GPCR Modulators and Uses Thereof

Abstract

The present invention relates to GPCR modulators and uses thereof, and in particular provides a compound represented by formula (I), or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma-ceutically acceptable solvate or pharma-ceutically acceptable ester of said compound: [Formula 1] JPEG2025514766000209.jpg3450

Description

[Technical field]

[0001] The present invention relates to the field of medicine, specifically to GPCR modulators and uses thereof. [Background technology]

[0002] G protein-coupled receptors (GPCRs) are a group of transmembrane proteins that transmit chemical signals from extracellular matrix proteins to cells, and are involved in manipulating and regulating physiological and pathological functions. Over 800 GPCRs have been identified in the human genome, which are classified into A, B, C, and F classes based on amino acid sequence similarity. Among these, class A (also known as rhodopsin-like GPCRs) has the largest family members, consisting of 719 GPCRs. Signal regulation of GPCRs requires ligands, GPCRs, effector proteins, and corresponding downstream signal pathways. After the ligand acts on the GPCR, the GPCR is activated, undergoes conformational rearrangement, and recruits effector proteins to exert its signaling function. GPCR signaling has a high degree of biological complexity and importance, which makes GPCRs highly valuable drug targets.

[0003] G protein-coupled receptor 132 (GPR132) is a seven-transmembrane G protein-coupled receptor and a GPCR (class A) of the rhodopsin family. In 1998, Weng et al. found that B cells and T cells can upregulate GPR132 expression under stress induction to cause cell cycle arrest in the G2 phase. Thus, the gene encoding this protein is called G2A (G2 accumulation) and is considered to be a potential tumor suppressor gene. GPR132 expression is tissue- and cell type-specific, and is mainly present in blood and lymphoid tissues. GPR132 expression is found mainly in blood cells such as macrophages, dendritic cells, neutrophils, T cells, and B lymphocytes, but its expression in immune cells is not specific.

[0004] As far as humans know, GPR132 mainly plays a role in immune cells, regulating immune function and being closely related to various immune-related diseases and malignancies. In 2001, Le et al. found that GPR132-deficient mice developed delayed autoimmune syndrome, and proposed that GPR132 is a potential target for autoimmune diseases. David et al. found that GPR132 deficiency promoted macrophage activation and aggravated atherosclerotic disease. In a dextran sulfate sodium-induced inflammatory bowel disease model, Frasch et al. found that monocytes lost GPR132, leading to reduced IFN-γ expression and aggravating the progression of colitis. In addition to immune diseases, GPR132 may play an important role in the hematopoietic tissue system. Li P et al. found that the GPR132 agonist 11,12-EET significantly increased the mRNA expression of hematopoietic tissue genes in a zebrafish model, and that in a mouse bone marrow transplantation model, the use of 11,12-EET to treat bone marrow cells significantly improved short-term and long-term chimerism of transplanted donors. Using a GPR132 knockout mouse model, Lahvic JL et al. found that GPR132 improves donor cell chimerism in bone marrow transplantation by promoting the embedding and homing of donor hematopoietic stem and progenitor cells. Thus, GPR132 agonists are expected to be used in autoimmune diseases and hematopoietic stem cell transplantation. Furthermore, Takenobu et al. found that the use of the small molecule ONC212 to stimulate GPR132 can promote apoptosis of acute myeloid leukemia cells and extend the survival of mice bearing transplanted tumors. Summary of the Invention [Problem to be solved by the invention]

[0005] However, those skilled in the art remain keen to obtain new types of GPR132 agonists useful in diseases such as atherosclerosis, colorectal inflammation and leukemia, or treatment procedures such as bone marrow transplantation. [Means for solving the problem]

[0006] The inventors of the present application, through intensive research and creative discovery, have obtained GPR132 modulators (e.g., agonists) having novel structures that may be useful in the prevention and / or treatment of diseases such as atherosclerosis, colorectal inflammation, leukemia, or treatment methods such as bone marrow transplantation.

[0007] To this end, in a first aspect, the present invention provides a compound of formula I, or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or pharma- ceutically acceptable ester of said compound,

[0008] [ka]

[0009] (In the formula, Ring A is selected from the group consisting of a benzofuran ring, a benzothiophene ring, an indole ring, and a benzene ring; R 0 teeth,

[0010] [ka]

[0011] is selected from the group consisting of L a is selected from the group consisting of C1 to C6 alkylene; R 1 is selected from the group consisting of hydroxyl, C1-C6 alkoxy and -NH-OH; R 2 is selected from the group consisting of hydrogen, halogen and C1-C6 alkyl; R 3is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, phenyl, naphthyl, and 5-10 membered heteroaryl, and phenyl, naphthyl, and 5-10 membered heteroaryl are R x or the phenyl, naphthyl and 5- to 10-membered heteroaryl are each independently substituted with two adjacent groups, and the two adjacent groups and the carbon atoms to which they are each attached may together form a 5- to 6-membered heterocyclic ring; R x is C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkynyl, cyano, phenyl and -NR m R n is selected from the group consisting of R m and R n are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; L 1 teeth,

[0012] [ka]

[0013] is selected from the group consisting of Preferably, L 1 teeth,

[0014] [ka]

[0015] is selected from the group consisting of L 2 teeth,

[0016] [ka]

[0017] is selected from the group consisting of n is selected from the group consisting of 1, 2, 3, 4, 5 and 6; m is selected from the group consisting of 1, 2, 3, 4, 5 and 6; p is selected from the group consisting of 0, 1, 2 and 3; R 4’ is phenyl-(CH2) r - and 5-10 membered heteroaryl-(CH2) r , phenyl and 5-10 membered heteroaryl are selected from the group consisting of R a each independently being substituted with 1 to 5 groups selected from the group consisting of r is selected from the group consisting of 0, 1, 2, 3, 4 and 5; R a is halogen, C1-C6 alkyl-OC(=O)- and 5-6 membered saturated heterocyclyl (

[0018] [ka]

[0019] and optionally substituted by R b is selected from the group consisting of hydrogen and C1-C6 alkyl. to provide.

[0020] In some embodiments, ring A is

[0021] [ka]

[0022] and X is selected from the group consisting of O, S and NH, and X is preferably O. In some embodiments, R 0 teeth,

[0023] [ka]

[0024] It is. In some embodiments, L a teeth,

[0025] [ka]

[0026] is selected from the group consisting of: In some embodiments, R 1 is selected from the group consisting of hydroxyl and C1-C6 alkoxy.

[0027] In some embodiments, R 1 is selected from the group consisting of hydroxyl and ethoxy. In some embodiments, R 1 is hydroxyl.

[0028] In some embodiments, R 1 is selected from the group consisting of hydroxyl, ethoxy and -NH-OH. In some embodiments, R 2 is selected from the group consisting of halogen and C1-C6 alkyl.

[0029] In some embodiments, R 2 is selected from the group consisting of fluorine, chlorine and methyl. In some embodiments, R 2 is selected from the group consisting of C1 to C6 alkyl. In some embodiments, R 2 is methyl.

[0030] In some embodiments, R 3 is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, phenyl, naphthyl, pyridyl, pyrrolyl, thienyl and indolyl, and phenyl, naphthyl, pyridyl, pyrrolyl, thienyl and indolyl are R xor phenyl, naphthyl, pyridyl, pyrrolyl, thienyl and indolyl are each independently substituted by two adjacent groups, and the two adjacent groups and the carbon atoms to which they are each linked may together form a 5- to 6-membered heterocyclic ring.

[0031] In some embodiments, R 3 is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, phenyl, naphthyl, pyridyl, pyrrolyl, thienyl and indolyl, and phenyl, pyridyl and thienyl are R x or the phenyl is substituted with two adjacent groups, and the two adjacent groups and the carbon atoms to which they are each attached are each independently substituted with one to two (preferably one) groups selected from the group consisting of:

[0032] [ka]

[0033] may be formed. In some embodiments, R 3 is the following: 1)

[0034] [ka]

[0035] (In the formula, R 4 , R 5 , R 6 , R 7 and R 8 is hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkynyl, cyano, phenyl and -NR m R n or R 4 , R 5and the carbon atoms to which they are each attached together form a 5- to 6-membered heterocyclic ring; R 6 , R 7 , R 8 is hydrogen, Preferably, R 4 , R 5 , R 6 , R 7 and R 8 One of the following (for example, R 5 , R 6 or R 7 ) is hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkynyl, cyano, phenyl and -NR m R n and the remainder are hydrogen; More preferably, R 4 , R 5 , R 6 , R 7 and R 8 One of the following (for example, R 5 , R 6 or R 7 ) is hydrogen, methyl, fluorine, chlorine, iodine, methoxy

[0036] [ka]

[0037] Trifluoromethyl

[0038] [ka]

[0039] Cyano, phenyl and

[0040] [ka]

[0041] and the remainder being hydrogen or Or, preferably, R 4 , R 5 and the carbon atoms to which they are each attached together are

[0042] [ka]

[0043] Form R 6 , R 7 and R 8 is hydrogen) 2)

[0044] [ka]

[0045] (In the formula, R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, and C1-C6 alkoxy; Preferably, R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkoxy; More preferably, R 9 , R 10 , R 11 and R 12 One of the following (e.g., R 10 or R 11 is selected from the group consisting of hydrogen, halogen and C1-C6 alkoxy, the remainder being hydrogen; Most preferably, R 9 , R 10 , R 11 and R 12 One of the following (e.g., R 10 or R 11 ) is selected from the group consisting of hydrogen, chlorine and methoxy, the remainder being hydrogen. 3)

[0046] [ka]

[0047] (In the formula, R 13 , R 14 and R 15 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen; Preferably, R 13 , R 14 and R 15 One of the following (e.g., R 13 ) is selected from the group consisting of hydrogen, C1-C6 alkyl and halogen, the remainder being hydrogen; More preferably, R 13 , R 14 and R 15 One of the following (e.g., R 13 ) is selected from the group consisting of hydrogen, methyl and chlorine, the remainder being hydrogen. 4)

[0048] [ka]

[0049] is selected from the group consisting of: In some embodiments, R 3 teeth,

[0050] [ka]

[0051] is selected from the group consisting of: In some embodiments, R x is methyl, fluorine, chlorine, iodine, methoxy

[0052] [ka]

[0053] Trifluoromethyl

[0054] [ka]

[0055] Cyano, phenyl and -NR m R n is selected from the group consisting of: In some embodiments, R m and R n One of these is hydrogen, and the other is selected from the group consisting of C1 to C6 alkyl.

[0056] In some embodiments, R m and R n One of these is hydrogen and the other is methyl. In some embodiments, R 4’ is phenyl-(CH2) r - and quinolyl-(CH2) r -, and phenyl and quinolyl are selected from the group consisting of R a and each independently may be substituted with a group selected from the group consisting of:

[0057] In some embodiments, R 4’ is phenyl-(CH2) r - and quinolyl-(CH2) r -, phenyl is selected from the group consisting of R a It may be substituted with a group selected from the group consisting of:

[0058] In some embodiments, r is selected from the group consisting of 0 and 1. In some embodiments, R a is halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0059] [ka]

[0060] and wherein In some embodiments, R a is halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0061] [ka]

[0062] and wherein In some embodiments, R a teeth, bromine

[0063] [ka]

[0064] is selected from the group consisting of: In some embodiments, R b is selected from the group consisting of C1 to C6 alkyl. In some embodiments, R b is methyl.

[0065] In some embodiments, R 4’ teeth,

[0066] [ka]

[0067] wherein: r' is selected from the group consisting of 0, 1, 2, 3, 4 and 5; Preferably, r' is selected from the group consisting of 0 and 1; R 5’ , R 6’ , R 7’ , R8’ and R 9’ is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and 5-6 membered saturated heterocyclyl (

[0068] [ka]

[0069] each independently selected from the group consisting of Preferably, R 5’ , R 6’ , R 7’ , R 8’ and R 9’ One of these (for example, R 7’ ) is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and 5-6 membered saturated heterocyclyl (

[0070] [ka]

[0071] and the remainder are hydrogen; More preferably, R 5’ , R 6’ , R 7’ , R 8’ , R 9’ One of these (for example, R 7’ ) is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0072] [ka]

[0073] and the remainder are hydrogen; More preferably, R 5’ , R 6’ , R 7’ , R 8’ and R9’ One of these (for example, R 7’ ) is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0074] [ka]

[0075] and the remainder are hydrogen; Most preferably, R 5’ , R 6’ , R 7’ , R 8’ and R 9’ One of these (for example, R 7’ ) is hydrogen, bromine

[0076] [ka]

[0077] and the remainder are hydrogen; R b’ is selected from the group consisting of hydrogen and C1-C6 alkyl; Preferably, R b’ is selected from the group consisting of C1 to C6 alkyl; More preferably, R b’ is methyl.

[0078] In some embodiments, R 4’ teeth,

[0079] [ka]

[0080] is selected from the group consisting of: In some embodiments, L 1 teeth,

[0081] [ka]

[0082] is selected from the group consisting of

[0083] [ka]

[0084] In the formula, the carbonyl end is L 2 and the amino terminus is linked to a benzene ring,

[0085] [ka]

[0086] In the 2 and the acyl terminus is linked to a benzene ring. In some embodiments, L 1 teeth,

[0087] [ka]

[0088] and

[0089] [ka]

[0090] In the formula, the carbonyl end is L 2 and the amino terminus is linked to a benzene ring. In some embodiments, L 2 teeth,

[0091] [ka]

[0092] is selected from the group consisting of

[0093] [ka]

[0094] In the formula, the carbonyl end is R 3 is linked to. In some embodiments, L 2 teeth,

[0095] [ka]

[0096] is selected from the group consisting of

[0097] [ka]

[0098] In the formula, the carbonyl end is R 3 is linked to. In some embodiments, L 2 teeth,

[0099] [ka]

[0100] is selected from the group consisting of

[0101] [ka]

[0102] In the formula, the carbonyl end is R 3 is linked to. In some embodiments, L 2 teeth,

[0103] [ka]

[0104] It is. In some embodiments, n is selected from the group consisting of 2, 3, and 4. In some embodiments, n is selected from the group consisting of 2 and 4.

[0105] In some embodiments, m is selected from the group consisting of 1, 2, and 3. In some embodiments, m is 2. In some embodiments, p is 0.

[0106] In a second aspect of the present invention, the present invention provides a compound represented by formula I-1, formula I-2 or formula I-3, or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or pharma- ceutically acceptable ester of said compound.

[0107] [ka]

[0108] (In the formula, X is selected from the group consisting of O, S and NH, preferably O; R 0 , R 2 , R 3 , L 1 and L 2 is defined as described in the first aspect, R 1’ is selected from the group consisting of hydrogen and C1-C6 alkyl; R 2’ is selected from the group consisting of hydrogen and C1-C6 alkyl; R 3’ is phenyl, which is optionally substituted by 1 to 5 groups selected from the group consisting of C1 to C6 alkyl; L 3 teeth,

[0109] [ka]

[0110] is selected from q is selected from the group consisting of 1, 2, 3, 4, 5, and 6; R 4’ is phenyl-(CH2) r - and 5-10 membered heteroaryl-(CH2) r -, phenyl and 5-10 membered heteroaryl are selected from the group consisting of R a each independently being substituted with 1 to 5 groups selected from the group consisting of r is selected from the group consisting of 0, 1, 2, 3, 4 and 5; R a is halogen, C1-C6 alkyl-OC(=O)- and 5-6 membered saturated heterocyclyl (

[0111] [ka]

[0112] and optionally substituted by R b is selected from the group consisting of hydrogen and C1-C6 alkyl. to provide.

[0113] In some embodiments, R 1’ is selected from the group consisting of hydrogen and ethyl. In some embodiments, R 1’ is hydrogen. In some embodiments, R 2’ is selected from the group consisting of C1 to C6 alkyl.

[0114] In some embodiments, R 2’ is methyl. In some embodiments, R 3’is phenyl, which may be substituted with one group selected from the group consisting of C1 to C6 alkyl.

[0115] In some embodiments, R 3’ is phenyl. In some embodiments, q is selected from the group consisting of 1, 2, and 3. In some embodiments, q is 2.

[0116] In some embodiments, R 4’ is phenyl-(CH2) r - and quinolyl-(CH2) r -, and phenyl and quinolyl are selected from the group consisting of R a and each independently may be substituted with one group selected from the group consisting of:

[0117] In some embodiments, R 4’ is phenyl-(CH2) r - and quinolyl-(CH2) r -, and the phenyl group is selected from the group consisting of R a may be substituted with one group selected from the group consisting of:

[0118] In some embodiments, r is selected from the group consisting of 0 and 1. In some embodiments, R a is halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0119] [ka]

[0120] and wherein In some embodiments, R a is halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0121] [ka]

[0122] and wherein In some embodiments, R a is bromine

[0123] [ka]

[0124] is selected from the group consisting of: In some embodiments, R b is selected from the group consisting of C1 to C6 alkyl. In some embodiments, R b is methyl.

[0125] In some embodiments, R 4’ teeth,

[0126] [ka]

[0127] wherein: r' is selected from the group consisting of 0, 1, 2, 3, 4 and 5; Preferably, r' is selected from the group consisting of 0 and 1; R 5’ , R 6’ , R 7’ , R 8’ and R 9’ is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and 5-6 membered saturated heterocyclyl (

[0128] [ka]

[0129] each independently selected from the group consisting of Preferably, R 5’ , R 6’ , R 7’ , R 8’ and R 9’ One of these (for example, R 7’ ) is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and 5-6 membered saturated heterocyclyl (

[0130] [ka]

[0131] and the remainder are hydrogen; More preferably, R 5’ , R 6’ , R 7’ , R 8’ and R 9’ One of these (for example, R 7’ ) is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0132] [ka]

[0133] and the remainder are hydrogen; More preferably, R 5’ , R 6’ , R 7’ , R 8’ and R 9’ One of these (for example, R 7’ ) is hydrogen, halogen, C1-C6 alkyl-OC(=O)- and piperazinyl (

[0134] [ka]

[0135] and the remainder are hydrogen; Most preferably, R 5’ , R 6’ , R 7’ , R 8’ and R 9’ One of these (for example, R 7’ ) is hydrogen, bromine

[0136] [ka]

[0137] and the remainder are hydrogen; R b’ is selected from the group consisting of hydrogen and C1-C6 alkyl; Preferably, R b’ is selected from the group consisting of C1 to C6 alkyl; More preferably, R b’ is methyl.

[0138] In some embodiments, R 4’ teeth,

[0139] [ka]

[0140] is selected from the group consisting of: In a third aspect of the present invention, the present invention provides a compound represented by formula I-1-1, or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate, or pharma- ceutically acceptable ester of said compound:

[0141] [ka]

[0142] (In the formula, X is selected from the group consisting of O, S and NH, and preferably O; R 1 , R 2 , R3 , L 1 and L 2 is defined as described in the first embodiment) to provide.

[0143] In a fourth aspect of the present invention, the present invention provides a compound represented by formula I-2-1, or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate, or pharma- ceutically acceptable ester of said compound:

[0144] [ka]

[0145] (In the formula, R 1 , R 2 , R 3 , L a , L 1 and L 2 is defined as described in the first embodiment) to provide.

[0146] In some embodiments, R 1 is hydroxyl. In some embodiments, R 2 is selected from the group consisting of halogens. In some embodiments, R 2 is fluorine.

[0147] In some embodiments, R 3 teeth,

[0148] [ka]

[0149] It is. In some embodiments, L a is selected from the group consisting of C1 to C6 alkylene. In some embodiments, L a teeth,

[0150] [ka]

[0151] is selected from the group consisting of: In some embodiments, L 1 teeth,

[0152] [ka]

[0153] is selected from the group consisting of

[0154] [ka]

[0155] In the formula, the carbonyl end is L 2 and the amino terminus is linked to a benzene ring. In some embodiments, L 1 teeth,

[0156] [ka]

[0157] and

[0158] [ka]

[0159] In the formula, the carbonyl end is L 2 and the amino terminus is linked to a benzene ring. In some embodiments, L 2 teeth,

[0160] [ka]

[0161] is selected from. In some embodiments, L 2 teeth,

[0162] [ka]

[0163] is selected from the group consisting of: In some embodiments, n is selected from the group consisting of 1, 2, 3, 4, 5, and 6. In some embodiments, n is selected from the group consisting of 2 and 3.

[0164] In some embodiments, the compound represented by formula I is selected from the group consisting of:

[0165] [Table 1-1]

[0166] [Table 1-2]

[0167] [Table 1-3]

[0168] [Table 2]

[0169] In a fifth aspect of the invention, the invention provides a pharmaceutical composition comprising the compound as described above or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or pharma- ceutically acceptable ester of said compound, and optionally a pharma- ceutically acceptable excipient.

[0170] The compounds of the present invention may be used as GPR132 modulators (e.g., agonists) for preventing and / or treating diseases associated with GPR132, or for hematopoietic stem cell transplantation, or for bone marrow transplantation, for example, for preventing and / or treating diseases such as atherosclerosis, colorectal inflammation, leukemia, etc., or for treatment procedures such as bone marrow transplantation.

[0171] Thus, in a sixth aspect of the invention, the present invention provides the use of the aforementioned compounds or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or pharma- ceutically acceptable ester of said compounds in the manufacture of a medicament, or the use of the aforementioned pharmaceutical composition in the manufacture of a medicament, or the use of the compounds as shown in Table A below or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or pharma- ceutically acceptable ester of said compounds in the manufacture of a medicament, wherein said medicament is used for the treatment and / or prevention of a disease associated with GPR132, or for hematopoietic stem cell transplantation, or for bone marrow transplantation.

[0172] [Table 3]

[0173] In some embodiments, the disease associated with GPR132 is selected from the group consisting of a tumor, a metabolic disease, an immune-related disease, and neuropathic pain. In some embodiments, the tumor is selected from the group consisting of breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, liver cancer (e.g., primary liver cancer), intraspinal tumor, longitudinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia (e.g., acute myeloid leukemia), gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma, and glioma.

[0174] In some embodiments, the metabolic disease is selected from the group consisting of atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver or non-alcoholic steatohepatitis (NASH)), metabolic syndrome, type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia) and secondary complications of these diseases (e.g., diabetic complications such as retinopathy, neuropathy, nephropathy and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension and stroke).

[0175] In some embodiments, the immune related disease is characterized by: Secondary immunodeficiencies: secondary immunodeficiencies caused, for example, by infections (e.g. rubella, measles, leprosy, tuberculosis, cytomegalovirus infection, HIV infection, coccidioidomycosis infection), protein depletion (e.g. nephrotic syndrome, protein-losing gastroenteropathy), insufficient immunoglobulin synthesis, lymphopenia (e.g. lymphopenia caused by drugs and / or systemic infections), secondary immunodeficiencies caused by other diseases (e.g. diabetes, cirrhosis of the liver, subacute sclerosing panencephalitis) and / or immunosuppressive therapy, and Autoimmune diseases: e.g., inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes mellitus, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, colorectal inflammation (e.g., ulcerative colitis), skin diseases, chronic liver disease is selected from the group consisting of:

[0176] In a seventh aspect of the invention, the invention provides a compound as described above or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or pharma- ceutically acceptable ester of said compound, or a pharmaceutical composition as described above, or a compound as shown in Table A above, or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or pharma- ceutically acceptable ester of said compound, for use in the treatment and / or prevention of diseases associated with GPR132, or for hematopoietic stem cell transplantation, or for bone marrow transplantation.

[0177] In some embodiments, the disease associated with GPR132 is selected from the group consisting of a tumor, a metabolic disease, an immune-related disease, and neuropathic pain. In some embodiments, the tumor is selected from the group consisting of breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, liver cancer (e.g., primary liver cancer), intraspinal tumor, longitudinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia (e.g., acute myeloid leukemia), gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma, and glioma.

[0178] In some embodiments, the metabolic disease is selected from the group consisting of atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver or non-alcoholic steatohepatitis (NASH)), metabolic syndrome, type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia) and secondary complications of these diseases (e.g., diabetic complications such as retinopathy, neuropathy, nephropathy and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension and stroke).

[0179] In some embodiments, the immune related disease is characterized by: Secondary immunodeficiencies: secondary immunodeficiencies caused, for example, by infections (e.g. rubella, measles, leprosy, tuberculosis, cytomegalovirus infection, HIV infection, coccidioidomycosis infection), protein depletion (e.g. nephrotic syndrome, protein-losing gastroenteropathy), insufficient immunoglobulin synthesis, lymphopenia (e.g. lymphopenia caused by drugs and / or systemic infections), secondary immunodeficiencies caused by other diseases (e.g. diabetes, cirrhosis of the liver, subacute sclerosing panencephalitis) and / or immunosuppressive therapy, and Autoimmune diseases: e.g., inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes mellitus, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, colorectal inflammation (e.g., ulcerative colitis), skin diseases, chronic liver disease is selected from the group consisting of:

[0180] In an eighth aspect of the invention, the invention provides a method of treating and / or preventing a disease associated with GPR132, a method of performing a hematopoietic stem cell transplant, and a method of performing a bone marrow transplant, each of which independently comprises the step of administering to a subject an effective amount of the compound as described above or a stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, pharma-ceutically acceptable solvate or pharma-ceutically acceptable ester of the compound, or a pharmaceutical composition as described above, or a compound shown in Table A above, or a stereoisomer, prodrug, crystalline form, pharma-ceutically acceptable salt, pharma-ceutically acceptable solvate or pharma-ceutically acceptable ester of the compound.

[0181] In some embodiments, the disease associated with GPR132 is selected from the group consisting of a tumor, a metabolic disease, an immune-related disease, and neuropathic pain. In some embodiments, the tumor is selected from the group consisting of breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, liver cancer (e.g., primary liver cancer), intraspinal tumor, longitudinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia (e.g., acute myeloid leukemia), gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma, and glioma.

[0182] In some embodiments, the metabolic disease is selected from the group consisting of atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver or non-alcoholic steatohepatitis (NASH)), metabolic syndrome, type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia) and secondary complications of these diseases (e.g., diabetic complications such as retinopathy, neuropathy, nephropathy and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension and stroke).

[0183] In some embodiments, the immune related disease is characterized by: Secondary immunodeficiencies: secondary immunodeficiencies caused, for example, by infections (e.g. rubella, measles, leprosy, tuberculosis, cytomegalovirus infection, HIV infection, coccidioidomycosis infection), protein depletion (e.g. nephrotic syndrome, protein-losing gastroenteropathy), insufficient immunoglobulin synthesis, lymphopenia (e.g. lymphopenia caused by drugs and / or systemic infections), secondary immunodeficiencies caused by other diseases (e.g. diabetes, cirrhosis of the liver, subacute sclerosing panencephalitis) and / or immunosuppressive therapy, and Autoimmune diseases: e.g., inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes mellitus, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, colorectal inflammation (e.g., ulcerative colitis), skin diseases, chronic liver disease is selected from the group consisting of: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0184] A concrete model for implementing the invention It should be understood that the terminology used herein is intended to describe particular embodiments and is not intended to be limiting. Moreover, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.

[0185] In the present invention, unless otherwise expressly stated, the expression "each independently selected from" used in the present specification can mean that specific options represented by the same symbol or different symbols in different groups do not influence each other, or that specific options represented by the same symbol or different symbols in the same group do not influence each other.

[0186] The substituents of the compounds of the present invention are disclosed according to group types or ranges. In particular, the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, which are independently disclosed.

[0187] The term "alkyl" refers to branched and straight chain saturated aliphatic hydrocarbonyl groups, including those having the specified number of carbon atoms. For example, "C1-C6 alkyl" refers to C1, C2, C3, C4, C5 and C6. Furthermore, for example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", more preferably "C1-C3 alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., N-propyl, isopropyl), butyl (e.g., N-butyl, isobutyl, tert-butyl), pentyl (e.g., N-pentyl, isopentyl, neopentyl), and the like.

[0188] The term "alkylene" means

[0189] [ka]

[0190] and the like, refers to a divalent group obtained by removing one hydrogen atom from any of the above alkyl groups (for example, C1 to C6 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, etc.).

[0191] The term "alkoxy" refers to any of the above alkyl groups (eg, C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) linked to the remainder of the molecule via an oxygen atom (-O-).

[0192] The term "C1-C6 haloalkyl" includes monofluoromethyl, difluoroethyl, trifluoromethyl,

[0193] [ka]

[0194] It refers to a group obtained by replacing one or more hydrogen atoms in any of the above alkyl groups (for example, C1 to C6 alkyl, C1 to C4 alkyl, C1 to C3 alkyl, etc.) with halogen (preferably fluorine or chlorine).

[0195] The term "C2-C6 alkenyl" refers to any straight or branched group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, and the like.

[0196] The term "C2-C6 alkynyl" refers to any straight or branched group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, and the like.

[0197] Heteroatom refers to N, O or S. Halogen refers to fluorine, chlorine, bromine or iodine. The term "heteroaryl" refers to substituted and unsubstituted 5- or 6-membered aromatic monocyclic groups, 8-, 9- or 10-membered aromatic bicyclic groups, and 11- to 14-membered aromatic tricyclic groups, having at least one heteroatom (N, O, or S) in at least one ring, and the heteroatom-containing ring optionally further has 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. Among them, the substituted and unsubstituted 8-, 9- or 10-membered aromatic bicyclic groups, and 11- to 14-membered aromatic tricyclic groups, having at least one heteroatom (N, O, or S) in at least one ring, are "fused heteroaryls". In the case of bicyclic or tricyclic heteroaryl groups, the entire bicyclic or tricyclic structure is required to form an aromatic system. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring. One of ordinary skill in the art can appreciate that two adjacent atoms, preferably carbon atoms, are shared between each two rings in a fused ring system.

[0198] Specifically, a "5- to 10-membered heteroaryl" can be a 5- or 6-membered monocyclic heteroaryl group, or an 8-, 9-, or 10-membered bicyclic heteroaryl group.

[0199] Exemplary monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and the like.

[0200] Exemplary bicyclic heteroaryl groups include, but are not limited to, indolyl, 5-azaindolyl, pyrrolo[2,3-d]pyrimidinyl, 5,6-diazaindolyl, 6-azaindolyl, 7-azaindolyl, pyrazolo[3,4-b]pyridinyl, pyrrolo[2,3-c]pyridazinyl, thieno[2,3-d]imidazolyl, thieno[2,3-d]imidazolyl, pyrazolo[3,4-c]pyridinyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinolyl, isoquinolyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furopyridinyl, isoindolyl, and the like.

[0201] The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3- to 7-membered (preferably 4- to 7-membered, more preferably 5- to 6-membered) monocyclic, 7- to 11-membered bicyclic and 10- to 15-membered tricyclic groups, which may contain one or more double bonds but are not aromatic rings and at least one ring has at least one heteroatom (N, O or S). The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms, may be saturated or partially unsaturated, and are not aromatic rings. The heterocyclyl may be attached to any available nitrogen or carbon atom.

[0202] Exemplary monocyclic heterocyclyls include azacyclobutyl, oxacyclobutyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazacycloheptatrienyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, and the like.

[0203] Here, "saturated heterocyclyl" means that the heterocyclic ring defined above does not contain unsaturated bonds such as double bonds. For example, "5-6-membered saturated heterocyclyl" can be pyrrolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, preferably piperidinyl and piperazinyl, more preferably piperazinyl.

[0204] The term "substituted" means that one or more hydrogen atoms of the specified atom or group are replaced with a selected specified group, provided that the normal valence of the specified atom is not exceeded.

[0205] In the present invention, the expression "phenyl-(CH2) r - and 5-10 membered heteroaryl-(CH2) r -, phenyl and 5-10 membered heteroaryl are R a " may be substituted with 1 to 5 groups selected from the group consisting of phenyl and 5 to 10 membered heteroaryl, each independently means that the phenyl or 5 to 10 membered heteroaryl may be substituted or unsubstituted. Among them, "phenyl and 5 to 10 membered heteroaryl are each independently substituted with 1 to 5 groups selected from the group consisting of R a "is independently substituted with 1 to 5 groups selected from the group consisting of phenyl, a or a 5-10 membered heteroaryl is substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of R a In addition, phenyl or 5-10 membered heteroaryl is substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of R a When substituted with 2, 3, 4 or 5 groups selected from the group consisting of a The options may be the same or different. Other similar definitions can be understood by referring to the above content.

[0206] In the present invention, the expression "phenyl, naphthyl and 5-10 membered heteroaryl are each independently substituted by two adjacent groups, and the two adjacent groups and the carbon atoms to which they are respectively connected together form a 5-6 membered heterocyclic ring" means that the phenyl is substituted by two groups, the two groups are adjacent, and the two adjacent groups and the carbon atoms to which they are respectively connected together form a 5-6 membered heterocyclic ring, or the naphthyl is substituted by two groups, the two groups are adjacent, and the two adjacent groups and the carbon atoms to which they are respectively connected together form a 5-6 membered heterocyclic ring, or the 5-10 membered heteroaryl is substituted by two groups, the two groups are adjacent, and the two adjacent groups and the carbon atoms to which they are respectively connected together form a 5-6 membered heterocyclic ring. Specifically, the phenyl group is substituted by two adjacent groups, and the two adjacent groups and the carbon atoms to which they are each attached together form a 5- to 6-membered heterocyclic ring, and the 5- to 6-membered heterocyclic ring is

[0207] [ka]

[0208] and the group formed is

[0209] [ka]

[0210] and the dotted double bond

[0211] [ka]

[0212] represents the fusion site of the heterocyclic ring and the phenyl. Other similar definitions can be understood by reference to the above. From all of the above description, it will be apparent to one skilled in the art that any group whose name is a composite name, for example, "C1-C6 alkyl-OC(=O)-", should be referred to as being conventionally constructed from the moieties derived therefrom from left to right, where "C1-C6 alkyl" is as defined above. For example, "C1-C6 alkyl-OC(=O)-" means:

[0213] [ka]

[0214] Other similar complex groups can be understood by reference to the above. In the present invention, L 2 but,

[0215] [ka]

[0216] When p is 0, the skilled artisan can 2 The structural formula is

[0217] [ka]

[0218] It can be understood that. In the present invention, R 4’ But phenyl-(CH2) r -, 5-10 membered heteroaryl-(CH2) r -, and when r is 0, the skilled artisan can 4’ It can be understood that the aryl group is selected from the group consisting of phenyl and 5-10 membered heteroaryl. Other similar definitions can be understood by referring to the above content.

[0219] In the present invention, the structural formula shown in Formula I

[0220] [ka]

[0221] means that ring A is substituted with three substituents, and the three substituents are selected from the group consisting of R 0 , R 2 and

[0222] [ka]

[0223] and the substitution positions and arrangement order of the three substituents can be arbitrarily adjusted. For example, in some embodiments, ring A is

[0224] [ka]

[0225] then the structural formula shown in formula I is represented by formula I-1, i.e.

[0226] [ka]

[0227] As another example, in some embodiments, ring A can be:

[0228] [ka]

[0229] then the structural formula shown in formula I is represented by formula I-2, i.e.

[0230] [ka]

[0231] It could be. In the present invention, "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. The effect can be preventive, based on complete or partial prevention of the disease or its symptoms, and / or therapeutic, based on partial or complete stabilization or cure of the disease and / or side effects caused by the disease. As used herein, "treatment" includes any treatment for a disease in a patient, including: (a) preventing the disease or condition from occurring in a patient susceptible to the disease or condition but not yet diagnosed with the disease; (b) arresting the symptoms of the disease, i.e., preventing its onset; or (c) relieving the symptoms of the disease, i.e., causing the regression of the disease or condition.

[0232] In the present invention, "subject" refers to a vertebrate. In certain embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, poultry (e.g., cows), pets (e.g., cats, dogs and horses), primates, mice and rats. In certain embodiments, mammals refer to humans.

[0233] In the present invention, an "effective amount" refers to an amount effective at a dosage and time required to achieve a desired therapeutic or preventive effect. The "therapeutically effective amount" of a substance / molecule of the present invention may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule to exert a desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or harmful consequences. A "prophylactically effective amount" refers to an amount effective at a dosage and time required to achieve a desired preventive effect. Usually, a prophylactic dose is administered to a subject before the onset of disease or at an early stage of disease, so that the prophylactically effective amount is less than the therapeutically effective amount, but this is not necessarily the case. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce the size of a tumor; inhibit (i.e., slow down to a certain extent, preferably stop) the invasion of cancer cells into surrounding organs; prevent (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0234] The pharmaceutical composition of the present invention may contain a pharma- ceutically acceptable excipient, including, but not limited to, an ion exchanger, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycerol, sorbic acid, potassium sorbate), a mixture of partial glycerides of vegetable saturated fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, etc.), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, etc.

[0235] The pharmaceutical composition of the present invention can be prepared in various forms according to various routes of administration. For example, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, intravaginal administration, topical administration, parenteral administration (such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion), or by explanted reservoir. Of these, oral administration or intravenous administration is preferred.

[0236] The compounds of the present invention may optionally be used in combination with one or more other active ingredients, the individual dosages and ratios of which may be adjusted by those skilled in the art according to the particular symptoms, patient condition and clinical needs.

[0237] As used herein, unless otherwise specified, the term "prodrug" refers to a derivative that can undergo hydrolysis, oxidation, or other reactions under biological conditions (in vitro or in vivo) to produce the compounds of the present invention. Prodrugs only become active compounds under biological conditions upon reaction, or they have no activity or only low activity in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) pp. 172-178, pp. 949-982 (Manfred E. Wolff (ed.), 5th ed.).

[0238] When the stereoisomers in the compounds described herein are specifically indicated as (R)- or (S)-isomers in the chemical name, it is to be understood that the predominant configuration is the (R)-isomer or (S)-isomer, respectively. Any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.

[0239] "Solvate" and "solvent" are used interchangeably and refer to a compound that exists in combination with a solvent molecule. This combination may contain a stoichiometric amount of the solvent, for example, it may be a monohydrate or dihydrate, or it may contain any amount of water. For example, methanol or ethanol may form an "alcoholate", which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, i.e., a compound in a solvent of solution may be solvated, but is not a solvate as described by the term used herein.

[0240] As used herein, the term "pharmaceutically acceptable salt" refers to (i) a salt of an acidic functional group (e.g., -COOH) present in the compounds provided by the present invention, including, but not limited to, alkali metal salts such as sodium salts, potassium salts, lithium salts; alkaline earth metal salts such as calcium salts, magnesium salts; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts; inorganic base salts such as ammonium salts; tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)amino salts, and the like. and (ii) salts formed with a basic functional group (e.g., -NH2) present in the compounds provided by the present invention and a suitable inorganic or organic cation (base), including salts of organic bases such as methanesulfonate; and (ii) salts formed with a basic functional group (e.g., -NH2) present in the compounds provided by the present invention and a suitable inorganic or organic anion (acid), including, but not limited to, hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; salts of inorganic acids such as nitrate, perchlorate, sulfate, phosphate; salts of lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate; salts of arylsulfonates such as benzenesulfonate, p-toluenesulfonate; salts of organic acids such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, and the like; and salts of amino acids such as glycinate, trimethylglycinate, alginate, ornithine, glutamate, aspartate, and the like.

[0241] As used herein, the term "pharmaceutically acceptable ester" refers to an ester formed by -COOH present in the compound provided by the present invention and a suitable alcohol, or an ester formed by -OH present in the compound provided by the present invention and a suitable acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethylsuccinate, stearate or palmitate. Esters can undergo hydrolysis in the presence of acid or base to generate the corresponding acid or alcohol. In some embodiments, the ester formed by -COOH present in the compound provided by the present invention and a suitable alcohol is an ethyl carboxylate, i.e., "pharmaceutically acceptable ester" refers to an ethyl ester.

[0242] As used herein, the term "crystalline form" refers to the crystalline structure of a substance. When a substance crystallizes, it is affected by various factors that change the intramolecular or intermolecular bonding patterns, causing molecules or atoms to arrange differently in lattice space, forming different crystalline structures. The compounds of the present invention can exist in one crystalline structure or in multiple crystalline structures (i.e., the compounds have "polymorphism"). The compounds of the present invention can exist in different crystalline forms.

[0243] As used herein, the term "modulator" refers to a molecule that can directly or indirectly interact with a target.Modulators include, but are not limited to, agonists, partial agonists, inverse agonists and antagonists.In some embodiments of the present application, the modulator is an agonist.

[0244] As used herein, the term "agonist" refers to a molecule that binds to a specific receptor in cells and causes a response.Agonists can mimic the action of endogenous ligands (e.g., LPA, prostaglandins, hormones or neurotransmitters) that bind to the same receptor.

[0245] As used herein, the term "antagonist" refers to a molecule that weakens, inhibits or blocks the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists.

[0246] The present invention is further described below in conjunction with specific examples. Unless otherwise specified, the materials used in the following examples can be purchased commercially. Example 1 Step 1: Ethyl 2-(4-acetylamino-2-acetylphenoxy)acetate

[0247] [ka]

[0248] N-(3-acetyl-4-hydroxyphenyl)acetamide (1.01 g, 5.23 mmol), ethyl bromoacetate (1 mL, 8.98 mmol), potassium carbonate (1.33 g, 9.62 mmol) and potassium iodide (0.16 g, 0.97 mmol) were added to a pear-shaped bottle, acetone (30 mL) was added, and the mixture was heated to reflux at 60° C. and reacted for 2 hours. When TLC monitoring showed that the reaction was complete, an appropriate amount of water was added. The system was extracted three times with dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (DCM / MeOH=30:1) to give 1.32 g of a white solid in 90.4% yield.

[0249] Step 2: Ethyl 5-bromo-3-ethylquinoline-2-carboxylate

[0250] [ka]

[0251] Ethyl 2-(4-acetylamino-2-acetylphenoxy)acetate (1.32 g, 4.72 mmol), potassium carbonate (0.85 g, 6.15 mmol) and DMF (41 mL) were added to a pear-shaped bottle, heated to reflux at 140° C. and reacted for 1 h. When TLC monitoring showed the reaction was complete, a small amount of EA was added. The system was filtered through diatomaceous earth. Saturated sodium chloride solution was added to the filtrate and extracted three times with EA. The organic phases were combined and washed twice with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (DCM / MeOH=50:1) to give 0.78 g of a white solid in 63.6% yield.

[0252] Step 3: Ethyl 5-amino-3-methylbenzofuran-2-carboxylate

[0253] [ka]

[0254] Ethyl 5-acetylamino-3-methylbenzofuran-2-carboxylate (0.78 g, 2.79 mmol) was dissolved in ethanol (16 mL), 3N HCl (16 mL) was added, and the mixture was heated to reflux at 80° C. and reacted for 2 h. When TLC monitoring showed the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to 7-8. Extraction was performed three times using EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH=30:1) to give 0.44 g of a light yellow solid in 71.2% yield.

[0255] Step 4: Ethyl 3-methyl-5-((2-phenylethyl)sulfonyl)benzofuran-2-carboxylate

[0256] [ka]

[0257] Phenylpropionic acid (0.08 g, 0.53 mmol) was dissolved in DMF (2 mL) and HATU (0.26 g, 0.68 mmol) and DIPEA (0.1 mL) were added and stirred at room temperature for 10 min, then ethyl 5-amino-3-methylbenzofuran-2-carboxylate (0.10 g, 0.46 mmol) was added and stirred at room temperature for 1 h until TLC monitoring showed the reaction was complete. Saturated sodium chloride solution was added and extraction was performed twice using EA. The organic phases were combined and washed once with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (DCM / MeOH=100:1) to give 188 mg of light yellow solid in 95.4% yield. 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.96 (s, 1H), 7.38 - 7.13 (m, 7H), 4.43 (q, J = 7.2 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.70 (t, J = 7.6 Hz, 2H), 2.45 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 171.11, 150.53, 151.21, 141.60, 140.61, 133.54, 129.27, 128.59, 128.32, 126.35, 125.74, 121.50, 112.73, 112.11, 61.25, 39.05, 31.60, 14.38, 9.36. Example 2: Ethyl 5-cinnamamido-3-methylbenzofuran-2-carboxylate

[0258] [ka]

[0259] The preparation method was the same as that of Example 1, except that cinnamic acid was used instead of phenylpropionic acid, to obtain the title compound. 236 mg of bright white solid was obtained in 98.7% yield. 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.15 (s, 1H), 7.77 (d, J = 15.6 Hz, 1H), 7.52 - 7.18 (m, 7H), 6.76 (d, J = 15.6 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.87, 160.50, 151.30, 142.20, 141.61, 134.53, 133.84, 129.9 4, 129.37, 128.79, 127.87, 125.78, 121.62, 121.03, 112.84, 112.22, 61.25, 14.38, 9.32. Example 3: (E)-Ethyl 5-(3-(3-iodophenyl)acrylamide)-3-methylbenzofuran-2-carboxylate

[0260] [ka]

[0261] The preparation method was the same as that of Example 1, except that (E)-3-(3-iodophenyl)acrylic acid was used instead of phenylpropionic acid, to obtain the title compound. 120 mg of a white solid was obtained in 70.2% yield. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 7.72 - 7.58 (m, 2H), 7.47 - 7.36 (m, 3H), 7.06 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 15.5 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.51 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). Example 4: Ethyl 3-methyl-5-((1S,2R)-2-phenylcyclopropane-1-carboxamido)benzofuran-2-carboxylate

[0262] [ka]

[0263] The preparation method was the same as that of Example 1, except that (1S,2R)-2-phenylcyclopropane-1-carboxylic acid was used instead of phenylpropionic acid, to obtain the title compound. 151 mg of a white solid was obtained in 55.5% yield. 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.09 (s, 1H), 7.43 - 7.17 (m, 5H), 7.09 (d, J = 7.6 Hz, 2H), 4.43 (q, J = 7.2 Hz, 2H), 2.64 - 2.56 (m, 1H), 2.50 (s, 3H), 1.91 - 1.83 (m, 1H), 1.78 - 1.70 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.39 -1.30 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ170.70, 16 0.53, 151.15, 141.66, 140.43, 133.77, 129.41, 128.51, 126.44, 126.02, 121.05, 112.33, 112.23, 61.23, 27.42, 25.92, 16.45, 14.38, 9.39. Example 5: Ethyl 3-methyl-5-(4-oxo-4-phenylbutylamino)benzofuran-2-carboxylate

[0264] [ka]

[0265] The preparation method was the same as that of Example 1, except that 4-oxo-4-phenylbutyric acid was used instead of phenylpropionic acid, to obtain the title compound. 231 mg of a yellow solid was obtained in 91.3% yield. 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.01 (m, 3H), 7.66 - 7.26 (m, 5H), 4.54 - 4.38 (m, 2H), 3.59 - 3.41 (m, 2H), 2.98 - 2.82 (m, 2H), 2.48 (d, J = 12.0 Hz, 3H), 1.45 (m, 3H). 13 C NMR (101 MHz, CDCl3) δ 199.55, 170.69, 160.44, 151.05, 141.55, 136.33, 133.80, 133.55, 129.24, 128.69, 128.13, 125.76, 121.00, 112.11, 112.04, 61.14, 33.99, 31.13, 14.38, 9.34. Example 6: Ethyl 3-methyl-5-(5-phenylpentanamido)benzofuran-2-carboxylate

[0266] [ka]

[0267] The preparation method was the same as that of Example 1, except that 4-oxo-4-phenylbutyric acid was used instead of phenylpropionic acid, to obtain the title compound. 0.2 g of a white solid was obtained in 72.2% yield. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.42 - 7.04 (m, 7H), 4.43 (q, J = 7.2 Hz, 2H), 2.59 (dd, J = 13.2, 5.6 Hz, 2H), 2.50 - 2.35 (m, 5H), 1.86 - 1.60 (m, 4H), 1.43 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 172.35, 160.56, 151.17, 142.01, 141.55, 133.9 2, 129.21, 128.32, 125.81, 125.71, 121.71, 112.74, 112.00, 61.26, 37.16, 35.67, 31.05, 25.41, 14.39, 9.34. Example 7: Ethyl 3-methyl-5-(3-phenylpropoxy)benzofuran-2-carboxylate

[0268] [ka]

[0269] Ethyl 5-hydroxy-3-methylbenzofuran-2-carboxylate (189 mg, 0.86 mmol), triphenylphosphine (458 mg, 1.74 mmol), 3-phenylpropanol (175 mg, 1.29 mmol), and diisopropyl azodicarboxylate (347 mg, 1.72 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL) and reacted at room temperature under argon for 4 hours. After TLC monitoring showed that the reaction was complete, water (10 mL) was added and extraction was performed three times using ethyl acetate (30 mL). The organic phase was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The crude product was isolated by column chromatography (PE / EA=15 / 1 10 / 1) to give 0.15 g of a yellow solid in 54% yield. 11H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 9.0 Hz, 1H), 7.33 - 7.16 (m, 5H), 7.06 (dd, J = 9.0, 2.6 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 4.01 (t, J = 6.2 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.54 (s, 3H), 2.20 - 2.08 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 160.6, 155.7, 149.6, 141.7, 129.6, 128.7, 128.6, 126.1, 125.7, 118.1, 113.0, 103.4, 67.8, 61.2, 32.3, 31.0, 14.5, 9.6. HRMS(ESI)[M+H] + C 21 H 23 Calculated value for C19H19O4: 339.1596; Measured value: 339.1592.

[0270] Example 8 Step 1: Ethyl 3-methylbenzofuran-2-carboxylate

[0271]

Chemical Structure

[0272] 2-Hydroxyacetophenone (2.72 g, 20 mmol), ethyl bromoacetate (5.01 g, 30 mmol) and potassium carbonate (5.52 g, 40 mmol) were added to N,N-dimethylformamide (25 mL) and heated to 160° C. for 3 h. After TLC monitoring showed the reaction was complete, the reaction mixture was cooled to room temperature and the solid was obtained by filtration under reduced pressure. The filter cake was rinsed with ethyl acetate (25 mL) three times. The filtrates were combined and the solvent was removed by distillation under reduced pressure, water (100 mL) was added to the residue to dissolve, and it was extracted with ether (100 mL) three times. The organic phase was washed with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The crude product was separated by column chromatography (PE / EA=15 / 1-10 / 1) to give 1.54 g of white solid in 38% yield.

[0273] Step 2: Ethyl 3-methyl-5-(chlorosulfonyl)benzofuran-2-carboxylate

[0274] [ka]

[0275] Ethyl 3-methylbenzofuran-2-carboxylate (3.06 g, 15 mmol) was added to chloroform (45 mL) and stirred at 0° C. for 10 min, and chlorosulfonic acid (8.70 g, 75 mmol) in chloroform (45 mL) was added dropwise and stirred at room temperature for 4 h. After TLC monitoring showed the reaction was complete, the reaction solution was poured into ice water and extracted three times with dichloromethane (150 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and the crude product was recrystallized from petroleum ether / ethyl acetate to give 2.07 g of white solid in 46% yield.

[0276] Step 3: Ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate

[0277] [ka]

[0278] Ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate (2.07 g, 6.86 mmol) and potassium carbonate (1.89 g, 13.72 mmol) were dissolved in anhydrous dichloromethane (80 mL), and phenylethylamine (0.97 g, 8.23 ​​mmol) in anhydrous dichloromethane (20 mL) was added dropwise at room temperature and stirred at room temperature for 3 h. After TLC monitoring showed that the reaction was complete, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in water (100 mL) and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The crude product was separated by column chromatography (PE / EA=10 / 1-5 / 1) to give 2.33 g of white solid in 88% yield. 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 8.8, 1.9 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.25 - 7.13 (m, 3H), 7.10 - 6.99 (m, 2H), 4.77 (t, J = 6.2 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.24 (q, J = 6.9 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.59 (s, 3H), 1.45 (t, J = 7.1 Hz, 3 H). 13 C NMR (101 MHz, CDCl3) δ 159.9, 155.8, 143.0, 137.6, 135.2, 129.4, 128.7, 126.8, 126.2, 125.6, 121.6, 113.0, 61.6, 44.3, 35.8, 14.4, 9.4.HRMS(ESI)[M+H] + C 20 H 22Calculated NO5S: 388.1219; Measured: 388.1213.

[0279] Step 4: Ethyl 3-methyl-5-(N-benzyl-N-phenylethylsulfamoyl)benzofuran-2-carboxylate

[0280] [ka]

[0281] Ethyl 3-methyl-5-(N-phenylethylsulfamoyl)benzofuran-2-carboxylate (195 mg, 0.5 mmol), benzyl bromide (171 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) were dissolved in anhydrous dichloromethane (10 mL) and stirred at 60° C. overnight. After TLC monitoring showed the reaction was complete, the solvent was removed by distillation under reduced pressure. The residue was dissolved in water (20 mL) and extracted three times with dichloromethane (20 mL). The organic phase was washed with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The crude product was separated by column chromatography (PE / EA=20 / 1-2 / 1) to give 229 mg of white solid in 96% yield. 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.5 Hz, 1H), 7.87 (dd, J = 8.8, 1.7 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.39 - 7.23 (m, 5H), 7.22 - 7.09 (m, 3H), 6.95 (d, J = 6.8 Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.40 (s, 2H), 3.45 - 3.28 (m, 2H), 2.71 - 2.62 (m, 2H), 2.60 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.9, 155.8, 143.0, 138.3, 136.0, 135.6, 129.4, 128.7, 128.7, 128.5, 128.5, 128.0, 126.5, 126.2, 125.6, 121.5, 113.1, 61.6, 52.2, 49.5, 35.3, 14.4, 9.4.HRMS(ESI)[M+H] + C 27 H 28 Calculated NO5S: 478.1688; Measured: 478.1680.

[0282] Example 9: Ethyl 3-methyl-5-(N-(4-bromobenzyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylate

[0283] [ka]

[0284] The preparation method was the same as in Example 8, except that 4-bromobenzyl bromide was used instead of benzyl bromide, to obtain the title compound. 193 mg of a white solid was obtained in 70% yield. 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.8, 1.9 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.17 (dd, J = 1 7.6, 7.7 Hz, 5H), 6.96 (d, J = 6.5 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 3.48 - 3.30 (m, 2H), 2.70 - 2.64 (m, 2H), 2.62 (s, 3H), 1.47 (t, J = 7.1Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.8, 155.8, 143.0, 138.1, 135.3, 135.2, 131.8, 130.0, 129.4, 128.6, 128.5, 126.6, 126.2, 125.5, 121.9, 121.5, 113.1, 61.6, 51.6, 49.6, 35.2, 14.4, 9.4. Example 10: Ethyl 3-methyl-5-(N-(4-(tert-butyloxycarbonyl)benzyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylate

[0285] [ka]

[0286] The title compound was prepared in the same manner as in Example 8, except that 4-(tert-butyloxycarbonyl)benzyl bromide was used instead of benzyl bromide. 273 mg of a white solid was obtained in 94% yield. 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.87 (dd, J = 8.8, 1.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8 (s, 9H), 1.45 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.3, 159.8, 155.8, 143.0, 140.8, 138.1, 135.3, 131.7, 129.7, 129.4, 128.6, 128.5, 128.1, 126.5, 126.2, 125.5, 121.5, 113.1, 81.1, 61.5, 51.9, 49.8, 35.2, 28.2, 14.4, 9.4. Example 11: Ethyl 3-methyl-5-(N-(quinolin-8-ylmethyl)-N-phenethylsulfamoyl)benzofuran-2-carboxylate

[0287] [ka]

[0288] The preparation method was the same as in Example 8, except that 8-(bromomethyl)quinoline was used instead of benzyl bromide, to obtain the title compound. 222 mg of a white solid was obtained in 84% yield. 1 H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.6 Hz, 1H), 8.19 - 8.07 (m, 2H), 7.95 (d, J = 7.1 Hz, 1H), 7.88 (d, J = 10.3 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1 H), 7.61 - 7.47 (m, 2H), 7.36 (dd, J = 8.2, 4.2 Hz, 1H), 7.11 (dq, J = 14.2, 7.0 Hz, 3H), 6.94 (d, J = 7.0 Hz, 2H), 5.22 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.71 - 3.50 (m, 2H), 2.91 - 2.66 (m, 2H), 2.56 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.9, 155.6, 149.5, δ 146. 2, 142.8, 138.4, 136.4, 135.7, 134.8, 129.7, 129.2, 128.7, 128.4, 128.1, 127.7, 126.5, 126.3, 126.3, 125.6, 121.4, 121.2, 11 2.8, 61.5, 50.8, 47.5, 35.3, 14.4, 9.4.HRMS(ESI)[M+H] + C 30 H 29 Calculated for N2O5S: 529.1797; Measured: 529.1790.

[0289] Example 12: Ethyl 3-methyl-5-(N-phenyl-N-phenethylsulfamoyl)benzofuran-2-carboxylate

[0290] [ka]

[0291] Ethyl 3-methyl-5-(chlorosulfonyl)benzofuran-2-carboxylate (91 mg, 0.3 mmol), N-phenethylaniline (59 mg, 0.3 mmol) and potassium carbonate (46 mg, 0.33 mmol) were dissolved in anhydrous dichloromethane (10 mL) and stirred at 60° C. overnight. After TLC monitoring showed the reaction was complete, the solvent was removed by distillation under reduced pressure. The residue was dissolved in water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phase was washed with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The crude product was separated by column chromatography (PE / EA=10 / 1-5 / 1) to give 90 mg of a yellow solid in 65% yield. 1 H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.39 - 7.31 (m, 3H), 7.30 - 7.24 (m, 2H), 7.23 - 7.1 8 (m, 1H), 7.17 - 7.10 (m, 2H), 7.09 - 7.00 (m, 2H), 4.48 (q, J = 7.1 Hz, 2H), 3.90 - 3.77 (m, 2H), 2.89 - 2.76 (m, 2H), 2.54 (s, 3H), 1.4 6 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.9, 155.9, 142.9, 139.0, 138.0, 133.6, 129.2, 128.9, 128.8, 128.5, 128.2, 126.8, 126.6, 125. 6, 122.0, 112.6, 61.5, 52.2, 35.2, 14.4, 9.3.HRMS(ESI)[M+H] + C 26 H 26 Calculated NO5S: 464.1532; Measured: 464.1525.

[0292] Example 13: Ethyl 3-methyl-5-(N,N-diphenylethylaminosulfonyl)benzofuran-2-carboxylate

[0293] [ka]

[0294] The preparation method was the same as that of Example 12, except that diphenylethylamine was used instead of N-phenylethylaniline, to obtain the title compound. 112 mg of white oil was obtained in 76% yield. 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.29 (t, J = 7.2 Hz, 4H), 7.22 (t, J = 7.3 Hz, 2H), 7.1 6 (d, J = 7.0 Hz, 4H), 4.49 (q, J = 7.1 Hz, 2H), 3.56 - 3.40 (m, 4H), 2.96 - 2.82 (m, 4H), 2.63 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR MHz, CDCl3) δ 159.9, 155.7, 142.9, 138.4, 135.4, 129.4, 128.8, 128.6, 126.6, 126.3, 125.6, 121.5, 113.0, 61.6, 50.0, 35.6, 14.4, 9.4.HRMS(ESI)[M+H] + C 28 H 30 Calculated NO5S: 492.1845; Measured: 492.1836.

[0295] Example 14 Step 1: 4-(4-(methylsulfonyl)piperazin-1-yl)-N-phenylethylaniline

[0296] [ka]

[0297] 4-(4-(methylsulfonyl)piperazin-1-yl)aniline (0.46 g, 1.8 mmol), 2-iodoethylbenzene (0.28 g, 1.2 mmol) and potassium carbonate (0.25 g, 2.7 mmol) were dissolved in acetonitrile (8 mL) and heated to 60° C. for 24 hours. After TLC monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. The solvent was removed by distillation under reduced pressure. Water (10 mL) was added to the residue and extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The crude product was separated by column chromatography to give 155 mg of a yellow solid in 36% yield. 1 H NMR (400 MHz, CDCl3) δ 7.26 (dt, J = 35.0, 7.5 Hz, 5H), 6.83 (d, J = 7.5 Hz, 2H), 6.57 (d, J = 8.3 Hz, 2H), 3.54 - 3.23 (m, 7H), 3.09 (s, 4H), 2.88 (t, J = 6.9 Hz, 2H), 2.79 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.4, 142.8, 139.4, 128.8, 128.6, 126.5, 119.7, 114.0, 51.1, 46.1, 4 5.7, 35.6, 34.2. Step 2: Ethyl 3-methyl-5-(N-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylate

[0298] [ka]

[0299] The preparation method was the same as that of Example 12, except that diphenylethylamine was used instead of N-phenylethylaniline, to obtain the title compound. 275 mg of yellow oil was obtained in 87% yield. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 8.8, 1.9 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 7.2 Hz, 2H), 7.13 (dd, J = 8.6, 5.9 Hz, 1H), 7.07 (d, J = 6.9 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.79 - 3.69 (m, 2H), 3.39 - 3.31 (m, 4H), 3.30 - 3.22 (m, 4H), 2.80 (s, 3H), 2.77 - 2.68 (m, 2H), 2.50 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.8, 15 5.8, 150.2, 142.8, 138.1, 133.8, 130.9, 129.9, 129.1, 128.8, 128.5, 126.9, 126.5, 125.5, 122.0, 116.6, 112.6, 61.5, 52.2, 48.7, 45.7, 35.0, 34.5, 14.4, 9.4. Example 15 Step 1: N-phenethyl-4-phenoxyaniline

[0300] [ka]

[0301] Phenylacetaldehyde (0.06 g, 0.5 mmol), 4-aminodiphenyl ether (0.09 g, 0.5 mmol) and trimethyl orthoformate (85 mg, 0.8 mmol) were dissolved in methanol (10 mL) and stirred at 0° C. Sodium cyanoborohydride (0.04 g, 0.6 mmol) was added in small portions and reacted at room temperature for 10 hours. After TLC monitoring showed the reaction was complete, the solvent was removed by distillation under reduced pressure. Water (10 mL) was added to the residue and extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The crude product was separated by column chromatography to give 140 mg of a yellow solid in 65% yield.

[0302] Step 2: Ethyl 3-methyl-5-(N-(4-phenoxyphenyl)-N-phenethylsulfamoyl)benzofuran-2-carboxylate

[0303] [ka]

[0304] The preparation method was the same as in Example 12, except that N-phenethyl-4-phenoxyaniline was used instead of N-phenethylaniline, to obtain the title compound. 123 mg of a white solid was obtained in 44% yield. 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 8.8, 1.9 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.18 (dt, J = 22.1, 7.0 Hz, 4H), 7.07 (t, J = 7.8 Hz, 2H), 7.02 - 6.97 (m, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.49 (q, J = 7.1Hz, 2H), 3.93 - 3.65 (m, 2H), 2.94 - 2.79 (m, 2H), 2.57 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.9, 157.3, 156.3, 155.9, 142.9, 1 38.0, 133.6, 133.6, 130.4, 129.9, 129.2, 128.8, 128.5, 126.8, 126.6, 125.6, 124.1, 122.0, 119.5, 118.6, 112.7, 61.6, 52.3, 35.2, 14.4, 9.3. Example 16: 3-Methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylic acid (GPR132-A-1)

[0305] [ka]

[0306] Ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate (0.19 g, 0.53 mmol) was dissolved in ethanol (8 mL), sodium hydroxide solution (0.11 g, 2.67 mmol, dissolved in 2 mL of water) was added, and the mixture was heated to reflux and reacted for 2 hours. After the reaction was completed, the ethanol was removed by concentration. After adding an appropriate amount of water to dilute, 3N HCl was added to adjust the pH to 2-3, and a large amount of white solid was precipitated. After filtration, the filter cake was washed with distilled water and dried, and 148.7 mg of light yellow solid was obtained with a yield of 85.9%. 1 H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.06 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.34 - 7.24 (m, 4H), 7.22 - 7.15 (m, 1H), 2.93 (t, J = 8.0 Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H), 2.49 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 170.81, 161.51, 150.27, 142.28, 141.64, 1 35.52, 129.12, 128.81, 128.71, 126.42, 124.84, 120.96, 112.41, 111.10, 38.35, 31.30, 9.58.HRMS(ESI)[MH] - C 19 H 16 Calculated NO4S: 322.1085; Measured: 322.1078.

[0307] Example 17: 5-Cinnamylamino-3-methylbenzofuran-2-carboxylic acid (GPR132-A-2)

[0308] [ka]

[0309] The preparation method was the same as that of Example 16, except that ethyl 5-cinnamylamino-3-methylbenzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to obtain the title compound. The obtained product was a bright yellow solid (155 mg) with a yield of 71.4%. 1 H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.37 (s, 1H), 8.23 ​​(d, J = 2.0 Hz, 1H), 7.69 - 7.61 (m, 4H), 7.60 (d, J = 5.6 Hz, 1H), 7.49 - 7.37 (m, 3H), 6.86 (d, J = 15.6 Hz, 1H), 2.52 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.98, 161.52, 150.46, 142.44, 140.59, 135.56, 135.17, 130.27, 129.51, 129.25, 128.20, 124.82, 122.68, 121.04, 112.57, 111.31, 9.61.HRMS(ESI)[MH] - C 19 H 14 Calculated NO4S: 320.0928; Measured: 320.0920.

[0310] Example 18: (E)-5-(3-(3-iodophenyl)acrylamide)-3-methylbenzofuran-2-carboxylic acid (GPR132-A-3)

[0311] [ka]

[0312] The preparation method was the same as that of Example 16, except that ethyl (E)-5-(3-(3-iodophenyl)acrylamido)-3-methylbenzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to obtain the title compound. 94 mg of a white solid was obtained in 83.2% yield. 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 10.34 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.82 - 7.44 (m, 5H), 7.22 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 2.50 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ163.60, 161.48, 150.48, 142.37, 138.80, 138.54, 137.61, 136.43, 135.45, 13 1.48, 129.23, 127.44, 124.86, 124.14, 120.98, 112.55, 111.27, 95.90, 9.59. Example 19: 3-Methyl-5-((1S,2R)-2-phenylcyclopropane-1-carboxamido)benzofuran-2-carboxylic acid (GPR132-A-4)

[0313] [ka]

[0314] The preparation method was the same as that of Example 16, except that ethyl (E)-5-(3-(3-iodophenyl)acrylamido)-3-methylbenzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to obtain the title compound. 121 mg of a white solid was obtained in 87.0% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.45 - 7.40 (m, 2H), 7.34 - 7.26 (m, 2H), 7.24 - 7.1 5 (m, 3H), 2.49 (s, 3H), 2.43 - 2.35 (m, 1H), 2.12 - 2.05 (m, 1H), 1.55 - 1.48 (m, 1H), 1.42 - 1.35 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 170.30, 161.53, 150.27, 142.38, 141.26, 135.57, 129.19, 128.83, 126.58, 126.37, 124.80, 120.77, 112.44, 111.00, 27.18, 25.35, 16.05, 9.55.HRMS(ESI)[MH] - C 20 H 16 Calculated NO4: 334.1085; Measured: 334.1083.

[0315] Example 20: 3-Methyl-5-(4-oxo-4-phenylbutylamino)benzofuran-2-carboxylic acid (GPR132-A-5)

[0316] [ka]

[0317] The preparation method was the same as in Example 16, except that ethyl 3-methyl-5-(4-oxo-4-phenylbutylamino)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to give the title compound. 38 mg of a white solid was obtained in 70.5% yield. 1H NMR (400 MHz, DMSO-d6) δ 13.39 (s, 1H), 10.20 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.05 - 7.98 (m, 2H), 7.68 - 7.62 (m, 1H), 7.60 - 7.51 (m, 4H), 3.37 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 199.31, 170.78, 161.50, 150.20, 142.24, 137.01, 135.69, 133.66, 129.20, 129.12, 128.34, 124.88, 120.82, 112.41, 110.86, 33.58, 30.66, 9.55. Example 21: 3-Methyl-5-(5-phenylvaleramido)benzofuran-2-carboxylic acid (GPR132-A-6)

[0318] [ka]

[0319] The preparation method was the same as that of Example 16, except that ethyl 3-methyl-5-(4-oxo-4-phenylbutylamino)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to obtain the title compound. 199 mg of a white solid was obtained in 99% yield. 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 10.01 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.8, 2.0 Hz, 1H), 7.3 0 - 7.23 (m, 2H), 7.21 - 7.12 (m, 3H), 2.60 (t, J = 7.2 Hz, 2H), 2.49 (s, 3H), 2.35 (d, J = 7.2 Hz, 2H), 1.67 - 1.57 (m, 4H). 13 C NMR (101 MHz, DM SO-d6) δ 171.58, 161.51, 150.26, 142.52, 142.28, 135.62, 129.12, 128.74, 128.70, 126.11, 124.84, 120.95, 112.33, 111.08, 36.68, 35.40, 31.11, 25.29, 9.56.HRMS(ESI)[MH] - C 21 H 20 Calculated NO4: 350.1398; Measured: 350.1390.

[0320] Example 22: 3-Methyl-5-(3-phenylpropoxy)benzofuran-2-carboxylic acid (GPR132-A-7)

[0321] [ka]

[0322] The preparation method was the same as that of Example 16, except that ethyl 3-methyl-5-(3-phenylpropyloxy)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to obtain the title compound. 111 mg of a white solid was obtained in 87% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 9.0 Hz, 1H), 7.34 - 7.15 (m, 6H), 7.11 (dd, J = 9.0, 2.6 Hz, 1H), 4.03 (t, J = 6.3 Hz, 2H), 2.81 - 2.73 (m, 2H), 2.50 (s, 3H), 2.10 - 2.01 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.1, 155.1, 148.5, 142.0, 141.4, 129.3, 128.4, 125.8, 124.4, 117.6, 112.6, 103.7, 67.4, 31.5, 30.4, 9.2.HRMS(ESI)[MH] - C 21 H 23 Calculated O4: 339.1596; Measured: 339.1592.

[0323] Example 23: 3-Methyl-5-(N-benzyl-N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-14)

[0324] [ka]

[0325] The preparation method was the same as that of Example 16, except that ethyl 3-methyl-5-(N-benzyl-N-phenylethylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to obtain the title compound. 75 mg of a white solid was obtained in 84% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 16.2, 3.9 Hz, 5H), 7.24 - 7.05 (m, 3H) , 6.97 (d, J = 7.1 Hz, 2H), 4.43 (s, 2H), 3.41 - 3.20 (m, 2H), 2.58 (s, 3H), 2.56 - 2.51 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.3, δ 155.5, 1 44.2, 138.7, 137.3, 135.3, 129.7, 129.0, 128.9, 128.8, 128.8, 128.1, 126.7, 126.5, 124.8, 122.0, 113.5, 51.8, 49.8, 34.8, 9.6.HRMS(ESI)[MH] - C 25 H 24 Calculated NO5S: 450.1375; Measured: 450.1378.

[0326] Example 24: 3-Methyl-5-(N-(4-bromobenzyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-9)

[0327] [ka]

[0328] The preparation method was the same as in Example 16, except that ethyl 3-methyl-5-(N-(4-bromobenzyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to give the title compound. 227 mg of a white solid was obtained in 85% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.93 - 7.69 (m, 2H), 7.42 (dd, J = 89.8, 8.2 Hz, 4H), 7.23 - 7.10 (m, 3H), 7.00 (d, J = 7.2 Hz, 2H), 4.39 (s, 2H), 3.39 - 3.27 (m, 2H), 2.56 (s, 5H). 13 C NMR (101 MHz, DMSO-d6) δ 162.0, 154.6, 148.2, 138.2, 136.7, 133.8, 131.3, 130.4, 130.0, 128.5, 128.3, 126.3, 124.7, 120.7, 120.7, 119.7, 112.6, 50.8, 49.6, 34.3, 9.1.HRMS(ESI)[MH] - C 25 H 21 Calculated for BrNO5S: 526.0329; Found: 506.0323.

[0329] Example 25: 3-Methyl-5-(N-(4-(tert-butyloxycarbonyl)benzyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-10)

[0330] [ka]

[0331] The preparation method was the same as in Example 16, except that ethyl 3-methyl-5-(N-(4-(tert-butyloxycarbonyl)benzyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to give the title compound. 200 mg of a white solid was obtained in 77% yield. 1H NMR (400 MHz, DMSO-d6) δ 13.61 (s, 1H), 8.21 (s, 1H), 7.88 (dd, J = 47.6, 7.6 Hz, 4H), 7.42 (d, J = 8.1 Hz, 2H), 7.15 (dt, J = 16.9, 7.1 Hz, 3H), 7.01 (d, J = 6.2 Hz, 2H), 4.50 (s, 2H), 3.37 (s, 2H), 2.58 (d, J = 19.8 Hz, 5H), 1.52 (s, 9H). 13 C NMR (101 MHz, DMSO) δ 165.1, 161.1, 155.5, 143.8, 142.5, 138.6, 135.2, 131.0, 129.9, 129.5, 129.0, 128.7, 128.6, 126.7, 126.6, 125.1, 122.0, 113.5, 81.1, 51.6, 50.3, 34.9, 28.2, 9.5.HRMS(ESI)[MH] - C 30 H 30 Calculated NO7S: 548.1748; Measured: 548.1738.

[0332] Example 26: 3-Methyl-5-(N-(quinolin-8-ylmethyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-11)

[0333] [ka]

[0334] The preparation method was the same as in Example 16, except that ethyl 3-methyl-5-(N-(4-(tert-butyloxycarbonyl)benzyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to give the title compound. 103 mg of a white solid was obtained in 99% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.36 (d, J = 7.9 Hz, 1H), 8.20 (s, 1H), 7.91 (t, J = 9.1 Hz, 2H), 7.80 (d, J = 5.6 Hz, 2H), 7.68 - 7.48 (m, 2H), 7.12 (dd, J = 15.3, 6.9 Hz, 3H), 6.95 (d, J = 7.0 Hz, 2H), 5.10 (s, 2H), 3.60 - 3.38 (m, 2H), 2.73 - 2.60 (m, 2H), 2.54 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 161.1, 155.4, 150.2, 145.8, 143.6, 138.7, 137.2, 135.4, 135.0, 129.8, 129.4, 129.0, 128.7, 128.2, 126.8, 126.7, 125.2, 122.0, 121.9, 113.4, 50.8, 47.7, 35.1, 9.5.HRMS(ESI)[MH] - C 28 H 23 Calculated for N2O5S: 499.1328; Measured: 499.1321.

[0335] Example 27: 3-Methyl-5-(N-phenethyl-N-phenylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-12)

[0336] [ka]

[0337] The preparation method was the same as in Example 16, except that ethyl 3-methyl-5-(N-phenethyl-N-phenylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to give the title compound. 50 mg of a white solid was obtained in 76% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 6.8 Hz, 3H), 7.21 (dt, J = 27.5, 7.2 Hz, 3H), 7.12 (d, J = 7.1 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H), 3.82 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 154.9, 139.2, 138.7, 132.2, 130.6, 129.4, 129.2, 129.0, 128.7, 128.3, 126.8, 124.9, 121.0, 112.5, 51.5, 34.6, 9.4.HRMS(ESI)[MH] - C 24 H 20 Calculated NO5S: 434.1062; Measured: 434.1054.

[0338] Example 28: 3-Methyl-5-(N,N-diphenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-15)

[0339] [ka]

[0340] The preparation method was the same as in Example 16, except that ethyl 3-methyl-5-(N,N-diphenylethylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to give the title compound. 54 mg of a white solid was obtained in 78% yield. 1H NMR (400 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.25 (s, 1H), 7.96 - 7.86 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.32 - 7.22 (m, 4H), 7.18 (d, J = 7.4 Hz, 6H), 3.49 - 3.29 (m, 4H), 2.86 - 2.66 (m, 4H), 2.58 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 161.2, 155.5, 143.8, 139.0, 135.3, 129.6, 129.2, 128.8, 126.8, 126.6, 125.2, 121.8, 113.5, 49.8, 35.2, 9.6.HRMS(ESI)[MH] - C 26 H 24 Calculated NO5S: 462.1375; Measured: 462.1377.

[0341] Example 29: 3-Methyl-5-(N-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-13)

[0342] [ka]

[0343] The preparation method was the same as that of Example 16, except that ethyl 3-methyl-5-(N,N-diphenylethylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to obtain the title compound. 126 mg of a white solid was obtained in 99% yield. H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 1.9 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.46 (dd, J = 8.7, 1.9 Hz, 1H), 7.26 (dd, J = 8.0, 6.5 Hz, 2H), 7.22 - 7.10 (m, 3H), 6.96 - 6.82 (m, 4H), 3.75 (t, J = 7.3 Hz, 2H), 3.25 (q, J = 5.7 Hz, 8H), 2.93 (s, 3H), 2.63 (t, J = 7.3 Hz, 2H), 2.46 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.7, 154.9, 150.1, 138.8, 132.5, 130.5, 130.2, 129.8, 129.2, 128.7, 126.7, 125.0, 121.1, 118.3, 116.1, 112.5, 51.7, 48.0, 45.7, 34.6, 34.4, 9.5.HRMS(ESI)[MH] - C 29 H 30 Calculated for N3O7S2: 596.1525; Found: 596.1525.

[0344] Example 30: 3-Methyl-5-(N-(4-phenoxyphenyl)-N-phenylethylsulfamoyl)benzofuran-2-carboxylic acid (GPR132-A-16)

[0345] [ka]

[0346] The preparation method was the same as in Example 16, except that ethyl 3-methyl-5-(N,N-diphenylethylsulfamoyl)benzofuran-2-carboxylate was used instead of ethyl 3-methyl-5-(3-phenylpropylamino)benzofuran-2-carboxylate, to give the title compound. 85 mg of a white solid was obtained in 81% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 1.9 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 8.7, 1.9 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.25 (t, J = 7. 1 Hz, 2H), 7.22 - 7.11 (m, 4H), 7.07 - 6.99 (m, 4H), 6.97 - 6.91 (m, 2H), 3.81 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.51 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.0, 156.7, 156.6, 155.3, 138.7, 134.1, 132.6, 130.8, 130.6, 130.0, 129.2, 128.7, 126.7, 126.0, 124.3, 121.7, 119.4, 119.1, 112.9, 51.6, 34.6, 9.4.HRMS(ESI)[MH] - C 30 H 24 Calculated NO6S: 526.1324; Measured: 526.1316.

[0347] [Table 4-1]

[0348] [Table 4-2]

[0349] [Table 4-3]

[0350] [Table 4-4]

[0351] [Table 4-5]

[0352] [Table 4-6]

[0353] [Table 4-7]

[0354] [Table 4-8]

[0355] The above compounds can be prepared by reference to the above methods. Biological activity testing 1.1 G protein activation Gi BRET probes were generated according to previous literature (Olsen et al., 2020) and included Gαi-RLuc8, Gβ3 and Gγ9-GFP2. HEK293 cells were transiently transfected with GPR132 and Gi BRET probes. 24 hours after transfection, cells were plated in 96-well microplates at 5 × 10 per well. 4 The cells were then washed twice with Tyrode's buffer and incubated at various concentrations (10 -12 ~10 -5The cells were stimulated with compound ligand (M) for 2 min. After addition of the luciferase substrate coelenterazine 400a (5 μM), the BRET signal was measured using a Mithras LB940 microplate reader equipped with a BRET filter set. The BRET signal was calculated as the ratio of emitted light at 510 nm / 400 nm.

[0356] In the above experiment, the lower EC 50 Compounds having a value had good GPR132 agonist activity. 1.2 Cell culture and subculture Human embryonic kidney cell line HEK293A was subcultured in MEM medium containing penicillin (final concentration 100 U / mL), streptomycin (final concentration 100 μg / mL) and 10% FBS and incubated at a constant temperature of 37°C in a humidified atmosphere containing 95% air and 5% carbon dioxide. When the cells were 90% confluent, the old medium was discarded and the cells were washed twice with 2 mL of PBS. After discarding the PBS, 2 mL of a mixed digestion solution of 0.25% trypsin-0.25% EDTA was added and the cells were observed under a microscope. When the cells became round, 2 mL of complete medium was quickly added to stop the digestion, and the cells were harvested by gently pipetting and centrifuged at 800 rpm and 4°C for 5 minutes. The supernatant was discarded. The cells were resuspended in complete medium and cultured in bottles, and the medium was changed every other day.

[0357] Human liver cancer cell line HepG2 was subcultured in DMEM medium containing penicillin (final concentration 100 U / mL), streptomycin (final concentration 100 μg / mL) and 10% FBS, and the remaining procedures were the same as those for HEK293A subculture.

[0358] 1.3 Cell proliferation inhibition experiment The inhibitory ability of compounds on cell proliferation was determined by MTT method. HepG2 and HEK293 cells were seeded in 96-well plates at a density of 30%. After 18 h of incubation, the cells were allowed to attach to the wall, the original culture medium was removed, and the compounds to be tested with a given concentration were added to each well. An equal amount of DMSO was added to the control group. Triplicate wells were set up for each compound. 48 h after drug administration, cell viability was determined by MTT method. The blank group was a well without cells. Then, OD readings were taken at 490 nm using a microplate reader. The calculation formula for cell viability was Cell Viability (%) = (OD 試験品 -OD ブランク ) / (OD 対照 -OD ブランク ) × 100.

[0359] In the above experiments, compounds with high viability and high CC50 value against HEK293 cells had good safety. Compounds with high inhibition rate and low EC50 value against HepG2 cells had good safety. 50 Compounds having this value were able to successfully inhibit the proliferation of tumor cells. 1.4 Determination of the level of tumor necrosis factor (TNF-α) as a marker of cellular inflammation HepG2 cells were seeded in a 96-well plate at a density of 30%. After 18 hours of incubation to allow the cells to adhere to the wall, the original culture medium was removed, and LPS culture medium (LPS concentration was 1 μg / mL) was added to each well of the drug group, and an equal amount of DMSO was added to the control group, and incubation was performed overnight. Then, the original culture medium was removed, the compound to be tested with a given concentration was added, and an equal amount of DMSO was added to the control group. Triplicate wells were set up for each compound. 48 hours after drug administration, the cell supernatant was collected in a sterile tube and centrifuged (2000-3000 rpm) for about 20 minutes. The supernatant was carefully collected. Then, the TNF-α level was determined using ELISA method. The specific steps were as follows: Addition of standards: Standard wells and sample wells were set up, and 50 μL of standards with various concentrations were added to each standard well.

[0360] · Sample addition: Blank wells (no sample and ELISA reagents were added to the blank control wells, the rest of the procedure was the same) and test sample wells were set up. First, 40 μL of sample dilution solution was added to each test sample well of the ELISA plate, then 10 μL of the sample to be tested (the final dilution ratio of the sample was 5) was added. The samples were added to the bottom of the ELISA plate wells, avoiding touching the well walls as much as possible, and then gently shaken to mix.

[0361] Enzyme addition: 100 μL of ELISA reagent was added to each well except the blank well. Incubation: The plate was sealed with sealing film and incubated at 37°C for 60 minutes.

[0362] Solution preparation: The 20x concentrated cleaning solution was diluted 20x with distilled water for further use. Washing: Carefully remove the sealing film, discard the liquid, and spin dry the plate. Fill each well with washing solution, leave for 30 seconds, then discard the washing solution. Repeat this process 5 times and pat dry.

[0363] Color development: First, 50 μL of color developer A was added to each well, then 50 μL of color developer B was added, mixed by gentle shaking, and color development was carried out in the dark at 37°C for 15 minutes. Stop: Add 50 μL of stop solution to each well to stop the reaction (blue color immediately turns to yellow).

[0364] Determination: The blank wells were set to zero and the absorbance (OD value) of each well was measured at 450 nm in sequence. Determination should be performed within 15 minutes after adding the stop solution. The TNF-α content in the samples to be tested could be calculated by drawing a standard curve based on the standard sample. The TNF-α reduction rate was further calculated. The formula for calculating the TNF-α reduction rate is: Reduction rate (%) = TNF-α content 対照 -TNF-α content試験品 / TNF-α content 対照 The value was ×100.

[0365] In the above experiment, high TNF-α reduction rate and low EC 50 Compounds with higher values ​​were better able to reduce the level of inflammation. 1.5 Determination of cell TC / TG Cell TC / TG was determined using Nanjing Jiancheng TG test kit and TC test kit. HepG2 cells were incubated with 0.5 mmol / L FFA (2:1 mixed oleate and palmitate) and vehicle or compounds at various concentrations (20 μM, 40 μM, 80 μM) for 24 h. The culture medium was discarded and cells were washed once with 0.01 M PBS (pH 7.4). Cells were scraped off with a cell scraper and 2-5 mL of 0.01 M PBS (pH 7.4) was added. The cell suspension was collected and centrifuged at 1000 × g and 4 °C for 10 min to collect the cells. 10 6 Isopropanol was added in a ratio of 300 μL to 500 μL of homogenization medium per 100 cells, and mechanical homogenization was performed to break the cells sufficiently until there was no obvious cell precipitation. Centrifugation was performed at 10,000 × g and 4 °C for 10 min. The supernatant was collected and placed on ice for later testing. 2.5 μL of distilled water; the standard or sample was taken and mixed with 250 μL of distilled water, respectively, and incubated at 37 °C for 10 min, and the absorbance of each well was measured at 510 nm using a microplate reader. The formula for calculating TC / TG concentration was: sample concentration (mmol / g protein) = (OD 試料 -OD ブランク ) / (OD 標準品 -OD ブランク ) × standard concentration (mmol / L) / protein concentration (g protein / L).

[0366] Protein quantification by BCA method Preparation of protein standards: 1.2mL of protein standard preparation solution was added to a tube of protein standard (30mg BSA) and dissolved completely to prepare a. 25mg / mL protein standard solution. b. An appropriate amount of 25mg / mL protein standard was diluted to a final concentration of 0.5mg / mL. Preparation of BCA working solution: According to the number of samples, an appropriate amount of BCA working solution was prepared by thoroughly mixing 50 volumes of BCA Reagent A and 1 volume of BCA Reagent B (50:1). Determination of protein concentration: a. 0, 1, 2, 4, 8, 12, 16 and 20μL of standard were added to the standard wells of a 96-well plate, respectively, and standard diluent was added to 20μL to obtain standard samples with concentrations of 0, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5mg / mL, respectively. b. An appropriate volume of sample was added to the sample wells of a 96-well plate. If the sample was less than 20 μL, standard diluent was added up to 20 μL. c. 200 μL of BCA working solution was added to each well and placed at 37°C for 20-30 minutes. d. The absorbance at wavelength of A562 nm was measured by a microplate reader. e. The protein concentration of the samples was calculated based on the standard curve and the amount of sample used.

[0367] In the above experiment, high TC / TG reduction rate and low EC 50 The compounds with higher values ​​were better able to reduce fat content in blood and / or liver. 1.6 Experiments on animals with acute hyperlipidemia Male C57BL / 6 mice were randomly divided into eight groups, including control, model, SIPI-7623 (10 mg / kg, 30 mg / kg, and 100 mg / kg) and test groups (three doses). The model, SIPI-7623, and test groups were intraperitoneally injected with 600 mg / kg Triton WR-1339, and the control group was injected with the same amount of saline. Test compounds were administered by gavage 1 hour before and 23 hours after the injection of inducer. Blood and tissue samples were collected 1 hour later.

[0368] 1.7 Experiments on animals using high-fat diets Male C57BL / 6 mice were randomly divided into six groups, including control, HFD, SIPI-7623 (40 mg / kg) and test groups (three doses). The control group was fed with normal chow, while the HFD, SIPI-7623 and test groups were fed with high-fat chow. The control and HFD groups were given the given solvent by gavage, while the other groups were administered the corresponding doses of test compounds for treatment. The body weights of the mice were recorded daily. After 8 weeks of gavage with the test compounds, blood and tissue samples were collected. The composition of the high-fat chow is shown in the table below.

[0369] [Table 5]

[0370] 1.8 Experiments on animals with diet-induced obesity Male C57BL / 6 mice were divided into two groups: a control group that received a normal diet, and a HFD group that received a high-fat diet. After 12 weeks of high-fat diet, the HFD group was randomly divided into nine groups: HFD group, test substance group (three doses), SIPI-7623 group (40 mg / kg), atorvastatin group (10 mg / kg), and test substance (10 mg / kg) + atorvastatin (10 mg / kg). The control and HFD groups were given the given vehicle by gavage, while the other groups were treated with the corresponding doses of the compounds. The weights of the mice were recorded every week. After 8 weeks of gavage treatment with the compounds, blood and tissue samples were taken. The composition of the high-fat diet is shown in the table above.

[0371] 1.9 Animal experiments on db / db mice Male db / db mice were randomly divided into five groups, the experimental groups were db / db group, test substance group (three doses) and pioglitazone (7mg / kg). The db / db group was treated with vehicle by gavage, and the other groups were treated with the corresponding compounds by gavage for 4 weeks. The body weight of the mice was recorded every week, and fasting blood glucose was examined. After 4 weeks of gavage treatment with the compounds, blood and tissue samples were taken for further experiments.

[0372] 2.0 Determination of Blood Glucose in Mice 1. Roche blood glucose meter including blood glucose meter, blood collection pen and blood glucose test strips.

[0373] 2. The tip of the mouse's tail was wiped with an alcohol cotton ball, and the sampling needle of the blood collection pen was opened and pierced into the tip of the mouse's tail. The blood from the tip of the tail was dipped into the blood glucose test strip, and the blood should completely cover the test area of ​​the test strip. The blood glucose meter was opened, and the blood glucose test strip was inserted into the blood glucose meter, and the blood glucose value was read and recorded. The sampling needle and blood glucose test strip should be replaced before each mouse is tested for blood glucose.

[0374] 2.1 Glucose tolerance test (GTT) Glucose tolerance test was performed 5 weeks after administration of the test substance by gavage (17th week of the experiment). After fasting for 16 hours, glucose (1.5g / kg) was injected intraperitoneally into the mice, and the blood glucose levels of the mice were measured by a glucometer at 0, 15, 30, 60, 90 and 120 minutes after glucose injection, respectively.

[0375] 2.2 Insulin Tolerance Test (ITT) Insulin tolerance test was performed 6 weeks after administration of test substances by gavage (18th week of the experiment). After fasting for 4 hours, mice were intraperitoneally injected with insulin (1U / kg), and blood glucose levels of mice were measured by a glucometer at 0, 15, 30, 60, 90 and 120 minutes after insulin injection, respectively.

[0376] 2.3 Animal sampling 1. After the mice were weighed, they were anesthetized by intraperitoneal injection of sodium pentobarbital.

[0377] 2. Blood was collected from the inner canthus of the eye, 20μL of whole blood was collected, diluted with whole blood diluent, and routine blood tests were performed. The remaining whole blood was left to stand at room temperature for 2 hours, centrifuged at 3000rpm and 4℃ for 10 minutes, and the upper serum was collected for blood biochemistry tests.

[0378] 3. After completing blood sampling of the mice, the thoracic and abdominal cavities were opened, and the liver, intestine, white adipose tissue and brown adipose tissue were removed, respectively. 4. For paraffin and frozen section preparation, a portion of the liver was fixed in 4% formaldehyde and the remaining tissue was frozen at -80°C.

[0379] 5. The intestinal tissue was rinsed with PBS, and the intestinal epithelial cells were scraped off and frozen at -80°C. 6. White and brown adipose tissues were weighed. 2.4 Detection of cholesterol and triglycerides in the liver 1. An appropriate amount of liver tissue was collected, and tissue homogenization was performed using grinding beads and PBS as a buffer.

[0380] 2. The homogenate was divided into two equal parts, and chloroform and methanol were added to one part for extraction to measure the concentration of cholesterol and triglycerides. Four times the volume of chloroform-methanol extraction solution (chloroform:methanol=2:1) ​​was added to one of the tubes, mixed thoroughly by vortexing, allowed to stand until stratified, and centrifuged at 2000 rpm and 4℃ for 30 minutes. The lower liquid layer was pipetted into a new centrifuge tube and solvent evaporated in a vacuum concentrator to remove the solvent, then an appropriate amount of 3% Triton X-100 was added and dissolution was carried out in a water bath shaker at a constant temperature of 50-60℃. The concentrations were determined using TC and TG kits.

[0381] 5. Another tube of homogenate was taken and centrifuged at 12000 rpm and 4°C for 15 minutes, the supernatant was collected and the protein concentration was determined using BCA kit. 6. Lipid content = lipid concentration / protein concentration 2.5 Liver staining with Oil Red O 1. Fresh liver tissues of the same size and location were collected, fixed in 4% neutral formaldehyde, sectioned, and sent to a testing company for oil red O staining.

[0382] 2. The prepared sections were removed, scanned with a scanner, and photographed. 2.6 HE staining of tissue 1. Fresh liver tissues of the same size and location were collected, fixed in 4% neutral formaldehyde, sectioned, and sent to a testing company for HE staining.

[0383] 2. The prepared sections were removed, scanned with a scanner, and photographed. 2.7 Animal studies on mice with inflammatory bowel disease Modeling with DSS DSS is a synthetic derivative of dextran and chlorosulfonic acid, with the molecular formula (C6H7Na3O 14 S3) n DSS is a polyanionic derivative of dextran with MW: 36000-50000 and sulfur content of 17%-20%. DSS is often used to induce colitis models, but its induction mechanism has not yet been clarified. Current research has shown that DSS increases intestinal permeability, destroys the intestinal mucosal barrier, upregulates certain cytokines (tumor necrosis factor, interleukin, interferon, IL-10 and IL-12), activates certain pathways (NF-κB pathway and TRPV1 pathway), or is mainly related to the imbalance of gut microbiota. According to the administration time and administration cycle, there are two types of colitis models: acute model and chronic model.

[0384] Male C57BL / 6 mice were randomly divided into six groups, including control and experimental groups. The experimental groups were model group, test group (three doses) and positive compound tofacitinib group (10 mg / kg). The control group was treated with vehicle by gavage, and the other groups were treated with the corresponding compounds by gavage. The body weight of the mice was recorded daily. After compound gavage treatment, blood and tissue samples were taken for later experiments.

[0385] Modeling chronic colitis A chronic colitis model could be established using low-concentration DSS, but with a longer administration period. For example, this model could be created by administering 1%-3% DSS to mice via ad libitum drinking water for several weeks. Signs of the chronic colitis model included the following in a small number of animals: obvious shortening of the mouse colon, epithelial hyperplasia, mucosal fibrosis and lymphadenopathy; as well as granulation tissue hyperplasia and tumor-like changes.

[0386] Male C57BL / 6 mice were randomly divided into six groups, including a control group and an experimental group. The experimental groups included a model group, a test group (three doses) and a positive compound, tofacitinib group (10 mg / kg). The control group was administered with vehicle by gavage, and the other groups were administered with the corresponding compounds by gavage. The body weights of the mice were recorded daily. After treatment with the compounds by gavage, blood and tissue samples were taken for further experiments.

[0387] Modeling acute colitis Acute colitis model is also one of the commonly used colitis models. Due to its simplicity of preparation, high success rate and similarity to human UC lesions, this model is an ideal model for studying the pathogenesis of UC and evaluating drug efficacy. Acute model is generally established using higher concentrations of DSS and shorter administration period. For example, this model can be made by administering 3%-5% DSS to hamsters with free drinking water for one week. The symptoms of acute colitis model included congestion, edema, shortening, fragility, and increased weight-to-length ratio in the colon, various degrees of colonic ulceration, mucosal edema, goblet cell loss, crypt swelling and destruction, various degrees of inflammatory cell infiltration in the mucosal layer and submucosa, and epithelial cell damage.

[0388] Male C57BL / 6 mice were randomly divided into six groups, including a control group and an experimental group. The experimental groups included a model group, a test group (three doses) and a positive compound, tofacitinib group (10 mg / kg). The control group was treated with vehicle by gavage, and the other groups were treated with the corresponding compounds by gavage. The body weights of the mice were recorded daily. After treatment with the compounds by gavage, blood and tissue samples were taken for later experiments.

[0389] Experimental Results The GPR132 agonist activity results showed the following: A: 0.01 μM <EC 50 <1 μM B: 1 μM <EC 50 <10 μM C: 10 μM <EC 50 <100 μM

[0390] [Table 6]

[0391] [Table 7]

[0392] [Table 8]

[0393] [Table 9]

[0394] Experimental results show that the compounds of the present invention have one or more of the following effects: (1) Good GPR132 agonist activity (2) Good safety (3) It can improve glucose tolerance (4) It can improve insulin resistance. (5) It can lower blood sugar levels (6) It can lower blood lipid levels. (7) It can reduce fat content in the liver. (8) Inhibits tumor cell proliferation (9) It can reduce inflammation levels; and (10) It can improve intestinal diseases.

[0395] In summary, the compounds of the present invention can be used as GPR132 agonists for the prevention and / or treatment of diseases related to GPR132, such as tumors, metabolic diseases or autoimmune diseases.

[0396] Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and these modifications are within the scope of protection of the present invention. The full scope of the present invention is indicated by the appended claims and any equivalents thereof.

Claims

1. A compound of formula I, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound 【Chemistry 1】 (In the formula, Ring A is selected from the group consisting of a benzofuran ring, a benzothiophene ring, an indole ring, and a benzene ring; Preferably, ring A is 【Chemistry 2】 wherein X is selected from the group consisting of O, S and NH, and X is preferably selected from O; R ０ teeth, 【Transformation 3】 selected from the group consisting of: Preferably, R ０ teeth, 【Chemistry 4】 and L ａ is selected from the group consisting of C1-C6 alkylene; Preferably, L ａ teeth, 【Transformation 5】 is selected from the group consisting of R １ is selected from the group consisting of hydroxyl, C1-C6 alkoxy, and —NH—OH; R ２ is selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; R ３ is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, phenyl, naphthyl, and 5-10 membered heteroaryl, and phenyl, naphthyl, and 5-10 membered heteroaryl are selected from the group consisting of R ｘ or the phenyl, naphthyl and 5- to 10-membered heteroaryl are each independently substituted with two adjacent groups, and the two adjacent groups and the carbon atoms to which they are each attached may together form a 5- to 6-membered heterocyclic ring; R ｘ is C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkynyl, cyano, phenyl, and —NR ｍ R ｎ is selected from the group consisting of R ｍ and R ｎ are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; L １ teeth, 【Transformation 6】 is selected from the group consisting of Preferably, L １ teeth, 【Transformation 7】 is selected from the group consisting of L ２ teeth, 【Transformation 8】 is selected from the group consisting of n is selected from the group consisting of 1, 2, 3, 4, 5 and 6; m is selected from the group consisting of 1, 2, 3, 4, 5 and 6; p is selected from the group consisting of 0, 1, 2 and 3; R ４’ is phenyl-(CH ２ ) ｒ - and 5- to 10-membered heteroaryl-(CH ２ ) ｒ -, and phenyl and 5-10 membered heteroaryl are selected from the group consisting of R ａ each independently substituted with 1 to 5 groups selected from the group consisting of r is selected from the group consisting of 0, 1, 2, 3, 4 and 5; R ａ is halogen, C1-C6 alkyl-O-C(=O)- and 5- to 6-membered saturated heterocyclyl ( 【Chemistry 9】 and R ｂ is selected from the group consisting of hydrogen and C1-C6 alkyl).

2. R １ is selected from the group consisting of hydroxyl and C1-C6 alkoxy; Preferably, R １ is selected from the group consisting of hydroxyl and ethoxy; More preferably, R １ is hydroxyl, or Or preferably, R １ is selected from the group consisting of hydroxyl, ethoxy, and —NH—OH; 10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

3. R ２ is selected from the group consisting of halogen and C1-C6 alkyl; Preferably, R ２ is selected from the group consisting of fluorine, chlorine and methyl; Or preferably, R ２ is selected from the group consisting of C1-C6 alkyl; Or more preferably, R ２ is methyl, 10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

4. R ３ is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, phenyl, naphthyl, pyridyl, pyrrolyl, thienyl, and indolyl, and phenyl, naphthyl, pyridyl, pyrrolyl, thienyl, and indolyl are selected from the group consisting of R ｘ or phenyl, naphthyl, pyridyl, pyrrolyl, thienyl and indolyl are each independently substituted with two adjacent groups, and the two adjacent groups and the carbon atoms to which they are respectively attached may together form a 5- to 6-membered heterocyclic ring; Preferably, R ３ is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, phenyl, naphthyl, pyridyl, pyrrolyl, thienyl, and indolyl, and phenyl, pyridyl, and thienyl are selected from the group consisting of R ｘ or the phenyl is substituted with two adjacent groups, and the two adjacent groups and the carbon atoms to which they are each attached are each independently substituted with one to two (preferably one) groups selected from the group consisting of: 【Chemistry 10】 may be formed, More preferably, R ３ but below: １） 【Chemistry 11】 (In the formula, R ４ , R ５ , R ６ , R ７ and R ８ is hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkynyl, cyano, phenyl, and —NR ｍ R ｎ or R ４ , R ５ and the carbon atoms to which they are each attached together form a 5- to 6-membered heterocyclic ring, R ６ , R ７ and R ８ is hydrogen, Preferably, R ４ , R ５ , R ６ , R ７ and R ８ any one of (for example, R ５ , R ６ or R ７ ) is selected from hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkynyl, cyano, phenyl, and —NR ｍ R ｎ and the remainder are hydrogen; More preferably, R ４ , R ５ , R ６ , R ７ and R ８ any one of (for example, R ５ , R ６ or R ７ ) is hydrogen, methyl, fluorine, chlorine, iodine, methoxy 【Chemistry 12】 trifluoromethyl, 【Chemistry 13】 Cyano, phenyl and 【Chemistry 14】 and the remainder are hydrogen or Or preferably, R ４ , R ５ and the carbon atoms to which they are each attached together are 【Chemistry 15】 and R ６ , R ７ and R ８ is hydrogen) ２） 【Chemistry 16】 (In the formula, R ９ , R １０ , R １１ and R １２ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, and C1-C6 alkoxy; Preferably, R ９ , R １０ , R １１ and R １２ are each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkoxy; More preferably, R ９ , R １０ , R １１ and R １２ Any one of (for example, R １０ or R １１ ) are selected from the group consisting of hydrogen, halogen, and C1-C6 alkoxy, the remainder being hydrogen; Most preferably, R ９ , R １０ , R １１ and R １２ Any one of (for example, R １０ or R １１ ) is selected from the group consisting of hydrogen, chlorine and methoxy, the remainder being hydrogen. ３） 【Chemistry 17】 (In the formula, R １３ , R １４ and R １５ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen; Preferably, R １３ , R １４ and R １５ Any one of (for example, R １３ ) are selected from the group consisting of hydrogen, C1-C6 alkyl and halogen, the remainder being hydrogen; More preferably, R １３ , R １４ and R １５ Any one of (for example, R １３ ) is selected from the group consisting of hydrogen, methyl and chlorine, the remainder being hydrogen. ４） [Chemistry 18] is selected from the group consisting of Most preferably, R ３ but, 【Chemistry 19】 is selected from the group consisting of Preferably, R ｘ However, methyl, fluorine, chlorine, iodine, methoxy 【Chemistry 20】 trifluoromethyl, 【Chemistry 21】 Cyano, phenyl and —NR ｍ R ｎ is selected from the group consisting of Preferably, R ｍ and R ｎ one of which is hydrogen and the other is selected from the group consisting of C1-C6 alkyl; Preferably, R ｍ and R ｎ one of which is hydrogen and the other is methyl; 10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

5. R ４’ is phenyl-(CH ２ ) ｒ - and quinolyl-(CH ２ ) ｒ -, phenyl and quinolyl are selected from the group consisting of R ａ each independently substituted with a group selected from the group consisting of Preferably, R ４’ However, phenyl-(CH ２ ) ｒ - and quinolyl-(CH ２ ) ｒ -, and phenyl is selected from the group consisting of R ａ and optionally substituted with a group selected from the group consisting of Preferably, r is selected from the group consisting of 0 and 1; Preferably, R ａ is halogen, C1-C6 alkyl-O-C(=O)- and piperazinyl ( 【Chemistry 22】 and More preferably, R ａ is halogen, C1-C6 alkyl-O-C(=O)- and piperazinyl ( 【Chemistry 23】 and Most preferably, R ａ But bromine 【Chemistry 24】 is selected from the group consisting of Preferably, R ｂ is selected from the group consisting of C1-C6 alkyl; More preferably, R ｂ is methyl, More preferably, R ４’ but, 【Chemistry 25】 wherein r' is selected from the group consisting of 0, 1, 2, 3, 4 and 5; Preferably, r' is selected from the group consisting of 0 and 1; R ５’ , R ６’ , R ７’ , R ８’ and R ９’ is hydrogen, halogen, C1-C6 alkyl-O-C(=O)- and 5- to 6-membered saturated heterocyclyl ( 【Chemistry 26】 and each independently selected from the group consisting of Preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, halogen, C1-C6 alkyl-O-C(=O)- and 5- to 6-membered saturated heterocyclyl ( 【Chemistry 27】 and the remainder are hydrogen; More preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, halogen, C1-C6 alkyl-O-C(=O)- and piperazinyl ( 【Chemistry 28】 and the remainder are hydrogen; More preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, halogen, C1-C6 alkyl-O-C(=O)- and piperazinyl ( 【Chemistry 29】 and the remainder are hydrogen; Most preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, bromine 【Transformation 30】 and the remainder are hydrogen; R ｂ’ is selected from the group consisting of hydrogen and C1-C6 alkyl; Preferably, R ｂ’ is selected from the group consisting of C1-C6 alkyl; More preferably, R ｂ’ is methyl) Most preferably, R ４’ but, 【Chemistry 31】 selected from the group consisting of 10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

6. L １ but, 【Chemistry 32】 is selected from the group consisting of 【Transformation 33】 In the formula, the carbonyl terminal is L ２ and the amino terminus is linked to a benzene ring, 【Transformation 34】 wherein the amino terminus is L ２ and the acyl end is connected to a benzene ring, Preferably, L １ but, 【Chemistry 35】 and 【Transformation 36】 In the formula, the carbonyl terminal is L ２ and the amino terminus is linked to a benzene ring; 10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

7. L ２ but, 【Chemistry 37】 is selected from the group consisting of 【Transformation 38】 In which the carbonyl terminal is R ３ It is connected to Preferably, L ２ but, 【Chemistry 39】 is selected from the group consisting of 【Chemistry 40】 In which the carbonyl terminal is R ３ It is connected to More preferably, L ２ but, 【Chemistry 41】 is selected from the group consisting of 【Chemistry 42】 In which the carbonyl terminal is R ３ It is connected to Most preferably, L ２ but, 【Chemistry 43】 and Preferably, n is selected from the group consisting of 2, 3 and 4; Preferably, n is selected from the group consisting of 2 and 4; Preferably, m is selected from the group consisting of 1, 2 and 3; Preferably, m is 2, Preferably, p is 0.

10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

8. The structural formula of the compound represented by Formula I is as follows: 【Chemistry 44】 (In the formula, X is selected from the group consisting of O, S and NH, preferably O; R ０ , R ２ , R ３ , L １ and L ２ is defined in claim 1, R １’ is selected from the group consisting of hydrogen and C1-C6 alkyl; Preferably, R １’ is selected from the group consisting of hydrogen and ethyl; More preferably, R １’ is selected from the group consisting of hydrogen; R ２’ is selected from the group consisting of hydrogen and C1-C6 alkyl; Preferably, R ２’ is selected from the group consisting of C1-C6 alkyl; More preferably, R ２’ is methyl, R ３’ is phenyl, which is optionally substituted with 1 to 5 groups selected from the group consisting of C1-C6 alkyl; Preferably, R ３’ is phenyl, which is optionally substituted with one group selected from the group consisting of C1-C6 alkyl; More preferably, R ３’ is phenyl, L ３ teeth, 【Chemistry 45】 is selected from q is selected from the group consisting of 1, 2, 3, 4, 5 and 6; Preferably, q is selected from the group consisting of 1, 2 and 3; More preferably, q is 2; R ４’ is phenyl-(CH ２ ) ｒ - and 5- to 10-membered heteroaryl-(CH ２ ) ｒ -, and phenyl and 5-10 membered heteroaryl are selected from the group consisting of R ａ each independently substituted with 1 to 5 groups selected from the group consisting of Preferably, R ４’ is phenyl-(CH ２ ) ｒ - and quinolyl-(CH ２ ) ｒ -, and phenyl and quinolyl are selected from the group consisting of R ａ each independently substituted with one group selected from the group consisting of More preferably, R ４’ is phenyl-(CH ２ ) ｒ - and quinolyl-(CH ２ ) ｒ -, and phenyl is selected from the group consisting of R ａ and optionally substituted with one group selected from the group consisting of: r is selected from the group consisting of 0, 1, 2, 3, 4 and 5; Preferably, r is selected from the group consisting of 0 and 1; R ａ is halogen, C1-C6 alkyl-O-C(=O)- and 5- to 6-membered saturated heterocyclyl ( 【Chemistry 46】 and optionally substituted by Preferably, R ａ is halogen, C1-C6 alkyl-O-C(=O)- and piperazinyl ( 【Chemistry 47】 and More preferably, R ａ is halogen, C1-C6 alkyl-O-C(=O)-, piperazinyl ( 【Chemistry 48】 and Most preferably, R ａ teeth, 【Chemistry 49】 is selected from the group consisting of R ｂ is selected from the group consisting of hydrogen and C1-C6 alkyl; Preferably, R ｂ is selected from the group consisting of C1-C6 alkyl; More preferably, R ｂ is methyl, More preferably, R ４’ teeth, [Transformation 50] (In the formula, r' is selected from the group consisting of 0, 1, 2, 3, 4 and 5; Preferably, r' is selected from the group consisting of 0 and 1; R ５’ , R ６’ , R ７’ , R ８’ and R ９’ is hydrogen, halogen, C1-C6 alkyl-O-C(=O)- and 5- to 6-membered saturated heterocyclyl ( 【Chemistry 51】 and each independently selected from the group consisting of Preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, halogen, C1-C6 alkyl-O-C(=O)- and 5- to 6-membered saturated heterocyclyl ( 【Chemistry 52】 and the remainder are hydrogen; More preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, halogen, C1-C6 alkyl-O-C(=O)-, piperazinyl ( 【Chemistry 53】 and the remainder are hydrogen; More preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, halogen, C1-C6 alkyl-O-C(=O)- and piperazinyl ( 【Chemistry 54】 and the remainder are hydrogen; Most preferably, R ５’ , R ６’ , R ７’ , R ８’ and R ９’ Any one of (for example, R ７’ ) is hydrogen, bromine 【Transformation 55】 and the remainder are hydrogen; R ｂ’ is selected from the group consisting of hydrogen and C1-C6 alkyl; Preferably, R ｂ’ is selected from the group consisting of C1-C6 alkyl; More preferably, R ｂ ' is methyl) is selected from the group consisting of Most preferably, R ４’ teeth, 【Transformation 56】 selected from the group consisting of 10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound, selected from the group consisting of:

9. The structural formula of the compound represented by formula I-1 is as follows: 【Chemistry 57】 (In the formula, X is selected from the group consisting of O, S and NH, preferably O; R 1 is selected from the group consisting of hydroxyl, C1-C6 alkoxy, and —NH—OH; R2, R ３ , L １ and L ２ is as defined in claim 8), 9. The compound of claim 8, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

10. The structural formula of the compound represented by formula I-2 is as follows: 【Chemical 58】 (In the formula, R 1 is selected from the group consisting of hydroxyl, C1-C6 alkoxy, and —NH—OH; L a is 【Chemistry 59】 is selected from the group consisting of R2, R ３ , L1 and L ２ is defined in claim 1, Preferably, R １ is hydroxyl, Preferably, R ２ is selected from the group consisting of halogens; More preferably, R ２ is fluorine, Preferably, R ３ teeth, 【Transformation 60】 and Preferably, L ａ is selected from the group consisting of C1-C6 alkylene; More preferably, L ａ teeth, 【Chemistry 61】 is selected from the group consisting of Preferably, L １ teeth, 【Transformation 62】 is selected from the group consisting of 【Transformation 63】 In the formula, the carbonyl end is L ２ and the amino terminus is linked to a benzene ring, More preferably, L １ teeth, 【Chemistry 64】 and 【Transformation 65】 In the formula, the carbonyl end is L ２ and the amino terminus is linked to a benzene ring, Preferably, L ２ teeth, 【Chemical Formula 66】 is selected from More preferably, L ２ teeth, 【Transformation 67】 is selected from the group consisting of Preferably, n is selected from the group consisting of 1, 2, 3, 4, 5 and 6; More preferably, n is selected from the group consisting of 2 and 3.

9. The compound of claim 8, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound.

11. below: Table 1-1 Table 1-2 Table 1-3 Table 2 10. The compound of claim 1, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said compound, selected from the group consisting of:

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of said compound, and optionally a pharmaceutically acceptable excipient.

13. 12. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of said compound, in the manufacture of a medicament, or use of a compound shown in the table below, or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or ester of said compound, in the manufacture of a medicament, wherein the medicament is used for the treatment and / or prevention of a disease associated with GPR132, or for hematopoietic stem cell transplantation, or for bone marrow transplantation, Table 3 Preferably, the disease associated with GPR132 is selected from the group consisting of tumors, metabolic diseases, immune-related diseases and neuropathic pain; Preferably, the tumor is selected from the group consisting of breast cancer, melanoma, meningioma, soft tissue sarcoma, salivary gland tumor, liver cancer (e.g., primary liver cancer), intraspinal tumor, longitudinal tumor, brain cancer, bone cancer, penile cancer, osteosarcoma, intracranial tumor, tongue cancer, maxillary sinus cancer, thyroid cancer, malignant lymphoma, multiple myeloma, pituitary adenoma, testicular tumor, non-Hodgkin's lymphoma, bladder cancer, leukemia (e.g., acute myeloid leukemia), gastric cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, esophageal cancer, lung cancer, kidney cancer, cervical cancer, choriocarcinoma, vulvar cancer, skin cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, Kaposi's sarcoma, non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), hemangioma and glioma; Preferably, the metabolic disease is selected from the group consisting of atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver or non-alcoholic steatohepatitis (NASH)), metabolic syndrome, type 2 diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, hyperlipidemia (e.g., hypercholesterolemia) and secondary complications of these diseases (e.g., diabetic complications such as retinopathy, neuropathy, nephropathy and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension and stroke), Preferably, the immune-related disease is one of the following: Secondary immunodeficiencies: for example, secondary immunodeficiencies caused by infections (e.g., rubella, measles, leprosy, tuberculosis, cytomegalovirus infection, HIV infection, coccidioides infection), protein depletion (e.g., nephrotic syndrome, protein-losing enteropathy), insufficient immunoglobulin synthesis, lymphopenia (e.g., lymphopenia caused by drugs and / or systemic infections), other diseases (e.g., diabetes, cirrhosis, subacute sclerosing panencephalitis) and / or immunosuppressive therapy, and Autoimmune diseases: e.g., inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, juvenile diabetes, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, colorectal inflammation (e.g., ulcerative colitis), skin diseases, chronic liver disease The use of any one of the following:

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