cs they are attached to together form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S, wherein each cycloalkyl group or heterocycloalkyl group is independently and optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C=O, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0045] 7) m is selected from the following groups: 2, 3, 4;

[0046] At least one R1 is selected from the group consisting of: hydroxyl, cyano, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, 3-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, and NR5R6.

[0047] 8) Cyclone B is selected from the following group: 6-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, and C5-C7 bridged cycloalkyl groups;

[0048] 9) R1 attached to the adjacent position of ring B, together with the C and R3 attached thereto and the N attached thereto, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S;

[0049] 10) Y3 is empty, Y4 is empty;

[0050] 11) The R7 located at the aryl ortho position together with the C it is attached to, and the R4 together with the N it is attached to form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by 1, 2 or 3 groups selected from the group consisting of: C1-C6 alkyl, halogen;

[0051] 12) Ring D is selected from the following group: none, C5-C7 bridged cycloalkyl rings, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S;

[0052] 13) The R8 located ortho to the aryl group and its attached C, and the R7 located ortho to the aryl group and its attached C together form a C5-C7 cycloalkyl group or a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S.

[0053] 14) The ring C is selected from the following group: 5-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; C5-C7 bridged cycloalkyl groups;

[0054] 15) Z is selected from the following group: -(C1-C6 alkylene)-COOH, -(C2-C6 alkenyl)-COOH, -(C2-C6 alkyneyl)-COOH, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, -B(OH)2;

[0055] 16) R2 located at the ortho position of ring A and its connected C and R3 together with the connected N to form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S;

[0056] 17) Two R2s attached to the same C and the C they are attached to together form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S;

[0057] 18) Ring A is a saturated 5-membered heterocyclic alkyl group containing two heteroatoms selected from N, O, or S;

[0058] 19) The heterocyclic alkyl group is substituted with 1, 2 or 3 R2 atoms;

[0059] Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl;

[0060] 20) m is 1, R1 is selected from the following group: NR5R6, -SF5;

[0061] 21) The ring C is selected from the following group: C5-C7 bridged cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S;

[0062] 22) Two R8s located at adjacent C and their respective connected Cs together form a substituted or unsubstituted saturated or partially unsaturated 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, or a 4-7 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0063] 23) Two R7s located at adjacent Cs together with their respective connected Cs form a saturated or partially unsaturated 4-7 membered heterocyclic alkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0064] In another preferred embodiment, when ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, ring A is... R2 is selected from the following group: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl.

[0065] In another preferred embodiment, when ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, ring A is... R2 is selected from the following group: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl.

[0066] In another preferred embodiment, when ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, the heterocyclic alkyl group is substituted with 2 R2 atoms, and ring A is selected from the group consisting of: R2 is selected from the following group: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1- 3-O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl.

[0067] In another preferred embodiment, when ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, the heterocyclic alkyl group is substituted with 2 R2 atoms, and ring A is selected from the group consisting of: R2 is selected from the following group: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl.

[0068] In another preferred embodiment, in ring A, the saturated 6-8 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S is selected from the group consisting of monocyclic heterocyclic alkyl, bridged heterocyclic alkyl, and spirocyclic heterocyclic alkyl.

[0069] In another preferred embodiment, ring A is a saturated 6-8 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, and is a bridged heterocyclic alkyl group.

[0070] In another preferred embodiment, for

[0071] R 1a Selected from the following group: C2-C6 alkynyl, halogenated C1-C6 alkoxy; R 1b Selected from the following group: H, halogens.

[0072] In another preferred embodiment, for

[0073] R 1a It is a halogenated C1-C6 alkoxy group;

[0074] R 1b Selected from the following group: H, halogens.

[0075] In another preferred example, exactly one of X1 and X2 is N.

[0076] In another preferred embodiment, ring A is selected from the group consisting of: partially unsaturated 3-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 3-4-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 6-8-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each heterocyclic alkyl group and heteroaryl group is optionally substituted by 1, 2 or 3 R2 groups independently;

[0077] Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl;

[0078] Alternatively, the two R2s attached to adjacent Cs together with their respective attached Cs form a phenyl or a C3-C6 spirocycloalkyl group;

[0079] Alternatively, two R2 atoms attached to the same C atom, together with the C atoms they are connected to, form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S.

[0080] In another preferred embodiment, ring A is selected from the group consisting of: partially unsaturated 3-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 6-8-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each heterocyclic alkyl group and heteroaryl group is optionally substituted by 1, 2 or 3 R2 groups independently.

[0081] Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl;

[0082] Alternatively, the two R2s attached to adjacent Cs together with their respective attached Cs form a phenyl or a C3-C6 spirocycloalkyl group;

[0083] Alternatively, two R2 atoms attached to the same C atom, together with the C atoms they are connected to, form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S.

[0084] In another preferred embodiment, R2 located at the ortho position of ring A and its connected C and R3 together with the connected N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S; and / or

[0085] R2 located at the position adjacent to ring A, together with C and R4 connected to it and N connected to it, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S.

[0086] In another preferred embodiment, the two R8s located at adjacent Cs together with their respective connected Cs form substituted or unsubstituted saturated or partially unsaturated 4-7 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, or 4-7 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by 1, 2 or 3 substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

[0087] In another preferred embodiment, each R8 is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

[0088] In another preferred embodiment, the deuterated C1-C6 alkyl group is -CD3.

[0089] In another preferred embodiment, the compound of the present invention has the structure of Formula II:

[0090] Where X3 is CH or N;

[0091] R2' is selected from: H, D, C1-C3 alkyl or deuterated C1-C3 alkyl;

[0092] R2”, R2”' and R2”” are all H; or R2” and R2”” are connected to form a C1-C2 alkylene group and R2”” is H; or any two adjacent R2”, R2”' and R2”” are connected to form a C1-C2 alkylene group, and the other one is H;

[0093] R1' is selected from: H, halogens, and C1-C6 alkyl groups;

[0094] R1” is selected from: C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl and -SF5;

[0095] R8' and R8” are independently selected from: H, C1-C6 alkyl;

[0096] Alternatively, R8' and R8" together with their respective connected C form a 5-6 membered heterocyclic alkyl group containing one heteroatom selected from N, O, or S, or a 5-6 membered heteroaryl group containing one heteroatom selected from N, O, or S; and the heterocyclic alkyl group or heteroaryl group is optionally substituted by one or more groups selected from the group consisting of D, C1-C3 alkyl, or deuterated C1-C3 alkyl.

[0097] In another preferred embodiment, X3 is CH.

[0098] In another preferred embodiment, R2' is -CH3 or -CD3.

[0099] In another preferred embodiment, R2” and R2”” are connected to form -CH2- and R2”’ is H.

[0100] In another preferred embodiment, R2” and R2”' are connected to form -CH2- and R2”” is H.

[0101] In another preferred embodiment, R2”' and R2”” are connected to form -CH2- and R2” is H.

[0102] In another preferred embodiment, R8' and R8” together with their respective connected C form a 5-membered heterocyclic alkyl group containing a heteroatom selected from O or N; and the heterocyclic alkyl or heteroaryl group is optionally substituted by one or more groups selected from the group consisting of D, C1-C3 alkyl or deuterated C1-C3 alkyl (preferably R8' and R8” together form -CH2CH2-O-, -CH(CH3)CH2-O- or -CH2CH2-NH-).

[0103] In another preferred embodiment, R8' and R8” together with their respective connected C form a 5-membered heteroaryl group containing a heteroatom selected from O or N (preferably R8' and R8” are connected together to form -CH=CH-O- or -CH=CH-NH-).

[0104] In another preferred embodiment, R8' and R8” together with their respective connected C form a 6-membered heterocyclic alkyl group containing one O heteroatom (R8' and R8” together form -CH2CH2-O- or -CH=CH-O-).

[0105] In another preferred embodiment, R1' is a halogen, and preferably R1' is F.

[0106] In another preferred embodiment, R1” is selected from: C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, C3-C4 cycloalkyl and -SF5.

[0107] In another preferred embodiment, R1' is F and R1" is selected from: C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkoxy.

[0108] In another preferred embodiment, R1' is F and R1” is CF3.

[0109] In another preferred embodiment, R1' is F and R1” is isopropyl.

[0110] In another preferred embodiment, R1' is H or F, and R1” is -OCF3.

[0111] In another preferred embodiment, the compound is selected from the group consisting of:

[0112] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, as a first active ingredient.

[0113] In another preferred embodiment, the pharmaceutical composition further comprises a second active ingredient, which is smegglutinin.

[0114] A third aspect of the invention provides the use of the compound described in the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, for the preparation of a medicament for the prevention and / or treatment of GIPR-related diseases.

[0115] In another preferred embodiment, the GIPR-related diseases are selected from the group consisting of diabetes and metabolic diseases.

[0116] In another preferred embodiment, the diabetes is selected from the group consisting of type 1 diabetes and type 2 diabetes.

[0117] In another preferred embodiment, the metabolic disease is selected from the group consisting of obesity and weight gain.

[0118] 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. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0119] Figure 1 shows the efficacy of compound hGIPR in inducing obesity in mice via HFD.

[0120] Figure 2 shows the efficacy of the combination of the compound in the example with smegglutinin hGIPR mice to induce obesity in HFD.

[0121] Figure 3 shows the effect of the combination of the compound in the examples with smegglutinin hGIPR mice on cumulative food intake. Detailed Implementation

[0122] Through long-term and in-depth research, the inventors unexpectedly prepared a novel compound of formula I with excellent GIPR antagonistic properties via structural optimization. Based on this, the inventors completed this invention.

[0123] the term

[0124] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0125] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0126] In this invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0127] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0128] In this invention, the term "C2-C6 ynyl" refers to a straight-chain or branched ynyl group having 2-6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0129] In this invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3-8 carbon atoms on a ring, and non-limitingly includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C6 cycloalkyl" has a similar meaning.

[0130] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is a C1-C4 alkoxy group.

[0131] In this invention, the term "heterocyclic alkyl" refers to a 3-8 membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. The heterocyclic alkyl group is saturated or partially saturated (e.g., having one or two double bonds), and includes (but is not limited to) the following groups:

[0132] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0133] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "C5-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 5 to 10 carbon atoms. The aromatic heterocycle may have 5 to 6 ring atoms, or 8 to 10 ring atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0134] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0135] In this invention, the term "deuterium substitution" refers to being replaced by deuterium.

[0136] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0137] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0138] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0139] compound

[0140] This invention provides compounds of formula I or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates or solvates thereof.

[0141] The groups are defined as described above.

[0142] In another preferred embodiment, in the compound, any one of R1, m, X1, X2, Y1, Y2, Y3, Y4, ring A, ring B, ring C, ring D, and Z is independently the corresponding group in the specific compound of the present invention.

[0143] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0144] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0145] The term "solvate" 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.

[0146] The embodiments of this invention specifically describe methods for preparing compounds of Formula I, but these specific methods do not constitute any limitation on the 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.

[0147] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased commercially unless otherwise specified.

[0148] Pharmaceutical Compositions and Administration

[0149] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof.

[0150] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0151] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0152] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0153] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0154] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0155] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0156] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as 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 of these substances.

[0157] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0158] In addition to the active compound, 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.

[0159] 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.

[0160] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0161] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0162] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0163] 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 50–1000 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.

[0164] Compared with the prior art, the present invention has the following main advantages:

[0165] (1) The compound has a novel structure and excellent GIPR antagonistic properties;

[0166] (2) The compound has excellent pharmacokinetic properties and safety;

[0167] (3) The compound has excellent solubility;

[0168] (4) The compound, when used alone or in combination with smegglutinin, has a significantly better therapeutic effect on obesity.

[0169] 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 as 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 by weight.

[0170] 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.

[0171] Preparation of intermediates

[0172] Synthesis of intermediate A1:

[0173] Intermediate A1 is synthesized via the following route:

[0174] Step 1: Synthesis of compound A1-1

[0175] Compound 3-trifluoromethyl-4-bromoaniline (2.7 g, 11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (45 mL). Di-tert-butyl dicarbonate (3.7 g, 17 mmol, 1.5 eq) and 4-dimethylaminopyridine (1.37 g, 11 mmol, 1.0 eq) were added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was quenched in water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-20%) to give compound A1-1 (3.2 g, yield 86%).

[0176] LC-MS (ESI+) m / z: 340.0 (M+H) + ;

[0177] Step 2: Synthesis of compound A1-2

[0178] Compound A1-1 (2.9 g, 8.5 mmol, 1.0 eq) and cyclopropylboronic acid (1.5 g, 17 mmol, 2.0 eq) were dissolved in a mixed solvent of dioxane (30 mL) and water (3 mL). 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (0.6 g, 0.9 mmol, 0.10 eq) and tripotassium phosphate (3.6 g, 17 mmol, 2.0 eq) were added. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 4 hours. After the reaction was completed, the mixture was concentrated. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-20%) to give compound A1-2 (2.3 g, 90% yield).

[0179] LC-MS (ESI+) m / z: 302.0 (M+H) +.

[0180] Step 3: Synthesis of intermediate A1

[0181] Compound A1-2 (2.0 g, 7.0 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (6 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into a saturated sodium bicarbonate solution (100 mL), extracted with dichloromethane (30 mL × 3), and the organic layers were combined. The organic layers were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude intermediate A1 (0.96 g, yield 67%).

[0182] LC-MS(ESI+) m / z: 202.0(M+H) + ;

[0183] Synthesis of intermediate A2:

[0184] Intermediate A2 is synthesized via the following route:

[0185] Step 1: Synthesis of compound A2-2

[0186] The synthesis of compound A2-2 is based on the synthesis of compound A1-2.

[0187] LC-MS (ESI+) m / z: 302.2 (M+H) + ;

[0188] Step 2: Synthesis of compound A2-3

[0189] Compound A2-2 (300 mg, 1 mmol, 1.0 eq) was dissolved in methanol (10 mL), and palladium on carbon (5%, 50 mg) was added. The mixture was stirred overnight at 50 °C under a hydrogen atmosphere of 50 PSI. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound A2-3 (300 mg), which could be used directly in the next reaction without further purification.

[0190] LC-MS (ESI+) m / z: 304.2 (M+H) + ;

[0191] Step 3: Synthesis of intermediate A2

[0192] The synthesis of intermediate A2 is based on the synthesis of intermediate A1.

[0193] LC-MS (ESI+) m / z: 204.2 (M+H) + .

[0194] Synthesis of intermediate A3:

[0195] Intermediate A3 is synthesized via the following route:

[0196] Compound 4-bromo-3-fluoroaniline (0.5 g, 2.63 mmol, 1.0 eq), 1-(trimethylsilyl)propyne (883.0 mg, 7.89 mmol, 3.0 eq), cuprous iodide (50.0 mg, 0.26 mmol, 0.1 eq), palladium dichloride bis(triphenylphosphine) (182 mg, 0.26 mmol, 0.1 eq), and tetrabutylammonium fluoride (1 M, 9.2 mL, 9.2 mmol, 3.5 eq) were sequentially added to a reaction flask containing N,N-dimethylformamide (5 mL). Nitrogen gas was purged three times, and the mixture was heated to 65 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 0-5%) to give intermediate A3 (300 mg, yield 77%).

[0197] LC-MS (ESI+) m / z: 150.2 (M+H) + .

[0198] Synthesis of intermediate A4:

[0199] Intermediate A4 is synthesized via the following route:

[0200] Step 1: Synthesis of compound A4-1

[0201] Compound 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (200 mg, 1 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and N-bromosuccinimide (178 mg, 1 mmol, 1.0 eq) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water (20 mL), extracted with dichloromethane (20 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-80%) to give compound A1-1 (90 mg, yield 33%).

[0202] Synthesis of intermediate A4

[0203] The remaining steps refer to the synthesis of compounds A2-2, A2-3 and intermediate A2.

[0204] LC-MS (ESI+) m / z: 244.2 (M+H)+ .

[0205] Synthesis of intermediate A5:

[0206] Intermediate A5 is synthesized via the following route:

[0207] Step 1: Synthesis of compound A5-1

[0208] At room temperature, tert-butyl (4-bromo-3-fluorophenyl)carbamate (15.0 g, 60.48 mmol, 1.0 eq) and furan-2-boronic acid (13.5 g, 129.0 mmol, 2.0 eq) were dissolved in a mixed solvent of N,N-dimethylformamide (375 mL) and water (70 mL). Tetra(triphenylphosphine)palladium (6.97 g, 6.0 mmol, 0.1 eq) and potassium carbonate (25.04 g, 181.2 mmol, 3.0 eq) were added sequentially to the above solution under a nitrogen atmosphere. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (3 × 30 mL), and the organic layers were combined. The organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A5-1 (11.37 g, yield 71%).

[0209] LC-MS (ESI+) m / z: 278.2 (M+H) + ;

[0210] Step 2: Synthesis of compound A5-2

[0211] Compound A5-1 (1 g, 3.61 mmol, 1.0 eq) was dissolved in a mixed solvent of dichloromethane / methanol (10 mL / 3 mL), and palladium on carbon (10%, 200 mg) was added. The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere at 1 atm. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product A5-2 (800 mg), which could be used directly in the next step without further purification.

[0212] LC-MS (ESI+) m / z: 282.2 (M+H) + ;

[0213] Step 3: Synthesis of intermediate A5

[0214] Compound A5-2 (800 mg, 2.8 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and a hydrochloric acid / dioxane (4 M, 2 mL) solution was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude intermediate A5 (500 mg). This compound was not further purified and was used directly in the next reaction.

[0215] LC-MS (ESI+) m / z: 182.2 (M+H) + .

[0216] Synthesis of intermediate A6:

[0217] Intermediate A6 is synthesized via the following route:

[0218] The synthesis of intermediate A6 is referenced to the synthesis of compounds A2-2 and A2-3.

[0219] LC-MS (ESI+) m / z: 230.2 (M+H) + .

[0220] Synthesis of intermediate A7:

[0221] Intermediate A7 is synthesized via the following route:

[0222] Step 1: Synthesis of compound A7-1:

[0223] 2-Bromo-4-fluorotrifluorotoluene (1.0 g, 4.0 mmol, 1.0 eq) was dissolved in concentrated sulfuric acid (10 mL) at 0 °C, and potassium nitrate (460 mg, 4.5 mmol, 1.1 eq) was added in portions. The reaction mixture was stirred at this temperature for half an hour, then gradually raised to room temperature, and the reaction was continued to be stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A7-1 (1.0 g, 90% yield).

[0224] 1 H-NMR(400MHz, CDCl3)δ:7.75(1H,d),8.45(1H,d).

[0225] Step 2: Synthesis of compound A7-2:

[0226] At 0 °C, 2-chloroethanol (2.0 g, 25 mmol) was dissolved in tetrahydrofuran (25 mL), and diisopropylaminolithium (2 M, 12.5 mL, 25 mmol) was added dropwise. After stirring the reaction mixture at room temperature for 15 minutes, a tetrahydrofuran solution of compound A7-1 (6 g, 21 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was monitored to be complete, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-25%) to give compound A7-2 (6.5 g, 92% yield).

[0227] Step 3: Synthesis of compound A7-3:

[0228] Compound A7-2 (6.5 g, 18.7 mmol, 1.0 eq) was dissolved in glacial acetic acid (20 mL), and iron powder (5.2 g, 93.6 mmol, 5.0 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was filtered, and the filtrate was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound A7-3 (5.3 g, 90% yield).

[0229] LC-MS (ESI+) m / z: 318.2 (M+H) + ;

[0230] Step 4: Synthesis of compound A7-4:

[0231] Compound 7-3 (5.3 g, 16.8 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, and potassium iodide (5.5 g, 33.6 mmol, 2 eq) and potassium carbonate (6.9 g, 50.4 mmol, 3.0 eq) were added. The mixture was stirred at 80 °C for 7 hours. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound A7-4 (4.2 g, 90% yield).

[0232] LC-MS (ESI+) m / z: 282.2 (M+H)+ ;

[0233] Synthesis of compound A7:

[0234] The remaining steps for the synthesis of compound A7 are the same as those for the synthesis of compounds A2-2 and A2-3.

[0235] LC-MS (ESI+) m / z: 246.1 (M+H) + .

[0236] Synthesis of intermediate A8:

[0237] Intermediate A8 is synthesized via the following route:

[0238] 5-Bromo-1-methyl-3-(trifluoromethyl)-1H-indazole (200 mg, 0.72 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), followed by the addition of tert-butyl carbamate (135 mg, 1.08 mmol, 1.5 eq), tris(dibenzylacetone)palladium (64 mg, 0.07 mmol, 0.1 eq), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (66 mg, 0.14 mmol, 0.2 eq), and cesium carbonate (467 mg, 1.43 mmol, 2.0 eq). The reaction mixture was incubated at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, and trifluoroacetic acid (1 mL) was added with stirring for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-25%) to give intermediate A8 (150 mg, yield 90%).

[0239] LC-MS (ESI+) m / z: 216.1 (M+H) + .

[0240] Synthesis of intermediate A9:

[0241] Intermediate A9 is synthesized via the following route:

[0242] The synthesis of intermediate A9 is based on the synthesis of intermediate A8.

[0243] LC-MS (ESI+) m / z: 166.1 (M+H) + .

[0244] Synthesis of intermediate A10:

[0245] Intermediate A10 is synthesized via the following route:

[0246] Synthesis of intermediate A10:

[0247] At room temperature, compound 6-amino-1-indanone (140 mg, 1 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and diethylaminotrifluoride (320 mg, 2 mmol, 2.0 eq) was added. The mixture was stirred overnight at room temperature. After the reaction was monitored to be complete, the reaction solution was quenched in water (10 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound A10 (10 mg, yield 6%).

[0248] LC-MS (ESI+) m / z: 170.1 (M+H) + .

[0249] Synthesis of intermediate A11:

[0250] Intermediate A11 is synthesized via the following route:

[0251] Synthesis of intermediate A11:

[0252] The synthesis of intermediate A11 is based on the synthesis of intermediate A2.

[0253] LC-MS (ESI+) m / z: 154.1 (M+H) + .

[0254] Synthesis of intermediate A12:

[0255] Intermediate A12 is synthesized via the following route:

[0256] Step 1: Synthesis of compound A12-1

[0257] Refer to the synthesis of compound A1-2.

[0258] Step 2: Synthesis of intermediate A12

[0259] Compound A12-1 (180 mg, 1 mmol, 1.0 eq) was dissolved in methanol (10 mL), and palladium on carbon (5%, 20 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at 1 atm. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give crude compound A12 (180 mg), which could be used directly in the next reaction without further purification.

[0260] LC-MS (ESI+) m / z: 152.2 (M+H) + .

[0261] Synthesis of intermediate A14:

[0262] Intermediate A14 is synthesized via the following route:

[0263] Synthesis of intermediate A14

[0264] The synthesis of intermediate A14 is based on patent WO2022 / 032484A1, which describes its synthesis from 3-trifluoromethyl-4-bromoaniline via a four-step reaction.

[0265] LC-MS (ESI+) m / z: 218.2 (M+H) + ;

[0266] Synthesis of intermediate B1:

[0267] Intermediate B1 is synthesized via the following route:

[0268] Compounds 2-amino-5-bromopyridine (643 mg, 3.72 mmol, 1.1 eq) and pinacol 4-(tert-butoxycarbonyl)phenylboronic acid (750 mg, 3.38 mmol, 1.0 eq) were dissolved in a mixed solvent of dioxane (10 mL) and water (2 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (124 mg, 0.169 mmol, 0.05 eq) and potassium carbonate (1.4 g, 10.1 mmol, 3.0 eq) were added. The mixture was stirred at 95 °C for 5 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 0-80%) to give intermediate B1 (669 mg, yield 73%).

[0269] LCMS(ESI)+m / z 271.1(M+H) + ;

[0270] Synthesis of intermediate B2:

[0271] Intermediate B2 is synthesized via the following route:

[0272] The synthesis of intermediate B2 is based on the synthesis of intermediate B1.

[0273] LCMS(ESI)+m / z 270.1(M+H) + ;

[0274] Synthesis of intermediate B3:

[0275] Intermediate B3 is synthesized via the following route:

[0276] Synthesis of intermediate B3

[0277] The synthesis of intermediate B3 is the same as that of intermediate B1. It is generated by coupling 5-bromodihydroindole with 4-tert-butoxycarbonylphenylboronic acid.

[0278] LCMS(ESI)+m / z 296.1(M+H) + ;

[0279] Synthesis of intermediate B4:

[0280] Intermediate B4 is synthesized via the following route:

[0281] The synthesis of intermediate B4 is based on the synthesis of intermediate B1.

[0282] LCMS(ESI)+m / z 289.1(M+H) + ;

[0283] Synthesis of intermediate B5:

[0284] Intermediate B5 is synthesized via the following route:

[0285] Synthesis of intermediate B5

[0286] Compound p-iodoaniline (1.0 g, 4.6 mmol, 1.0 eq), tert-butylpropynate (693.0 mg, 5.5 mmol, 1.2 eq), cuprous iodide (175 mg, 0.92 mmol, 0.2 eq), and bis(triphenylphosphine)palladium dichloride (323 mg, 0.46 mmol, 0.1 eq) were sequentially added to diisopropylamine (10 mL). The reaction mixture was purged with nitrogen three times and heated to 85 °C with stirring for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 0-80%) to give intermediate B5 (700 mg, yield 69%).

[0287] LC-MS (ESI+) m / z: 218.2 (M+H) + ;

[0288] Synthesis of intermediate B6:

[0289] Intermediate B6 is synthesized via the following route:

[0290] Step 1: Synthesis of compound B6-1

[0291] The synthesis of compound B6-1 is referenced to the synthesis of intermediate B1.

[0292] LC-MS (ESI+) m / z: 295.2 (M+H) + ;

[0293] Step 2: Synthesis of compound B6-2

[0294] Compound B6-1 (294 mg, 1 mmol, 1.0 eq) was dissolved in ethanol (10 mL) at room temperature, and potassium carbonate (250 mg, 1.8 mmol, 1.8 eq) and hydroxylamine hydrochloride (124 mg, 1.8 mmol, 1.8 eq) were added. The reaction mixture was heated under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and a precipitate formed. The precipitate was filtered. The filter cake was dried under vacuum to give compound B6-2 (130 mg, 40% yield).

[0295] LC-MS (ESI+) m / z: 328.2 (M+H) + ;

[0296] Step 3: Synthesis of compound B6-3

[0297] Compound B6-2 (130 mg, 0.40 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), and N,N'-carbonyldiimidazole (78 mg, 0.48 mmol, 1.2 eq) and 1,8-diazacyclo[5,4,0]undecene-7 (156 mg, 0.48 mmol, 1.2 eq) were added. The reaction mixture was heated to 100 °C and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and dilute hydrochloric acid (3 M) was added dropwise until the pH of the reaction mixture was 2. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude intermediate B6-3 (100 mg). This compound was not purified and was used directly in the next step.

[0298] LC-MS (ESI+) m / z: 354.2 (M+H) + ;

[0299] Step 4: Synthesis of intermediate B6

[0300] A 4M, 5mL solution of dioxane hydrochloride was added to intermediate B6-3 (100mg). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude intermediate B6 (80mg).

[0301] LC-MS (ESI+) m / z: 254.2 (M+H) + ;

[0302] Synthesis of intermediate B7:

[0303] Intermediate B7 is synthesized via the following route:

[0304] Step 1: Synthesis of compound B7-1

[0305] The synthesis of compound B7-1 is referenced to the synthesis of intermediate B1.

[0306] LC-MS (ESI+) m / z: 306.2 (M+H) + ;

[0307] Step 2: Synthesis of compound B7

[0308] Compound B7-1 (300 mg, 1 mmol, 1.0 eq) was dissolved in methanol (10 mL), and palladium on carbon (5%, 30 mg) was added. The reaction mixture was stirred for 5 hours under a hydrogen atmosphere at 1 atm. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude intermediate B7 (300 mg), which could be used directly in the next step without purification.

[0309] LC-MS (ESI+) m / z: 276.2 (M+H) + ;

[0310] Synthesis of intermediate B8:

[0311] Intermediate B8 is synthesized via the following route:

[0312] Step 1: Synthesis of compound B8-1

[0313] The synthesis of compound B8-1 is based on the synthesis of compound B5.

[0314] Step 2: Synthesis of compound B8

[0315] The synthesis of compound B8 is based on the synthesis of compound B7.

[0316] LC-MS (ESI+) m / z: 275.2 (M+H) + ;

[0317] Synthesis of intermediate B9:

[0318] Intermediate B9 is synthesized via the following route:

[0319] Step 1: Synthesis of compound B9-1

[0320] At 0 °C, compound 3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (4 g, 18 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL), and 4-dimethylaminopyridine (439 mg, 3.6 mmol, 0.2 eq) and N-hydroxyphthalimide (3.2 g, 20 mmol, 1.1 eq) were added. After stirring the reaction mixture at 0 °C for half an hour, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.1 g, 27 mmol, 1.5 eq) was added. The mixture was stirred at 0 °C for another 2 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL), extracted with dichloromethane (20 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 0-80%) to give compound B9-1 (2.5 g, yield 40%).

[0321] LC-MS (ESI+) m / z: 358.2 (M+H) + ;

[0322] Step 2: Synthesis of compound B9-2

[0323] At room temperature, under a nitrogen atmosphere, 4,4'-di-tert-butyl-2,2'-dipyridine (0.973 g, 3.63 mmol) was added to a solution of nickel(II) bromide trihydrate (0.79 g, 2.90 mmol) in N,N-dimethylacetamide (80 mL). The resulting mixture was stirred at 50 °C for 30 min and then cooled to room temperature. At room temperature, compound B9-1 (4.3 g, 12 mmol, 1.0 eq), 4-nitroiodobenzene (3.0 g, 12.09 mmol, 1.0 eq), trimethylchlorosilane (0.131 g, 1.2 mmol, 0.1 eq), and zinc (3.95 g, 60 mmol, 5.0 eq) were added to the above mixture. The resulting mixture was stirred at room temperature for 2 h. After the reaction was monitored for acceptance, the reaction was quenched with brine (150 mL) and extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 0-40%) to give compound B9-2 (1.7 g, 50% yield).

[0324] LC-MS (ESI+) m / z: 290.1 ​​(M+H) + ;

[0325] Step 3: Synthesis of intermediate B9

[0326] The hydrogenation of intermediate B9 is referenced to the hydrogenation reaction of intermediate B7.

[0327] LC-MS (ESI+) m / z: 260.1 (M+H) + ;

[0328] Synthesis of intermediate B10:

[0329] Intermediate B10 is synthesized via the following route:

[0330] Synthesis of compound B10-2:

[0331] The synthesis of compound B10-2 is referenced to the synthesis of intermediate B9-2.

[0332] Synthesis of compound B10-3:

[0333] Compound B10-2 (302 mg, 1 mmol, 1.0 eq) was dissolved in a mixture of methanol (5 mL) and water (1 mL), and lithium hydroxide monohydrate (84 mg, 2 mmol, 2.0 eq) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and the mixture was then diluted with water (15 mL) and the pH was adjusted to 5 using dilute hydrochloric acid (1 N). The mixture was extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound B10-3 (200 mg, 69% yield).

[0334] Synthesis of compound B10-4:

[0335] At room temperature, diphenyl azidophosphate (210 mg, 0.76 mmol, 1.1 eq) was added dropwise to a solution of compound B10-3 (200 mg, 0.69 mmol, 1.0 eq) and triethylamine (83 mg, 0.82 mmol, 1.2 eq) in toluene (10 mL). The reaction mixture was heated to 100 °C and stirred for 3 hours. Then, benzyl alcohol (88 mg, 0.82 mmol, 1.2 eq) was added to the reaction mixture. The mixture was stirred at 100 °C for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 0-40%) to give compound B10-4 (120 mg, 40% yield).

[0336] LC-MS (ESI+) m / z: 394.1 (M+H) + ;

[0337] Synthesis of intermediate B10:

[0338] The synthesis of intermediate 10 follows the same hydrogenation steps as the synthesis of intermediate 9.

[0339] LC-MS (ESI+) m / z: 260.1 (M+H) + ;

[0340] Synthesis of intermediate B11:

[0341] Intermediate B11 is synthesized via the following route:

[0342] The synthesis of intermediate B11 is based on the synthesis of intermediate B1.

[0343] LC-MS (ESI+) m / z: 334.1 (M+H) + ;

[0344] Synthesis of intermediate B12:

[0345] Intermediate B12 is synthesized via the following route:

[0346] Step 1: Synthesis of compound B12-1

[0347] At room temperature, 4-tert-butoxycarbonylaminopiperidine (200 mg, 1 mmol) and methyl p-bromobenzoate (214 mg, 1 mmol) were dissolved in dioxane (2 mL), and palladium acetate (22.42 mg, 0.09 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (57.78 mg, 0.09 mmol), and cesium carbonate (650 mg, 2 mmol) were added. The reaction mixture was heated to 110 °C under nitrogen protection and stirred at this temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel rapid chromatography (petroleum ether: ethyl acetate = 3:1) to give compound B12-1 (200 mg, 60% yield).

[0348] LC-MS (ESI+) m / z: 335.2 (M+H) + ;

[0349] Step 2: Synthesis of compound B12

[0350] Compound B12-1 (150 mg, 0.45 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, and dioxane hydrochloride solution (4 M, 2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was diluted with a mixture of dichloromethane and methanol (5 mL, Vdichloromethane:Vmethanol = 10:1). Sodium carbonate solid was added to adjust the pH to 9. The mixture was stirred at room temperature for half an hour and then filtered. The filtrate was concentrated under reduced pressure to give free compound B12 (100 mg, 95% yield).

[0351] LC-MS (ESI+) m / z: 235.2 (M+H) + ;

[0352] Synthesis of intermediate B13:

[0353] Intermediate B13 is synthesized via the following route:

[0354] Step 1: Synthesis of compound B13-1

[0355] Under nitrogen protection, tert-butyl 4-bromo-2-fluorobenzoate (5 g, 18.2 mmol) was dissolved in tetrahydrofuran (100 mL). The reaction mixture was cooled to -78 °C, and then lithium diisopropylaminophosphate solution (2 M, 9.1 mL, 18.2 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 4 hours. Subsequently, ethylene oxide solution (2.5 M in THF, 21.8 mL, 54.6 mmol) was added dropwise to the reaction mixture. The mixture was stirred at -78 °C for another 6 hours. After the reaction was monitored to be complete, the reaction mixture was quenched in saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-20%) to give compound B13-1 (1.1 g, yield 19%).

[0356] LC-MS (ESI+) m / z: 319.2 (M+H) + ;

[0357] Step 2: Synthesis of compound B13-2

[0358] Under nitrogen protection, compound B13-1 (5 g, 15.6 mmol) was dissolved in N,N-dimethylformamide (50 mL), and cesium carbonate (7.66 g, 23.5 mmol) was added. The reaction mixture was stirred at 90 °C for 14 hours. After the reaction was completed, the mixture was diluted in water (100 mL). Extraction was performed with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to give compound B13-2 (3.25 g, yield 69%).

[0359] LC-MS (ESI+) m / z: 299.2 (M+H) + ;

[0360] Step 3: Synthesis of intermediate B13

[0361] The synthesis of intermediate B13 is based on the synthesis of intermediate B2.

[0362] LC-MS (ESI+) m / z: 312.2 (M+H) +

[0363] Synthesis of intermediate B14:

[0364] Intermediate B14 is synthesized via the following route:

[0365] The synthesis of intermediate B14 is similar to that of intermediate B1:

[0366] LC-MS (ESI+) m / z: 284.2 (M+H) + ;

[0367] Synthesis of intermediate B15:

[0368] Intermediate B15 is synthesized via the following route:

[0369] Step 1: Synthesis of compound B15-1

[0370] Under nitrogen protection, pinacol isopropenylborate (294 mg, 1.75 mmol), methyl 4-bromo-3-iodobenzoate (545 mg, 1.6 mmol), potassium phosphate (1.01 g, 4.75 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (130 mg, 0.16 mmol) were dissolved in 1,4-dioxane (25 mL). The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound B15-1 (220 mg, yield 49%).

[0371] Step 2: Synthesis of compound B15-2

[0372] The synthesis of compound B15-2 is based on the synthesis of compound B2.

[0373] LC-MS (ESI+) m / z: 268.2 (M+H) + ;

[0374] Step 3: Synthesis of compound B15

[0375] Compound B15-2 (267 mg, 1 mmol) was dissolved in methanol (5 mL) at room temperature, and palladium on carbon (5%, 30 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at 1 atm. After the reaction was completed, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to give crude compound B15 (250 mg), which could be used directly in the next step without purification.

[0376] LC-MS (ESI+) m / z: 270.2 (M+H) + ;

[0377] Synthesis of intermediate B16:

[0378] Intermediate B16 is synthesized via the following route

[0379] The synthesis of intermediate B16 is based on the synthesis of intermediate B2.

[0380] LC-MS (ESI+) m / z: 285.2 (M+H) +

[0381] Synthesis of intermediate B17:

[0382] Intermediate B17 is synthesized via the following route

[0383] The synthesis of compound B17-1 is referenced to the synthesis of intermediate B2.

[0384] LC-MS (ESI+) m / z: 396.2 (M+H) + ;

[0385] Synthesis of intermediate B17:

[0386] Compound B17-1 (400 mg, 1 mmol) was dissolved in dioxane (10 mL), and dioxane hydrochloride (4 M, 10 mL) solution was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude intermediate B17 (350 mg). The product was used directly in the next step without purification.

[0387] LC-MS (ESI+) m / z: 296.2 (M+H) +

[0388] Synthesis of intermediate B18:

[0389] Intermediate B18 is synthesized via the following route:

[0390] The synthesis of intermediate B18 is based on the synthesis of intermediate B2.

[0391] LC-MS (ESI+) m / z: 228.2 (M+H) +

[0392] Synthesis of intermediate B19:

[0393] Intermediate B19 is synthesized via the following route:

[0394] The synthesis of intermediate B19 is based on the synthesis of intermediate B1.

[0395] LC-MS (ESI+) m / z: 229.2 (M+H) +

[0396] Synthesis of intermediate B20:

[0397] Intermediate B20 is synthesized via the following route

[0398] The synthesis of intermediate B20 is based on the synthesis of intermediate B2.

[0399] LC-MS (ESI+) m / z: 243.2 (M+H) +

[0400] Synthesis of intermediate B21:

[0401] Intermediate B21 is synthesized via the following route

[0402] The synthesis of intermediate B21 is based on the synthesis of intermediate B2.

[0403] LC-MS (ESI+) m / z: 285.2 (M+H) +

[0404] Synthesis of intermediate B22:

[0405] Intermediate B22 is synthesized via the following route

[0406] The synthesis of intermediate B22 is based on the synthesis of intermediate B2.

[0407] LC-MS (ESI+) m / z: 285.2 (M+H) +

[0408] Synthesis of intermediate B23:

[0409] Intermediate B23 is synthesized via the following route

[0410] The synthesis of intermediate B23 is based on the synthesis of intermediate B2.

[0411] LC-MS (ESI+) m / z: 313.2 (M+H) +

[0412] Synthesis of intermediate B24:

[0413] Intermediate B24 is synthesized via the following route:

[0414] The synthesis of intermediate B24 is based on the synthesis of intermediate B2.

[0415] LC-MS (ESI+) m / z: 270.2 (M+H) +

[0416] Synthesis of intermediate B25:

[0417] Intermediate B25 is synthesized via the following route:

[0418] The synthesis of intermediate B25 is based on the synthesis of intermediate B2.

[0419] LC-MS (ESI+) m / z: 286.2 (M+H) +

[0420] Synthesis of intermediate B26:

[0421] Intermediate B26 is synthesized via the following route:

[0422] The synthesis of intermediate B26 is based on the synthesis of intermediate B2.

[0423] LC-MS (ESI+) m / z: 270.2 (M+H) +

[0424] Synthesis of intermediate B27

[0425] Intermediate B27 is synthesized via the following route:

[0426] Step 1: Synthesis of compound B27-1

[0427] Sodium hydride (60% dispersed in mineral oil, 1.2 g, 30.0 mmol) was added to a solution of methyl 4-bromo-2-hydroxybenzoate (4.6 g, 20.0 mmol) in N,N-dimethylformamide (50 mL) at 0 °C, and the mixture was stirred at this temperature for 30 min. Subsequently, a solution of 3-bromopropyne (3.5 g, 30.0 mmol) in N,N-dimethylformamide (5 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was slowly brought to room temperature and stirred for 6 h. After the reaction was monitored to be complete, the reaction mixture was quenched in water (100 mL). Extraction was performed with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-20%) to give compound B27-1 (4.2 g, 79% yield).

[0428] LC-MS (ESI+) m / z: 269.2 (M+H) +

[0429] Step 2: Synthesis of compound B27-2

[0430] N,N-diethylaniline (40 mL) was added to compound B27-1 (4.2 g, 0.016 g), and the reaction mixture was heated to 220 °C and stirred at this temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted in water (100 mL). Extraction was performed with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound B27-2 (2 g, yield 47%).

[0431] LC-MS (ESI+) m / z: 269.2 (M+H) +

[0432] Step 3: Synthesis of intermediate B27

[0433] The synthesis of intermediate B27 is based on the synthesis of intermediate B2.

[0434] LC-MS (ESI+) m / z: 282.2 (M+H) +

[0435] Synthesis of intermediate B28:

[0436] Intermediate B28 is synthesized via the following route:

[0437] The synthesis of intermediate B28 is based on the synthesis of intermediate B2.

[0438] LC-MS (ESI+) m / z: 271.2 (M+H) +

[0439] Synthesis of intermediate B29:

[0440] Intermediate B29 is synthesized via the following route:

[0441] The synthesis of intermediate B29 is based on the synthesis of intermediate B2.

[0442] LC-MS (ESI+) m / z: 270.2 (M+H) +

[0443] Synthesis of intermediate B30:

[0444] Intermediate B30 is synthesized via the following route:

[0445] The synthesis of intermediate B30 is based on the synthesis of intermediate B2.

[0446] LC-MS (ESI+) m / z: 267.2 (M+H) +

[0447] Synthesis of intermediate B31:

[0448] Intermediate B31 is synthesized via the following route:

[0449] The synthesis of intermediate B31 is based on the synthesis of intermediate B2.

[0450] LC-MS (ESI+) m / z: 267.2 (M+H) +

[0451] Synthesis of intermediate B32:

[0452] Intermediate B32 is synthesized via the following route:

[0453] The synthesis of intermediate B32 is based on the synthesis of intermediate B2.

[0454] LC-MS (ESI+) m / z: 268.2 (M+H) +

[0455] Synthesis of intermediate B33:

[0456] Intermediate B33 is synthesized via the following route:

[0457] The synthesis of intermediate B33 is based on the synthesis of intermediate B2.

[0458] LC-MS (ESI+) m / z: 279.2 (M+H) +

[0459] Synthesis of intermediate B34:

[0460] Intermediate B34 is synthesized via the following route:

[0461] The synthesis of intermediate B34 is based on the synthesis of intermediate B2.

[0462] LC-MS (ESI+) m / z: 284.2 (M+H) +

[0463] Synthesis of intermediate B35:

[0464] Intermediate B35 is synthesized via the following route:

[0465] The synthesis of intermediate B35 is based on the synthesis of intermediate B1.

[0466] LC-MS (ESI+) m / z: 312.2 (M+H) +

[0467] Synthesis of intermediate B36:

[0468] Intermediate B36 is synthesized via the following route:

[0469] The synthesis of intermediate B36 is based on the synthesis of intermediate B1.

[0470] LC-MS (ESI+) m / z: 312.2 (M+H) +

[0471] Synthesis of intermediate B37:

[0472] Intermediate B37 is synthesized via the following route:

[0473] Step 1: Synthesis of compound B37-1

[0474] Compound 4-nitrophenylboronic acid (1 g, 6.0 mmol) and 2-bromo-5-iodotoluene (2.1 g, 7.2 mmol) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (5 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (0.25 g, 0.3 mmol) and potassium phosphate (2.54 g, 12 mmol) were added. The mixture was heated to 90 °C under nitrogen protection and stirred at this temperature for 18 hours. After the reaction was complete as monitored by TLC, the reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-3%) to give compound B37-1 (1.7 g, yield 95%). 1 H NMR (400MHz, CDCl3) δ8.28(d,J=8.6Hz,2H),7.71(d,J=8.6Hz,2H),7.48(s,1H),7.30(d,J=8.2,1H),2.49(s,3H).

[0475] Step 2: Synthesis of compound B37-2

[0476] At room temperature, compound B37-1 (1.7 g, 5.7 mmol) and pinacol diborate (1.7 g, 6.8 mmol) were dissolved in dioxane (40 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (0.21 g, 0.28 mmol) and potassium acetate (1.12 g, 11.4 mmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and stirred at this temperature for 3 hours. After the reaction was completed by TLC monitoring, the reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-3%) to give compound B37-2 (2.5 g, crude).

[0477] Step 3: Synthesis of compound B37-3

[0478] Compound B37-2 (2.5 g, 7.4 mmol) was dissolved in carbon tetrachloride (40 mL), and N-bromosuccinimide (1.4 g, 8.1 mmol) and benzoyl peroxide (0.09 g, 0.37 mmol) were added. The reaction mixture was heated to 75 °C under nitrogen protection and stirred at this temperature for 18 hours. After the reaction was completed by TLC monitoring, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (ethyl acetate: petroleum ether = 0-10%) to give compound B37-3 (1.4 g, yield 46%).

[0479] Step 4: Synthesis of compound B37-4

[0480] Compound B37-3 (1.8 g, 4.3 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and a solution of potassium hydroxide (0.48 g, 8.6 mmol) in water (5 mL) was added. The mixture was heated to 60 °C under nitrogen protection and stirred at this temperature for 3 hours. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, diluted in water (20 mL), and extracted with ethyl acetate (20 mL × 3). The aqueous phase was adjusted to pH 2-3 with dilute hydrochloric acid (1 mol) and extracted again with ethyl acetate (30 mL × 3). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound B37-4 (613 mg, yield 56%).

[0481] Step 5: Synthesis of intermediate B37

[0482] Compound B37-4 (613 mg, 2.4 mmol) was dissolved in a mixture of ethyl acetate (12 mL) and methanol (12 mL), and Pd / C (10%, 65 mg) was added. The reaction mixture was reacted at room temperature for 18 hours under a hydrogen atmosphere at 1 atm. After the reaction was complete as monitored by TLC, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate B37 (513 mg, 95% yield). LC-MS (ESI+) m / z: 226.1 (M+H) + ;

[0483] Synthesis of intermediate B38:

[0484] Intermediate B38 is synthesized via the following route:

[0485] The synthesis of intermediate B38 is based on the synthesis of intermediate B1.

[0486] LC-MS (ESI+) m / z: 285.2 (M+H) +

[0487] Synthesis of intermediate B39:

[0488] Intermediate B39 is synthesized via the following route:

[0489] Step 1: Synthesis of compound B39-1

[0490] Compound B13-1 (166 mg, 0.52 mmol) was dissolved in a mixed solvent of carbon tetrachloride (2 mL) and acetonitrile (2 mL) at room temperature. Sodium periodate (445.0 mg, 2.08 mmol), water (3 mL), and ruthenium trichloride hydrate (6.7 mg, 0.026 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was filtered. The filtrate was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound B39-1 (167 mg, 96% yield). LC-MS (ESI+) m / z: 333.2 (M+H) +

[0491] Step 2: Synthesis of compound B39-2

[0492] Compound B39-1 (150 mg, 0.45 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 5 minutes. Then, pentafluorophenol (82 mg, 0.45 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 21 hours. After the reaction was complete, the reaction mixture was diluted in dichloromethane (10 mL) and washed with saturated sodium bicarbonate aqueous solution (20 mL). The organic layer was extracted, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound B39-2 (130 mg, yield 58%). LC-MS (ESI+) m / z: 499.2 (M+H) +

[0493] Step 3: Synthesis of compound B39-3

[0494] Compound B39-2 (130 mg, 0.26 mmol), triethylamine (65 mg, 0.65 mmol), and heavy water (130 mg, 6.50 mmol) were dissolved in tetrahydrofuran (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was diluted in water (10 mL), quenched with dilute hydrochloric acid (1 N, 1 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound B39-3 (70 mg, yield 81%). LC-MS (ESI+) m / z: 335.2 (M+H) +

[0495] Step 4: Synthesis of compound B39-4

[0496] Compound B39-3 (50 mg, 0.15 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, and a boranetetrahydrofuran solution (1 M, 0.6 mL, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, methanol (10 mL) was added to quench the reaction mixture. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL). Extraction was performed with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound B39-4 (40 mg). This compound could be used directly in the next reaction without purification. LC-MS (ESI+) m / z: 321.2 (M+H) +

[0497] Synthesis of intermediate B39

[0498] The remaining synthetic steps for intermediate B39 are described in the sections on the synthesis of compound B13-2 and intermediate B13. LC-MS (ESI+) m / z: 314.2 (M+H) +

[0499] Synthesis of intermediate B40:

[0500] Intermediate B40 is synthesized via the following route:

[0501] Step 1: Synthesis of compound B40-1

[0502] 4-Bromo-2-hydroxybenzoate (460 mg, 2 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 0 °C. Sodium iodide (450 mg, 3 mmol) and potassium carbonate (552 mg, 4 mmol) were added sequentially, followed by the slow addition of tert-butyl 2-bromoacetate (582 mg, 3 mmol). The mixture was heated to room temperature and stirred at this temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into ice water (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound B40-1 (520 mg, 75% yield). LC-MS (ESI+) m / z: 345.2 (M+H) +

[0503] Step 2: Synthesis of compound B40-2

[0504] Compound B40-1 (500 mg, 1.45 mmol) was dissolved in dichloromethane (10 mL) at 0 °C, and trifluoroacetic acid (5 mL) was added. The mixture was then heated to room temperature and stirred for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude B40-2 (420 mg), which could be used directly in the next reaction without purification. LC-MS (ESI+) m / z: 289.2 (M+H) +

[0505] Step 3: Synthesis of compound B40-3

[0506] Compound B40-2 (420 mg, 1.45 mmol) was dissolved in dichloromethane (10 mL) at 0 °C, and oxaloyl chloride (479 mg, 3.77 mmol) and one drop of N,N-dimethylformamide were added. The mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was redissolved in 1,2-dichloroethane (10 mL). The mixture was cooled to 0 °C, and aluminum trichloride (543 mg, 3.6 mmol) was added. The mixture was then heated to 50 °C and stirred at this temperature for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and poured into ice water (20 mL). It was extracted with ethyl acetate (20 mL × 3), the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound B40-3 (210 mg, yield 53%). LC-MS (ESI+) m / z: 271.2 (M+H) +

[0507] Step 4: Synthesis of compound B40-4

[0508] At 0 °C, methyltriphenylphosphine bromide (264 mg, 0.74 mmol) was dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide tetrahydrofuran solution (1 M, 0.74 mL, 0.74 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere, followed by the addition of compound B40-3 (200 mg, 0.74 mmol). The reaction mixture was heated to 25 °C and stirred for 16 hours. After the reaction was completed, the mixture was diluted with water (25 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound B40-4 (180 mg, 90% yield). LC-MS (ESI+) m / z: 269.2 (M+H) +

[0509] Step 5: Synthesis of compound B40-5

[0510] At room temperature, trimethyl sulfoxide (220 mg, 1.0 mmol) was dissolved in DMSO (10 mL), and sodium hydride (60%, 36 mg, 0.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then a DMSO (2 mL) solution of compound B40-4 (150 mg, 0.56 mmol) was added. The reaction mixture was stirred at room temperature for another 3 hours. After the reaction was monitored for completion, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 15:1) to give compound B40-5 (200 mg, 71% yield). LC-MS (ESI+) m / z: 283.2 (M+H) +

[0511] Step 6: Synthesis of compound B40

[0512] The synthesis of compound B40 was performed following the same procedure as intermediate B2. LC-MS (ESI+) m / z: 296.2 (M+H) +

[0513] Synthesis of intermediate B41:

[0514] Intermediate B41 is synthesized via the following route:

[0515] The synthesis of intermediate B41 was performed with reference to the synthesis of intermediate B1. LC-MS (ESI+) m / z: 286.2 (M+H) +

[0516] Synthesis of intermediate B42:

[0517] Intermediate B42 is synthesized via the following route

[0518] The synthesis of intermediate B42 was performed with reference to the synthesis of intermediate B2. LC-MS (ESI+) m / z: 243.2 (M+H) +

[0519] Synthesis of intermediate B43:

[0520] Intermediate B43 is synthesized via the following route

[0521] The synthesis of intermediate B43-1 was performed with reference to the synthesis of intermediate B2. LC-MS (ESI+) m / z: 282.4 (M+H) +

[0522] The synthesis of intermediate B43 was performed with reference to the synthesis of intermediate B15. LC-MS (ESI+) m / z: 284.2 (M+H) +

[0523] Synthesis of intermediate B44:

[0524] Intermediate B44 is synthesized via the following route

[0525] Step 1: Synthesis of compound B44-1

[0526] Under nitrogen protection, tert-butyl 4-bromo-2-fluorobenzoate (1 g, 3.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The reaction mixture was cooled to -78 °C, and a solution of diisopropylaminolithium tetrahydrofuran (2.1 mL, 4.2 mmol, 2.0 M) was added dropwise. The reaction mixture was stirred at -78 °C for 1 hour, and then tert-butyl 1,2,3-oxathiazolidin-3-carboxylic acid ester 2,2-dioxide (0.97 g, 4.3 mmol) was added. The reaction mixture was slowly raised to room temperature and stirred at this temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound B44-1 (2.55 g). This compound did not require purification and was used directly in the next reaction.

[0527] Step 2: Synthesis of compound B44-2

[0528] Compound B44-1 (2.5 g, 6.0 mmol) was dissolved in methanol (80 mL), and a hydrochloric acid-dioxane solution (4 M, 80 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound B44-2 (2.11 g). This compound did not require purification and was used directly in the next reaction. LC-MS (ESI+) m / z: 276.4 (M+H) +

[0529] Step 3: Synthesis of compound B44-3

[0530] Compound B44-2 (2.11 g, 7.6 mmol) was dissolved in N,N-dimethylformamide (84 mL) at room temperature, and cesium carbonate (8.39 g, 25.8 mmol) was added. The reaction mixture was then heated to 90 °C and stirred at this temperature for 18 hours. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-25%) to give compound B44-3 (422 mg, yield 22%). LC-MS (ESI+) m / z: 256.4 (M+H) +

[0531] Step 4: Synthesis of compound B44

[0532] Under nitrogen protection, compound B44-3 (80 mg, 0.31 mmol) was dissolved in a mixed solvent of anhydrous 1,4-dioxane (5 mL) and water (1 mL), and 4-aminophenylboronic acid pinacol ester (82 mg, 0.38 mmol), potassium carbonate (129.51 mg, 0.937 mmol), and Pd(dppf)Cl2 (45.71 mg, 0.062 mmol) were added. The reaction mixture was stirred at 85 °C for 16 hours. After the reaction was completed, the mixture was diluted with water (20 mL). Extraction was performed with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-25%) to give compound B44 (77 mg, 92% yield). LC-MS (ESI+) m / z: 269.2 (M+H) +

[0533] Synthesis of intermediate B45:

[0534] Intermediate B45 is synthesized via the following route

[0535] Step 1: Synthesis of compound B45-1:

[0536] Under a nitrogen atmosphere, sec-butyllithium (1.3 M, 10.8 mL, 14.05 mmol) was added dropwise to a tetrahydrofuran (10 mL) solution of N,N,N',N'-tetramethylethylenediamine (1.63 g, 14.05 mmol), maintaining the temperature below -50 °C. After the addition was complete, the reaction mixture was cooled to -90 °C, and a tetrahydrofuran (10 mL) solution of p-chlorobenzoic acid (1.0 g, 6.4 mmol) was added dropwise, maintaining the reaction mixture at -90 °C and stirring at this temperature for 1 hour. Subsequently, the reaction mixture was heated to -80 °C, and deuterated iodomethane (1.85 g, 12.8 mmol) was slowly added dropwise while stirring for 10 minutes. After the reaction was monitored to be complete, the reaction mixture was quenched by slowly adding water (20 mL) and gradually heated to room temperature. The mixture was extracted with ethyl acetate (2 × 20 mL). The aqueous phase was adjusted to pH 4-5 using dilute hydrochloric acid (2.5N), followed by extraction with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound B45-1 (350 mg, yield 32%). LC-MS (ESI+) m / z: 174.2 (M+H) +

[0537] Step 2: Synthesis of compound B45-2

[0538] Compound B45-1 (350 mg) was dissolved in methanol (6 mL) at room temperature, and 0.5 mL of thionyl chloride was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude compound B45-2 (377 mg). LC-MS (ESI+) m / z: 188.2 (M+H) +

[0539] Step 3: Synthesis of compound B45:

[0540] The synthesis of compound B45 was performed with reference to the synthesis of compound B1. LC-MS (ESI+) m / z: 246.2 (M+H) +

[0541] Synthesis of intermediate B46:

[0542] Intermediate B46 is synthesized via the following route:

[0543] At room temperature, methyl 4-bromobenzoate (214 mg, 1 mmol) and 3-aminopyrazole (767 mg, 2 mmol) were dissolved in N,N-dimethylformamide (25 mL), and copper iodide (38 mg, 0.2 mmol) and cesium carbonate (65 mg, 2 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 100 °C for 19 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was diluted with ethyl acetate (50 mL), and the resulting mixture was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5%–70%) to give intermediate B46 (130 mg, 60% yield). LC-MS (ESI+) m / z: 218.2 (M+H) +

[0544] Synthesis of intermediate B47:

[0545] Intermediate B47 is synthesized via the following route:

[0546] The synthesis of intermediate B47 followed the same procedure as intermediate B46, involving the coupling of compound B13-2 with 3-aminopyrazole. LC-MS (ESI+) m / z: 302.2 (M+H) +

[0547] Synthesis of intermediate B48:

[0548] Intermediate B48 is synthesized via the following route:

[0549] The synthesis of intermediate B48 followed the same procedure as intermediate B46, involving the coupling of compound B27-2 with 3-aminopyrazole. LC-MS (ESI+) m / z: 272.2 (M+H) +

[0550] Synthesis of intermediate C1:

[0551] Intermediate C1 is synthesized via the following route:

[0552] Step 1: Synthesis of compound C1-1

[0553] At room temperature, compound Fmoc-D-proline (7.5 g, 22 mmol, 1.0 eq) and intermediate B2 (6.00 g, 22 mmol, 1.0 eq) were dissolved in dichloromethane (200 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.4 g, 28.6 mmol, 1.3 eq) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was monitored and completed, the reaction solution was poured into water (100 mL) and extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound C1-1 (13 g), which could be used directly in the next step without purification.

[0554] LC-MS (ESI+) m / z: 589.1 (M+H) + ;

[0555] Step 2: Synthesis of intermediate C1

[0556] Compound C1-1 (13 g, 22 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (130 mL) at room temperature, and piperidine (10 mL, 110 mmol, 5.0 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (methanol:dichloromethane = 0-5%) to give intermediate C1 (5.6 g, 70% yield).

[0557] LC-MS (ESI+) m / z: 367.1 (M+H) + ;

[0558] Synthesis of intermediate C2:

[0559] Intermediate C2 is synthesized via the following route:

[0560] The synthesis of intermediate C2 is based on intermediate C1. Intermediate C2 is obtained from Fmoc-D-proline and intermediate B1 through a two-step reaction.

[0561] LC-MS (ESI+) m / z: 368.1 (M+H) + ;

[0562] Synthesis of intermediate C3:

[0563] Intermediate C3 is synthesized via the following route:

[0564] Step 1: Synthesis of compound C3-1:

[0565] At room temperature, 5-bromodihydroindole (0.88 g, 4.45 mmol, 1.0 eq) and Fmoc-D-proline (1.5 g, 4.45 mmol, 1.0 eq) were dissolved in dichloromethane (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 g, 5.34 mmol, 1.2 eq) was added. The reaction mixture was stirred at 25 °C under nitrogen protection for 12 hours, and a white solid was formed. After the reaction was completed, the mixture was filtered under reduced pressure, and the filter cake was washed with dichloromethane (5 mL) and dried under vacuum to give compound C3-1 (1.3 g, 57% yield).

[0566] LC-MS (ESI+) m / z: 517.1 (M+H) +

[0567] Step 2: Synthesis of compound C3:

[0568] Compound C3-1 (500 mg, 0.97 mmol, 1.0 eq), compound 4-(tert-butoxycarbonyl)phenylboronic acid (382 mg, 1.26 mmol, 1.3 eq), potassium carbonate (334 mg, 2.4 mmol, 2.5 eq), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (70 mg, 0.097 mmol, 0.1 eq) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) at room temperature. The reaction mixture was heated to 85 °C under nitrogen protection and stirred at this temperature for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (dichloromethane:methanol = 0-10%) to give compound C3 (180 mg, yield 46%).

[0569] LC-MS (ESI+) m / z: 393.1 (M+H) +

[0570] Synthesis of intermediate C4:

[0571] Intermediate C4 is synthesized via the following route:

[0572] The synthesis of intermediate C4 is based on the synthesis of intermediate C3.

[0573] LC-MS (ESI+) m / z: 393.1 (M+H) +

[0574] Synthesis of intermediate C5:

[0575] Intermediate C5 is synthesized via the following route

[0576] Step 1: Synthesis of compound C5-1

[0577] Methyl 4-bromobenzoate (550 mg, 2.56 mmol) and pinacol 4-(Boc-amino)-1-cyclohexene-1-boronate (909 mg, 2.81 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1.5 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (93.57 mg, 0.127 mmol) and potassium carbonate (706 mg, 5.12 mmol) were added. The reaction mixture was heated to 90 °C under a nitrogen atmosphere and stirred at this temperature for 3 hours. After the reaction was monitored for completion, the mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound C5-1 (790 mg, yield 93.2%).

[0578] LC-MS (ESI+) m / z: 331.9 (M+H) +

[0579] Step 2: Synthesis of compound C5-2

[0580] Compound C5-1 (200 mg, 0.603 mmol) was dissolved in dioxane (2 mL) at room temperature, and dioxane hydrochloride solution (4 M, 2 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, and a precipitate formed. After the reaction was completed, the reaction mixture was filtered. The filter cake was washed with dioxane (1 mL) and dried under vacuum to give compound C5-2 (69 mg, yield, 49%).

[0581] LC-MS (ESI+) m / z: 231.8 (M+H) +

[0582] Step 3: Synthesis of compound C5-3

[0583] The synthesis of compound C5-3 references the synthesis of compound C1-1 in intermediate C1. Compound C5-3 was synthesized from Fmoc-D-proline and compound C5-2 as starting materials.

[0584] LC-MS (ESI+) m / z: 550.9 (M+H) +

[0585] Step 4: Synthesis of intermediate C5

[0586] The synthesis of intermediate C5 is similar to that of intermediate C1. Intermediate C5 is obtained by deprotecting compound C5-3.

[0587] LC-MS (ESI+) m / z: 328.9 (M+H) +

[0588] Synthesis of intermediate C6

[0589] Intermediate C6 is synthesized via the following route

[0590] Step 1: Synthesis of compound C6-1

[0591] Compound C5-1 (200 mg, 0.603 mmol) was dissolved in methanol (5 mL), and palladium on carbon (10%, 64.22 mg) was added. The reaction mixture was stirred for 18 hours at room temperature under a hydrogen atmosphere at 1 atm. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give compound C6-1 (195 mg, 99% yield).

[0592] LC-MS (ESI+) m / z: 333.9 (M+H) +

[0593] The synthesis of intermediate C6 is performed with reference to the synthesis of intermediate C5.

[0594] LC-MS (ESI+) m / z: 330.8 (M+H) +

[0595] Synthesis of intermediate C7

[0596] Intermediate C7 is synthesized via the following route:

[0597] The synthesis of intermediate C7 is based on the synthesis of intermediate C1. Intermediate C7 is obtained through a two-step reaction using 2-(((9H-fluorene-9-yl)methoxy)carbonyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid and intermediate B2 as starting materials.

[0598] LC-MS (ESI+) m / z: 379.3 (M+H) +

[0599] Synthesis of intermediate C8

[0600] Intermediate C8 is synthesized via the following route:

[0601] Step 1: Synthesis of compound C8-1

[0602] Fmoc-D-proline (1.14 g, 3.38 mmol) was dissolved in anhydrous dichloromethane (25 mL) at 0 °C under nitrogen protection. Oxaloyl chloride (0.57 mL, 6.76 mmol) and 2 drops of N,N-dimethylformamide were then added. The reaction mixture was slowly heated to 25 °C and stirred at this temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give compound C8-1 (1.2 g, 99.81% yield).

[0603] LC-MS (ESI+) m / z: 352.2 (M+H) + (Dissolved in methanol).

[0604] Step 2: Synthesis of compound C8-2

[0605] Under nitrogen protection, compound 7-bromo-3,4-dihydro-2H-1,4-benzoxazine (331 mg, 1.55 mmol) and triethylamine (0.22 mL, 1.55 mmol) were dissolved in anhydrous dichloromethane (20 mL). The reaction solution was cooled to 0 °C, and a dichloromethane solution of compound C8-1 (500 mg, 1.41 mmol) (10 mL) was added dropwise. The reaction solution was then slowly heated to 25 °C and stirred at this temperature for 18 hours. After the reaction was monitored to be complete, the reaction solution was quenched with water (20 mL), extracted with dichloromethane (50 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0-33%) to give compound C8-2 (741 mg, 98% yield).

[0606] LC-MS (ESI+) m / z: 533.3 (M+H) +

[0607] Step 3: Synthesis of intermediate C8

[0608] The synthesis of intermediate C8 is based on the synthesis of intermediate C3.

[0609] LC-MS (ESI+) m / z: 409.3 (M+H) +

[0610] Synthesis of intermediate C9

[0611] Intermediate C9 is synthesized via the following route:

[0612] The synthesis of intermediate C9 is based on the synthesis of intermediate C8. Intermediate C9 is obtained through a two-step reaction using compound C8-1 and 5-bromo-2,3-dihydro-1H-pyrrole[2,3-B]pyridine as starting materials.

[0613] LC-MS (ESI+) m / z: 394.3 (M+H) +

[0614] Synthesis of intermediate C10

[0615] Intermediate C10 is synthesized via the following route:

[0616] Step 1: Synthesis of compound C10-1

[0617] At room temperature, 134 mg (1 mmol) of compound 2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine was dissolved in chloroform (10 mL), and N-bromosuccinimide (196 mg, 1.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into saturated sodium sulfite solution (20 mL), extracted with dichloromethane (50 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound C10-1 (76 mg, yield 36%).

[0618] The synthesis of intermediate C10 is similar to that of intermediate C9. Starting from compounds C10-1 and C8-1, intermediate C10 is obtained through a two-step reaction.

[0619] LC-MS (ESI+) m / z: 408.3 (M+H) +

[0620] Synthesis of intermediate C11:

[0621] Intermediate C11 is synthesized via the following route:

[0622] The synthesis of intermediate C11 is based on the synthesis of intermediate C1. Intermediate C11 was synthesized from intermediate B13 and Fmoc-D-proline.

[0623] LC-MS (ESI+) m / z: 409.3 (M+H) +

[0624] Synthesis of intermediate C12:

[0625] Intermediate C12 is synthesized via the following route:

[0626] The synthesis of intermediate C12 is similar to that of intermediate C3. Intermediate C12 was synthesized from 5-bromodihydroindole and Fmoc-α-methyl-D-proline.

[0627] LC-MS (ESI+) m / z: 407.3 (M+H) +

[0628] Synthesis of intermediate C13:

[0629] Intermediate C13 is synthesized via the following route:

[0630] The synthesis of intermediate C13 is based on the synthesis of intermediate C3. Intermediate C13 was synthesized from compound C3-1 and pinacol ester of 2-methyl-6-(methoxycarbonyl)pyridine-3-boronate.

[0631] LC-MS (ESI+) m / z: 366.3 (M+H) +

[0632] Synthesis of intermediate C14:

[0633] Intermediate C14 is synthesized via the following route:

[0634] The synthesis of intermediate C14 follows the same procedure as intermediate C3. Intermediate C14 was synthesized from compounds 5-bromo-4-methylindoline and Fmoc-D-proline.

[0635] LC-MS (ESI+) m / z: 407.3 (M+H) +

[0636] Synthesis of intermediate C15:

[0637] Intermediate C15 is synthesized via the following route:

[0638] The synthesis of intermediate C15 follows the same procedure as intermediate C1. Intermediate C15 was synthesized from intermediate B17 and Fmoc-D-proline.

[0639] LC-MS (ESI+) m / z: 393.3 (M+H) +

[0640] Synthesis of intermediate C16:

[0641] Intermediate C16 is synthesized via the following route:

[0642] The synthesis of intermediate C16 follows the same procedure as intermediate C3. Intermediate C16 was synthesized from compounds 5-bromospiro[cyclopropane-1,3-indoline] and Fmoc-D-proline.

[0643] LC-MS (ESI+) m / z: 419.3 (M+H) +

[0644] Synthesis of intermediate C17:

[0645] Intermediate C17 is synthesized via the following route:

[0646] The synthesis of intermediate C17 follows the same procedure as intermediate C3. Intermediate C17 was synthesized from 5-bromo-3,3-difluoroindole and Fmoc-D-proline.

[0647] LC-MS (ESI+) m / z: 429.3 (M+H) +

[0648] Synthesis of intermediate C18

[0649] Intermediate C18 is synthesized via the following route:

[0650] The synthesis of intermediate C18 is similar to that of intermediate C9. It is obtained by two-step reaction using compound C8-1 and 5-bromo-2,3-dihydro-1H-pyrrolo[3,2-B]pyridine as starting materials.

[0651] LC-MS (ESI+) m / z: 394.2 (M+H) +

[0652] Synthesis of intermediate C19

[0653] Intermediate C19 is synthesized via the following route:

[0654] The synthesis of intermediate C19 is based on that of intermediate C1. Intermediate C19 was synthesized from intermediate B23 and Fmoc-D-proline.

[0655] LC-MS (ESI+) m / z: 410.3 (M+H) +

[0656] Synthesis of intermediate C20:

[0657] Intermediate C20 is synthesized via the following route:

[0658] The synthesis of intermediate C20 is based on that of intermediate C1. Intermediate C20 was synthesized from intermediate B35 and Fmoc-D-proline.

[0659] LC-MS (ESI+) m / z: 409.2 (M+H) +

[0660] Synthesis of intermediate C21:

[0661] Intermediate C21 is synthesized via the following route:

[0662] The synthesis of intermediate C21 is based on the synthesis of intermediate C1. Intermediate C21 was synthesized from intermediate B36 and Fmoc-D-proline.

[0663] LC-MS (ESI+) m / z: 409.1 (M+H) +

[0664] Synthesis of intermediate C22:

[0665] Intermediate C22 is synthesized via the following route:

[0666] The synthesis of intermediate C22 is similar to that of intermediate C1. Intermediate C22 is obtained from intermediate B37 and Fmoc-D-proline through a two-step reaction.

[0667] LC-MS (ESI+) m / z: 323.1 (M+H) +

[0668] Synthesis of intermediate C23:

[0669] Intermediate C23 is synthesized via the following route:

[0670] The synthesis of intermediate C23 is similar to that of intermediate C1. Intermediate C23 is obtained from intermediate B16 and Fmoc-D-proline through a two-step reaction.

[0671] LC-MS (ESI+) m / z: 382.1 (M+H) +

[0672] Synthesis of intermediate C24:

[0673] Intermediate C24 is synthesized via the following route:

[0674] Step 1: Synthesis of compound C24-1

[0675] Compound D15-1 (800 mg, 3.2 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (2 mL) at room temperature, and a solution of lithium hydroxide monohydrate (1.09 g, 26.0 mmol) in water (10 mL) was added. The reaction mixture was then heated to 50 °C and stirred at this temperature for 48 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure. The residue was diluted with water (10 mL), the pH was adjusted to 5-6 with dilute hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound C24-1 (708 mg, 94% yield).

[0676] Step 2: Synthesis of compound C24-2

[0677] Compound C24-1 (708 mg, 3.0 mmol) was dissolved in dichloromethane (15 mL), and intermediate B18 (693 mg, 3.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (643 mg, 3.3 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 4:1) to give compound C24-2 (1.09 g, yield 81%).

[0678] LC-MS (ESI+) m / z: 442.4 (M+H) +

[0679] Step 3: Synthesis of intermediate C24

[0680] Compound C24-2 (1.09 g, 2.5 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude intermediate C24 (1.03 g). This compound did not require purification and was used directly in the next reaction.

[0681] LC-MS (ESI+) m / z: 342.4 (M+H) +

[0682] Synthesis of intermediate C24-R:

[0683] Referring to the synthesis of C24, using the R-configuration monomer of commercial C24-1 as the starting material, C24-R was obtained through a two-step reaction of condensation and deprotection.

[0684] LC-MS (ESI+) m / z: 342.2 (M+H) +

[0685] Synthesis of intermediate C25:

[0686] Intermediate C25 is synthesized via the following route:

[0687] Step 1: Synthesis of compound C25-1

[0688] At room temperature, D-proline (25 g, 217 mmol) and 4A molecular sieve (2.5 g) were dispersed in anhydrous acetonitrile (380 mL), and trichloroacetaldehyde (48 g, 326 mmol) and a catalytic amount of trifluoroacetic acid were added. The reaction mixture was purged with nitrogen three times, heated to 55 °C, and stirred at this temperature for 36 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth while hot, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound C25-1 (21.2 g, 86.7 mmol, yield 40%). LC-MS (ESI+) m / z: 244.2 (M+H) +

[0689] Step 2: Synthesis of compound C25-2

[0690] Under nitrogen protection, compound C25-1 (13 g, 53.2 mmol) was dissolved in anhydrous tetrahydrofuran (220 mL). The reaction solution was cooled to -70 °C, and a solution of diisopropylaminolithium tetrahydrofuran (2 M, 34.5 mL, 69.1 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 1 hour. Subsequently, deuterated iodomethane (11.6 g, 79.8 mmol) was added to the solution. The reaction solution was stirred at -70 °C for another 4 hours. After the reaction was monitored to be complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound C25-2 (7.25 g, 27.7 mmol, yield 52%). LC-MS (ESI+) m / z: 261.2 (M+H) +

[0691] Step 3: Synthesis of compound C25-3

[0692] Compound C25-2 (5.3 g, 20.3 mmol) was dissolved in anhydrous methanol (30 mL) at room temperature. The reaction solution was cooled to 0 °C, and thionyl chloride (2.9 g, 24.3 mmol) was slowly added. After the addition was complete, the reaction mixture was heated to 65 °C and stirred at this temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by slurrying with petroleum ether (30 mL) to give crude compound C25-3 (3.56 g).

[0693] Step 4: Synthesis of compound C25-4

[0694] Compound C25-3 (3.4 g) was dissolved in anhydrous dichloromethane (45 mL), and triethylamine (11.8 g, 116 mmol) was added. Di-tert-butyl dicarbonate (6.1 g, 27.9 mmol) was added dropwise to the reaction mixture under ice bath conditions. After the addition was complete, the reaction mixture was slowly brought to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound C25-4 (3.31 g, 13.4 mmol, two-step yield 66%). LC-MS (ESI+) m / z: 247.2 (M+H) +

[0695] Step 5: Synthesis of compound C25-5

[0696] Compound C25-4 (3.3 g, 13.4 mmol) was dissolved in a mixture of tetrahydrofuran (30 mL) and methanol (15 mL), and an aqueous solution of lithium hydroxide monohydrate (3.37 g, 80.4 mmol) (30 mL) was added. The reaction mixture was stirred at 50 °C for 48 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the organic solvent. Then, it was diluted with ice water (30 mL). The solution was adjusted to pH 5 with dilute hydrochloric acid (2 N) at 0 °C in an ice bath, and then extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 10%) to give compound C25-5 (2.8 g, 90% yield).

[0697] Synthesis of intermediate C25

[0698] The synthesis of intermediate C25 is performed with reference to the synthesis of intermediate C24.

[0699] LC-MS (ESI+) m / z: 396.2 (M+H) +

[0700] Synthesis of intermediate C26:

[0701] Intermediate C26 is synthesized via the following route:

[0702] The synthesis steps for compound C26 are the same as those for the synthesis of compound C25-6 and intermediate C25.

[0703] LC-MS (ESI+) m / z: 386.2 (M+H) +

[0704] Synthesis of intermediate C27:

[0705] Intermediate C27 is synthesized via the following route:

[0706] The synthesis steps for compound C27 are the same as those for the synthesis of compound C25-6 and intermediate C25.

[0707] LC-MS (ESI+) m / z: 386.2 (M+H) +

[0708] Synthesis of intermediate C28:

[0709] Intermediate C28 is synthesized via the following route:

[0710] The synthesis of compound C28 was performed with reference to the synthesis of compound C25-6 and intermediate C25. LC-MS (ESI+) m / z: 344.2 (M+H) +

[0711] Synthesis of intermediate D1:

[0712] Intermediate D1 is synthesized via the following route:

[0713] At 0 °C, N,N'-carbonyldiimidazole (13 g, 81 mmol, 1.1 eq) was dissolved in acetonitrile (150 mL), and intermediate A11 (11 g, 74 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). D-proline (10 g, 89 mmol, 1.2 eq) was dissolved in tetrahydrofuran (10 mL), and N-methylmorpholine (9.0 g, 89 mmol, 1.2 eq) and the above residue in tetrahydrofuran solution (10 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into saturated sodium bicarbonate solution (50 mL), and the aqueous phase was washed with methyl tert-butyl ether (20 mL × 2). The aqueous phase was acidified to pH 3 with dilute hydrochloric acid (4 M), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (methanol:dichloromethane = 0-5%) to give intermediate D1 (8 g, yield 38%).

[0714] LC-MS (ESI+) m / z: 295.2 (M+H) + ;

[0715] Synthesis of intermediate D2:

[0716] Intermediate D2 is synthesized via the following route:

[0717] The synthesis of intermediate D2 is based on intermediate D1. Intermediate D2 is obtained by reacting D-proline and intermediate A1 as starting materials.

[0718] LC-MS (ESI+) m / z: 343.1 (M+H) + ;

[0719] Synthesis of intermediate D3:

[0720] Refer to the synthesis of intermediate D1. Intermediate D3 was obtained by reacting D-proline and intermediate A12 as starting materials.

[0721] LC-MS (ESI+) m / z: 293.1 (M+H) + ;

[0722] Synthesis of intermediate D4:

[0723] Refer to the synthesis of intermediate D1. Intermediate D4 is obtained by reacting D-proline and intermediate A2 as starting materials.

[0724] LC-MS (ESI+) m / z: 345.1 (M+H) + ;

[0725] Synthesis of intermediate D5:

[0726] The synthesis of intermediate D5 is based on intermediate D1. Intermediate D5 is obtained by reacting (R)-2-methylproline and intermediate A11 as starting materials.

[0727] LC-MS (ESI+) m / z: 309.1 (M+H) + ;

[0728] Synthesis of intermediate D6:

[0729] The synthesis of intermediate D6 is based on intermediate D1. Intermediate D6 is obtained by reacting (R)-2-methylproline and 4-aminobenzocyclobutene as starting materials.

[0730] LC-MS (ESI+) m / z: 275.1 (M+H) + ;

[0731] Synthesis of intermediate D7:

[0732] Intermediate D7 is synthesized via the following route:

[0733] Step 1: Synthesis of compound D7-1

[0734] At 0°C and under a nitrogen atmosphere, methyl (S)-(-)-1-triphenylmethylaziridine-2-carboxylic acid (5.0 g, 14.6 mmol) was dissolved in a mixture of chloroform (15 mL) and methanol (15 mL), and trifluoroacetic acid (3.3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was then cooled to 0°C, and a solution of N,N-diisopropylethylamine (15 mL) and 1,4-dioxane (15 mL) of fluorenyl chloroformate (3.6 g, 13.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and 30 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL). The mixture was then washed successively with water (20 mL), saturated ammonium chloride aqueous solution (20 mL), and saturated brine (20 mL). The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound D7-1 (3.8 g, yield 81%).

[0735] LC-MS (ESI+) m / z: 324.1 (M+H) + ;

[0736] Step 2: Synthesis of compound D7-2

[0737] Compound D7-1 (5 g, 15.5 mmol) was dissolved in dichloromethane (30 mL) at room temperature under a nitrogen atmosphere, and cyclopropanol (1.5 g, 26.3 mmol) was added. The reaction mixture was then cooled to 0 °C, and a boron trifluoride diethyl ether complex (326 mg, 2.3 mmol) was added. The mixture was stirred at this temperature for 2 hours. After the reaction was monitored to be complete, the mixture was quenched with a saturated sodium bicarbonate aqueous solution (20 mL). The mixture was separated, the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound D7-2 (4.2 g, 71% yield).

[0738] LC-MS (ESI+) m / z: 382.1 (M+H) + ;

[0739] Step 3: Synthesis of compound D7-3

[0740] Compound D7-2 (0.9 g, 2.45 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and piperidine (1.2 mL, 12 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 2%) to give compound D7-3 (300 mg, 70% yield).

[0741] LC-MS (ESI+) m / z: 160.1 (M+H) + ;

[0742] Step 4: Synthesis of compound D7-4

[0743] Compound D7-3 (4.0 g, 25 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature, and potassium carbonate (6.9 g, 50 mmol), sodium iodide (3.75 g, 25 mmol), and 3-bromopropanol (5.52 g, 40 mmol) were added. The reaction mixture was stirred at 70 °C for 2 hours. After the reaction was completed, the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound D7-4 (5.0 g), which could be used directly in the next step without further purification.

[0744] LC-MS (ESI+) m / z: 218.1 (M+H) + ;

[0745] Step 5: Synthesis of compound D7-5

[0746] Compound D7-4 (5.0 g, 23 mol) was dissolved in dichloromethane (50 mL), and di-tert-butyl dicarbonate (6.65 g, 30 mmol) and diisopropylethylamine (4.90 mL, 28 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, saturated ammonium chloride aqueous solution (25 mL) was added to the mixture, and the mixture was extracted with dichloromethane (25 mL × 3). The combined layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound D7-5 (4.5 g, yield 62%).

[0747] LC-MS (ESI+) m / z: 318.1 (M+H) + ;

[0748] Step 6: Synthesis of compound D7-6

[0749] Compound D7-5 (3.17 g, 10 mmol) was dissolved in anhydrous pyridine (5 mL) at 0 °C under a nitrogen atmosphere, and methanesulfonyl chloride (1.25 g, 11 mmol) was added. The reaction mixture was stirred at this temperature for 4 hours. After the reaction was monitored to be complete, the reaction mixture was quenched in water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed successively with dilute hydrochloric acid (10%, 30 mL) and sodium bicarbonate aqueous solution (10%, 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was obtained and could be used directly for the next step without further purification.

[0750] The residue was dissolved in acetone (20 mL), and a solution of sodium iodide (2.25 g, 15 mol) in acetone (20 mL) was added. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to give compound D7-6 (2.2 g, yield 52%).

[0751] Step 7: Synthesis of compound D7-7

[0752] Cesium hydroxide (60 mg, 0.4 mmol) was added to anhydrous DMSO (1 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 minutes to form a suspension. Then, an anhydrous DMSO (1.5 mL) solution of compound D7-6 (107 mg, 0.25 mmol) was added to the suspension. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was monitored to be complete, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with saturated sodium bicarbonate aqueous solution (25 mL) and saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound D7-7 (38 mg, 74% yield).

[0753] LC-MS (ESI+) m / z: 300.1 (M+H) + ;

[0754] Step 8: Synthesis of Compounds D7-8

[0755] Compound D7-7 (300 mg, 1 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL) at room temperature, and sodium hydroxide (80 mg, 2 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was diluted with water (5 mL), and the pH was adjusted to 5-6 with dilute hydrochloric acid (1 N). A precipitate formed, which was filtered. The filter cake was washed with water (1 mL) and dried under vacuum to give compound D7-8 (200 mg, 70% yield).

[0756] LC-MS (ESI+) m / z: 286.1 (M+H) + ;

[0757] Step 9: Synthesis of intermediate D7-9

[0758] Compound D7-8 (200 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound D7-9 (130 mg), which could be used directly in the next step without purification.

[0759] Step 10: Synthesis of intermediate D7

[0760] The synthesis of intermediate D7 is based on intermediate D1. Intermediate D7 is obtained by reacting compound D7-9 with 3-bromo-4-trifluoromethoxyaniline as a starting material.

[0761] LC-MS (ESI+) m / z: 407.1 (M+H) + ;

[0762] Synthesis of intermediate D8:

[0763] Intermediate D8 is synthesized via the following route:

[0764] The synthesis of intermediate D8 is based on intermediate D1. Intermediate D8 is obtained by reacting (R)-2-methylproline and 3-fluoro-4-(trifluoromethoxy)aniline as starting materials.

[0765] LC-MS (ESI+) m / z: 351.1 (M+H) +

[0766] Synthesis of intermediate D9:

[0767] Intermediate D9 is synthesized via the following route:

[0768] The synthesis of intermediate D9 is based on intermediate D1. Intermediate D9 is obtained by reacting (R)-2-methylproline and (4-aminophenyl)sulfonium pentafluoride as starting materials.

[0769] LC-MS (ESI+) m / z: 375.1 (M+H) + ;

[0770] Synthesis of intermediate D10:

[0771] Intermediate D10 is synthesized via the following route:

[0772] The synthesis of intermediate D10 is based on intermediate D1. Intermediate D10 is obtained by reacting (R)-2-methylproline and 3-fluoro-4-(difluoromethoxy)aniline as starting materials.

[0773] LC-MS (ESI+) m / z: 333.1 (M+H) + ;

[0774] Synthesis of intermediate D11:

[0775] Intermediate D11 is synthesized via the following route:

[0776] The synthesis of intermediate D11 is based on intermediate D1. Intermediate D11 is obtained by reacting (R)-2-methylproline and 3-methyl-4-trifluoromethoxyaniline as starting materials.

[0777] LC-MS (ESI+) m / z: 347.1 (M+H) + ;

[0778] Synthesis of intermediate D12:

[0779] Intermediate D12 is synthesized via the following route:

[0780] The synthesis of intermediate D12 is based on intermediate D1. Intermediate D12 is obtained by reacting (R)-2-methylproline and 1,1-difluoro-2,3-dihydro-1H-inden-5-amine as starting materials.

[0781] LC-MS (ESI+) m / z: 325.1 (M+H) + ;

[0782] Synthesis of intermediate D13:

[0783] Intermediate D13 is synthesized via the following route:

[0784] The synthesis of intermediate D13 is based on intermediate D1. Intermediate D13 is obtained by reacting D-proline and 4-isopropylaniline as starting materials.

[0785] LC-MS (ESI+) m / z: 277.1 (M+H) +

[0786] Synthesis of intermediate D14:

[0787] Intermediate D14 is synthesized via the following route:

[0788] Step 1: Synthesis of compound D14-1

[0789] At 0 °C, methyl 1-Boc-2-(hydroxymethyl)pyrrolidine-2-carboxylate (1.00 g, 3.8 mmol) and deuterated iodomethane (580 mg, 4.0 mmol) were dissolved in tetrahydrofuran (8 mL), and sodium hydride (304 mg, 7.6 mmol, 60% purity) was added. The reaction mixture was stirred at 0 °C for 1 hour, then heated to 25 °C and stirred for another 2 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound D14-1 (472 mg, 45% yield).

[0790] LC-MS (ESI+) m / z: 277.1 (M+H) + .

[0791] Synthesis of intermediate D14

[0792] The remaining steps for the synthesis of intermediate D14 are described in the synthesis of compounds D7-8, D7-9 and D7.

[0793] LC-MS (ESI+) m / z: 384.1 (M+H) +

[0794] Synthesis of intermediate D15

[0795] Intermediate D15 is synthesized via the following route:

[0796] Step 1: Synthesis of compound D15-1

[0797] At 0 °C, 1-(tert-butyl)-2-methyl(R)-pyrrolidine-1,2-dicarboxylic acid ester (870 mg, 3.8 mmol) and deuterated iodomethane (580 mg, 4.0 mmol) were dissolved in tetrahydrofuran (10 mL), and sodium hydride (304 mg, 7.6 mmol, 60% purity) was added. The reaction mixture was stirred at 0 °C for 1 hour, then heated to 25 °C and stirred for another 2 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound D14-1 (472 mg, 50% yield).

[0798] LC-MS (ESI+) m / z: 247.1 (M+H) + .

[0799] Synthesis of intermediate D15

[0800] The remaining steps of intermediate D15 are synthesized with reference to the synthesis of compounds D7-8, D7-9 and D7.

[0801] LC-MS (ESI+) m / z: 354.1 (M+H) +

[0802] Synthesis of intermediate D16

[0803] Intermediate D16 is synthesized via the following route:

[0804] Synthesis of intermediate D16

[0805] The synthesis steps for intermediate D16 are the same as those for compound D1.

[0806] LC-MS (ESI+) m / z: 360.1 (M+H) +

[0807] Synthesis of intermediate D17

[0808] Intermediate D17 is synthesized via the following route:

[0809] Step 1: Synthesis of compound D17-1

[0810] Compound 2-(tert-Butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-3-carboxylic acid (181 mg, 0.80 mmol) and benzyl bromide (205 mg, 1.20 mmol) were dissolved in N,N-dimethylformamide (5 mL), and triethylamine (121 mg, 1.20 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0–5%) to give compound D17-1 (200 mg, yield 79%).

[0811] LC-MS (ESI+) m / z: 318.1 (M+H) +

[0812] Step 2: Synthesis of compound D17-2

[0813] Diisopropylamine (82 mg, 0.82 mmol) was dissolved in tetrahydrofuran (10 mL) at -78 °C, and a solution of n-butyllithium (2.5 M, 0.4 mL, 0.94 mmol) was slowly added. The reaction mixture was heated to -30 °C and stirred at this temperature for 1 hour. A solution of compound D17-1 (200 mg, 0.63 mmol) in tetrahydrofuran (5 mL) was added over 10 minutes, and the mixture was stirred at -30 °C for 1 hour. The reaction mixture was then heated to -5 °C, and heavy water (50 mg, 2.52 mmol) was added. The reaction mixture was slowly heated to room temperature and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with a saturated sodium chloride aqueous solution (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0–5%) to give compound D17-2 (150 mg, 75% yield).

[0814] LC-MS (ESI+) m / z: 319.1 (M+H) +

[0815] Step 3: Synthesis of compound D17-3

[0816] Compound D17-2 (150 mg, 0.47 mmol) was dissolved in methanol (2 mL), and a solution of dioxane hydrochloride (4 M, 5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude compound D17-3 (150 mg), which could be used directly in the next step of the reaction without purification.

[0817] LC-MS (ESI+) m / z: 219.1 (M+H) +

[0818] Step 4: Synthesis of compound D17-4

[0819] The synthesis of compound D17-4 is based on the synthesis of compound D1.

[0820] LC-MS (ESI+) m / z: 440.1 (M+H) +

[0821] Step 5: Synthesis of intermediate D17

[0822] Compound D17-4 (150 mg, 0.47 mmol) was dissolved in ethanol (10 mL), and potassium carbonate (64 mg, 0.47 mmol) and palladium on carbon (10 wt%, 15 mg) were added. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere at 1 atm. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give crude compound D17 (110 mg), which could be used directly in the next reaction without purification.

[0823] LC-MS (ESI+) m / z: 350.1 (M+H) +

[0824] Synthesis of intermediate D18

[0825] Intermediate D18 is synthesized via the following route:

[0826] The synthesis of intermediate D18 is based on the synthesis of intermediate D17. Intermediate D18 is obtained from intermediate D17-3 and intermediate A1 through a two-step reaction.

[0827] LC-MS (ESI+) m / z: 356.1 (M+H) +

[0828] Synthesis of intermediate D19

[0829] Intermediate D19 is synthesized via the following route:

[0830] The synthesis of intermediate D19 is based on the synthesis of intermediate D17.

[0831] LC-MS (ESI+) m / z: 344.1 (M+H) +

[0832] Compound Synthesis

[0833] Example 1: Synthesis of compound (R)-4'-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)-2,5-dihydro-1H-pyrrole-2-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (1)

[0834] Step 1: Synthesis of Compound 1-1

[0835] The synthesis of compound 1-1 is referenced to the synthesis of intermediate D1.

[0836] LC-MS (ESI+) m / z: 293.2 (M+H) + ;

[0837] Step 2: Synthesis of Compounds 1-2

[0838] The synthesis of compounds 1-2 is based on the synthesis of intermediate C1-1, which is produced by the reaction of compound 1-1 and intermediate B2.

[0839] LC-MS (ESI+) m / z: 544.2 (M+H) + ;

[0840] Step 3: Synthesis of Compound 1

[0841] Compounds 1-2 (200 mg, 0.37 mmol, 1.0 eq) were dissolved in hexafluoroisopropanol (10 mL) at room temperature, and methanesulfonic acid (38 mg, 0.41 mmol, 1.1 eq) was added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase C18 rapid column chromatography (acetonitrile:water (containing 0.05% trifluoroacetic acid) = 0-70%) to give compound 1 (90 mg, 50% yield).

[0842] LC-MS (ESI+) m / z: 488.2 (M+H) + .

[0843] The following compounds were synthesized according to Example 1:

[0844] Example 2: Synthesis of compound (R)-4'-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-3-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (17)

[0845] Step 1: Synthesis of Compound 17-1

[0846] Compound (R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-3-carboxylic acid (800 mg, 3.52 mmol) was dissolved in dichloromethane (15 mL), and methyl 4'-amino-[1,1'-biphenyl]-4-carboxylic acid (80 mg, 3.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (742 mg, 3.87 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude product compound 17-1 (2 g). This product did not require purification and was used directly in the next step.

[0847] LC-MS (ESI+) m / z: 437.2 (M+H) + ;

[0848] Step 2: Synthesis of Compound 17-2

[0849] Compound 17-1 (2 g) was dissolved in dioxane hydrochloride (4 N, 15 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was neutralized with saturated sodium bicarbonate aqueous solution (40 mL), extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (dichloromethane:methanol = 90:10) to give compound 17-2 (1 g, 85% yield in two steps).

[0850] LC-MS (ESI+) m / z: 337.2 (M+H) + ;

[0851] Step 3: Synthesis of Compound 17-3

[0852] The synthesis of compound 17-3 is based on the synthesis of intermediate D1. Compound 17-3 was synthesized from compound 17-2 and intermediate A11.

[0853] LC-MS (ESI+) m / z: 516.2 (M+H) + ;

[0854] Step 4: Synthesis of Compound 17

[0855] Compound 17-3 (140 mg, 0.281 mmol) was dissolved in a mixture of methanol (10 mL) and water (10 mL), and sodium hydroxide (112 mg, 2.81 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 5 with dilute hydrochloric acid (3N). The mixture was extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (C18, acetonitrile:water (containing 0.05% trifluoroacetic acid) = 0–60%) to give compound 17 (30 mg, yield 22%).

[0856] LC-MS (ESI+) m / z: 502.2 (M+H) + ;

[0857] 1 HNMR(400MHz,DMSO-d6)δ10.20(s,1H),8.76(s,1H),8.00(d,J=8.4Hz,2H),7.87–7.67(m,6H),7.44(m,2H),7.28–7.14(m,2H), 4.78–4.71(m,1H),4.55(m,1H),3.14–3.00(m,2H),2.10(m,1H),1.96(m,1H),1.84(m,1H),1.43(m,1H),1.18(d,J=6.8Hz,6H).

[0858] The following compounds were synthesized according to Example 2:

[0859] Example 3: Synthesis of compound (R)-4-(6-(1-(bicyclo[4.2.0]oct-1,3,5-trien-3-ylcarbamoyl)pyrrolidine-2-carbamoyl)pyridin-3-yl)benzoic acid (30)

[0860] Step 1: Synthesis of Compound 30-1

[0861] At 0 °C, compound N,N'-carbonyldiimidazole (21 mg, 0.13 mmol, 1.0 eq) was dissolved in acetonitrile (1 mL), and 4-aminobenzocyclobutene (15 mg, 0.13 mmol, 1.0 eq) was added. The reaction mixture was stirred at 0 °C for 40 minutes, and then intermediate C2 (47 mg, 0.13 mmol, 1.0 eq) was added. The reaction mixture was stirred for another 2.5 hours. After the reaction was completed, the reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine, dried, filtered, and concentrated under reduced pressure to give crude compound 30-1 (35 mg). This compound was used directly in the next step without purification.

[0862] LC-MS (ESI+) m / z: 513.1 (M+H) + ;

[0863] Step 2: Synthesis of Compound 30

[0864] The synthesis of compound 30 is based on the third step of the synthesis of intermediate A1.

[0865] LC-MS (ESI+) m / z: 457.1 (M+H) + .

[0866] The following compounds were synthesized according to the method in Example 3:

[0867] Example 4: Synthesis of compound 4-(1-(((4-cyclopropyl-3-fluorophenyl)carbamoyl)-D-prolyl)dihydroindole-5-yl)benzoic acid (50)

[0868] Step 1: Synthesis of Compound 50-1:

[0869] The synthesis of compound 50-1 is based on the synthesis of compound C1-1, obtained by condensation of intermediates D3 and B3.

[0870] LCMS(ESI) + m / z 570.2(M+H) +

[0871] Step 2: Synthesis of Compound 50:

[0872] The synthesis of compound 50 is performed according to the third step of Example 1.

[0873] LCMS(ESI) + m / z 514.2(M+H)+ .

[0874] The following compounds were synthesized according to Example 4:

[0875] Example 5: Synthesis of compound 4-(1-(((4-isopropylphenyl)carbamoyl)-D-prolyl)dihydroindole-5-yl)benzoic acid (77)

[0876] Step 1: Synthesis of Compound 77-1

[0877] At room temperature, intermediate C3 (73 mg, 0.19 mmol, 1.0 eq) and 4-isopropylphenyl isocyanate (30 mg, 0.19 mmol, 1.0 eq) were dissolved in tetrahydrofuran (5 mL), and N-methylmorpholine (56 mg, 0.56 mmol, 3.0 eq) was added. The mixture was stirred at 25 °C under nitrogen protection for 5 hours. After the reaction was monitored to be complete, the reaction solution was quenched with water (10 mL). Extraction was performed with ethyl acetate (10 mL × 2), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 77-1 (90 mg, 87% yield). This compound did not require purification and was used directly in the next reaction.

[0878] LC-MS (ESI+) m / z: 554.3 (M+H) +

[0879] Step 2: Synthesis of Compound 77

[0880] Compound 77-1 (90 mg, 0.16 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C under nitrogen protection for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (C18, MeCN:H2O = 0-50%) to give compound 77 (22 mg, yield 27%).

[0881] LC-MS (ESI+) m / z: 498.3 (M+H) +

[0882] 1H NMR (400MHz, DMSO-d6) δ12.85(br,1H),8.21(brs,1H),8.13(d,J=8.4Hz,1H),7.98(d,J=8 .6Hz,2H),7.77(d,J=8.6Hz,2H),7.66(s,1H),7.56(d,J=8.4Hz,1H),7.38(d,J=8.6Hz,2H ),7.08(d,J=8.6Hz,2H),4.72(m,1H),4.38-4.36(m,1H),4.24–4.22(m,1H),3.63(m,2H), 3.27(t,J=8.4Hz,2H),2.81-2.78(m,1H),2.26(m,1H),1.99(m,3H),1.16(d,J=6.8Hz,6H).

[0883] Example 6: Synthesis of compound 4-(1-(((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-D-prolyl)dihydroindole-5-yl)benzoic acid (78)

[0884] Step 1: Synthesis of Compound 78-1

[0885] At 0 °C, 25 mg of 3-fluoro-4-(trifluoromethoxy)aniline (0.13 mmol, 1.0 eq) was dissolved in acetonitrile (2 mL), and N,N'-carbonyldiimidazole (23 mg, 0.13 mmol, 1.0 eq) was added. The reaction mixture was slowly brought to room temperature and stirred at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL).

[0886] Intermediate C3 (60 mg, 0.15 mmol, 1.1 eq) was dissolved in tetrahydrofuran (5 mL), and N-methylmorpholine (0.017 mL, 0.15 mmol, 1.1 eq) and the aforementioned tetrahydrofuran solution of the residue were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 78-1 (55 mg, yield 68%).

[0887] LC-MS (ESI+) m / z: 614.3 (M+H) +

[0888] Step 2: Synthesis of Compound 78

[0889] The synthesis of compound 78 is referenced to the synthesis of compound 23 in step 3 of intermediate A1.

[0890] LC-MS (ESI+) m / z: 558.3 ​​(M+H) +

[0891] 1 H NMR (400MHz, DMSO-d6) δ12.93 (brs, 1H) 8.73 (s, 1H), 8.13 (d, J = 8.4Hz, 1H), 8.00(d,J=8.0Hz,2H),7.78(d,J=8.0Hz,2H),7.75–7.69(m,1H),7.67(m,1H) ,7.56(m,1H),7.46–7.34(m,2H),4.74(m,1H),4.35(m,1H),4.28–4.16(m,1H ),3.70–3.62(m,2H),3.28(t,J=9.2Hz,2H),2.30(m,1H),2.10–1.92(m,3H).

[0892] The following compounds were synthesized according to Example 6:

[0893] Example 7: Synthesis of compound (R)-4'-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-methylpyrrolidine-2-carboxamido)-2-isopropyl-[1,1'-biphenyl]-4-carboxylic acid (104)

[0894] Step 1: Synthesis of Compound 104-1

[0895] The synthesis of compound 104-1 is based on the synthesis of intermediate C1-1, which is obtained by reacting intermediate D8 and intermediate B15.

[0896] LC-MS (ESI+) m / z: 602.2 (M+H) +

[0897] Step 2: Synthesis of Compound 104

[0898] The synthesis of compound 104 is based on the second step of the synthesis of compound 220.

[0899] LC-MS (ESI+) m / z: 588.2 (M+H) + .

[0900] The following compounds were synthesized according to the method in Example 7.

[0901] Example 8: Synthesis of compound 5-(1-(((3-fluoro-4-isopropylphenyl)carbamoyl)-D-prolyl)dihydroindol-5-yl)-6-methylo-o-pyridinecarboxylic acid (107)

[0902] Step 1: Synthesis of Compound 107-1

[0903] The synthesis of compound 107-1 is described in reference to the synthesis of compound 30-1 in Example 3.

[0904] LC-MS (ESI+) m / z: 545.2 (M+H) +

[0905] Step 2: Synthesis of Compound 107

[0906] The synthesis of compound 107 is based on the second step of the synthesis of compound 220.

[0907] LC-MS (ESI+) m / z: 531.2 (M+H) + .

[0908] Example 9: Synthesis of compound (R)-4'-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (133)

[0909] The synthesis of compound 133-2 followed the steps outlined in Example 2 for the synthesis of compounds 17-3 and 17. Compound 133-2 was synthesized from intermediate C24 and 3-fluoro-4-(trifluoromethoxy)aniline via a two-step reaction. The compound was resolved by chiral resolution (instrument model: GILSON GX-281, column: ...). IC, 10μm, 30*250mm. Mobile phase A: HEX + 0.2% FA. Mobile phase B: IPA + 0.2% FA. Detection wavelength: 214nm / 254nm. Flow rate: 25mL / min. Column temperature: RT. Isocratic elution program: Mobile phase A: Mobile phase B = 70:30 (V / V) to obtain compound 133 and compound 133A.

[0910] Compound 133:

[0911] LC-MS (ESI+) m / z: 549.4 (M+H) +

[0912] 1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.56(s,1H),8.04 -7.94(m,2H),7.81–7.67(m,7H),7.48-7.37(m,2H),3.82(m,1H),3.62(m,1H),2.18(m,1H),2.00(m,2H),1.91(m,1H).

[0913] Chiral HPLC Rt = 8.820 min Instrument model: WATERS e2695 / 2998 Column: IC, 5μm, 4.6mm*250mm Mobile Phase A: HEX + 0.2% TFA Mobile Phase B: IPA + 0.2% TFA Detection Wavelength: 214nm / 254nm Flow Rate: 1.0mL / min Column Temperature: 30℃ Isocratic Elution Program: Mobile Phase A: Mobile Phase B = 80:20 (V / V)

[0914] Chiral HPLC Rt = 9.826 min; Instrument model: WATERS E2695; Detector: WATERS 2998; Column: DAICEL IC, 5μm, 4.6*250mm; Mobile phase A: HEX + 0.2% TFA; Mobile phase B: IPA + 0.2% DEA; Detection wavelength: 254nm; Flow rate: 1mL / min; Column temperature: 30℃; Isocratic elution program: A:B = 80:20

[0915] Compound 133A:

[0916] LC-MS (ESI+) m / z: 549.4 (M+H) +

[0917] Chiral HPLC Rt = 5.982 min. Instrument model: WATERS e2695 / 2998. Column: IC, 5μm, 4.6mm*250mm Mobile Phase A: HEX + 0.2% TFA Mobile Phase B: IPA + 0.2% TFA Detection Wavelength: 214nm / 254nm Flow Rate: 1.0mL / min Column Temperature: 30℃ Isocratic Elution Program: Mobile Phase A: Mobile Phase B = 80:20 (V / V)

[0918] Chiral HPLC Rt = 6.774 min. Instrument model: WATERS E2695; Detector: WATERS 2998; Column: DAICEL. IC, 5μm, 4.6*250mm; Mobile phase A: HEX + 0.2% TFA; Mobile phase B: IPA + 0.2% DEA; Detection wavelength: 254nm; Flow rate: 1mL / min; Column temperature: 30℃; Isocratic elution program: A:B = 80:20

[0919] The following compounds were synthesized according to Example 9:

[0920] Example 10: Synthesis of compound 4-(4-((1R,2R,5S)-3-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid (149)

[0921] The synthesis steps of compound 149 are the same as those of compounds 17-1, 17-2, 17-3 and 17 in Example 2. Compound 149 was synthesized from (1R,2R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and intermediate B26 through a four-step reaction.

[0922] LC-MS (ESI+) m / z: 586.2 (M+H) + .

[0923] Example 11: Synthesis of compound (R)-7-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-1,3-dihydroisobenzofuran-4-carboxylic acid (150)

[0924] The synthesis steps of compound 150 are the same as those for compounds 17-1, 17-2, 17-3 and 17 in Example 2. Compound 150 was synthesized from Boc-D-proline and intermediate B24 through four reaction steps.

[0925] LC-MS (ESI+) m / z: 574.2 (M+H) + .

[0926] The following compounds were synthesized according to Example 11:

[0927] Example 12: Synthesis of compound 4'-((1R,3R,5R)-2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (154)

[0928] The synthesis steps of compound 154 are the same as those of compounds 17-1, 17-2, 17-3 and 17 in Example 2. Compound 154 was synthesized from (1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid and intermediate B18 through a 4-step reaction.

[0929] LC-MS (ESI+) m / z: 544.2 (M+H) + .

[0930] 1 ¹H NMR (400MHz, DMSO-d6) δ 12.92 (br, ¹H), 10.03 (s, ¹H), 9.10 (s, ¹H), 7.99 (m, 2H), 7.79–7.70 (m, 7H), 7.47–7.42 (m, 2H), 4.29–4.25 (m, ¹H), 3.75–3.71 (m, ¹H), 2.38–2.35 (m, ¹H), 2.21–2.14 (m, ¹H), 1.87–1.80 (m, ¹H), 0.89–0.84 (m, ¹H), 0.62–0.58 (m, ¹H). The following compounds were synthesized according to Example 12:

[0931] Example 13: (Synthetic Method 1): Synthesis of compounds (R)-4-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-2-carbamoyl)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid (155) and (S)-4-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-2-carbamoyl)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid (155A)

[0932] The synthesis of compound 155 was performed following the procedure described in Example 9 for the synthesis of compound C24,133-1. Chiral resolution was used (instrument model: GILSON GX-281, column: ...). IA, 10μm, 30*250mm Mobile phase A: HEX + 0.2% FA Mobile phase B: IPA + 0.2% FA Detection wavelength: 214nm / 254nm Flow rate: 25mL / min Column temperature: RT Isocratic elution program: Mobile phase A: Mobile phase B = 60:40 (V / V)) to obtain compounds 155 and 155A.

[0933] Compound 155

[0934] LC-MS (ESI) + m / z: 591.2(M+H) + ;

[0935] 1 H NMR (400MHz, DMSO-d6) δ12.64(brs,1H),9.47(s,1H),8.57(s,1H),7.80–7.63(m,4H),7.55–7.36(m,4H),6.96(d,J=8.0Hz,1H ),4.60(t,J=8.8Hz,2H),3.83(m,1H),3.62(m,1H),3.28(t,J=8.8Hz,2H),2.19(m,1H),2.09-1.97(m,2H),1.96-1.84(m,1H).

[0936] Chiral HPLC Rt = 3.695 min Instrument model: WATERS e2695 / 2998 Column: IA, 5μm, 4.6mm*250mm Mobile phase A: HEX + 0.2% TFA Mobile phase B: ETOH + 0.2% TFA Detection wavelength: 254nm Flow rate: 1.0mL / min Column temperature: 30℃ Isocratic elution program: Mobile phase A: Mobile phase B = 60:40 (V / V)

[0937] Compound 155A

[0938] LC-MS (ESI) + m / z: 591.4(M+H) + ;

[0939] Chiral HPLC Rt = 5.421 min Instrument model: WATERS e2695 / 2998 Column: IA, 5μm, 4.6mm*250mm Mobile phase A: HEX + 0.2% TFA Mobile phase B: ETOH + 0.2% TFA Detection wavelength: 254nm Flow rate: 1.0mL / min Column temperature: 30℃ Isocratic elution program: Mobile phase A: Mobile phase B = 60:40 (V / V)

[0940] (Synthetic Method 2): Synthesis of compound (R)-4-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid (155)

[0941] Step 1: Synthesis of Compound 155-1A

[0942] Compound C25-5 (1.40 g, 6.03 mmol) and intermediate B13 (1.88 g, 6.03 mmol) were dissolved in anhydrous dichloromethane (40 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.46 g, 7.59 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with dichloromethane (200 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to give compound 155-1A (2.62 g, yield 82.64%). LC-MS (ESI+) m / z: 526.2 (M+H) +

[0943] Step 2: Synthesis of compound 155-2A

[0944] Under nitrogen protection, compound 155-1A (2.59 g, 4.93 mmol) was dissolved in 1,4-dioxane hydrochloric acid solution (4 M, 80 mL). The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give crude compound 155-2A (1.82 g), which was used directly in the next reaction without purification. LC-MS (ESI+) m / z: 370.3 (M+H) +

[0945] Step 3: Synthesis of Compound 155

[0946] Under nitrogen protection, 3-fluoro-4-(trifluoromethoxy)aniline (0.960 g, 4.93 mmol) was dissolved in anhydrous acetonitrile (40 mL), and N,N'-carbonyldiimidazole (0.880 g, 5.42 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL), and compound 155-2A (1.82 g, 4.93 mmol) and N-methylmorpholine (7.43 mL, 67.5 mmol) were added. The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL), the pH was adjusted to 3 with dilute hydrochloric acid (3N), and extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel rapid column chromatography (dichloromethane:methanol = 20:1) to give compound 155 (2.148 g, yield 73.83%).

[0947] LC-MS (ESI) + m / z: 591.2(M+H) + ;

[0948] 1 H NMR (400MHz, DMSO-d6) δ12.64(brs,1H),9.47(s,1H),8.57(s,1H),7.80–7.63(m,4H),7.55–7.36(m,4H),6.96(d,J=8.0Hz,1H ),4.60(t,J=8.8Hz,2H),3.83(m,1H),3.62(m,1H),3.28(t,J=8.8Hz,2H),2.19(m,1H),2.09-1.97(m,2H),1.96-1.84(m,1H).

[0949] The following compounds were synthesized according to Example 13:

[0950] Example 14: Synthesis of compound (R)-4-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)indoline-7-carboxylic acid (158)

[0951] The synthesis steps of compound 158-3 are the same as those for compounds 17-1, 17-2, and 17-3 in Example 2. Compound 158-3 was synthesized from Boc-D-proline and intermediate B30 through a three-step reaction.

[0952] LC-MS (ESI+) m / z: 585.2 (M+H) + ;

[0953] Synthesis of compound 158-4:

[0954] Compound 158-3 (584 mg, 1.0 mmol) and boranetrimethylamine (291 mg, 4.0 mmol) were dissolved in 1,4-dioxane (10 mL), and concentrated hydrochloric acid (2 mL) was added. The reaction mixture was heated to 110 °C and stirred at this temperature for 0.5 h. The reaction mixture was then cooled to room temperature, and hydrochloric acid (5 mL, 6 M) was added. The mixture was stirred at 110 °C for 15 min. After the reaction was completed, the reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 8 with NaOH (4 M) aqueous solution. The mixture was extracted with ethyl acetate (25 mL × 3), and the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether:ethyl acetate = 50:1) to give compound 158-4 (150 mg, 25% yield).

[0955] LC-MS (ESI+) m / z: 587.2 (M+H) + ;

[0956] Synthesis of compound 158:

[0957] The synthesis steps for compound 158 are the same as those for compound 17 in Example 2. Compound 158 is obtained by hydrolysis of compound 158-4.

[0958] LC-MS (ESI+) m / z: 573.2 (M+H) + .

[0959] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.71(s,1H),7.78-7.72(m,1H),7.72-7.67(m,2H),7.507.38(m,5H),6.54(d,J=8.4Hz,1H),4.49(m,1H),3.71 3.62(m,1H),3.623.49(m,3H),3.04(t,J=8.4Hz,2H),2.28-2.16(m,1H),2.10-1.87(m,3H).

[0960] The following compounds were synthesized according to Example 14:

[0961] Example 15: Synthesis of compound (R)-4-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-1-methylindole-7-carboxylic acid (161)

[0962] Synthesis of compound 161-1:

[0963] Compound 158-4 (58 mg, 0.1 mmol) was dissolved in a mixture of methanol (10 mL) and acetic acid (0.5 mL), and then an aqueous formaldehyde solution (37%, 23 mg, 0.3 mmol) was added. The reaction solution...

[0964] The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (18 mg, 0.3 mmol) was added, and the reaction mixture was stirred at room temperature for another hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 161-1 (36 mg, yield 60%).

[0965] LC-MS (ESI+) m / z: 601.2 (M+H) + ;

[0966] Synthesis of compound 161:

[0967] The synthesis steps for compound 161 are the same as those for compound 17 in Example 2. Compound 161 is obtained by hydrolysis of compound 161-1.

[0968] LC-MS (ESI+) m / z: 587.2 (M+H) + .

[0969] 1 H NMR (400MHz, DMSO-d6) δ12.48(brs,1H),10.13(s,1H),8.71(s,1H),7.79–7.71(m,1H),7.72–7.66(m,2H),7.47–7.35(m,5H),6.66(d,J=8.0Hz, 1H),4.49(m,1H),3.71–3.61(m,1H),3.59–3.49(m,1H),3.39(m,2H),2. 97(t,J=8.4Hz,2H),2.80(s,3H),2.28–2.14(m,1H),2.10–1.88(m,3H).

[0970] Example 16: Synthesis of compounds 4'-((1R,3R,5R)-2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-3-(methyl-d3)-2-azabicyclo[3.1.0]hexane-3-carbamoyl)-[1,1'-biphenyl]-4-carboxylic acid (183A) and 4'-((1R,3S,5R)-2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-3-(methyl-d3)-2-azabicyclo[3.1.0]hexane-3-carbamoyl)-[1,1'-biphenyl]-4-carboxylic acid (183B)

[0971] The synthesis of compound 183 referenced intermediate C24. The synthesis of compounds 133-1 and 133-2 was achieved by using 2-(tert-butyl)-3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid ester as the starting material in a 6-step reaction to yield compound 183. Compound 183 was resolved by chiral chromatography (instrument model: GILSON GX-281, column: ...). IG, 10μm, 30*250mm, mobile phase A: HEX + 0.2% FA, mobile phase B: ETOH + 0.2% FA, detection wavelength: 214nm, flow rate: 25mL / min, column temperature: RT, isocratic elution program: mobile phase A: mobile phase B = 40:60 (V / V) to obtain compounds 183A and 183B.

[0972] 183A:LC-MS(ESI+)m / z:561.4(M+H) +

[0973] 1 H NMR(400MHz,DMSO-d6)δ12.90(brs,1H),9.23(s,1H),8.80(s,1H),8.03–7.96(m,2H),7.83–7.66(m,7H),7.47(m,1 H),7.41(t,J=8.8Hz,1H),3.61–3.51(m,1H),2.23–2.20(m,1H),1.77(m,1H),1.25–1.17(m,2H),0.92–0.80(m,1H).

[0974] Chiral HPLC Rt = 10.788 min (Instrument model: WATERS E2695, Detector: WATERS 2998, Column: DAICEL) IA / IC / ID / IE / IF / IG / IH, 5μm, 4.6*250mm, Mobile phase A: HEX + 0.2% TFA, Mobile phase B: ETOH + 0.2% TFA, Detection wavelength: 304nm, Flow rate: 1mL / min, Column temperature: RT, Run time: 22min, Gradient elution program: Mobile phase A: Mobile phase B = 40:60 (V / V)

[0975] 183B:LC-MS(ESI+)m / z:561.4(M+H) +

[0976] Chiral HPLC Rt = 12.419 min. Instrument model: WATERS E2695, detector: WATERS 2998, column: DAICEL. IA / IC / ID / IE / IF / IG / IH, 5μm, 4.6*250mm, Mobile phase A: HEX + 0.2% TFA, Mobile phase B: ETOH + 0.2% TFA, Detection wavelength: 304nm, Flow rate: 1mL / min, Column temperature: RT, Run time: 22min, Gradient elution program: Mobile phase A: Mobile phase B = 40:60 (V / V)

[0977] The following compounds were synthesized according to Example 16:

[0978] Example 17: Synthesis of compound 4'-((1R,3R,5R)-2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido-3-d)-[1,1'-biphenyl]-4-carboxylic acid (184)

[0979] Step 1: Synthesis of Compound 184-1

[0980] The synthesis of compound 184-1 is based on the synthesis of compound D17-2.

[0981] Synthesis of Compound 184

[0982] The remaining synthetic steps for compound 184 were the same as those for compound 183. 184 was resolved chirally (instrument model: GILSON GX-281, column: ...). IG, 10μm, 30*250mm, mobile phase A: HEX + 0.2% FA, mobile phase B: ETOH + 0.2% FA, detection wavelength: 214nm, flow rate: 25mL / min, column temperature: RT, isocratic elution program: mobile phase A: mobile phase B = 45:55 (V / V) to obtain compounds 184A and 184B.

[0983] 184A:LC-MS(ESI+)m / z:545.4(M+H) +

[0984] 184B:LC-MS(ESI+)m / z:545.4(M+H) +

[0985] Example 18: Synthesis of compound (R)-4-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid-3,3-d2 acid (187)

[0986] Step 1: Synthesis of Compound 187-1

[0987] Compound D15-1 was separated by chirality (instrument model: GILSON GX-281 column: IC, 10μm, 30*250mm. Mobile phase A: HEX + 0.2% FA. Mobile phase B: IPA + 0.2% FA. Detection wavelength: 214nm / 254nm. Flow rate: 25mL / min. Column temperature: RT. Isocratic elution program: Mobile phase A: Mobile phase B = 95:5 (V / V) to obtain compound 187-1.

[0988] Chiral HPLC Rt = 9.21 min (Instrument model: WATERS e2695 / 2998, chiral analysis method, chromatographic column:) IC, 5μm, 4.6*250mm; Mobile phase A: HEX + 0.2% TFA; Mobile phase B: IPA + 0.2% TFA; Detection wavelength: 214nm / 254nm; Flow rate: 1.0mL / min; Column temperature: 30℃; Isocratic elution program: Mobile phase A: Mobile phase B = 95:5 (V / V)

[0989] Step 2: Synthesis of Compound 187-2

[0990] The synthesis steps for compound 187-2 are the same as those for compound D15-2.

[0991] Synthesis of Compound 187

[0992] The remaining synthetic steps of compound 187 are as described in Example 2, which describes the synthesis of compounds 17-1, 17-2 and 17-3.

[0993] LC-MS (ESI+) m / z: 593.4 (M+H) + .

[0994] Example 19: Synthesis of compound (R)-4-(4-(1-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-2-carboxamido)phenyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carboxylic acid (188)

[0995] The synthesis steps of compound 188 are the same as those for compounds 17-1, 17-2, 17-3 and 17 in Example 2. Compound 188 was synthesized from 187-2 and intermediate B40 through four reaction steps.

[0996] LC-MS (ESI+) m / z: 617.4 (M+H) + .

[0997] The following compounds were synthesized according to Example 19:

[0998] Example 20: Synthesis of compounds (R)-4'-(2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-3-(methyl-d3)-2-azabicyclo[2.1.1]hexane-3-carbamoyl)-[1,1'-biphenyl]-4-carboxylic acid (207A) and (S)-4'-(2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-3-(methyl-d3)-2-azabicyclo[2.1.1]hexane-3-carbamoyl)-[1,1'-biphenyl]-4-carboxylic acid (207B)

[0999] Step 1: Synthesis of Compound 207-1

[1000] Under nitrogen protection, compound (S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-3-carboxylic acid (100 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (91 mg, 0.66 mmol) and methyl iodide (0.04 mL, 0.66 mmol) were added. The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was completed, the reaction mixture was quenched with water (20 mL). Extraction was performed with ethyl acetate (25 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 207-1 (94 mg, 89% yield).

[1001] LC-MS (ESI+) m / z: 186.2 (Mt-Bu+H) +

[1002] Synthesis of compound 207-5

[1003] The synthesis of compound 207-5 references the synthesis of intermediate C24, and 207-5 is obtained from compound 207-1 through 4 reaction steps.

[1004] LC-MS (ESI+) m / z: 354.4 (M+H) +

[1005] The remaining synthetic steps of compound 207 are as described in Example 9, which describes the synthesis of compounds 133-1 and 133-2.

[1006] Compound 207 was separated by chirality (instrument model: GILSON GX-281 column: IG, 10μm, 30*250mm, mobile phase A: HEX + 0.2% FA, mobile phase B: IPA + 0.2% FA, detection wavelength: 214nm, flow rate: 25mL / min, column temperature: RT, isocratic elution program: mobile phase A: mobile phase B = 90:10 (V / V)) to obtain compounds 207A and 207B.

[1007] Compound 207A: LC-MS (ESI+) m / z: 561.4 (M+H) +

[1008] Compound 207B: LC-MS (ESI+) m / z: 561.4 (M+H) +

[1009] The following compounds were synthesized according to Example 20:

[1010] Example 21: Synthesis of compound (R)-5-(4-(2-(methyl-d3)-1-((4-(trifluoromethoxy)phenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-2H-chromene-8-carboxylic acid (220)

[1011] Step 1: Synthesis of Compound 220-1

[1012] At 0 °C, compound 4-(trifluoromethoxy)aniline (99 mg, 0.56 mmol) was dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (90 mg, 0.56 mmol) was added. The reaction mixture was slowly raised to room temperature and stirred at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). Compound C25 (200 mg, 0.51 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol) were added to this mixture. The mixture was stirred at room temperature for 1 hour. After the reaction was monitored to be complete, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 220-1 (200 mg, 0.33 mmol, yield 64%).

[1013] LC-MS (ESI+) m / z: 599.2 (M+H) +

[1014] Step 2: Synthesis of Compound 220

[1015] Compound 220-1 (200 mg, 0.33 mmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL) at room temperature, and a solution of lithium hydroxide (16 mg, 0.66 mmol) in water (1 mL) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the organic solvent. The residue was diluted with water (10 mL), the pH was adjusted to 5-6 with dilute hydrochloric acid (1 N), and extracted with ethyl acetate (20 mL × 3). The organic layers were combined. The organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (C18, acetonitrile:water (containing 0.05% trifluoroacetic acid) = 0-70%) to give compound 220 (90 mg, 0.15 mmol, yield 46%).

[1016] LC-MS (ESI+) m / z: 585.2 (M+H) +

[1017] 1 H NMR (400MHz, DMSO-d6) δ12.63(brs,1H),9.52(s,1H),8.36(s,1H),7.75–7.69(m,2H),7.67–7.61(m,2H),7.56(d,J=8.0Hz,1H),7.31– 7.19(m,4H),6.91(d,J=8.0Hz,1H),6.37(m,1H),5.95(m,1H),4.80(s,2H),3.82(m,1H),3.62(m,1H),2.21(m,1H),2.03–1.86(m,3H).

[1018] The following compounds were synthesized according to Example 21.

[1019] Example 22: Synthesis of compound 4'-((1R,3R,5R)-3-(methyl-d3)-2-((4-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (216)

[1020] Step 1: Synthesis of Compound 216-1

[1021] Synthesize compound 216-1 according to WO2023 / 138583.

[1022] Under nitrogen protection, 2-(tert-butyl)-3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid ester (2.2 g, 8.62 mmol) was dissolved in tetrahydrofuran (80 mL). The reaction mixture was cooled to -78 °C, and lithium bis(trimethylsilylamino)amine (1 M, 17.2 mL, 17.2 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78 °C for 1 hour, then slowly heated to -30 °C and stirred for 30 minutes. The reaction mixture was then cooled to -78 °C, and deuterated iodomethane (1.07 mL, 17.2 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour, then slowly heated to 25 °C and stirred for 4 hours. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL), diluted with water (50 mL), and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound 216-1 (2.19 g, yield 93.3%).

[1023] LC-MS (ESI+) m / z: 273.3 (M+H)+

[1024] Step 2: Synthesis of compound 216-2

[1025] Compound 216-1 (2.19 g, 8.04 mmol) was dissolved in a mixture of methanol (30 mL) and tetrahydrofuran (30 mL), and a solution of lithium hydroxide monohydrate (3.37 g, 80.4 mmol) in water (15 mL) was added. The reaction mixture was stirred at 50 °C for 48 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure. The aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (3N) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 216-2 (2.04 g), which did not require purification and was used directly in the next reaction. LC-MS (ESI+) m / z: 245.3 (M+H) +

[1026] Step 3: Synthesis of compound 216-3

[1027] Compound 216-2 (2.04 g, 8.35 mmol) and intermediate B18 (1.90 g, 8.35 mmol) were dissolved in anhydrous dichloromethane (60 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.02 g, 10.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to give compound 216-3 (2.64 g, yield 69.6%). LC-MS (ESI+) m / z: 454.5 (M+H) +

[1028] Step 4: Synthesis of compound 216-4

[1029] Under nitrogen protection, compound 216-3 (2.64 g, 5.81 mmol) was dissolved in 1,4-dioxane hydrochloric acid solution (4 M, 50 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude compound 216-4 (2.05 g), which did not require purification and was used directly in the next reaction. LC-MS (ESI+) m / z: 354.4 (M+H) +

[1030] Step 5: Synthesis of compound 216-5

[1031] Under nitrogen protection, 4-(trifluoromethoxy)aniline (1.03 g, 5.81 mmol) was dissolved in anhydrous acetonitrile (40 mL), and N,N'-carbonyldiimidazole (1.04 g, 6.39 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in tetrahydrofuran (40 mL), and compound 216-4 (2.05 g, 5.81 mmol) and 4-methylmorpholine (8.76 mL, 79.6 mmol) were added. The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL), the pH was adjusted to 3 with dilute hydrochloric acid (3N), and extracted with ethyl acetate (3 × 150 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 216-5 (2.4 g, yield 74.2%).

[1032] LC-MS (ESI+) m / z: 557.4 (M+H) +

[1033] Step 6: Synthesis of Compound 216

[1034] Compound 216-5 (2.38 g, 4.28 mmol) was dissolved in a mixture of methanol (60 mL) and tetrahydrofuran (60 mL), and a solution of lithium hydroxide monohydrate (0.54 g, 12.8 mmol) in water (30 mL) was added. The reaction mixture was stirred at 25 °C for 18 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure. The remaining aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (3N) and extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give compound 216 (1.88 g, yield 81.1%). LC-MS (ESI+) m / z: 543.3 (M+H) +

[1035] 1 H NMR(400MHz,DMSO-d6)δ12.91(brs,1H),9.25(s,1H),8.62(s,1H),8.03–7.96(m,2H),7.81–7.63(m,8H),7.27– 7.17(m,2H),3.64–3.51(m,1H),2.21(d,J=4.0Hz,2H),1.84–1.68(m,1H),1.25–1.15(m,1H),0.94–0.77(m,1H).

[1036] The following compounds were synthesized according to Example 22:

[1037] Example 23: Synthesis of compounds (R)-4'-(2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-1-carbamoyl)-[1,1'-biphenyl]-4-carboxylic acid (199A) and (S)-4'-(2-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-(methyl-d3)pyrrolidine-1-carbamoyl)-[1,1'-biphenyl]-4-carboxylic acid (199B)

[1038] Step 1: Synthesis of Compound 199-1

[1039] Under nitrogen protection, methyl 1-BOC-2-pyrrolidinecarboxylate (500 mg, 2.2 mmol) was dissolved in tetrahydrofuran (10 mL). The reaction mixture was cooled to -20 °C, and a solution of bis(trimethylsilylamino)lithium tetrahydrofuran (4.8 mL, 4.8 mmol, 1 M) was added dropwise. The reaction mixture was stirred at this temperature for 2 hours, followed by the dropwise addition of deuterated iodomethyl (474 ​​mg, 3.3 mmol). The mixture was stirred at -20 °C for another 2 hours. After the reaction was monitored for completion, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound 199-1 (380 mg, 71% yield).

[1040] Step 2: Synthesis of compound 199-2:

[1041] Compound 199-1 (380 mg, 1.5 mmol) was dissolved in dichloromethane (6 mL) at room temperature, and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude compound 199-2 (487 mg). This compound did not require purification and was used directly in the next reaction.

[1042] Synthesis of compounds 199A and 199B

[1043] The remaining synthetic steps for compounds 199A and 199B are the same as those for compound 155, with chiral resolution (instrument model: GILSON GX-281, column: ...). IG, 10μm, 30*250mm, mobile phase A: HEX + 0.2% FA, mobile phase B: ETOH + 0.2% FA, detection wavelength: 214nm, flow rate: 25mL / min, column temperature: RT, isocratic elution program: mobile phase A: mobile phase B = 40:60 (V / V) to obtain compounds 199A and 199B.

[1044] Compound 199A

[1045] 1 H NMR(400MHz,DMSO-d6)δ12.88(brs,1H),9.69(s,1H),8.34

[1046] (s,1H),8.02–7.95(m,2H),7.88(d,J=12.0Hz,1H),7.80–7.73(m,2H),7.69–7.60(m,4H),7.5 7–7.47(m,2H),3.83(m,1H),3.74–3.57(m,1H),2.15(m,1H),2.03(m,2H),1.94–1.80(m,1H).

[1047] LC-MS (ESI+) m / z: 549.4 (M+H) +

[1048] Chiral HPLC Rt = 3.458 min (Instrument model: WATERS E2695 / 2998; Column: ...) IG, 5μm, 4.6*250mm, Mobile phase A: HEX + 0.2% TFA, Mobile phase B: ETOH + 0.2% TFA, Detection wavelength: 254nm, Flow rate: 1mL / min, Column temperature: 30℃, Isocratic elution program: Mobile phase A: Mobile phase B = 40:60 (V / V)

[1049] Compound 199B

[1050] 1 H NMR(400MHz,DMSO-d6)δ12.90(brs,1H),δ9.70(s,1H),8.35

[1051] (s,1H),8.02–7.94(m,2H),7.88(d,J=12.0Hz,1H),7.79–7.73(m,2H),7.71–7.60(m,4H),7.5 6–7.46(m,2H),3.83(m,1H),3.64(m,1H),2.15(m,1H),2.11–1.95(m,2H),1.94–1.84(m,1H).

[1052] LC-MS (ESI+) m / z: 549.4 (M+H) +

[1053] Chiral HPLC Rt = 5.968 min (Instrument model: WATERS E2695 / 2998 column: IG, 5μm, 4.6*250mm, Mobile phase A: HEX + 0.2% TFA, Mobile phase B: ETOH + 0.2% TFA, Detection wavelength: 254nm, Flow rate: 1mL / min, Column temperature: 30℃, Isocratic elution program: Mobile phase A: Mobile phase B = 40:60 (V / V)

[1054] The following compounds were synthesized according to Example 23:

[1055] Example 24: Synthesis of compound 4'-((1R,3R,5R)-3-((3-fluoro-4-(trifluoromethoxy)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxamido)-[1,1'-biphenyl]-4-carboxylic acid (200)

[1056] Step 1: Synthesis of Compound 200-1

[1057] The synthesis of compound 200-1 is based on the synthesis of compound 155. It is given by the reaction of (1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid and 3-fluoro-4-(trifluoromethoxy)aniline.

[1058] LC-MS (ESI) + m / z: 405.2(M+H) +

[1059] Step 2: Synthesis of Compound 200-2

[1060] The synthesis of compound 200-2 is based on the synthesis of compound 155.

[1061] LC-MS (ESI) + m / z: 305.2(M+H) +

[1062] Step 3: Synthesis of Compound 200-3

[1063] The synthesis of compound 200-3 is based on the synthesis of compound 155. It is obtained by reacting compound 200-2 with intermediate B2.

[1064] LC-MS (ESI)+ m / z: 600.2(M+H) +

[1065] Step 4: Synthesis of Compound 200

[1066] The synthesis of compound 200 is based on the synthesis of compound 155.

[1067] LC-MS (ESI+) m / z: 544.2 (M+H) +

[1068] 1 H NMR (400MHz, DMSO-d6) δ12.88(brs,1H),10.45(s,1H),8.76(s,1H),7.98(d,J=8.4Hz, 2H),7.82(m,1H),7.77(d,J=8.4Hz,2H),7.69–7.63(m,4H),7.51(t,J=8.8Hz,1H),7.40 -7.35(m,1H),4.79(m,1H),3.74-3.67(m,1H),2.69-2.58(m,1H),1.94(m,1H),1.79 -1.70(m,1H),1.22(m,1H),0.78(m,1H).

[1069] Reference compound A

[1070] The synthesis steps for compound A are referenced in WO2025163561A1 for the synthesis of compound 1.

[1071] Test Example 1: In vitro GIPR antagonist activity test of compounds

[1072] In this embodiment, the antagonistic activity of the compound against GIPR was determined using CHO-K1 cells stably expressing human GIPR by detecting changes in intracellular cAMP levels. Upon agonist activation, human GIPR binds to the G protein complex, causing the Gαs subunit to exchange bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP), thus dissociating and activating the Gα subunit from the G protein trimer. The activated Gα subunit enters the cytoplasm and activates downstream effector factors, regulating the intracellular second messenger, or cAMP, levels. Therefore, measuring intracellular cAMP levels allows for pharmacological activity characterization.

[1073] Cells and reagents: hGIPR / CHO-K1 stable transfected cells, culture medium (Ham's F12 + 10% fetal bovine serum + 1% penicillin-streptomycin), experimental buffer (0.1% BSA + 20mM HEPES + 200μM IBMX 1×HBSS buffer (containing Ca2+ and Mg2+)), and assay kit (LANCE Ultra cAMP HTRF kit).

[1074] Experimental steps:

[1075] 1) Determination of hGIP EC50 agonist: Cells were resuspended in experimental buffer at a density of 1×10⁻⁶. 5 Cells were added at a rate of 1000 cells / well (10 μL / well) to 384-well plates. Then, 10 nmol / well of DMSO was added, and the plates were incubated at 37°C for 2 hours. Subsequently, different concentrations of hGIP were added to the 384-well plates (10 nmol / well), and the plates were incubated at 37°C for another 30 hours. Intracellular cAMP levels were detected using a cAMP HTRF assay kit, and dose-response curves of hGIP were fitted. The hGIP EC80 concentration was selected for determining the compound's antagonistic activity.

[1076] 2) Assay for compound antagonistic activity: The compound was prepared into a 10 mM stock solution using DMSO, and then serially diluted with DMSO to prepare working solutions of different concentrations. Cells were resuspended in experimental buffer at a density of 1 × 10⁻⁶ m³. 5 Cells were added to 384-well plates at a rate of 1000 cells / well (10 μL / well). Then, 10 nmL / well of different concentrations of the compound working solution was added, and the plates were incubated at 37°C for 2 hours. Afterward, 10 nmL of an hGIPR agonist mixture (hGIP dissolved in H₂O, final experimental concentration at EC80 of hGIP) was added to each well, and the plates were incubated at 37°C for another 30 minutes. Intracellular cAMP levels were detected using a cAMP HTRF assay kit, and the antagonistic activity of the compounds against human GIPR was calculated.

[1077] Data calculation: The signal-to-weight ratio (665nm / 615nm) was calculated, and the antagonistic activity of the compound against human GIPR was calculated using the following formula:

[1078] In this context, cpd refers to the compound, LC refers to low control, and HC refers to high control.

[1079] The inhibitory activity (%) was nonlinearly fitted to the sample concentration using a four-parameter equation using software to obtain the IC50 value.

[1080] The inhibitory activity of the compounds against human GIPR is shown in Table 1. The experimental results show that most of the compounds provided in this invention exhibit good antagonistic activity against human GIPR. Specifically, AAA ≤ 5 nM, 5 nM < AA ≤ 10 nM, 10 nM < A ≤ 50 nM, 50 nM < B ≤ 100 nM, 100 nM < C ≤ 500 nM, and D > 500 nM.

[1081] Table 1. Antagonistic activity of compounds against GIPR

[1082] Test Example 2: Pharmacokinetic Evaluation of Compounds in Mice

[1083] Using ICR mice as test animals, the in vivo pharmacokinetic characteristics of the compound of this embodiment after a single oral administration at a dose of 5 mg / kg were investigated.

[1084] 1. Laboratory animals

[1085] ICR mice, 3 males per group, from Spifor (Suzhou) Biotechnology Co., Ltd.

[1086] 2. Preparation of drug formulations

[1087] The administration solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh an appropriate amount of the compound (calibrated as needed), and add 5% DMSO according to the total volume ratio of the dosage form. Vortex and sonicate for 2 minutes to dissolve completely. Then add 10% Solutol HS15, vortex and sonicate for 2 minutes to dissolve completely. Finally, add 85% PBS, vortex and sonicate for 5 minutes to obtain a colorless, transparent, and clear solution, which is the test formulation of the required concentration.

[1088] 3. Administration

[1089] 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 light / dark cycle of 12 hours. All mice were acclimatized for 3 days before the start of the animal experiments. Mice were randomly divided into groups of 3 according to their body weight. They were fasted overnight before administration of the drug via gavage. The dose was 5 mg / kg, and the administration volume was 10 mL / kg. They were fed 4 hours after administration.

[1090] 4. Sample collection and biological analysis

[1091] Plasma samples were collected from mice before administration and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentrations of compounds in the plasma were determined using a tandem triple quadrupole mass spectrometer.

[1092] 5. Data Analysis

[1093] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method. The results of the mouse pharmacokinetic experiments of the compounds in the examples are shown in Table 2.

[1094] Table 2. Pharmacokinetic parameters of the compounds in this embodiment after oral administration to mice.

[1095] The compounds of the present invention exhibit good pharmacokinetic characteristics and, compared with the control compounds, have better pharmacokinetics in animals, thus exhibiting better pharmacodynamics and therapeutic effects.

[1096] Test Example 3: Pharmacokinetic Evaluation of Compounds in Rats

[1097] Using SD rats as test animals, the in vivo pharmacokinetic characteristics of the compound of this example after being administered a single oral dose of 5 mg / kg or a single intravenous injection of 1 mg / kg were investigated.

[1098] 1. Laboratory animals

[1099] SD rats, 3 males per group, from Spifor (Suzhou) Biotechnology Co., Ltd.

[1100] 2. Preparation of drug formulations

[1101] The administration solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS. Weigh an appropriate amount of the compound (calibrated is required), and add 5% DMSO according to the total volume ratio of the administration formulation. Vortex and sonicate for 2 minutes to completely dissolve. Then add 10% Solutol HS15, vortex and sonicate for 2 minutes to completely dissolve. Finally, add 85% PBS, vortex and sonicate for 5 minutes. For intravenous administration, filter through a 0.22 μm PES membrane; for oral administration, no sterile filtration is required. This yields the test formulation at the desired concentration.

[1102] 3. Administration

[1103] Male SD rats aged 6-8 weeks were housed in an SPF-protected environment. Throughout the experiment, the temperature and relative humidity in 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 3 (n=3 per group) according to body weight. Rats were fasted overnight before gavage administration of 5 mg / kg at a volume of 10 mL / kg, and fed 4 hours after administration. Intravenous administration of 1 mg / kg at a volume of 5 mL / kg was also administered.

[1104] 4. Sample collection and biological analysis

[1105] Plasma samples were collected from rats that received oral administration at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Plasma samples were also collected from rats that received intravenous administration at 0.0833, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentrations of compounds in the plasma were determined using a chromatography-tandem triple quadrupole mass spectrometer.

[1106] 5. Data Analysis

[1107] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method.

[1108] The results of the pharmacokinetic experiments on rats with the compound from the examples are shown in Tables 3A and 3B. The compound from the examples exhibited good pharmacokinetic characteristics. Compared with the control compound, the compound of the present invention has better pharmacokinetics in animals, and therefore better pharmacodynamics and therapeutic effects.

[1109] Table 3A shows the pharmacokinetic parameters of the compounds administered orally to rats in this embodiment.

[1110] Table 3B shows the pharmacokinetic parameters of the compounds administered via rat tail vein in this embodiment.

[1111] Test Example 4: High-Dose Pharmacokinetic Evaluation of Compounds in Mice

[1112] Using ICR mice as test animals, the in vivo pharmacokinetic characteristics of the compound of this embodiment after a single oral administration at a dose of 30 mg / kg were investigated.

[1113] 1. Laboratory animals

[1114] ICR mice, 3 males per group, from Hunan Slack Jingda Experimental Animal Co., Ltd.

[1115] 2. Preparation of drug formulations

[1116] The drug delivery solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS (pH = 9). Take appropriate amounts of the solvent components according to the proportions, add them to a suitable container, vortex and mix well, and adjust the pH to 9 to obtain the solvent solution. Weigh an appropriate amount of the test sample powder (which needs calibration) and place it in a suitable container. Then add an appropriate amount of solvent, vortex, and sonicate for 5 minutes to obtain the test sample preparation of the required concentration.

[1117] 3. Administration

[1118] Male ICR mice aged 6-8 weeks were housed in an SPF-protected environment. Throughout the experiment, the temperature and relative humidity in the animal room were controlled at 23±2℃ and 50±10%, respectively, with a constant light / dark cycle of 12 hours. All mice were acclimatized for 3 days before the start of the animal experiments. Mice were randomly divided into groups of 3 mice each according to their body weight. They were fasted overnight before administration of the drug via gavage. The dose was 30 mg / kg, and the administration volume was 10 mL / kg. They were fed 4 hours after administration.

[1119] 4. Sample collection and biological analysis

[1120] Plasma samples were collected from mice before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The concentrations of compounds in the plasma were determined using a tandem triple quadrupole mass spectrometer.

[1121] 5. Data Analysis

[1122] Pharmacokinetic parameters were calculated using a non-compartmental model analysis method.

[1123] Table 4. Pharmacokinetic parameters of the compounds in this embodiment after high-dose oral administration to mice.

[1124] As can be seen from Table 4, the compounds of the present invention exhibit good pharmacokinetic characteristics. Compared with the control compounds, the compounds of the present invention have better pharmacokinetics in animals, and therefore have better pharmacodynamics and therapeutic effects.

[1125] Test Example 5: Determination of Kinetic Solubility of Compounds

[1126] 1. Experimental Objective

[1127] This experiment aims to evaluate the kinetic solubility of the compounds of this invention under physiologically relevant pH conditions.

[1128] 2. Test System

[1129] Solution: 50mM phosphate buffer (PB) (pH=7.4).

[1130] Solution preparation: Weigh 3.549 g Na₂HPO₄ and dissolve it in 500 mL H₂O to prepare a 50 mM Na₂HPO₄ solution. Weigh 3.000 g NaH₂PO₄ and dissolve it in 500 mL H₂O to prepare a 50 mM NaH₂PO₄ solution. Take 15 mL of the 50 mM Na₂HPO₄ solution into a suitable container and adjust the pH to 7.4 ± 0.05 using the 50 mM NaH₂PO₄ solution to obtain a 50 mM PB (pH = 7.4) solution.

[1131] 3. Experimental Procedure

[1132] The compound was prepared as a 10 mM stock solution using DMSO. 10 μL of the stock solution was added to a 96-well plate, followed by 490 μL of 50 mM PB buffer (pH 7.4). The plate was vortexed for 2 minutes, then placed on a shaker and incubated at 800 rpm for 24 hours at room temperature. Afterward, the plate was centrifuged at 25°C and 4000 rpm for 10 minutes. The supernatant was transferred to a filter plate, and the filtrate was collected into a new 96-well plate by centrifugation for at least 5 minutes. The concentration of the filtrate was quantitatively analyzed using LC-UV and LC-MS / MS systems.

[1133] 4. Results

[1134] Table 5. Kinetic solubility of tested compounds

[1135] As can be seen from Table 5, the compounds of the present invention have good solubility, and their solubility is significantly better than that of control compound A, thereby improving the bioavailability of the drug.

[1136] Test Example 6: Efficacy Test of hGIPR Mouse Obesity Model Induced by High-Fat Diet

[1137] An obesity model was induced by feeding humanized GIPR mice with a high-fat diet. After gavage administration of the compounds from the examples, the effects of the compounds on the body weight of the obese hGIPR mice were analyzed.

[1138] 1. Laboratory animals

[1139] hGIPR mice, 5 males per group, from Shanghai Southern Model Biotechnology Co., Ltd.

[1140] 2. Preparation of drug formulations

[1141] The drug delivery solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS (pH = 9). Take appropriate amounts of the solvent components in the correct proportions, add them to a suitable container, vortex and mix well, and adjust the pH to 9 to obtain the solvent.

[1142] Preparation of drug administration formulation: Accurately weigh an appropriate amount of the test sample powder (after purity correction) and place it in a suitable container. Then add an appropriate amount of solvent, vortex and sonicate for 5 minutes to prepare a solution with a concentration of 3 mg / mL, which is the drug administration formulation.

[1143] 3. Administration

[1144] hGIPR mice were induced to weigh approximately 44g at 6 weeks of age with an HFD diet for 14 weeks, and then solvent adaptation was initiated. After about one week, when the weight stabilized, the mice were randomly divided into groups of 5 mice each. The solvent group received 5% DMSO + 10% Solutol HS15 + 85% PBS (pH=9) at a volume of 10 mL / kg. The drug-adapted group received 30 mg / kg at a volume of 10 mL / kg once daily for a total of 28 days. Day 0 was defined as the day of the first administration.

[1145] 4. Detection indicators

[1146] Starting from Day 0 of drug administration, the weight of the mice was recorded daily.

[1147] 5. Data Analysis

[1148] The effects of the compound in the examples on the body weight of the hGIPR mouse obesity model are shown in Table 6 and Figure 1. The results show that after 28 days of administration, the compound in the examples was superior to the Pfizer patented molecule in reducing the body weight of obese mice.

[1149] Table 6. Efficacy of compound hGIPR in inducing obesity in mice with HFD in the examples.

[1150] Test Example 7: Efficacy test of hGIPR mouse high-fat diet-induced obesity model combined with semaglutide administration

[1151] Humanized GIPR mice were fed a high-fat diet to induce an obesity model. The effects of administration of smegglutinin and compound A (or control compound A) in combination with smegglutinin on the body weight of obese hGIPR mice were analyzed.

[1152] 1. Laboratory animals

[1153] hGIPR mice, 5 males per group, Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd.

[1154] 2. Preparation of drug formulations

[1155] Solvent 1: The drug delivery solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS (pH = 9). Take appropriate amounts of the solvent components in the correct proportions, add them to a suitable container, vortex and mix well, and adjust the pH to 9 to obtain the solvent.

[1156] Solvent 2: 1.35% PG + 98.65% (0.01M DPBS (pH=7.4)): Take appropriate amounts of the solvent components in the correct proportions and add them to a suitable container. Vortex and mix well to obtain the solvent 2 solution.

[1157] Preparation of the drug administration formulation of the compound (or control compound A) in the example: Accurately weigh an appropriate amount of the test sample powder (after purity correction) and place it in a suitable container. Then add an appropriate amount of solvent 1, vortex and sonicate for 5 minutes to prepare a solution with a concentration of 3 mg / mL, which is the drug administration formulation.

[1158] Preparation of semaglutide drug delivery formulation: Accurately weigh an appropriate amount of semaglutide, add an appropriate amount of solvent 2, vortex and sonicate for 5 minutes to prepare stock solution 1 with a concentration of 15 nmol / mL. Pipette 0.1 mL of stock solution 1 into 0.9 mL of solvent 2, vortex to mix, thus preparing the drug delivery formulation with the required concentration of 1.5 nmol / mL.

[1159] 3. Administration

[1160] hGIPR mice, at 6 weeks of age, were induced to weigh approximately 45g by HFD diet for 15 weeks, and then solvent adaptation was initiated. After about one week, when body weight stabilized, the mice were randomly divided into groups of 5 mice each. The solvent group received 5% DMSO + 10% Solutol HS15 + 85% PBS (pH=9), with a dosage volume of 10 mL / kg. The treatment groups received semaglutide and the example compound (or control compound A) simultaneously, or semaglutide alone. Semaglutide was administered subcutaneously at a dose of 3 nmol / kg, with a dosage volume of 2 mL / kg, once daily. The example compound (or control compound A) was administered by gavage at a dose of 30 mg / kg, with a dosage volume of 10 mL / kg, once daily. Day 1 was defined as the day of the first administration, and the treatment lasted for 28 days.

[1161] 4. Detection indicators

[1162] Starting from Day 1 of drug administration, the weight and food intake of the mice were recorded daily.

[1163] 5. Data Analysis

[1164] The effects of the combination of the example compounds and semaglutide on body weight and food intake in an hGIPR mouse obesity model are shown in Table 7a and Figure 2, and Table 7b and Figure 3, respectively. The results show that after 28 days of administration, the combination of the example compounds and semaglutide significantly reduced body weight in obese mice compared to the combination of Pfizer's patented molecules and semaglutide alone. Body weight loss was correlated with food intake.

[1165] Table 7a shows the efficacy results of the combination of the compounds in the examples with semaglutide hGIPR mice in inducing obesity due to HFD.

[1166] Table 7b shows the efficacy results of the combination of the compounds in the examples with semaglutide hGIPR in inducing obesity in HFD mice.

[1167] Test Example 8: Pharmacokinetic Evaluation of Compounds in Beagle Dogs

[1168] 1. Experimental Objective

[1169] Using beagle dogs as test animals, the pharmacokinetic characteristics of the compound of the present invention were studied in beagle dogs after oral administration at a dose of 2 mg / kg.

[1170] 2. Test System

[1171] Beagles, 3 per group, male, from Hengxing, Hunan.

[1172] 3. Preparation of drug formulations

[1173] The oral administration solvent is 5% DMSO + 10% Solutol HS15 + 85% PBS.

[1174] Preparation of drug delivery formulation: 1) Weigh an appropriate amount of compound (needs to be calibrated), add 5% DMSO according to the total volume ratio of the drug, vortex and sonicate for 2 minutes to completely dissolve it;

[1175] 2) Add 10% Solutol HS15, vortex and sonicate for 2 minutes to completely dissolve it;

[1176] 3) Finally, add 85% PBS, vortex and sonicate for 5 minutes. For intravenous administration, pass the formulation through a 0.22 μm PES filter membrane. For oral administration, no sterilization filtration is required. A colorless, transparent, and clear solution is obtained, which is the test formulation of the required concentration.

[1177] 4. Administration

[1178] Beagles, 3 dogs per group, were fasted overnight before administration and given 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.

[1179] 5. Sample collection and biological analysis

[1180] Plasma samples were collected from beagles 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 determined using a tandem triple quadrupole mass spectrometer.

[1181] 6. Data Analysis

[1182] Pharmacokinetic parameters were calculated using a non-compartmental model.

[1183] Table 8. Pharmacokinetic parameters of the tested compounds after oral administration to beagle dogs.

[1184] As can be seen from Table 8, the compounds of the present invention exhibit good pharmacokinetic characteristics. Compared with the control compounds, the compounds of the present invention have better pharmacokinetics in animals, and therefore have better pharmacodynamics and therapeutic effects.

[1185] Test Example 9: Pharmacokinetic Evaluation of Compounds in Cynomolgus Monkeys

[1186] 1. Experimental Objective

[1187] 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.

[1188] 2. Test System

[1189] Crab-eating macaques, 3 in each group, male, from Xiongsen, Guangxi.

[1190] 3. Preparation of drug formulations

[1191] The oral administration solvent is 5% DMSO + 10% HP-β-CD + (95% PBS, pH=9) (v:w:v).

[1192] The oral preparation process is as follows:

[1193] 1) Adjust the pH of PBS to 9 using NaOH.

[1194] 2) Take appropriate amounts of DMSO and (PBS, pH=9) according to the volume ratio, and vortex to mix.

[1195] 3) Weigh an appropriate amount of HP-β-CD and add it to the solution from step 2 according to the weight:volume ratio. After complete dissolution, bring the volume to a final volume to obtain the blank solvent (e.g., 10g of HP-β-CD, added to 80mL of the solution from step 2, dissolved, and then brought to a final volume of 100mL). This is the blank solvent for drug administration.

[1196] 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.

[1197] 4. Sample collection and biological analysis

[1198] Plasma samples were collected from cynomolgus monkeys before and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after drug administration. The content of the test compounds was detected using a chromatography-tandem triple quadrupole mass spectrometer.

[1199] 5. Data Analysis

[1200] Pharmacokinetic parameters were calculated using a non-compartmental model.

[1201] Table 9. Pharmacokinetic parameters of the tested compounds after oral administration to cynomolgus monkeys.

[1202] As can be seen from Table 9, the compounds of the present invention exhibit good pharmacokinetic characteristics. Compared with the control compounds, the compounds of the present invention have better pharmacokinetics in animals, and therefore have better pharmacodynamics and therapeutic effects.

[1203] 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 formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof. in, Ring A is selected from the group consisting of: saturated 5-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; partially unsaturated 3-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 3-4-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 6-8-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each heterocyclic alkyl group and heteroaryl group is independently and optionally substituted with 1, 2 or 3 R2 groups. Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl; Alternatively, the two R2s attached to adjacent Cs together with their respective attached Cs form a phenyl, a C3-C6 cycloalkyl, or a C3-C6 spirocycloalkyl; Alternatively, two R2s attached to the same C and their common C-attached C together form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S; X1 is selected from the following group: N, CH, C; X2 is selected from the following group: N, CH, C; Y1 is selected from the following groups: -(C=O)-, None, -(C=S)-; Y2 is selected from the following group: NR3, None; R3 is selected from the following group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; Alternatively, R2 located at the position adjacent to ring A and its connected C and R3 together with the connected N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S; Y3 is selected from the following groups: -(C=O)-, None, -(C=S)-; Y4 is selected from the following group: NR4, -NR4-(CH2)-, none; R4 is selected from the following group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; Alternatively, R2 located at the position adjacent to ring A and its connected C and R4 together with the connected N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S; Ring B is selected from the following group: C6-C10 aryl, 6-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, and C5-C7 bridged cycloalkyl; Each R1 is independently selected from the following group: H, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, -NR5R6, -SF5; m is selected from the following group: 0, 1, 2, 3, 4; Alternatively, the two R1s attached to adjacent Cs together with the Cs they are attached to form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S, wherein each cycloalkyl group or heterocycloalkyl group is independently and optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C=O, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; Alternatively, R1 attached to the adjacent position of ring B, together with its attached C, and R3 attached to its attached N, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S; R5 and R6 are each independently selected from the following group: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; The ring C is selected from the group consisting of: C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, C5-C7 bridged cycloalkyl, and 4-7 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, wherein each aryl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2 or 3 R7 atoms independently; Each R7 is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl. Alternatively, two R7s located at adjacent Cs together with their respective connected Cs form a saturated or partially unsaturated 4-7 membered heterocyclic alkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S; Alternatively, R7 located at the aryl or heteroaryl position together with its attached C, and R4 together with its attached N, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by 1, 2 or 3 groups selected from the group consisting of: C1-C6 alkyl groups, halogens; The ring D is selected from the group consisting of: C6-C10 aryl, none, C5-C7 bridged cycloalkyl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein each of the aryl, cycloalkyl, and heteroaryl groups is independently and optionally substituted by 1, 2 or 3 R8 atoms. Each R8 is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and deuterated C1-C6 alkyl. Alternatively, the R8 located ortho to the aryl group and its attached C, and the R7 located ortho to the aryl group and its attached C, together form a C5-C7 cycloalkyl group or a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S. Alternatively, two R8s located at adjacent Cs together with their respective connected Cs form substituted or unsubstituted saturated or partially unsaturated 4-7 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, or 4-7 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; Alternatively, Z is -B(OH)2, and the R8 in the ortho position together with one OH of Z forms a 5-6 membered heterocyclic alkyl group containing B and O; Z is selected from the group consisting of: -COOH, -(C1-C6 alkylene)-COOH, -(C2-C6 alkenyl)-COOH, -(C2-C6 alkyne)-COOH, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, and -B(OH)2, wherein the heteroaryl group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: halogen, hydroxyl, cyano, C=O, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkyne.

2. The compound according to claim 1, characterized in that, The additional condition is that when ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, the compound has one or more characteristics selected from the group consisting of: 1) Two R2s attached to adjacent C atoms, together with their respective attached C atoms, form a phenyl or C3-C6 spirocyclic cycloalkyl group; 2) X1 is CH, X2 is N; 3) Y1 is zero, Y2 is zero; 4) R2 located at the ortho position of ring A and its connected C and R4 together with the connected N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S; 5) Y1 is -(C=S)-; 6) Two R1s attached to adjacent C and the Cs they are attached to together form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S, wherein each cycloalkyl group or heterocycloalkyl group is independently and optionally substituted by 1, 2 or 3 groups selected from the group consisting of: halogen, hydroxyl, cyano, C=O, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; 7) m is selected from the following groups: 2, 3, 4; At least one R1 is selected from the group consisting of: hydroxyl, cyano, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, 3-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, and NR5R6. 8) Cyclone B is selected from the following group: 6-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, and C5-C7 bridged cycloalkyl groups; 9) R1 attached to the adjacent position of ring B, together with the C and R3 attached thereto and the N attached thereto, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S; 10) Y3 is empty, Y4 is empty; 11) The R7 located at the aryl ortho position together with the C it is attached to, and the R4 together with the N it is attached to form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by 1, 2 or 3 groups selected from the group consisting of: C1-C6 alkyl, halogen; 12) Ring D is selected from the following group: none, C5-C7 bridged cycloalkyl rings, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; 13) The R8 located ortho to the aryl group and its attached C, and the R7 located ortho to the aryl group and its attached C together form a C5-C7 cycloalkyl group or a 4-7 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S. 14) The ring C is selected from the following group: 5-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; C5-C7 bridged cycloalkyl groups; 15) Z is selected from the following group: -(C1-C6 alkylene)-COOH, -(C2-C6 alkenyl)-COOH, -(C2-C6 alkyneyl)-COOH, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, -B(OH)2; 16) R2 located at the ortho position of ring A and its connected C and R3 together with the connected N to form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S; 17) Two R2s attached to the same C and the C they are attached to together form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S; 18) Ring A is a saturated 5-membered heterocyclic alkyl group containing two heteroatoms selected from N, O, or S; 19) The heterocyclic alkyl group is substituted with 1, 2 or 3 R2 atoms; Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl; 20) m is 1, R1 is selected from the following group: NR5R6, -SF5; 21) The ring C is selected from the following group: C5-C7 bridged cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S; 22) Two R8s located at adjacent C and their respective connected Cs together form a substituted or unsubstituted saturated or partially unsaturated 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, or a 4-7 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; 23) Two R7s located at adjacent Cs together with their respective connected Cs form a saturated or partially unsaturated 4-7 membered heterocyclic alkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

3. The compound according to claim 1, characterized in that, In ring A, the saturated 6-8 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S is selected from the group consisting of monocyclic heterocyclic alkyl, bridged heterocyclic alkyl, and spirocyclic heterocyclic alkyl.

4. The compound according to claim 1, characterized in that, There is exactly one N among X1 and X2.

5. The compound according to claim 1, characterized in that, Ring A is selected from the group consisting of: partially unsaturated 3-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 3-4-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 6-8-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each heterocyclic alkyl group and heteroaryl group is independently and optionally substituted with 1, 2 or 3 R2 groups. Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl; Alternatively, the two R2s attached to adjacent Cs together with their respective attached Cs form a phenyl or a C3-C6 spirocycloalkyl group; Alternatively, two R2 atoms attached to the same C atom, together with the C atoms they are connected to, form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S.

6. The compound according to claim 1, characterized in that, Ring A is selected from the group consisting of: partially unsaturated 3-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; saturated 6-8-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, wherein each heterocyclic alkyl group and heteroaryl group is optionally substituted by 1, 2 or 3 R2 groups independently. Each R2 is independently selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl; Alternatively, the two R2s attached to adjacent Cs together with their respective attached Cs form a phenyl or a C3-C6 spirocycloalkyl group; Alternatively, two R2 atoms attached to the same C atom, together with the C atoms they are connected to, form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S.

7. The compound according to claim 1, characterized in that, R2 located ortho to ring A and its attached C and R3 together with the attached N form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S; and / or R2 located at the position adjacent to ring A, together with C and R4 connected to it and N connected to it, form a 4-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S.

8. The compound according to claim 1, characterized in that, When ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, ring A is... R2 is selected from the following group: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl.

9. The compound according to claim 1, characterized in that, When ring A is a saturated 5-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, the heterocyclic alkyl group is substituted with 2 R2 atoms, and ring A is selected from the group consisting of: R2 is selected from the following group: deuterium, halogen, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -(CH2). 1-3 -O-C3-C6 cycloalkyl, -(CH2) 1-3 -O-C1-C6 alkyl, -(CH2) 1-3 -O-halogenated C1-C6 alkyl group, -(CH2) 1-3 -O-deuterated C1-C6 alkyl, deuterated C1-C6 alkyl.

10. The compound according to claim 1, characterized in that, Ring A is a saturated 6-8 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, and is a bridged heterocyclic alkyl group.

11. The compound according to claim 1, characterized in that, for R 1a Selected from the following groups: C2-C6 alkynyl, halo-C1-C6 alkoxy; R 1b Selected from the following group: H, halogens.

12. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

13. A pharmaceutical composition, characterized in that, The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate or solvate thereof contains a pharmaceutically acceptable carrier and a safe and effective amount thereof.

14. Use of the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, or solvate thereof, characterized in that, Used to prepare a drug for the prevention and / or treatment of GIPR-related diseases.

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