GPR97 targeting small molecule compound and application thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a GPR97 targeting small molecule compound and application thereof in anti-tumor and anti-inflammatory treatment. The invention provides a class of innovative small molecule compounds targeting GPR97 and application thereof, the structural general formula of the compounds is as shown in formula (I), or tautomers, stereoisomers, hydrates, deuterated compounds, solvates, non-aqueous solvates, pharmaceutically acceptable salts or prodrugs and the like of the compounds, and the compounds have GPR97 regulating activity, can be used for preparing drugs, and can be used for preparing drugs, such as medicines, medicines and the like. The compound is suitable for preventing and / or treating GPR97-mediated diseases, including but not limited to autoimmune diseases, cancers, nervous system diseases and inflammation-related diseases, such as gastric cancer, colorectal cancer and inflammatory bowel disease.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a kind of GPR97 targeting small molecule compound and its application in anti-tumor and anti-inflammatory treatment. BACKGROUND

[0002] G protein-coupled receptors (GPCRs) can sense a variety of extracellular signals and transduce signals into cells, causing a series of intracellular reactions, which is important for maintaining homeostasis. Studies have shown that GPCR dysfunction is closely related to the occurrence and development of many serious human diseases, so GPCR has always been a popular target for drug development and design. According to statistics, more than 30% of the approved clinical drugs target GPCRs. Therefore, developing new GPCR-targeting drugs has important clinical and social value for the treatment of complex diseases.

[0003] G protein-coupled receptor 97 (GPR97) belongs to the adhesion GPCR family, and its downstream is coupled to G αi / o protein. Studies have found that GPR97 deletion can reduce renal interstitial fibrosis and acute kidney injury in mice with hypertensive nephropathy; at the same time, the up-regulation of GPR97 expression in activated neutrophils is positively correlated with the disease activity of various inflammatory diseases. In addition, GPR97 can bind to glucocorticoids to regulate immune responses and inflammatory pathways.

[0004] Currently, there are still limited reports on the modulators of GPR97, including agonists and antagonists. Therefore, designing novel GPR97 modulators is expected to provide new treatment options for GPR97-mediated autoimmune diseases, cancer, nervous system diseases, and inflammation-related diseases. SUMMARY

[0005] The present application aims to at least solve one of the technical problems in the related art. To this end, one object of the present application is to provide an innovative small molecule compound targeting GPR97 and its application, the structural formula of the compound is shown in formula (I), or its tautomer, stereoisomer, hydrate, deuteride, solvate, non-water solvate, pharmaceutically acceptable salt or prodrug, etc. The compound has GPR97 modulating activity and can be used for the preparation of drugs, which is suitable for preventing and / or treating diseases mediated by GPR97, including but not limited to autoimmune diseases, cancer, nervous system diseases, and inflammation-related diseases, such as gastric cancer, colorectal cancer, and inflammatory bowel disease, etc.

[0006] To this end, the present application provides, in a first aspect, a compound. According to embodiments of the present application, the compound is a compound of Formula (I) or a tautomer, stereoisomer, hydrate, deuterated form, solvate, non-water solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula (I):

[0007] (I) wherein A is selected from the following groups unsubstituted or substituted with at least one R1and / or R2: C3-C 20 cycloalkyl, C2-C 20 heterocycloalkyl, C6-C 20 aryl, C2-C 20 heteroaryl, C7-C 24 fused ring aryl, C7-C 24 fused ring heteroaryl; or fused aryl-heterocycloalkyl, fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl is C4-C 10 and the number of skeletal carbon atoms in the cycloalkyl is C3-C 10 ; R 1 , R 2 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COCH3, -NO2, -COOH, -CONH2, -COCH3, -SO2NH2, ester, C 1-20 alkyl, C 1-20 alkoxy, halogen-substituted C 1-20 alkyl, halogen-substituted C 1-20 alkoxy, C 1-8 alkylamino, C 1-6 dialkylamino, C 3-8 cycloalkylamino, C 1-3 alkylsulfonyl, halogen-substituted C 1-3 alkylsulfonyl, -NR 7 R 8 , -NHCO(CH2) n CH3, -CONR 7 R 8 , -SO2NR 7 R 8 , n = 1-5; R 7 , R 8 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl; or NR 7 R 8R is selected from the group consisting of hydrogen, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 2-8 unsaturated aliphatic chain hydrocarbon radical, C 3-8 unsaturated aliphatic cyclic radical, C 3-8 saturated aliphatic heterocyclic radical; the cyclic amine is selected from the group consisting of morpholine, piperazine, methylpiperazine, pyrrolidine, piperidine; L 1 and L 2 are each independently selected from the group consisting of a bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from an integer from 0 to 3; R 9 , R 10 are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 unsaturated aliphatic chain hydrocarbon radical, C 3-8 unsaturated aliphatic cyclic radical, C 3-8 saturated aliphatic heterocyclic radical; B is selected from the group consisting of no substitution or substitution with at least one R 3 and / or R 4 ; , , , , , , , , , , , ; R 3 R 4 Each group is independently selected from hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester group, and C. 1-20 Alkyl, C 1-20 alkoxy- or halogen-substituted C 1-20 Alkyl, halogen-substituted C 1-20 Alkoxy, C 1-8 alkylamine group, C 1-6 Dialkylamine group, C 3-8 Cycloalkylamine, C 1-3 Alkyl sulfone, halogen-substituted C 1-3 Alkyl sulfone group; In formula (I), C is selected from unsubstituted or via at least one R 5 and / or R 6 The following groups are substituted: C 1-20 Alkyl, C3-C 20 cycloalkyl, C2-C 20 Heterocyclic alkyl, C6-C 20 Aryl, C2-C 20 heteroaryl, C7-C 24 Fused ring aryl, C7-C 24 Fused ring heteroaryl groups; Alternatively, fused aryl-cycloalkyl or fused heteroaryl-cycloalkyl compounds, wherein the aryl or heteroaryl group has a skeletal carbon number of C4-C5. 10 The skeletal carbon number in cycloalkyl groups is C4-C5. 10 ; Alternatively, it can be a diheterocyclic alkyl group linked by carbon atoms, wherein each heterocyclic alkyl group has a skeletal carbon number of C2-C3. 10 ; R 5 and R 6 Each group is independently selected from hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester group, and C. 1-20 Alkyl, C 1-20 alkoxy- or halogen-substituted C 1-20 Alkyl, halogen-substituted C 1-20 Alkoxy, C 1-8 alkylamine group, C 1-6 Dialkylamine group, C 3-8cycloalkylamino, C 1-3 alkylsulfonyl, halogen-substituted C 1-3 alkylsulfonyl, wherein, in the group containing a heteroatom, the heteroatom is O, N, or S.

[0008] The compound represented by formula (I) or a tautomer, a stereoisomer, a hydrate, a deuteride, a solvate, a non-aqueous solvate, a pharmaceutically acceptable salt, or a prodrug thereof provided by the present application can target GPR97, has GPR97 modulating activity, and can be used for preparing a drug for preventing and / or treating a disease mediated by GPR97, and can be applied to treating an autoimmune disease, cancer, a neurological disease, an inflammation-related disease, and the like mediated by GPR97.

[0009] According to an embodiment of the present application, in the compound represented by formula (I), A is selected from the following groups which are unsubstituted or substituted with at least one R1and / or R2: C3-C 10 cycloalkyl, C2-C 10 heterocycloalkyl, C6-C 10 aryl, C2-C 10 heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; or a fused aryl-heterocycloalkyl, a fused heteroaryl-cycloalkyl, wherein the number of skeleton carbon atoms in the aryl or heteroaryl is C4-C 10 , and the number of skeleton carbon atoms in the cycloalkyl is C3-C8; and / or, R 1 , R 2 each independently is selected from hydrogen, -OH, halogen, -CN, -COCH3, -NO2, -COOH, -CONH2, -COCH3, -SO2NH2, C 1-10 alkyl, C 1-10 alkoxy, -NR 7 R 8 , -NHCO(CH2) n CH3, -CONR 7 R 8 , -SO2NR 7 R 8 , n = 1-5; R 7 , R 8 each independently is selected from hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl; or NR 7 R 8R is selected from the group consisting of hydrogen, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 2-8 unsaturated aliphatic chain hydrocarbon, C 3-8 unsaturated aliphatic cyclic, C 3-8 saturated aliphatic heterocyclic; the cyclic amine is selected from the group consisting of morpholine, piperazine, methylpiperazine, pyrrolidine, piperidine; and / or, L 1 and L 2 are each independently selected from the group consisting of a bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from the group consisting of an integer from 0 to 3; R 9 , R 10 are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy; and / or, B is selected from the group consisting of no substitution or substitution with at least one R 3 and / or R 4 substituted from the group consisting of: , , , , , , , , , 、 、 ; R 3 、R 4 each independently is selected from the group consisting of hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester, C 1-10 alkyl, C 1-10 alkoxy; and / or, in formula (I) C is selected from the group consisting of the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 ; C 1-10 alkyl, C3-C 10 cycloalkyl, C2-C 10 heterocycloalkyl, C6-C 10 aryl, C2-C 10 heteroaryl, C7-C 18 fused ring aryl, C7-C 18 fused ring heteroaryl; or fused aryl-cycloalkyl, fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl group is C4-C 10 and the number of skeletal carbon atoms in the cycloalkyl group is C4-C 10 ; or a bisheterocycloalkyl group, which is attached via carbon atoms, wherein the number of skeletal carbon atoms in each heterocycloalkyl group is C2-C 10 ; and / or R 5 and R 6 each independently is selected from the group consisting of hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, C 1-10 alkyl, C 1-10 alkoxy.

[0010] According to an embodiment of the present application, in the compound of formula (I) A is selected from the group consisting of the following groups, which are unsubstituted or substituted by at least one R1and / or R2: C2-C 10 heterocycloalkyl, C6-C 10 aryl, C2-C 10 heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; or fused aryl-heterocycloalkyl, fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl group is C4-C 10 and the number of skeletal carbon atoms in the cycloalkyl group is C3-C8; and / or R1 , R 2 each independently is selected from the group consisting of hydrogen, -OH, halogen, -CN, -COCH3, -NO2, -COOH, -CONH2, -COCH3, -SO2NH2, C 1-10 alkyl, C 1-10 alkoxy; and / or, L 1 and L 2 each independently is selected from the group consisting of a bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q - wherein p and q are each selected from an integer from 0 to 1 ; R 9 , R 10 each independently is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl; and / or, B is selected from the group consisting of no substitution or substitution with at least one R 3 and / or R 4 substituted: , , , , , , , , , , , ; R 3 , R 4Each is independently selected from hydrogen, -OH, halogen, -CN, -COOH, ester group, C 1-10 Alkyl, C 1-10 Alkoxy; And / or, in formula (I), C is selected from unsubstituted or via at least one R 5 and / or R 6 The following groups are substituted: C 1-10 Alkyl, C3-C8 cycloalkyl, C4-C8 heterocycloalkyl, C6-C 10 Aryl, C3-C5 heteroaryl, C7-C 10 Fused ring aryl, C7-C 10 Fused ring heteroaryl groups; Alternatively, fused aryl-cycloalkyl or fused heteroaryl-cycloalkyl compounds, wherein the aryl or heteroaryl group has a skeletal carbon number of C4-C5. 10 The skeletal carbon number in cycloalkyl groups is C4-C5. 10 ; Alternatively, it can be a diheteroalkyl group linked by carbon atoms, wherein each heteroalkyl group has a skeletal carbon number of C2-C8; And / or, R 5 and R 6 Each is independently selected from hydrogen, -OH, halogen, -COOH, C 1-10 Alkyl, C 1-10 Alkyl group.

[0011] According to embodiments of the present invention, in the compound represented by formula (I), A is selected from the following groups that are unsubstituted or substituted with at least one R1 and / or R2: , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 ; and / or, R 1 , R 2 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COCH3, -COOH, -CONH2, C 1-10 alkyl; and / or, L 1 and L 2 are each independently selected from the group consisting of a direct bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from an integer from 0 to 1 ; R 9 , R 10 are hydrogen; and / or, B is selected from the group consisting of no substitution or substitution with at least one R 3 and / or R 4 ; 、 、 、 、 、 ; R 3 , R 4 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COOH, C 1-10 alkyl, C 1-10 alkoxy; and / or, C in formula (I) is selected from the group consisting of no substitution or substitution with at least one R 5 and / or R 6substituted by at least one R1and / or R2: C 1-10 alkyl, C3-C8cycloalkyl, C4-C8heterocycloalkyl, C6-C 10 aryl, C3-C5heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; or a fused aryl-cycloalkyl, a fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl is C4-C8and the number of skeletal carbon atoms in the cycloalkyl is C4-C8; or a diheterocycloalkyl linked via carbon atoms, wherein the number of skeletal carbon atoms in each heterocycloalkyl is C2-C5; and / or, R 5 and R 6 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COCH3, -COOH, C 1-10 alkyl.

[0012] According to an embodiment of the present application, in the compound of formula (I), A is selected from the group consisting of the following groups, which are unsubstituted or substituted by at least one R1and / or R2: , , , , , , , , , , , , , , ; and / or, R 1 , R 2 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COCH3, -COOH, C 1-10 alkyl; and / or, L 1 and L 2 are each independently selected from the group consisting of -S(=O)2-, -CH2-, -C(=O)NH-, -CH2-NH-, -CONH-CH2-, -CO-; and / or, B is selected from the group consisting of the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 are each independently selected from the group consisting of the following groups, which are unsubstituted or substituted by at least one R1and / or R2: , , , , , ; R 3 R 4 Each is independently selected from hydrogen, -OH, halogen, -CN, -COOH, C 1-10 alkyl; And / or, in formula (I), C is selected from unsubstituted or via at least one R 5 and / or R 6 The following groups are substituted: C 1-10 Alkyl, C3-C8 cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C3-C5 heteroaryl, C7-C 10 Fused ring aryl, C7-C 10 Fused ring heteroaryl groups; Or fused aryl-cycloalkyl or fused heteroaryl-cycloalkyl, wherein the aryl or heteroaryl group has a skeletal carbon number of C5-C8, and the cycloalkyl group has a skeletal carbon number of C4-C8; Alternatively, it can be a diheterocyclic alkyl group linked by carbon atoms, wherein each heterocyclic alkyl group has a skeletal carbon number of C2-C5; And / or, R 5 and R 6 Each is independently selected from hydrogen, -OH, halogen, C 1-10 alkyl.

[0013] According to embodiments of the present invention, in the compound represented by formula (I), A is selected from the following groups that are unsubstituted or substituted with at least one R1 and / or R2: , , , , , , , , , , , , , , ; R 1 R 2 Each is independently selected from hydrogen, -OH, halogen, -COCH3, C 1-10 alkyl; L 1 Selected from -S(=O)2- or -CH2-; L2 selected from -C(=0)NH-, -CH2-NH-, -CONH-CH2-, -CO-; B is selected from the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 substituted by at least one R , , , , , ; R 3 , R 4 each independently is selected from hydrogen, -OH, halogen, -CN, C 1-10 alkyl; C in formula (I) is selected from the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 substituted by at least one R , , , , ,

[0014] , , , , , , , , , , , , , , and phenyl, C 1-10 alkyl; R 5 , R 6 each independently is selected from C 1-10 alkyl.

[0015] According to an embodiment of the present application, the compound is selected from any one of the following:

[0016] A second aspect of the present application provides a pharmaceutical composition. According to embodiments of the present application, the pharmaceutical composition comprises: a therapeutically effective amount of the compound of the first aspect, the pharmaceutical composition is used for treating a disease associated with GPR97.

[0017] According to embodiments of the present application, the disease associated with GPR97 comprises autoimmune diseases, solid tumors, non-solid tumors, nervous system diseases, and inflammation-related diseases.

[0018] According to embodiments of the present application, the solid tumors comprise lung cancer, kidney cancer, colon cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, thyroid cancer, salivary gland cancer, fibrosarcoma, skin cancer, brain tumor, and malignant melanoma. The non-solid tumors comprise leukemia, malignant lymphoma, and inflammatory bowel disease.

[0019] According to embodiments of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, and / or excipient.

[0020] A third aspect of the present application provides use of the compound of the first aspect in the preparation of a medicament for treating a disease associated with GPR97.

[0021] According to embodiments of the present application, the disease associated with GPR97 comprises autoimmune diseases, solid tumors, non-solid tumors, nervous system diseases, and inflammation-related diseases.

[0022] According to embodiments of the present application, the solid tumors comprise lung cancer, kidney cancer, colon cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, thyroid cancer, salivary gland cancer, fibrosarcoma, skin cancer, brain tumor, and malignant melanoma. The non-solid tumors comprise leukemia, malignant lymphoma, and inflammatory bowel disease.

[0023] Additional aspects and advantages of the present application will be given, partially in the following description, partially will become obvious from the following description, or will be learned by practice of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0024] The above and / or additional aspects and advantages of the present application will become apparent and be readily understood from the following description, taken in conjunction with the accompanying drawings, in which: Figure 1 A result graph for detecting the antagonistic activity of compound 02 on GPR97 in vitro by bioluminescence resonance energy transfer (BRET) experiment; Figure 2 Bar graphs of the antagonistic activity of Compound 02 in vitro against G protein-coupled receptor 34 (GPR34), melanocortin 5 receptor (MC5R), and GPR97. DETAILED DESCRIPTION

[0025] Embodiments of the present application are described in detail below. The embodiments described below are examples only and are not intended to limit the present application, as interpreted in the broadest light possible.

[0026] It should be noted that the terms "first", "second" are used only for descriptive purposes and are not to be construed as indicating or implying relative importance or an indicated order of elements. Thus, a feature defined with "first", "second" can include one or more of the features. Further, in the description of the present application, the meaning of "a plurality" is two or more, unless otherwise specified.

[0027] The endpoints of the ranges and any values described herein are not limited to the precise values stated. The endpoints of the ranges and any values are provided as approximate descriptions of the ranges and are accomplished by varying the values within the range. Each range endpoint is thus stated to be the approximate distance and should be applied mutatis mutandis to other ranges as appropriate. For ranges having a minimum and maximum value, the minimum and maximum values are included in the range.

[0028] In order that the present application can be more readily understood, certain technical and scientific terms are specifically defined below. Unless specifically defined herein, all other technical and scientific terms used in this document concur in meaning with the general use of their respective fields.

[0029] In this document, the terms "comprises" or "comprising" are open-ended, that is, they mean including, but not limited to, the indicated features.

[0030] In this document, the terms "optionally", "optional" or "optional" generally mean that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0031] Definitions and explanations of terms Unless otherwise indicated, the definitions of groups and terms in the specification and claims of this application, including definitions of examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other in any manner. The group definitions and compound structures after such combination should belong to the scope recited in the specification of this application.

[0032] The term "pharmaceutically acceptable salt" refers to a non-toxic acid or base salt, including salts of inorganic acids and bases, salts of organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts, such as salts of Al, Ca, Li, Mg, K, Na and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, including substituted or unsubstituted amine, cyclic amines and basic ion-exchange resins, such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzylpiperazine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, or polyamine resins; salts derived from inorganic and organic acids include, but are not limited to, salts of sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfosalicylic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropanoic acid, oxalic acid, glycolic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, camphorsulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like. Organic base salts: such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, triethylamine, t-butylamine, and the like; inorganic base salts: such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like.

[0033] The term "stereoisomer" refers to isomers that have the same molecular formula but different spatial arrangement of atoms. Stereoisomers include enantiomers (mirror image isomers), diastereomers (isomers that are not mirror image isomers), and conformational isomers.

[0034] The term "tautomer" refers to isomers that differ from each other only in the position of a proton. The compounds of the present application can exhibit tautomerism. Compounds that exist in two or more tautomeric forms can exist in equilibrium with each other. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with mixtures of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds.

[0035] The term "pharmaceutical" means a mixture of one or more compounds of the present application or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical is to facilitate administration of the compound to an organism and to facilitate absorption of the active ingredient into the organism to thereby exert its biological activity.

[0036] The term "solvate" means a compound of the present application or a salt thereof, including stoichiometric or non-stoichiometric amounts of a solvent such as water, methanol, ethanol, and acetic acid, and the like, which is in a molecular complex with the compound. When the solvent is water, the solvate is a hydrate.

[0037] The term "prodrug" means a compound of the present application which can be converted in vivo into a biologically active compound. Prodrugs of the present application are prepared by modifying functional groups in such a way that their activity is not only retained upon administration but is improved for biological purposes. Prodrugs are prepared by modifying functional groups in such a way that their activity is not only retained upon administration but is improved for biological purposes.

[0038] The term "C1-C 20 alkyl" is to be understood as meaning a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Said alkyl group is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1 -dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 -dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, and the like; "C1-C6 alkyl" is to be understood as meaning a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0039] The term "C6-C 20 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular a ring having 6 carbon atoms ("C6 aryl"), for example a phenyl group; or a ring having 9 carbon atoms ("C9 aryl"), for example an indane or indenyl group, or a ring having 10 carbon atoms ("C 10 aryl") for example a tetrahydronaphthyl, dihydronaphthyl or naphthyl group, or a ring having 13 carbon atoms ("C 13 aryl") for example a fluorenyl group, or a ring having 14 carbon atoms ("C 14 aryl") for example an anthryl group.

[0040] The term "C2-C" 20 "Heteroaryl" should be understood as a heteroaryl group containing 2 to 20 carbon atoms, an aromatic group in which at least one carbon atom in the aromatic ring is replaced by a non-carbon atom (heteroatom). The heteroatom is usually N, O, S, P, etc., and can be a monocyclic heteroaryl or a fused-ring heteroaryl. Preferably, C2-C 20 The heteroaryl group contains 1 to 3 heteroatoms, each independently selected from N, O, and S, and in each case, it can be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, and their benzo[derivatives]; or terpenolyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc.

[0041] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations by increasing flowability and / or adhesion, making the formulation more suitable for direct compression. Typical examples of pharmaceutically acceptable carriers suitable for the above-mentioned formulations include: sugars, such as lactose, sucrose, mannitol, and sorbitol, or corn starch, tapioca starch, and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; nonionic, cationic, and anionic surfactants; ethylene glycol polymers; fatty alcohols; and hydrolyzed cereal solids and other nontoxic and compatible excipients commonly used in pharmaceutical formulations, such as fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, and colorants.

[0042] According to a specific embodiment of the present invention, the present invention provides a compound, said compound being a compound of formula (I) or a tautomer, stereoisomer, hydrate, deuterated product, solvate, non-aqueous solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I);

[0043] (I) wherein A is selected from the following groups, which are unsubstituted or substituted with at least one R1and / or R2: C3-C 20 cycloalkyl, C2-C 20 heterocycloalkyl, C6-C 20 aryl, C2-C 20 heteroaryl, C7-C 24 fused ring aryl, C7-C 24 fused ring heteroaryl; or fused aryl-heterocycloalkyl, fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl group is C4-C 10 and the number of skeletal carbon atoms in the cycloalkyl group is C3-C 10 ; R 1 , R 2 each independently is selected from the group consisting of hydrogen, -OH, halogen, -CN, -COCH3, -NO2, -COOH, -CONH2, -COCH3, -SO2NH2, ester, C 1-20 alkyl, C 1-20 alkoxy, halogen-substituted C 1-20 alkyl, halogen-substituted C 1-20 alkoxy, C 1-8 alkylamino, C 1-6 dialkylamino, C 3-8 cycloalkylamino, C 1-3 alkylsulfonyl, halogen-substituted C 1-3 alkylsulfonyl, -NR 7 R 8 , -NHCO(CH2) n CH3, -CONR 7 R 8 , -SO2NR 7 R 8 , n = 1-5; R 7 , R 8 each independently is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl; or NR 7 R 8 is a 3-8 membered cyclic amine or substituted cyclic amine, the substituents being selected from the group consisting of hydrogen, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 2-8 unsaturated aliphatic alkyl, C 3-8unsaturated aliphatic cyclic group, C 3-8 saturated aliphatic heterocyclic group; the cyclic amine is selected from the group consisting of morpholine, piperazine, methylpiperazine, pyrrolidine, piperidine; L 1 and L 2 are each independently selected from the group consisting of a bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from an integer from 0 to 3; R 9 , R 10 are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 unsaturated aliphatic chain group, C 3-8 unsaturated aliphatic cyclic group, C 3-8 saturated aliphatic heterocyclic group; B is selected from the group consisting of no substitution or substitution with at least one R 3 and / or R 4 ; , , , , , , , , , , , ; R 3 , R4 each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester, C 1-20 alkyl, C 1-20 alkoxy, halogen-substituted C 1-20 alkyl, halogen-substituted C 1-20 alkoxy, C 1-8 alkylamino, C 1-6 dialkylamino, C 3-8 cycloalkylamino, C 1-3 alkylsulfone, halogen-substituted C 1-3 alkylsulfone; C in formula (I) is selected from the group consisting of unsubstituted or substituted by at least one R 5 and / or R 6 substituted by: C 1-20 alkyl, C3-C 20 cycloalkyl, C2-C 20 heterocycloalkyl, C6-C 20 aryl, C2-C 20 heteroaryl, C7-C 24 fused ring aryl, C7-C 24 fused ring heteroaryl; or fused aryl-cycloalkyl, fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl is C4-C 10 and the number of skeletal carbon atoms in the cycloalkyl is C4-C 10 ; or diheterocycloalkyl connected by carbon atoms, wherein the number of skeletal carbon atoms in each heterocycloalkyl is C2-C 10 ; R 5 and R 6 each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester, C 1-20 alkyl, C 1-20 alkoxy, halogen-substituted C 1-20 alkyl, halogen-substituted C 1-20 alkoxy, C 1-8 alkylamino, C 1-6 dialkylamino, C 3-8 cycloalkylamino, C 1-3 alkylsulfone, halogen-substituted C 1-3 alkylsulfone, wherein the heteroatom in the heteroatom-containing group is O, N, S.

[0044] The researches of the present application show that one of the key targets of the compound having the structural general formula (I) and its pharmaceutically acceptable forms is GPR97, and the compound can regulate the function of GPR97 to exert the pharmacological effect. Therefore, the compound provided by the present application can be used for treating autoimmune diseases, solid tumors and / or non-solid tumors, nervous system diseases and inflammation-related diseases, wherein the solid tumors include but are not limited to lung cancer, kidney cancer, colon cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, thyroid cancer, salivary gland cancer, fibrosarcoma, skin cancer, brain tumor and malignant melanoma; the non-solid tumors include but are not limited to leukemia, malignant lymphoma and inflammatory bowel disease.

[0045] According to a specific embodiment of the present application, the present application also provides a pharmaceutical composition containing a therapeutically effective amount of one or more compounds as described above, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a deuteride or a non-aqueous solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0046] According to a specific embodiment of the present application, the active component of the pharmaceutical preparation is any one or more of the compounds of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, prodrug or deuteride or non-aqueous solvate thereof. The carrier can be an excipient, a filler, a disintegrant, a diluent, a surfactant, an absorption enhancer, an adsorption carrier, a binder, a lubricant, a humectant, a flavoring agent, a sweetener and the like commonly used in the pharmaceutical field. The pharmaceutical preparation can be prepared according to the conventional methods of pharmacy, including but not limited to capsules, granules, powders, tablets, oral solutions and injections, etc.

[0047] According to a specific embodiment of the present application, the compound provided by the present application can also be used in combination with existing drugs, wherein the compound can be administered alone or in combination with one or more treatment modalities selected from surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy and gene therapy.

[0048] According to a specific embodiment of the present application, the present application also provides "polymorphs" containing the compound of formula (I) and its salts and solvates simultaneously. That is, the compound of formula (I) or its salts or solvates can show polymorphism, produce different crystalline forms, and have different physical properties such as density, stability and solubility.

[0049] According to a specific embodiment of the present application, the compound is administered alone or in combination with one or more therapies selected from surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy.

[0050] The present application will be explained below with reference to examples. Those skilled in the art will understand that the examples below are only for illustration of the present application and should not be considered as limiting the scope of the present application. If a specific technique or condition is not mentioned in the examples, it is performed according to the technique or condition described in the literature in the art or according to the product manual. If a reagent or instrument is not mentioned by the manufacturer, it is a conventional product that can be obtained commercially.

[0051] Example 1

[0052] Synthetic method (1) Step a: Preparation of IM1 (3-ethylbenzo[ d ]thiazole-2(3 H )-one)

[0053] Take 100 mL single-mouth bottle, dissolve SM1 (500 mg, 1.0 eq) in 6 mL N,N- dimethylformamide (DMF), place in ice bath, add sodium hydride (NaH, 266 mg, 2.0 eq), stir for 15 min. Then add SM2 (1.03 g, 2.0 eq), after addition, react at room temperature for 2 h.

[0054] Thin layer chromatography (TLC) detection shows that the raw material is almost completely reacted, stop the reaction, PE:EA (petroleum ether: ethyl acetate) = 3:1, Rf = 0.7.

[0055] Extract with ethyl acetate (EA, 30 mL x 2) and 30 mL saturated sodium chloride solution, combine the organic phase, dry with anhydrous sodium sulfate (Na2SO4), concentrate to dryness under reduced pressure, prepare sand, purify by column chromatography, PE:EA = 5:1-3:1, elute, stand at room temperature for 12 h, solidify into white solid compound 328 mg. Y%: 91.62%.

[0056] (2) Step b: Preparation of IM2 (3-ethyl-2-oxo-2,3-dihydrobenzo[ d ]thiazole-6-sulfonyl chloride)

[0057] Take 100 mL single-mouth bottle, dissolve IM1 (200 mg, 1.0 eq) in 2 mL acetonitrile (ACN), add chlorosulfonic acid (0.22 ml, 3.0 eq) under ice bath condition, after addition, warm up to 50 ℃ for reaction for 12 h after 30 min.

[0058] TLC analysis showed that the raw materials had basically reacted completely. After the reaction was complete, the reaction was stopped. The ratio of PE to EA was 3:1. f = 0.4.

[0059] The reaction system was cooled to room temperature and concentrated under reduced pressure to obtain a crude yellow oily substance. This crude substance was then processed into sand and purified by column chromatography (PE:EA = 5:1-3:1). Elution yielded 280 mg of a white solid compound. Y%: 90.35%.

[0060] (3) Step c: IM3 (( S Preparation of 1-tert-butoxycarbonyl-4-[(1,2,3,4-tetrahydro-1-naphthyl)carbamoyl]piperidine

[0061] Take a 100 mL single-necked flask, dissolve compound SM3 (300 mg, 1.0 eq) in 10 mL tetrahydrofuran (THF), add SM4 (467 mg, 1.0 eq), N,N-diisopropylethylamine (DIEA, 0.71 mL, 2.0 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 1.16 g, 1.5 eq), and react at room temperature for 2 h.

[0062] TLC analysis showed that the raw materials had basically reacted completely, and the reaction had stopped. PE:EA = 1:1, R f = 0.5.

[0063] The reaction system was concentrated to dryness under reduced pressure at 40 °C, sand was prepared, and purified by column chromatography with PE:EA = 5:1-1:1 elution to give 505 mg of white solid compound, Y%: 69.17%.

[0064] (4) Step d: IM4 (( S )- N Synthesis of (1,2,3,4-tetrahydronaphth-1-yl)piperidine-4-carboxamide

[0065] Take a 25 mL single-necked bottle, dissolve compound IM3 (100 mg, 1.0 eq) in 3 mL of dichloromethane (DCM), and add trifluoroacetic acid (TFA, 0.2 mL, 3.0 eq).

[0066] TLC analysis showed that the raw materials had almost completely reacted, and the reaction had stopped. PE:EA = 3:1, R f = 0.5.

[0067] After the reaction was completed, the reaction system was concentrated to dryness under reduced pressure to obtain a yellow oily crude product 68 mg.

[0068] (5) Preparation of compound 01

[0069] Take a 10 mL single-mouth bottle, dissolve compound IM4 (89 mg, 1.2 eq) in 3 mL DMF, add N,N-diisopropylethylamine (DIEA, 94 μL, 2.0 eq), stir for 5 min, add IM2 (130 mg, 1.0 eq), after adding, react at room temperature for 3 h.

[0070] TLC detection showed that the raw material was almost completely reacted, the reaction was stopped, PE:EA = 1:1, R f = 0.40.

[0071] The reaction system was concentrated to dryness under reduced pressure at 40°C, and the sand was prepared, and purified by column chromatography, eluted with PE:EA = 5:1-1:1, to obtain white solid compound 85 mg, Y%: 52.79%.

[0072] 1 H NMR (400 MHz, Chloroform- d ) δ 7.85 (d, J = 1.8 Hz, 1H), 7.72 (dd, J =8.4, 2.0 Hz, 1H), 7.22 – 7.12 (m, 4H), 7.10 (dt, J = 7.2, 1.2 Hz, 1H), 5.60 (d, J = 8.4 Hz, 1H), 5.17 – 5.11 (m, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.77 (dd, J =11.6, 4.0 Hz, 2H), 2.85 – 2.70 (m, 2H), 2.55 – 2.44 (m, 2H), 2.12 – 1.71 (m,9H), 1.37 (t, J = 7.2 Hz, 3H). LCMS=[M+H] + =500.64, purity 97.48% The remaining representative target compounds of the application were prepared according to the method of Example 1. The structures and characterization data of the obtained target compounds are shown in Table 1.

[0073] Table 1. Structures and Characterization

[0074] Biological Test Example 1: Evaluation of the antagonistic activity of the compounds of the present application on GPR97 in vitro Detection Step: HTLA cells were seeded in 96-well cell culture plates at a density of about 1.5-2.0 x 10 4 cells per well and incubated. Subsequently, the Tango fusion protein expression plasmid containing the GPR97 gene was mixed with polyethyleneimine (PEI) at a mass ratio of 1:4 to form a DNA-PEI complex (150 ng of GPR97-Tango plasmid was transfected per well), which was added to the seeded HTLA cells for transfection. The culture plates were incubated in an incubator at 37 °C, 5% CO2for 18-24 h to ensure sufficient expression of the GPR97-Tango protein.

[0075] After transfection, the culture medium containing PEI was discarded and replaced with DMEM medium. Dimethyl sulfoxide (DMSO) was used to prepare different concentrations of test compound solutions and ligand solutions (beclometasone propionate, BDP) respectively. The test compound was added to the culture plate, so that the cells were incubated with different concentrations of inhibitors for 1 h; then the ligand solution was added, and the incubation was continued overnight at 37 °C, 5% CO2to activate GPR97 and induce the expression of the downstream reporter gene.

[0076] The next day, remove the medium from the wells, add 20 μL NP-40, and incubate at 4 °C overnight. Take 5 μL of the lysate from each well and add to a white, high-binding plate. Add 15 μL of the luciferase assay reagent (Bright-Glo™ Luciferase Assay System), and read the relative light units (RLU) for each well using a luminometer. Calculate the IC50values by comparing the RLU values. 50 ).

[0077] The results of the detection (Table 2) are as follows: “+++” indicates that the IC 50 is 1 μM or less; “++” indicates that the IC 50 is 1-10 μM; “+” indicates that the IC 50 is 10 μM or more or no obvious activity is observed.

[0078] Table 2. Antagonistic activity of the compounds of the present application on GPR97

[0079] Biological Test Example 2: BRET experiment for detecting the antagonistic activity of compound 02 on GPR97 in vitro To detect the antagonistic activity of the examples on GPR97, we carried out a BRET recruitment experiment. The human GPR97 plasmid with a C-terminal Renilla luciferase (RLuc8) and the Venus-labeled miniGii plasmid were co-transfected into HEK293T cells at a ratio of 1:5. After 20-24 h of transfection, the transfected cells were seeded into 96-well white-bottom plates coated with polylysine at a density of 1.0-2.0 × 10 4 The next day, remove the medium from the wells, add 20 μL NP-40, and incubate at 4 °C overnight. Take 5 μL of the lysate from each well and add to a white, high-binding plate. Add 15 μL of the luciferase assay reagent (Bright-Glo™ Luciferase Assay System), and read the relative light units (RLU) for each well using a luminometer. Calculate the IC50values by comparing the RLU values. 80A concentration of the agonist (beclomethasone propionate, BDP) was diluted with a buffer solution and incubated at room temperature in the dark for 15 min. After drug incubation, the emission signal at 485 nm and the fluorescence emission signal of eYFP at 530 nm were read from each well using an LB940 Mithras microplate reader, with a detection time of 2 seconds per well. The eYFP / RLuc ratio of each well was calculated, and the net BRET ratio was then calculated. The concentration-response relationship was fitted to characterize the inhibitory effect of the GPR97 compound.

[0080] Test results ( Figure 1 In the BRET assay system, compound O2 dose-dependently inhibited the activity of GPR97, IC50. 50 It is 141.8 nM.

[0081] Biological Experiment Example 3: Evaluation of the antagonistic activity of compound 02 against G protein-coupled receptor 34 (GPR34), melanocortin 5 receptor (MC5R), and GPR97 in vitro. Detection procedure: In a 96-well cell culture plate, use approximately 1.5-2.0 × 10⁶ cells per well. 4 HTLA cells were seeded at a density of [number] cells and cultured. Subsequently, a Tango fusion protein expression plasmid containing human GPR34, MC5R, and GPR97 genes was mixed with polyethyleneimine (PEI) at a mass ratio of 1:4 to form a DNA-PEI complex (150 ng of Tango plasmid per well), which was then added to the seeded HTLA cells for transfection. The culture plates were incubated at 37 ℃ and 5% CO2 for 18–24 h to ensure adequate receptor protein expression. Different concentrations of the test compound O2 and various agonist solutions (LysoPS for GPR34; α-melanocyte-stimulating hormone (α-MSH) for MC5R; and beclomethasone propionate (BDP) for GPR97) were prepared using dimethyl sulfoxide (DMSO). The test compound O2 was added to the culture plates, and the cells were incubated with different concentrations of compound O2 for 1 h. The agonist solution was then added, and the mixture was incubated overnight at 37 °C with 5% CO2 to activate the receptor and induce the expression of the downstream reporter gene. The next day, the culture medium in the wells was removed, 20 μL of NP-40 was added, and the mixture was incubated overnight on a shaker at 4 °C. 5 μL of lysis buffer from each well was added to a white high-binding ELISA plate, followed by 15 μL of luciferase assay reagent (Bright-Glo™ Luciferase Assay System). The relative luminescent units (RLU) of each well were read using a luminescence counter, and the inhibitory levels of compound O2 on GPR34, MC5R, and GPR97 were calculated based on the RLU ratio.

[0082] Test results (Figure 2 Definitions and explanations of terms Figure 1 Figure 2 Definitions and ): Compound 02 had no inhibitory effect on GPR34 and MC5R, but had a significant inhibitory effect on GPR97 in the Tango test system, showing that Compound 02 specifically inhibits GPR97.

[0083] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", "some embodiments" or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative expressions of the above terms are not necessarily directed to the same embodiment or example. Also, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. Furthermore, the person skilled in the art can combine and combine the different embodiments or examples described in the present specification and the features of the different embodiments or examples without contradiction.

[0084] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and the person skilled in the art can make changes, modifications, substitutions and variations to the above-described embodiments within the scope of the present application.

Claims

1. A compound, characterized in that, The compound is a compound shown in formula (I) or a tautomer, stereoisomer, hydrate, deuteride, solvate, non-water solvate, pharmaceutically acceptable salt or prodrug of the compound shown in formula (I); （I） A is selected from the following groups without substitution or substitution by at least one R1 and / or R2: C3-C 20 cycloalkyl, C2-C 20 heterocycloalkyl, C6-C 20 aryl, C2-C 20 heteroaryl, C7-C 24 fused ring aryl, C7-C 24 fused ring heteroaryl; or a condensed aryl-heterocycloalkyl, condensed heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl is C4-Ci2 10 , and the number of skeletal carbon atoms in the cycloalkyl is C3-Ci0 10 ; R 1 , R 2 each independently is selected from hydrogen, -OH, halogen, -CN, -COCH3, -NO2, -COOH, -CONH2, -COCH3, -SO2NH2, ester, C 1-20 alkyl, C 1-20 alkoxy, halogen substituted C 1-20 alkyl, halogen substituted C 1-20 alkoxy, C 1-8 alkylamino, C 1-6 dialkylamino, C 3-8 cycloalkylamino, C 1-3 alkylsulfone, halogen substituted C 1-3 alkylsulfone, -NR 7 R 8 , -NHCO(CH2) n CH3, -CONR 7 R 8 , -SO2NR 7 R 8 , n = 1-5; R 7 , R 8 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl; or NR 7 R 8 is a 3-8 membered cyclic amine or substituted cyclic amine, the substituents being selected from the group consisting of hydrogen, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 2-8 unsaturated aliphatic chain alkyl, C 3-8 unsaturated aliphatic cyclic, C 3-8 saturated aliphatic heterocyclic; the cyclic amine being selected from the group consisting of morpholine, piperazine, methylpiperazine, pyrrolidine, piperidine; L 1 and L 2 are each independently selected from a bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from an integer from 0 to 3; R 9 , R 10 are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-6 unsaturated aliphatic chain hydrocarbon group, C 3-8 unsaturated aliphatic cyclic group, C 3-8 saturated aliphatic heterocyclic group; B is selected from the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 substituted by at least one R 、 、 、 、 、 、 、 、 、 、 、 ； R 3 , R 4 each independently is selected from hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester, C 1-20 alkyl, C 1-20 alkoxy, halogen-substituted C 1-20 alkyl, halogen-substituted C 1-20 alkoxy, C 1-8 alkylamino, C 1-6 dialkylamino, C 3-8 cycloalkylamino, C 1-3 alkylsulfone, halogen-substituted C 1-3 alkylsulfone; C in formula (I) is selected from the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 substituted by at least one R C 1-20 alkyl, C3-C 20 cycloalkyl, C2-C 20 heterocycloalkyl, C6-C 20 aryl, C2-C 20 heteroaryl, C7-C 24 fused ring aryl, C7-C 24 fused ring heteroaryl; or a condensed aryl-cycloalkyl, condensed heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl is C4-Ci2 10 , and the number of skeletal carbon atoms in the cycloalkyl is C4-Ci2 10 ; or a diheterocycloalkyl linked through carbon atoms, wherein the number of skeletal carbon atoms in each heterocycloalkyl group is C2-C 10 ; R 5 and R 6 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester, C 1-20 alkyl, C 1-20 alkoxy, halogen-substituted C 1-20 alkyl, halogen-substituted C 1-20 alkoxy, C 1-8 alkylamino, C 1-6 dialkylamino, C 3-8 cycloalkylamino, C 1-3 alkylsulfonyl, halogen-substituted C 1-3 alkylsulfonyl, In the group containing a heteroatom, the heteroatom is O, N or S.

2. The compound of claim 1, wherein A is selected from the following groups without substitution or substitution by at least one R1 and / or R2: C3-C 10 cycloalkyl, C2-C 10 heterocycloalkyl, C6-C 10 aryl, C2-C 10 heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; Alternatively, fused aryl-heterocyclic alkyl groups or fused heteroaryl-cycloalkyl groups, wherein the aryl or heteroaryl group has a skeletal carbon number of C4-C5. 10 The skeletal carbon number in cycloalkyl groups is C3-C8; and / or, R 1 , R 2 each independently selected from hydrogen, -OH, halogen, -CN, -COCH3, -NO2, -COOH, -CONH2, -COCH3, -SO2NH2, C 1-10 alkyl, C 1-10 alkoxy, -NR 7 R 8 , -NHCO(CH2) n CH3, -CONR 7 R 8 , -SO2NR 7 R 8 , n = 1-5; R 7 , R 8 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl; or NR 7 R 8 is a 3-8 membered cyclic amine or substituted cyclic amine, the substituents being selected from the group consisting of hydrogen, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 2-8 unsaturated aliphatic chain alkyl, C 3-8 unsaturated aliphatic cyclic, C 3-8 saturated aliphatic heterocyclic; the cyclic amine being selected from the group consisting of morpholine, piperazine, methylpiperazine, pyrrolidine, piperidine; and / or, L 1 and L 2 are each independently selected from a direct bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from an integer from 0 to 3; R 9 , R 10 are each independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 alkoxy; and / or B is selected from the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 substituted by at least one R 、 、 、 、 、 、 、 、 、 、 、 ； R 3 , R 4 each independently is selected from hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, ester, C 1-10 alkyl, C 1-10 alkoxy; and / or, in formula (I), C is selected from the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 substituted by at least one R C 1-10 alkyl, C3-C 10 cycloalkyl, C2-C 10 heterocycloalkyl, C6-C 10 aryl, C2-C 10 heteroaryl, C7-C 18 fused ring aryl, C7-C 18 fused ring heteroaryl; or a condensed aryl-cycloalkyl, condensed heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl is C4-Ci2 10 , and the number of skeletal carbon atoms in the cycloalkyl is C4-Ci2 10 ; or a diheterocycloalkyl linked through carbon atoms, wherein the number of skeletal carbon atoms in each heterocycloalkyl group is C2-C 10 ; and / or, R 5 and R 6 each independently is selected from hydrogen, -OH, halogen, -CN, -NO2, -COOH, -CONH2, -SO2NH2, C 1-10 alkyl, C 1-10 alkoxy.

3. The compound of claim 1, wherein A is selected from the following groups without substitution or substitution by at least one R1 and / or R2: C2-C 10 heterocycloalkyl, C6-C 10 aryl, C2-C 10 heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; Alternatively, fused aryl-heterocyclic alkyl groups or fused heteroaryl-cycloalkyl groups, wherein the aryl or heteroaryl group has a skeletal carbon number of C4-C5. 10 The skeletal carbon number in cycloalkyl groups is C3-C8; and / or, R 1 , R 2 each independently is selected from hydrogen, -OH, halogen, -CN, -COCH3, -NO2, -COOH, -CONH2, -COCH3, -SO2NH2, C 1-10 alkyl, C 1-10 alkoxy; and / or, L 1 and L 2 are each independently selected from a bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from integers from 0 to 1 ; R 9 , R 10 are each independently selected from hydrogen, halogen, C 1-4 alkyl; and / or B is selected from the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 substituted by at least one R 、 、 、 、 、 、 、 、 、 、 、 ； R 3 , R 4 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COOH, ester, C 1-10 alkyl, C 1-10 alkoxy; and / or, in formula (I), C is selected from the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 substituted by at least one R C 1-10 alkyl, C3-C8cycloalkyl, C4-C8heterocycloalkyl, C6-C 10 aryl, C3-C5heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; or a condensed aryl-cycloalkyl, condensed heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in the aryl or heteroaryl is C4-Ci2 10 and the number of skeletal carbon atoms in the cycloalkyl is C4-Ci2 10 ; or a diheterocycloalkyl connected by a carbon atom, wherein the number of skeletal carbon atoms in each heterocycloalkyl is C2-C8; and / or, R 5 and R 6 each independently is selected from hydrogen, -OH, halogen, -COOH, C 1-10 alkyl, C 1-10 alkoxy.

4. The compound of claim 1, wherein A is selected from the following groups without substitution or substitution by at least one R1 and / or R2: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； and / or, R 1 , R 2 each independently is selected from hydrogen, -OH, halogen, -CN, -COCH3, -COOH, -CONH2, C 1-10 alkyl; and / or, L 1 and L 2 are each independently selected from a direct bond, -(CR 9 R 10 ) p CONH(CR 9 R 10 ) q -, -(CR 9 R 10 ) p SO2(CR 9 R 10 ) q -, -(CR 9 R 10 ) p CO(CR 9 R 10 ) q -, -(CR 9 R 10 ) p -, -(CR 9 R 10 ) p NH(CR 9 R 10 ) q -, wherein p and q are each selected from integers from 0 to 1 ; R 9 , R 10 is hydrogen; and / or B is selected from the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 substituted by at least one R 、 、 、 、 、 ； R 3 , R 4 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COOH, C 1-10 alkyl, C 1-10 alkoxy; and / or, in formula (I), C is selected from the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 substituted by at least one R C 1-10 alkyl, C3-C8cycloalkyl, C4-C8heterocycloalkyl, C6-C 10 aryl, C3-C5heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; or a fused aryl-cycloalkyl, fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in aryl or heteroaryl is C4-C8 and the number of skeletal carbon atoms in cycloalkyl is C4-C8; or a diheterocycloalkyl connected by a carbon atom, wherein the number of skeletal carbon atoms in each heterocycloalkyl is C2-C5; and / or, R 5 and R 6 each independently is selected from hydrogen, -OH, halogen, -COOH, C 1-10 alkyl.

5. The compound of claim 1, wherein A is selected from the following groups without substitution or substitution by at least one R1 and / or R2: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； and / or, R 1 , R 2 each independently is selected from hydrogen, -OH, halogen, -CN, -COCH3, -COOH, C 1-10 alkyl; and / or, L 1 and L 2 each independently is selected from -S(=0)2-, -CH2-, -C(=0)NH-, -CH2-NH-, -CONH-CH2-, -CO-; and / or B is selected from the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 substituted by at least one R 、 、 、 、 、 ； R 3 , R 4 are each independently selected from the group consisting of hydrogen, -OH, halogen, -CN, -COOH, C 1-10 alkyl; and / or, in formula (I), C is selected from the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 substituted by at least one R C 1-10 alkyl, C3-C8cycloalkyl, C4-C6heterocycloalkyl, C6-C 10 aryl, C3-C5heteroaryl, C7-C 10 fused ring aryl, C7-C 10 fused ring heteroaryl; or a fused aryl-cycloalkyl, fused heteroaryl-cycloalkyl, wherein the number of skeletal carbon atoms in aryl or heteroaryl is C5-C8 and the number of skeletal carbon atoms in cycloalkyl is C4-C8; or a diheterocycloalkyl connected by a carbon atom, wherein the number of skeletal carbon atoms in each heterocycloalkyl is C2-C5; and / or, R 5 and R 6 each independently is selected from hydrogen, -OH, halogen, C 1-10 alkyl.

6. The compound of claim 1, wherein A is selected from the following groups without substitution or substitution by at least one R1 and / or R2: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； R 1 , R 2 are each independently selected from the group consisting of hydrogen, -OH, halogen, -COCH3, C 1-10 alkyl; L 1 is selected from -S(=0)2- or -CH2-; L 2 selected from -C(=0)NH-, -CH2-NH-, -CONH-CH2-, -CO-; B is selected from the following groups, which are unsubstituted or substituted by at least one R 3 and / or R 4 substituted by at least one R 、 、 、 、 、 ； R 3 , R 4 are each independently selected from hydrogen, -OH, halogen, -CN, C 1-10 alkyl; C in formula (I) is selected from the following groups, which are unsubstituted or substituted by at least one R 5 and / or R 6 substituted by at least one R 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and phenyl, C 1-10 alkyl; R 5 , R 6 are each independently selected from C 1-10 alkyl.

7. The compound of claim 1, wherein The compound is selected from any one of the following:

8. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises: a therapeutically effective amount of the compound of any one of claims 1-7, The pharmaceutical composition is used for treating a disease related to GPR97.

9. The pharmaceutical composition of claim 8, wherein, The disease related to GPR97 includes autoimmune diseases, solid tumors, non-solid tumors, nervous system diseases and inflammation-related diseases; Optionally, the solid tumors include lung cancer, kidney cancer, colon cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, thyroid cancer, salivary gland cancer, fibrosarcoma, skin cancer, brain tumor and malignant melanoma; The non-solid tumors include leukemia, malignant lymphoma and inflammatory bowel disease; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant and / or excipient.

10. Use of the compound of any one of claims 1-7 in the preparation of a medicament for treating a disease related to GPR97.

11. Use according to claim 10, characterized in that, The disease related to GPR97 includes autoimmune diseases, solid tumors, non-solid tumors, nervous system diseases and inflammation-related diseases; Optionally, the solid tumors include lung cancer, kidney cancer, colon cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, thyroid cancer, salivary gland cancer, fibrosarcoma, skin cancer, brain tumor and malignant melanoma; The non-solid tumors include leukemias, malignant lymphomas and inflammatory bowel disease.

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