Compound with Mrgpr X4 receptor inhibition effect and application thereof

Abstract

The invention provides a compound with an Mrgpr X4 receptor inhibition effect and application thereof, the structural formula of the compound is as shown in formula I: # imgabs0. The compound with a specific structure provided by the invention can effectively inhibit an Mrgpr X4 receptor, can effectively treat cholestatic pruritus, and is good in stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug research and development, and specifically relates to a compound having Mrgpr X4 receptor inhibitory effect and application thereof, and in particular relates to a compound having excellent Mrgpr X4 receptor inhibitory effect and application thereof. Background Art

[0002] Pruritus is a symptom of skin disease with only itching of the skin without primary skin damage. It can be divided into two categories: systemic and localized. Severe itching can make patients unbearable, seriously affecting their normal life, and even leading to sleep deprivation, depression and even suicide. In addition, some drugs can also cause itching, which in some cases seriously affects the compliance of patients.

[0003] It is known that some pruritus is mediated by histamine, called histamine pruritus, which can be treated with antihistamines; but another part of pruritus is not dependent on histamine, called non-histamine pruritus, such as cholestatic pruritus or chloroquine-induced pruritus, which are difficult to treat with antihistamines. Non-histamine pruritus accounts for about two-thirds of all pruritus, and the disease urgently needs to develop corresponding drugs for treatment.

[0004] Studies have shown that the MAS-related G protein-coupled receptor family (Mrgpr) is closely related to non-histamine pruritus (Cell 2001, 106 (5): 619). This family has only four genes in humans: Mrgpr X1-X4, which are expressed in human sensory neurons. Other studies have shown that Mrgpr X4 is a receptor that mediates human cholestatic pruritus (eLife 2019; 8: e48431), which is enriched in dorsal root ganglia (hDRG).

[0005] The above studies show that it is feasible to treat cholestatic pruritus by inhibiting Mrgpr X4 receptor. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide a pharmaceutical compound or a composition thereof having an Mrgpr X4 receptor inhibitory effect for preventing or treating pruritus, wherein the compound includes or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and has good application prospects in the treatment of pain, pruritus, cholestatic pruritus, drug side effects, autoimmune diseases, multiple sclerosis and other diseases.

[0007] The present application develops a class of compounds with a new structure, confirming their inhibitory effect on Mrgpr X4 receptors, and the compounds have excellent safety and in vivo pharmacokinetic properties. To achieve this invention objective, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a compound having Mrgpr X4 receptor inhibitory effect or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or an isotope-labeled substance thereof, wherein the compound has a structural formula as shown in the following formula I:

[0009]

[0010] Wherein, n is selected from 0, 1, 2 or 3, m is selected from 0, 1, 2 or 3, k is selected from 0, 1, 2, 3 or 4, and p is selected from 0, 1, 2, 3 or 4. When n, m, k and p are each 0, the group does not exist.

[0011] R 1 Selected from hydrogen, halogen, carbonyl, hydroxyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, cyano, ester, nitro, amino, C 6-12 Aryl, C 6-12 Aromatic or C 4-7 Heterocyclic rings, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms.

[0012] R 1 independently selected from m identical or different substitutions above; when m is 2 or 3, two adjacent R 1 Stand alone or together with their connected rings, form C 3-8 Aliphatic ring, C 3-8 Heterocyclic or C 6-10 Aromatic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms.

[0013] Cy1 is selected from C 3-7 Cycloalkyl, C 6-10 Aromatic ring, C 8-14 Fused heterobicyclic group, C 6-10 Aromatic heterocyclic group or C 5-7 Monocyclic heterocyclyl.

[0014] R 2 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, acyl, cyano, ester, nitro, amino, C 6-12 Aryl, C 6-12 Aryloxy, C 6-12 Aromatic or C 4-7Heterocyclic rings, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms.

[0015] R 2 independently selected from k identical or different substitutions above; when k is 2, 3 or 4, two adjacent R 2 Stand alone or together with their connected rings, form C 3-8 Aliphatic ring, C 3-8 Heterocyclic or C 6-10 An aromatic ring group, wherein the above group is unsubstituted or substituted with 1 to 5 halogen atoms.

[0016] R 3 Selected from C 1-6 Alkylcarboxyl, -C(=O)OR 5 , C 2-6 Alkyl, amino, C 1-6 Alkylamino, C 1-6 Alkylamide, imidazole, triazolyl, tetrazolyl, cyano, nitro or -C(=O)NH-SO2-R 7 , where R 5 Selected from hydrogen, R 6 Substituted C 1-6 Alkyl, C 6-10 Aromatic ring group, C 6-10 Aromatic or C 4-7 Heterocyclic ring, wherein the C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur.

[0017] R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl or C 1-6 Alkoxy groups, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms.

[0018] R 7 Selected from hydrogen, R 8 Substituted C 1-6 Alkyl, C 3-7 Cycloalkyl, benzyl, phenyl, naphthyl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, in which C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur; R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy groups, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms.

[0019] Cy2 is selected from C 3-8 Cycloalkyl, C 6-10Aryl, C 8-14 Fused heterobicyclic group, C 6-10 Aromatic heterocyclic group or C 5-7 Monocyclic heterocyclyl.

[0020] R 4 is selected from hydrogen, halogen, hydroxyl, cyano, ester, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkoxy, C 6-12 Aryl, C 6-12 Aryloxy or C 4-7 Heterocycle; wherein the above groups are unsubstituted or substituted by 1-5 halogen atoms.

[0021] R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Stand alone or together with their connected rings, form C 3-7 Aliphatic ring, C 3-8 Heterocyclic or C 6-10 Aromatic rings, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms.

[0022] The above-mentioned specific structural compound can effectively inhibit the MRGPRX4 receptor, can effectively treat cholestatic pruritus, and has good stability.

[0023] Preferably, R 1 Selected from hydrogen, fluorine, chlorine, bromine, iodine, carbonyl, hydroxyl, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, cyano, ester, nitro, amino, C 6-12 Aryl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms.

[0024] Preferably, R 1 independently selected from m identical or different substitutions above; when m is 2 or 3, two adjacent R 1 Independently or together with the rings they are connected to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-8 Heterocyclic or C 6-10 An aromatic ring wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0025] Preferably, Cy1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridinyl, benzofuran, benzimidazole, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrimidinyl, purinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl or piperazinyl.

[0026] Preferably, R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, acyl, hydroxyl, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, cyano, ester, nitro, amino, phenyl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms.

[0027] Preferably, R 2 independently selected from k identical or different substitutions above; when k is 2, 3 or 4, two adjacent R 2 Independently or together with the rings they are connected to form cyclopropyl, cyclobutyl, cyclopentyl, C 3-8 Heterocyclic or C 6-10 An aromatic ring group, wherein the above group is unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0028] Preferably, R 3 Selected from formate, acetate, propionate, -C(=O)OR 5 , acetate, propionate, acetonitrile, cyano, nitro, amino, formamide, acetamide, propionamide, imidazole, triazolyl, tetrazolyl or -C(=O)NH-SO2-R 7 .

[0029] Preferably, R 5 Selected from hydrogen, R 6 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, C 6-10 Aromatic or C 4-7 Heterocyclic ring, wherein the C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur.

[0030] Preferably, R 6 Selected from hydrogen, fluorine, chlorine, C 1-3 Alkyl, C 3-7 Cycloalkyl or C 1-3 Alkoxy groups, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0031] Preferably, R 7 Selected from hydrogen, R 8 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, in which C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur.

[0032] Preferably, R 8 Selected from hydrogen, fluorine, chlorine, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy groups, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0033] Preferably, Cy2 is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl, furanyl, pyrrolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrimidinyl, purinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl or piperazinyl.

[0034] Preferably, R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, ester, nitro, amino, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy or C 4-7 Heterocycle; wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms.

[0035] Preferably, R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Independently or together with the rings they are connected to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-8 Heterocyclic or C 6-10 An aromatic ring wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0036] Preferably, the structural formula of the compound is as shown in Formula II below:

[0037]

[0038] Wherein, n is selected from 1 or 2, m is selected from 0, 1 or 2, k is selected from 0, 1, 2 or 3, and p is selected from 0, 1, 2, 3 or 4. When m, k and p are each 0, the group does not exist.

[0039] Ar1 is selected from phenyl, naphthyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridinyl, benzofuran, benzimidazole, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrimidinyl or purinyl.

[0040] R 1 , R 2 , R 3 , R 4 , Cy2 limitation range is the same as above.

[0041] Preferably, R 1 is selected from hydrogen, fluorine, chlorine, bromine, carbonyl, hydroxyl or substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyloxy, cyano, ester, nitro, amino, phenyl, naphthyl, anthracenyl, phenanthrenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridinyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, morpholinyl, piperidinyl or piperazinyl, wherein the substituted group is fluorine or chlorine, and the number of substitutions is 1-5.

[0042] Preferably, when m is 2, two adjacent R 1 Together with the ring to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, epoxypropyl, epoxybutyl, epoxypentyl, pyrrolidinyl, tetrahydrofuranyl, phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl or quinolyl, wherein the above groups are unsubstituted or substituted with 1-5 fluorine or chlorine atoms.

[0043] Preferably, R 2 is selected from hydrogen, fluorine, chlorine, bromine, carbonyl, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyloxy, acetyl, cyano, ester, nitro, amino, phenyl, C 6-12 Aromatic or C 4-7 Heterocyclic rings, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine or chlorine atoms.

[0044] Preferably, R 3 Selected from formate, acetate, -C(=O)OR 5 , acetate, acetonitrile, cyano, nitro, amino, formamide, acetamide, imidazole, triazolyl, tetrazolyl or -C(=O)NH-SO2-R 7 .

[0045] Preferably, R 5 Selected from hydrogen, R 6Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl or C 4-7 Heterocyclic ring, wherein the C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur.

[0046] Preferably, R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0047] Preferably, R 7 Selected from hydrogen, R 8 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl or C 4-7 Heterocyclic ring, in which C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur.

[0048] Preferably, R 8 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0049] Preferably, Cy2 is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, naphthyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, benzofuran, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl.

[0050] Preferably, R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, ester, nitro, amino, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, phenoxy, benzyloxy or C 4-7 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms.

[0051] Preferably, R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Independently or together with the rings to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl or C 3-8 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms.

[0052] Preferably, Ar1 is selected from phenyl, naphthyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl or quinolinyl.

[0053] Preferably, R 1 Selected from hydrogen, fluorine, chlorine, carbonyl, hydroxyl or substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, cyclopropyloxy, cyano, ester, nitro, amino, phenyl, naphthyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, benzofuran, benzoxazolyl, morpholinyl, piperidinyl or piperazinyl, the substituted group is fluorine or chlorine, and the number of substitutions is 1-5.

[0054] Preferably, when m is 2, two adjacent R 1 Together with the ring to which they are attached, they form cyclopropyl, cyclobutyl, epoxypropyl, epoxybutyl, pyrrolidinyl, phenyl, oxazolyl, thiazolyl, pyrrolyl or pyridyl, wherein the above groups are unsubstituted or substituted with 1-5 fluorine or chlorine atoms.

[0055] Preferably, R 2 is selected from hydrogen, fluorine, chlorine, bromine, carbonyl, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyloxy, acetyl, cyano, ester, nitro, amino, pyrrolidinyl, phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl or pyridyl, wherein the above groups are unsubstituted or substituted by 1-5 fluorine or chlorine atoms.

[0056] Preferably, R 3 Selected from formate, acetate, -C(=O)OR 5 , methyl acetate, cyano, amino, formamide, imidazole, triazolyl, tetrazolyl or -C(=O)NH-SO2-R 7 .

[0057] Preferably, R 5 Selected from hydrogen, R 6 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl or phenyl.

[0058] Preferably, R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl or propyl, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0059] Preferably, R 7 Selected from hydrogen, R 8Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl or phenyl.

[0060] Preferably, R 8 is selected from hydrogen, fluorine, chlorine, methyl, ethyl or propyl, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

[0061] Preferably, Cy2 is selected from cyclobutane, cyclopentane, cyclohexane, phenyl, naphthyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, benzofuran, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinolyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl.

[0062] Preferably, R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, ester, nitro, amino, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, phenoxy, benzyloxy or C 4-7 Heterocyclic rings, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms.

[0063] Preferably, R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Independently or together with the rings to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, epoxypropyl, epoxybutyl, epoxypentyl, pyrrolidinyl, phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl or pyridyl, wherein the above groups are unsubstituted or substituted with 1-5 fluorine atoms or chlorine atoms.

[0064] Preferably, the structural formula of the compound is as shown in the following formula III, formula IV, and formula V:

[0065]

[0066] wherein Ar1 is selected from phenyl, naphthyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl or quinolyl.

[0067] Cy2 is selected from cyclobutane, cyclopentane, cyclohexane, benzyl, phenyl, naphthyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, benzofuran, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinolyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl.

[0068] q is independently selected from 0, 1 or 2. When q is 0, it means that the group does not exist.

[0069] R 1 , R2 , R 4 The limited ranges of Cy2, m, n, p, and k are the same as above.

[0070] Preferably, the compound is selected from the following structures:

[0071]

[0072]

[0073]

[0074]

[0075] Among them, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or stereoisomers or prodrugs of the compounds of the present application are compounds prepared by introducing aliphatic, halogen, heterocyclic or aromatic substituents into the ring of the compound molecule shown in Formula I.

[0076] In a second aspect, the present invention provides a pharmaceutical composition, which comprises the compound having Mrgpr X4 receptor inhibitory effect as described above and a pharmaceutically acceptable adjuvant, wherein the adjuvant comprises any one of a carrier, an excipient, a diluent, a binder, a wetting agent, a disintegrant, an emulsifier, a solubilizer, a solubilizing agent, an osmotic pressure regulator, a surfactant, a colorant, a pH regulator, an antioxidant, an antibacterial agent or a buffer, or a combination of at least two thereof.

[0077] In a third aspect, the present invention provides use of the compound having MrgprX4 receptor inhibitory effect as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotope-labeled product thereof, or the pharmaceutical composition as described above, in the preparation of a MrgprX4 receptor inhibitor.

[0078] In a fourth aspect, the present invention provides the use of the compound having Mrgpr X4 receptor inhibitory effect as described above or its pharmaceutically acceptable salt or stereoisomer or isotope label or the pharmaceutical composition as described above in the preparation of a drug for treating skin itching caused by a disease, characterized in that the disease includes neurodermatitis, pain, liver, biliary tract disease, chronic nephritis, chronic pyelonephritis, diabetes, thyroid disease, drug allergy, vitamin deficiency, external genital infection, autoimmune disease, multiple sclerosis, chickenpox, measles, flat warts, bacterial skin diseases, herpes, folliculitis, fungal skin diseases, tinea capitis, tinea manuum, tinea pedis, tinea corporis, tinea cruris, Tinea versicolor, parasitic and animal skin diseases, hookworm dermatitis, schistosoma dermatitis, creeping eruption, lice, mosquito bites, mite dermatitis, mulberry caterpillar dermatitis, scabies, prickly heat, polymorphic light eruption, solar dermatitis, chilblain, frictional lichenoid eruption, herpetic skin diseases, dermatitis herpetiformis, bullous pemphigoid, herpes gestationis, cirrhosis of the liver, cholelithiasis, bile duct tumor diseases, neurological dysfunction skin diseases, pruritus, prurigo, nodular prurigo, prurigo gestationis, exudative discoid and lichen dermatitis, diabetes, iron deficiency anemia, high bile acid concentration, lymphatic system tumors, granuloma herpetiformis, Hodgkin's disease or myeloproliferation.

[0079] In a fifth aspect, the present invention also provides the use of the compound having Mrgpr X4 receptor inhibitory effect as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotope-labeled product thereof, or the pharmaceutical composition as described above, in the preparation of a drug for treating cholestatic pruritus.

[0080] Compared with the prior art, the present invention has the following beneficial effects:

[0081] The specific structural compound provided by the present invention can effectively inhibit Mrgpr X4 receptor, can effectively treat cholestatic pruritus, and has good stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 is the chiral preparative chromatogram of methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoate in Example 20;

[0083] Figure 2 This is the chiral preparative chromatogram of methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoate in Example 49.

[0084] Figure 3 This is the optical resolution spectrum of 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-trifluoromethylbenzoic acid in Example 96. DETAILED DESCRIPTION

[0085] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0086] As used herein, "alkyl" refers to a saturated hydrocarbon group or an unsaturated chain alkyl group, and "chain alkyl" refers to a straight-chain or branched alkyl group, such as C1-C6 chain alkyl refers to a saturated or unsaturated, straight-chain or branched alkyl group having 1 to 6 carbon atoms, wherein examples of saturated straight-chain alkyl groups include but are not limited to ethyl, n-propyl, etc., examples of saturated branched-chain alkyl groups include but are not limited to isopropyl, tert-butyl, etc., examples of unsaturated straight-chain alkyl groups include but are not limited to vinyl, propenyl, etc., and examples of unsaturated branched-chain alkyl groups include but are not limited to 2-methylpropenyl, etc.; "cycloalkyl" refers to an alkyl group having a cyclic structure, such as C3-C6 cycloalkyl refers to a saturated or unsaturated alkyl group having a cyclic structure having 3 to 6 carbon atoms, wherein examples of saturated cyclic alkyl groups include but are not limited to cyclopropyl, cyclopentyl, ethyl-substituted cyclohexyl, etc., and examples of unsaturated cyclic alkyl groups include but are not limited to cyclopentene, etc.

[0087] The term "halogen" means F, Cl, Br, I and the like, preferably F, Cl, Br, particularly preferably F and Cl.

[0088] The term "alkoxy" refers to an alkyl group directly linked to oxygen, such as methoxy, ethoxy, and the like.

[0089] The term "substituted" refers to the replacement of a hydrogen radical in a particular structure with a group of a specified substituent. In the general formula, a short line drawn from outside the ring into the ring indicates that the substituent is not fixed in the position on the ring and can be substituted at any position allowed by chemical bonds.

[0090] The present application includes the free form of the compound of formula I, and also includes its pharmaceutically acceptable salt and stereoisomer. The pharmaceutically acceptable salt of the present application can be synthesized from the present application compound containing the basic part or the acidic part by conventional chemical methods. Usually, the salt of the basic compound is prepared by ion exchange chromatography or by reacting the inorganic or organic acid of the desired salt form in a suitable solvent or a combination of multiple solvents with a free base and a stoichiometric amount or an excess. Similarly, the salt of the acidic compound is formed by reacting with a suitable inorganic or organic base.

[0091] Therefore, the pharmaceutically acceptable salts of the compounds of the present application include conventional non-toxic salts of the compounds of the present application formed by reacting the alkaline compounds of the present application with inorganic or organic acids. For example, conventional non-toxic salts include salts prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

[0092] If the compound of the present application is acidic, then suitable "pharmaceutically acceptable salts" refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0093] The compounds defined in the present invention can be prepared by conventional preparation methods in the art. Illustratively, the present invention provides the following preparation methods, but it does not mean that the compounds of the present invention can only be prepared by the following methods.

[0094] The following synthesis scheme lists the experimental steps for preparing the compounds disclosed in this application. 1 , R 2 , R 3 , R 4 , R 5 , R 7 , m, n, k, p, q have the definitions as described in this application.

[0095] Synthesis Scheme 1:

[0096]

[0097] A halogenated aromatic compound (1) and a boronic acid compound (2) are coupled under the action of a palladium catalyst to generate a compound (3), the compound (3) is hydrogenated and reduced to generate a compound (4), the compound (4) is deprotected under acidic conditions to generate a compound (5), the compound (5) is coupled with a compound (6) under the action of a palladium catalyst to generate a compound (7), and the compound (7) is hydrolyzed to generate a compound (8).

[0098] Synthesis Scheme 2:

[0099]

[0100] The carboxylic acid compound (8) is coupled with the sulfonamide compound (9) to generate the compound (10)

[0101] Synthesis Scheme 3:

[0102]

[0103] A halogenated aromatic compound (1) and a boric acid compound (11) are coupled under the action of a palladium catalyst to generate a compound (12), the compound (12) is hydrogenated and reduced to generate a compound (13), the compound (13) is deprotected under acidic conditions to generate a compound (14), the compound (14) is coupled with a compound (6) under the action of a palladium catalyst to generate a compound (15), the compound (15) is hydrolyzed to generate a compound (16), and the compound (16) is coupled with a sulfonamide compound (9) to generate a compound (17).

[0104] Synthesis Scheme 4:

[0105]

[0106] The arylboronic acid compound (18) and the halogenated pyridyl compound (19) are coupled in the presence of a palladium catalyst to generate a compound (20), the compound (20) is hydrogenated and reduced to generate a compound (21), the compound (21) is coupled with the compound (6) in the presence of a palladium catalyst to generate a compound (22), and the compound (22) is hydrolyzed to generate a compound (23).

[0107] Synthesis Scheme 5:

[0108]

[0109] The aryl ester compound (8) is aminolyzed to form an aryl amide compound (24), and the aryl amide compound (24) reacts with an azide compound (25) to form a compound (26).

[0110] Example 1 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0111]

[0112] Step 1) tert-butyl 3-(2-fluoro-3-methoxycarbonyl)phenyl-1H-pyrrole-1-carboxylate

[0113]

[0114] Dissolve 3-bromo-2-fluorobenzoic acid methyl ester (10mmol, 2.13g) and 1-Boc-3-pyrrole boronic acid pinacol ester (10mmol, 2.93g) in 50mL of a mixed solvent of ethylene glycol dimethyl ether and water (v:v=4:1), add bistriphenylphosphine palladium dichloride (Pd(dppf)Cl2) (1mmol, 700mg), sodium carbonate (50mmol, 4.2g), protect with nitrogen, react at 80°C for 4 hours, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (dichloromethane:methanol=200:1) to obtain the title compound as a white solid (2.80g, 88%). Identified as the target compound by mass spectrometry: MS-ESI (m / z)=302[M+H] + .

[0115] Step 2) tert-Butyl 3-(2-fluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

[0116]

[0117] Dissolve tert-butyl 3-(2-fluoro-3-methoxycarbonyl)phenyl-1H-pyrrole-1-carboxylate (9.17mmol, 2.80g) in 2mL of methanol, add 2mL of concentrated HCl, add palladium hydroxide (2mmol, 280mg), and react at 90°C for 48 hours under 5bar of hydrogen pressure. Filter out palladium hydroxide, and concentrate under reduced pressure to remove the solvent to obtain a crude product of tert-butyl 3-(2-fluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate, which is used directly in the next step without further purification.

[0118] Step 3) Methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate

[0119]

[0120] The crude product tert-butyl 3-(2-fluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at 20°C for 1 hour. The solvent was removed by concentration under reduced pressure, and a sodium hydroxide aqueous solution (1M) was added to adjust the pH value to neutral. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, and anhydrous sodium sulfate was filtered off. The solvent was removed by concentration under reduced pressure to obtain a crude product. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate as a transparent viscous oil (1.60 g, two-step yield 83%). MS-ESI (m / z) = 224 [M+H] + .

[0121] Step 4) 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester

[0122]

[0123] Dissolve methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate (0.2mmol, 41mg) in 5mL toluene, add 3-chloro-4-iodotrifluoromethylbenzene (0.25mmol, 76mg), palladium acetate (0.02mmol, 4.5mg), BINAP (1.0mmol, 622mg), cesium carbonate (0.6mmol, 194mg), protect with nitrogen, react at 100℃ for 4 hours, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the product methyl 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoate as a white solid (17mg, 25%). MS-ESI (m / z) = 402 [M+H] + .

[0124] Step 5) 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0125]

[0126] Methyl 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoate (0.042mmol, 17mg) was dissolved in 2mL of tetrahydrofuran, 0.5mL of 1M sodium hydroxide aqueous solution was added, methanol was added dropwise until the reaction solution was clear, and stirred at 20°C overnight. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid as a white solid (13mg, 79%). 1H NMR (400MHz, CDCl3) δ7.95-7.91 (m, 1H), 7.62-7.49 (m, 2H), 7.38 (d, J=8.2Hz, 1H), 7.24-722 (m, 1H), 6.86 (d, J= 8.6Hz, 1H), 3.89-3.79(m, 2H), 3.76-3.61(m, 3H), 2.44-2.40(m, 1H), 2.20-2.11(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0127] Example 2 2-Fluoro-3-(1-(naphthalen-1-yl)pyrrolidin-3-yl)benzoic acid

[0128]

[0129] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 1-iodonaphthalene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 35%.

[0130] 1 H NMR (400MHz, CDCl3) δ8.26–8.13(m, 1H), 7.92-7.90(m, 1H), 7.83-7.81(m, 1 H), 7.76-7.73(m, 1H), 7.57-7.33(m, 4H), 7.26-7.22(m, 1H), 7.02(d, J=6.6 Hz, 1H), 4.01–3.84 (m, 1H), 3.84–3.72 (m, 1H), 3.58 (t, J=6.8Hz, 2H), 3.57– 3.45(m, 1H), 2.59-2.50(m, 1H), 2.23-2.14(dm, 1H).MS-ESI(m / z)=336[M+H] + .

[0131] Example 3 2-Fluoro-3-(1-phenylpyrrolidin-3-yl)benzoic acid

[0132]

[0133] Using methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate and iodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 37%.

[0134] 1H NMR (400MHz, CDCl3) δ7.91-7.88 (m, 1H), 7.55-7.45 (m, 1H), 7.33-7.23 (m, 2H), 7.20-7.16 (m, 1H), 6.71 (t, J=7.3Hz, 1H), 6.61 (d, J= 8.1Hz, 2H), 3.92-3.88(m, 1H), 3.78-3.74(m, 1H), 3.53-3.37(m, 3H), 2.50-2.37(m, 1H), 2.20-2.11(m, 1H).MS-ESI(m / z)=286[M+H] + .

[0135] Example 4 3-(1-(2,4-difluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0136]

[0137] Using methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate and 2,4-difluoroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 39%.

[0138] 1 H NMR (400MHz, CDCl3) δ8.04–7.79 (m, 1H), 7.69–7.45 (m, 1H), 7.34–7.12 (m, 2H), 6.91–6.71 (m, 2H), 6.71–6.49 (m, 1H), 4.03–3.64 (m, 2H), 3.62–3.32 (m, 3H), 2.57–2.32 (m, 1H), 2.25–1.95 (m, 1H).MS-ESI (m / z)=322[M+H] + .

[0139] Example 5 3-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluorobenzamide

[0140]

[0141] 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester was used as raw material (0.08mmol, 32mg) and dissolved in 5mL of ammonia water. The reaction was carried out at 70°C for 4 hours. The solvent was removed by concentration under reduced pressure. The obtained residue was purified to obtain the product 3-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluorobenzamide as a white solid (11mg, 33%).

[0142] 1H NMR (400MHz, CDCl3) δ8.03-8.00 (m, 1H), 7.55-7.48 (m, 1H), 7.39-7.37 (m, 1H), 7.28–7.25 (m, 1H), 6.86 (d, J=8.7Hz, 1H ), 6.67(br, 1H), 5.87(br, 1H), 3.88-3.61(m, 5H), 2.44-3.40(m, 5.1Hz, 1H), 2.21-2.14(m, 1H).MS-ESI(m / z)=387[M+H] + .

[0143] Example 6 3-(1-(2-chlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0144]

[0145] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 13%.

[0146] 1 H NMR (400MHz, CDCl3) δ7.91 (t, J=6.7Hz, 1H), 7.66 (t, J=6.6Hz, 1H), 7.32 (dd, J=7.9, 1.5Hz, 1H), 7.29–7.13 (m, 2H), 6.93 (dd, J=8.2, 1.1Hz, 1H ), 6.89–6.73(m, 1H), 3.92–3.78(m, 1H), 3.77–3.66(m, 1H), 3.64–3.44(m, 3H), 2.52–2.36(m, 1H), 2.15-2.05(m, 1H).MS-ESI(m / z)=320[M+H] + .

[0147] Example 7 2-Fluoro-3-(1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)benzoic acid

[0148]

[0149] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 4-iodotrifluorotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 48%.

[0150] 1H NMR (400MHz, MeOD) δ7.83-7.77 (m, 1H), 7.56-7.51 (m, 1H), 7.43 (d, J = 8.8Hz, 2H), 7.22 (t, J = 7.7Hz, 1H), 6.68 (d, J = 8.7Hz, 2H), 3.92-3.85(m, 1H), 3.81-3.77(m, 1H), 357–3.36(m, 3H), 2.50-2.43(m, 1H), 2.29–2.17(m, 1H).MS-ESI(m / z)=354[M+H] + .

[0151] Example 8 3-(1-(3,4-difluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0152]

[0153] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3,4-difluoroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 21%.

[0154] 1 H NMR (400MHz, CDCl3) δ7.91 (t, J=6.9Hz, 1H), 7.62 (t, J=6.3Hz, 1H), 7.31–7.07 (m, 3H), 6.76-6.71 (m, 1H), 3.94–3 .76(m, 1H), 3.72-3.63(m, 1H), 3.57–3.39(m, 3H), 2.45-2.36(m, 1H), 2.16-2.07(m, 1H).MS-ESI(m / z)=322[M+H] + .

[0155] Example 9 2-Fluoro-3-(1-(m-tolyl)pyrrolidin-3-yl)benzoic acid

[0156]

[0157] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-iodotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 13%.

[0158] 1H NMR (400MHz, CDCl3) δ7.85-7.81(m, 1H), 7.44-7.41(m, 1H), 7.13-7.06(m, 2H), 6.4-6.37(m, 3H), 3.87–3.75(m, 1H) , 3.70-3.66(m, 1H), 3.50-3.17(m, 4H), 2.38-2.36(m, 1H), 2.26(s, 3H), 2.20-1.92(m, 1H).MS-ESI(m / z)=300[M+H] + .

[0159] Example 10 3-(1-(3-chlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0160]

[0161] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 25%.

[0162] 1 H NMR (400MHz, CDCl3) δ7.97–7.87(m, 1H), 7.49-7.45(m, 1H), 7.22-7.15(m, 2H) , 6.67 (dd, J=7.9, 1.2Hz, 1H), 6.57 (t, J=2.1Hz, 1H), 6.46 (dd, J=8.3, 1.9Hz, 1 H), 3.95–3.82(m, 1H), 3.80–3.70(m, 1H), 3.52–3.42(m, 2H), 3.42–3.32(m, 1H ), 2.50-2.42(m, 1H), 2.24-2.15(m, 12.4, 7.9Hz, 1H).MS-ESI(m / z)=320[M+H] + .

[0163] Example 11 3-(1-(3-cyanophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0164]

[0165] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-iodobenzonitrile as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 35%.

[0166] 1H NMR (400MHz, CDCl3) δ7.91 (t, J=7.2Hz, 1H), 7.45 (t, J=6.5Hz, 1H), 7.32–7.14 (m, 2H), 6.96 (d, J=7.6Hz, 1H), 6.77-7.75 (d, J=8.4Hz, 2H), 3.90-3.86(m, 1H), 3.78-3.74(m, 1H), 3.50-3.44(m, 2H), 3.39-3.36(m, 1H), 2.51-2.43(m, 1H), 2.25–2.15(m, 3H).MS-ESI(m / z)=311[M+H] + .

[0167] Example 12 2-Fluoro-3-(1-(pyridin-3-yl)pyrrolidin-3-yl)benzoic acid

[0168]

[0169] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-iodopyridine as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 36%.

[0170] 1 H NMR (400MHz, DMSO) δ8.04 (d, J=2.6Hz, 1H), 7.94 (d, J=4.6Hz, 1H), 7.77-7.73 (m, 1H), 7.64-7.61 (m, 1H), 7.43-7.40 (m, 1H), 7.30–7.23 (m, 2H), 3.86–3.35 (m, 5H), 2.44-2.33 (m, 4.2Hz, 1H), 2.23–2.08 (m, 1H). MS-ESI (m / z) = 287 [M+H] + .

[0171] Example 13 3-(1-cyclohexylpyrrolidin-3-yl)-2-fluorobenzoic acid

[0172]

[0173] Step 1) Methyl 3-(1-cyclohexylpyrrolidin-3-yl)-2-fluorobenzoate

[0174] At 20°C, methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate (0.05mmol, 110mg) and cyclohexanone (0.06mmol, 54mg) were dissolved in 5mL of dichloromethane, reacted at 20°C for 0.5h, sodium cyanoborohydride (0.10mmol, 62mg) was added, and the solvent was removed by concentration under reduced pressure. A saturated sodium bicarbonate solution (10mL) was added, and the mixture was extracted with ethyl acetate (10mL×3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product (85mg, 66%).

[0175] Step 2) 3-(1-cyclohexylpyrrolidin-3-yl)-2-fluorobenzoic acid

[0176] At 20°C, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoate (85 mg, 0.28 mmol) was dissolved in tetrahydrofuran / water / methanol (2 / 1 / 2, 5 mL). Sodium hydroxide (25 mg, 0.62 mmol) was added at 20°C, and the resulting mixture was reacted at 20°C for 2 hours. The reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, water (10 mL) was added, and ethyl acetate was extracted (10 mL×3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain the target products 12A (30 mg) and 12B (34 mg). The total yield was 82%.

[0177] 12A: 1 H NMR (400MHz, MeOD) δ7.55-7.51 (m, 1H), 7.37-7.33 (m, 1H), 7.13 (t, J=7.6Hz, 1H), 3.84–3.69 (m, 2H), 3.59-3.55 (m, 1H), 3.54–3.4 3(m, 2H), 3.08-3.01(m, 1H), 2.48-2.43(m, 1H), 2.28-2.16(m, 3H), 1.81–1.64(m, 2H), 1.49–1.14(m, 6H).MS-ESI(m / z)=292[M+H] + .

[0178] 12B: 1H NMR (400MHz, MeOD) δ7.92-7.82(m, 1H), 7.66-7.62(m, 1H), 7.29(t, J=7.8Hz, 1H), 3.98-3.92(m, 1H), 3.84-3.73(d, J=34.4Hz, 2H), 3.62-3.48(m , 1H), 3.26-3.20m, 1H), 2.57-2.51(m, 1H), 2.22-2.20(m, 3H), 1.94-1.9 1(m, 2H), 1.74-1.71(m, 1H), 1.52–1.17(m, 6H).MS-ESI(m / z)=292[M+H] + .

[0179] Example 14 3-(1-cyclopentylpyrrolidin-3-yl)-2-fluorobenzoic acid

[0180]

[0181] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and cyclopentanone as raw materials, the preparation method was the same as Example 13, and the product was a white solid powder with a two-step yield of 56%.

[0182] 1 H NMR (400MHz, MeOD) δ7.63-7.60 (m, 1H), 7.44-7.40 (m, 1H), 7.17 (t, J=7.7Hz, 1H), 3.91-3.86 (m, 2H), 3.76–3.50 (m, 3H), 3.48-3.34(m, 1H), 2.55-2.47(m, 1H), 2.36–2.23(m, 1H), 2.21-2.14(m, 2H), 1.94–1.63(m, 6H).MS-ESI(m / z)=278[M+H] + .

[0183] Example 15 2-Fluoro-3-(1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)benzoic acid

[0184]

[0185] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-iodotrifluorotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 34%.

[0186] 1H NMR (400MHz, CDCl3) δ7.94-7.91(m, 1H), 7.51-7.47(m, 1H), 7.35-7.31(m, 1H), 7.23-7.19(m, 2H), 6.95-6.93(m, 1H), 6.87–6.59 (m, 2H), 3.92–3.86 (m, 1H), 3.82-3.77 (m, 1H), 3.53–3.39 (m, 3H), 2.51-2.44 (m, 1H), 2.24–2.19 (m, 1H).MS-ESI (m / z)=354[M+H] + .

[0187] Example 16 3-(1-(4-chlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0188]

[0189] Using methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate and 4-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 39%.

[0190] 1 H NMR (400MHz, CDCl3) δ7.92 (t, J=7.2Hz, 1H), 7.48 (t, J=7.0Hz, 1H), 7.23-7.18 (m, 3H), 6.51 (d, J=8.7Hz, 2H), 3.98 –3.82(m, 1H), 3.75-3.71(m, 1H), 3.50–3.34(m, 3H), 2.50-2.42(m, 1H), 2.23-2.14(m, 1H).MS-ESI(m / z)=320[M+H] + .

[0191] Example 17 3-(1-(4-cyanophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0192]

[0193] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 4-iodobenzonitrile as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 45%.

[0194] 1H NMR (400MHz, CDCl3) δ7.96-7.93 (m, 1H), 7.50-7.46 (m, 3H), 7.25-7.21 (m, 1H), 6.56 (d, J=8.8Hz, 2H) , 3.94-3.81(m, 2H), 3.59–3.40(m, 3H), 2.53-2.46(m, 1H), 2.29-2.20(m, 1H).MS-ESI(m / z)=311[M+H] + .

[0195] Example 18 5-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

[0196]

[0197] Using 5-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one and 3-chloro-4-iodobenzotrifluoride as raw materials, the preparation method is the same as that in Example 1. The product is a white solid powder, and the total yield of 4 steps is 13%.

[0198] 1 H NMR (400MHz, CDCl3) δ8.06-8.05 (m, 1H), 7.55-7.54 (m, 1H), 7.45-7.43 (m, 1H), 7.40–7.30 (m, 2H), 6.84 (d, J=8.6Hz, 1H), 3.85– 3.70(m, 2H), 3.70–3.50(m, 5H), 3.17(s, 3H), 3.09-3.05(m, 2H), 2.38-2.31(m, 1H), 2.20–2.08(m, 1H).MS-ESI(m / z)=409[M+H] + .

[0199] Example 19 3-(1-(4-chloro-2-methylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0200]

[0201] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-iodo-6-chlorotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 35%.

[0202] 1H NMR (400MHz, CDCl3) δ7.92-7.88 (m, 1H), 7.65-7.62 (m, 1H), 7.23-7.19 (m, 1H), 7.11–7.07 (m, 2H), 6.84 (d, J=8.5Hz, 1H), 3.87- 3.79(m, 1H), 3.55–3.51(m, 1H), 3.41-3.29(m, 3H), 2.47-2.38(m, 1H), 2.30(s, 3H), 2.14–2.05(m, 1H).MS-ESI(m / z)=334[M+H] + .

[0203] Example 20 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0204]

[0205] Step 1) 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester

[0206]

[0207] Dissolve methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate (1mmol, 205mg) in 5mL toluene, add 3,4-dichloroiodobenzene (1.25mmol, 335mg), palladium acetate (0.1mmol, 22.5mg), BINAP (5.0mmol, 3.1g), cesium carbonate (3mmol, 970mg), protect with nitrogen, react at 100℃ for 4 hours, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the product methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoate as a white solid (195mg, 60%). MS-ESI (m / z) = 368 [M+H] + .

[0208] Step 2) 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0209]

[0210] Dissolve methyl 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoate (0.11mmol, 39mg) in 2mL tetrahydrofuran, add 0.5mL of 1M sodium hydroxide aqueous solution, add methanol dropwise until the reaction solution is clear, and stir overnight at 20°C. Concentrate under reduced pressure to remove the solvent, and the resulting residue is purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid as a white solid (36mg, 90%)

[0211] 1 H NMR (400MHz, CDCl3) δ8.00–7.87 (m, 1H), 7.50–7.42 (m, 1H), 7.24-7.19 (m, 2H), 6.64 (d, J=2.8Hz, 1H), 6.41 (dd, J=8.9, 2.8Hz, 1H), 3.9 4–3.83 (m, 1H), 3.80–3.68 (m, 1H), 3.51–3.38 (m, 2H), 3.37–3.27 (m, 1H), 2.54–2.42 (m, 1H), 2.24–2.13 (m, 1H). MS-ESI (m / z) = 354 [M+H] + .

[0212] Chromatographic Separation of Methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoate

[0213] Chiral separation was performed on 60 mg of the target compound 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester synthesized in step 1) under the separation conditions (n-hexane:isopropanol=85:15, flow rate: 3.5 mL / min, peak A retention time: 18 min, peak B retention time: 23 min, Y1 chiral preparative column, 10*250 mm, 1 μm), and the peak A product was obtained as a white solid of 24 mg, and the peak B product was obtained as a white solid of 23 mg. The chiral preparative chromatogram is shown as follows Figure 1 shown.

[0214] 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid 20A, 20B

[0215] The above 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester peak A and peak B were used as raw materials, respectively, and the preparation method was the same as Example 1 (step 5) to obtain the target compound 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid A (20A) as a white solid 19 mg, with a yield of 80%, and 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid B (20B) as a white solid 18 mg, with a yield of 80%.

[0216] Example 21 3-(1-(4-ethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0217]

[0218] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 4-iodoethylbenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 36%.

[0219] 1 H NMR (400MHz, CDCl3) δ7.91-7.85 (m, 1H), 7.50-7.47 (m, 1H), 7.19-7.15 (m, 1H), 7.10 (d, J=8.4Hz, 2H), 6.56 (d, J=8.5Hz, 2H), 3.91-3.83 (m, 1H), 3 .75-3.71(m, 1H), 3.51-3.36(m, 3H), 2.57(q, J=7.6Hz, 2H), 2.45–2.39( m, 1H), 2.18–2.11 (m, 1H), 1.21 (t, J=7.6Hz, 3H).MS-ESI(m / z)=314[M+H] + .

[0220] Example 22 2-Fluoro-3-(1-(4-isopropylphenyl)pyrrolidin-3-yl)benzoic acid

[0221]

[0222] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 4-iodoisopropylbenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 25%.

[0223] 1H NMR (400MHz, CDCl3) δ7.90-7.86 (m, 1H), 7.54–7.43 (m, 1H), 7.21–7.10 (m, 3H), 6.57 (d, J=8.3Hz, 2H), 3.89–3.77 (m, 1H), 3.75 -3.71(m, 1H), 3.50-3.36(m, 3H), 2.85–2.82(m, 1H), 2.47-2.39(m, 1H), 2.16–2.11(m, 1H), 1.23(d, J=6.9Hz, 6H).MS-ESI(m / z)=328[M+H] + .

[0224] Example 23 3-(1-(3-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0225]

[0226] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-chloro-4-iodobenzotrifluoride as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 51%.

[0227] 1 H NMR (400MHz, CDCl3) δ7.86–7.61 (m, 1H), 7.47–7.21 (m, 2H), 7.08–6.87 (m, 1H), 6.62–6.42 (m, 1H), 6.42–6.19 (m, 1H), 3.84–3.52 (m, 2H), 3.49–3.05 (m, 3H), 2.34–2.26 (m, 1H), 2.06–1.96 (m, 1H). MS-ESI (m / z) = 388 [M+H] + .

[0228] Example 24 2-Fluoro-3-(1-(o-tolyl)pyrrolidin-3-yl)benzoic acid

[0229]

[0230] Using methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate and 2-iodotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 34%.

[0231] 1H NMR (400MHz, CDCl3) δ7.91-7.87 (m, 1H), 7.68 -7.65(m, 1H), 7.22-7.20(m, 1H), 7.18-7.12(m, 2H), 6.95-6.92(m, 1H), 6.88-686(m, 1H), 3.95–3.80(m, 1H), 3. 59–3.55(m, 1H), 3.41-3.77(m, 3H), 2.50-2.39(m, 1H), 2.34(s, 3H), 2.13-2.04(m, 1H).MS-ESI(m / z)=300[M+H] + .

[0232] Example 25 2-Fluoro-3-(1-(2-methoxyphenyl)pyrrolidin-3-yl)benzoic acid

[0233]

[0234] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-iodoanisole as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a two-step yield of 43%.

[0235] 1 H NMR (400MHz, CDCl3) δ7.90 -7.86(m, 1H), 7.66-7.62(m, 1H), 7.20(t, J=7.8Hz, 1H), 6.95–6.84(m, 3H), 6.81-6.79(m, 1H), 3.88–3.79(m, 4H), 3. 72-3.69(m, 1H), 3.60-3.54(m, 1H), 3.51–3.41(m, 2H), 2.46-2.38(m, 1H), 2.12–2.03(m, 1H).MS-ESI(m / z)=316[M+H] + .

[0236] Example 26 2-Fluoro-3-(1-(4-methoxyphenyl)pyrrolidin-3-yl)benzoic acid

[0237]

[0238] 2-Fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 4-iodoanisole are used as raw materials. The preparation method is the same as that in Example 1. The product is a white solid powder. The two-step yield is 36%.

[0239] 1H NMR (400MHz, CDCl3) δ7.95–7.87(m, 1H), 7.51-7.48(m, 1H), 7.22-7.15(m, 2H), 6.31-6.29(m, 1H), 6.25-6.23(m, 1H), 6.16-6.15(m, 1H) ), 3.95–3.84(m, 1H), 3.81(s, 3H), 3.78–3.69(m, 1H), 3.52-3.37(m, 3H), 2.48-2.41(m, 1H), 2.20-2.11(m, 1H).MS-ESI(m / z)=316[M+H] + .

[0240] Example 27 2-Fluoro-3-(1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)benzoic acid

[0241]

[0242] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-iodotrifluorotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 41%.

[0243] 1 H NMR (400MHz, CDCl3) δ7.92-7.88 (m, 1H), 7.62-7.60 (m, 2H), 7.44-7.40 (m, 1H), 7.23-7.20 (m, 1H), 7.10 -7.07(m, 1H), 6.99-6.93(m, 1H), 3.92–3.77(m, 1H), 3.76–3.63(m, 1H), 3.57 –3.32(m, 3H), 2.47–2.36(m, 2H), 2.15-2.06(m, 1H).MS-ESI(m / z)=354[M+H] + .

[0244] Example 28 3-(1-(3-chloro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0245]

[0246] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-chloro-5-iodo-trifluorotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 37%.

[0247] 1H NMR (400MHz, CDCl3) δ7.96-7.92 (m, 1H), 7.49 -7.46 (m, 1H), 7.25 -7.21(m, 1H), 6.90(s, 1H), 6.67(d, J=15.4Hz, 2H), 3.94-3.86(m, 1H), 3.81–3.77(m, 1H), 3.55 –3.38(m, 2H), 3.42-3.38(m, 1H), 2.53-2.45(m, 1H), 2.28-2.18(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0248] Example 29 3-(1-(3,5-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0249]

[0250] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3,5-dichloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 51%.

[0251] 1 H NMR (400MHz, DMSO) δ7.75-7.71 (m, 1H), 7.60-7.57 (m, 1H), 7.28 -7.26(m, 1H), 6.69(s, 1H), 6.58(s, 2H), 3.92–3.76(m, 1H), 3.76–3.66(m, 1H), 3 .53–3.14(m, 3H), 2.46–2.30(m, 1H), 2.28–2.06(m, 1H).MS-ESI(m / z)=354[M+H] + .

[0252] Example 30 3-(1-(2,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0253]

[0254] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2,4-dichloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 37%.

[0255] 1H NMR (400MHz, MeOD) δ7.78-7.74(m, 1H), 7.64-7.60(m, 1H), 7.32-7.31(m, 1H), 7.26–7.11(m, 2H), 7.00-6.97 (m, 1H), 3.84-3.77 (m, 1H), 3.68–3.45 (m, 4H), 2.47–2.34 (m, 1H), 2.20–2.04 (m, 1H).MS-ESI (m / z)=354[M+H] + .

[0256] Example 31 3-(1-(2,5-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0257]

[0258] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2,5-dichloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 45%.

[0259] 1 H NMR (400MHz, CDCl3) δ7.93-7.91 (m, 1H), 7.62-7.58 (m, 1H), 7.25-7.22 (m, 2H), 6.85-6.84 (m, 1H), 6.79 -6.76 (m, 1H), 3.84 -3.72(m, 2H), 3.68–3.51(m, 3H), 2.46-2.38(m, 1H), 2.17–2.04(m, 1H).MS-ESI(m / z)=354[M+H] + .

[0260] Example 32 3-(1-(2,3-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0261]

[0262] Using methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate and 2,3-dichloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 41%.

[0263] 1H NMR (400MHz, MeOD) δ7.87–7.75 (m, 1H), 7.68-7.64 (m, 1H), 7.25-7.22 (m, 1H), 7.17 -7.13(m, 1H), 7.05-7.03(m, 1H), 7.00-6.98(m, 1H), 3.88–3.75(m, 1H), 3.71–3.44(m, 4H), 2.46-2.38(m, 1H), 2.19 -2.08(m,1H).MS-ESI(m / z)=354[M+H] + .

[0264] Example 33 3-(1-(3-ethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0265]

[0266] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 1-ethyl-3-iodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 29%.

[0267] 1 H NMR (400MHz, CDCl3) δ7.92-7.88(m, 1H), 7.52-7.49(m, 1H), 7.21–7.16(m, 2H), 6.59-6.57(m, 1H), 6.46-6.44(m, 2H), 3.95–3.83(m, 1H), 3.83 –3.70(m, 1H), 3.54-3.38(m, 3H), 2.62(q, J=7.6Hz, 2H), 2.48–2.37(m, 1H), 2.20-2.11(m, 1H), 1.25(t, J=7.6Hz, 3H).MS-ESI(m / z)=314[M+H] + .

[0268] Example 34 3-(1-(4-bromophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0269]

[0270] Using methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate and 4-iodobromobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 25%.

[0271] 1H NMR (400MHz, CDCl3) δ7.92-7.89 (m, 1H), 7.49 -7.45(m, 1H), 7.33-7.31(m, 2H), 7.22-7.18(m, 1H), 6.48-6.45(m, 2H), 3.90 -3.84(m, 1H), 3.74-3.70(m, 1H), 3.51–3.38(m, 2H), 3.37-3.33(m, 1H), 2.47 -2.42(m, 1H), 2.22-2.13(m, 1H).MS-ESI(m / z)=364[M+H] + .

[0272] Example 35 3-(1-(4-bromo-3-chlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0273]

[0274] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-chloro-4-bromoiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 19%.

[0275] 1 H NMR (400MHz, CDCl3) δ7.92-7.88 (m, 1H), 7.45 -7.37(m, 2H), 7.21-7.17(m, 1H), 6.65(s, 1H), 6.35-6.33(m, 1H), 3.98–3.79(m, 1H), 3.73-3.69(m, 1H ), 3.52–3.38(m, 2H), 3.35-3.31(m, 1H), 2.48-2.44(m, 1H), 2.23-2.16(m, 1H).MS-ESI(m / z)=398[M+H] + .

[0276] Example 36 3-(1-(3-bromo-4-chlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0277]

[0278] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-bromo-4-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 23%.

[0279] 1H NMR (400MHz, CDCl3) δ7.84 -7.81 (m, 1H), 7.38 -7.35(m, 1H), 7.21-7.17(m, 1H), 7.14-7.10(m, 1H), 6.74-6.73(m, 1H), 6.47–6.16(m, 1H), 3.86–3.76(m, 1H), 3.70–3.59(m, 1H), 3.48–3.18(m, 3H), 2.40–2.26(m, 1H), 2.17 -2.09(m,1H).MS-ESI(m / z)=398[M+H] + .

[0280] Example 37 3-(1-(4,5-dichloro-2-fluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0281]

[0282] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 1-bromo-4,5-dichloro-2-fluorobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 25%.

[0283] 1 H NMR (400MHz, CDCl3) δ7.94 -7.90(m, 1H), 7.53-7.50(m, 1H), 7.24-7.20(m, 1H), 7.22(d, J=7.7Hz, 1H), 6.96(d, J=29.4Hz, 1H), 3.88–3.7 7(m, 1H), 3.77–3.71(m, 1H), 3.69–3.44(m, 3H), 2.43-2.39(m, 1H), 2.18-2.09(m, 1H).MS-ESI(m / z)=372[M+H] + .

[0284] Example 38 2-Fluoro-3-(1-(2,4,5-trichlorophenyl)pyrrolidin-3-yl)benzoic acid

[0285]

[0286] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2,4,5-trichlorobromobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 37%.

[0287] 1H NMR (400MHz, CDCl3) δ7.94 -7.91(m, 1H), 7.60-7.57(m, 1H), 7.38(s, 1H), 7.26-7.21(m, 1H), 6.92(s, 1H), 3.88–3.77(m, 1H), 3 .77–3.71(m, 1H), 3.69–3.44(m, 3H), 2.44-2.38(m, 1H), 2.18-2.09(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0288] Example 39 6-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)picolinic acid

[0289]

[0290] Step 1) Methyl 6-(1-tert-butyloxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)picolinate

[0291]

[0292] Methyl 6-bromo-2-pyridinecarboxylate (10 mmol, 2.16 g) and 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (10 mmol, 2.95 g) were dissolved in 50 mL of a mixed solvent of ethylene glycol dimethyl ether and water (v:v=4:1). Bistriphenylphosphine palladium dichloride (Pd(dppf)Cl2) (1 mmol, 700 mg) and sodium carbonate (50 mmol, 4.2 g) were added. The mixture was reacted at 80°C for 4 hours under nitrogen protection. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=200:1) to give the title compound as a white solid (2.80 g, 88%).

[0293] Step 2) Methyl 6-(1-tert-butyloxycarbonyl)pyrrolidin-3-yl)picolinate

[0294]

[0295] Methyl 6-(1-tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)picolinate (9.17mmol, 3.04g) was dissolved in 2mL methanol, 5% palladium carbon 212mg was added, and the mixture was reacted at 20°C for 24 hours under a hydrogen balloon. The palladium carbon was filtered off, and the solvent was removed by concentration under reduced pressure to obtain a crude product of methyl 6-(1-tert-butoxycarbonyl)pyrrolidin-3-yl)picolinate, which was used directly in the next step without further purification.

[0296] Step 3) Methyl 6-(pyrrolidin-3-yl)picolinate

[0297]

[0298] The crude product methyl 6-(1-tert-butyloxycarbonyl)pyrrolidin-3-yl)picolinate was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at 20°C for 1 hour. The solvent was removed by concentration under reduced pressure, and a sodium hydroxide aqueous solution (1M) was added to adjust the pH value to neutral. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, and anhydrous sodium sulfate was filtered off. The solvent was removed by concentration under reduced pressure to obtain a crude product. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain methyl 6-(pyrrolidin-3-yl)picolinate as a transparent viscous oil (1.60 g, two-step yield 83%). MS-ESI (m / z) = 207 [M+H] + .

[0299] Step 4) Methyl 6-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)picolinate

[0300]

[0301] Dissolve 6-(pyrrolidin-3-yl)picolinic acid methyl ester (0.2mmol, 41mg) in 5mL toluene, add 3,4-dichloroiodobenzene (0.25mmol, 68mg), palladium acetate (0.02mmol, 4.5mg), BINAP (1.0mmol, 622mg), cesium carbonate (0.6mmol, 194mg), protect with nitrogen, react at 100℃ for 4 hours, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the product 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester as a white solid (17mg, 25%). MS-ESI (m / z) = 385 [M+H] + .

[0302] Step 5) 6-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)picolinic acid

[0303]

[0304] Methyl 6-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)picolinate (0.042mmol, 17mg) was dissolved in 2mL of tetrahydrofuran, 0.5mL of 1M sodium hydroxide aqueous solution was added, methanol was added dropwise until the reaction solution was clear, and stirred at 20°C overnight. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 6-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)picolinic acid as a white solid (13mg, 79%).

[0305] 1 H NMR (400MHz, MeOD) δ8.02-800 (m, 1H), 7.94-7.90 (m, 1H), 7.57-7.55 (m, 1H), 7.24-7.22 (m, 1H), 6.69-6.67 (s, 1H), 6.52 -6.49 (m, 1H), 3.89 -3.81(m, 1H), 3.73-3.68(m, 1H), 3.54–3.39(m, 3H), 2.50 -2.43(m, 1H), 2.38-2.29(m, 1H).MS-ESI(m / z)=371[M+H] + .

[0306] Example 40 5-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)nicotinic acid

[0307]

[0308] Using 5-bromonicotinoic acid methyl ester and 3,4-dichloroiodobenzene as raw materials, the preparation method is the same as Example 39, and the product is a white solid powder with a total yield of 12%. 1 H NMR(400MHz,DMSO)δ8.95-8.94(m,1H),8.76-8.75(m,1H),8.20-8.19(m,1H),7.36 (d,J=8.9Hz,1H),6.78(d,J=2.7Hz,1H),6.60-6.57(m,1H),3.81–3.71(m,1H),3.68 -3.62(m,1H),3.52–3.19(m,3H),2.18-3.11(m,1H),2.05–1.99(m,1H).MS-ESI(m / z)=337[M+H] +

[0309] Example 41 3-(1-(3-chloro-4-fluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0310]

[0311] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-chloro-4-fluoroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 24%.

[0312] 1H NMR (400MHz, MeOD) δ7.81 -7.77 (m, 1H), 7.67 -7.62 (m, 1H), 7.58 -7.51 (s, 1H), 7.23-7.19 (m, 1H), 7.06-7.02 (m, 1H), 6.82 -6.80 (m, 1H), 6.52 -6.48(m, 1H), 3.90–3.82(m, 1H), 3.70 -3.63(m, 1H), 3.47–3.28(m, 3H), 2.48-2.41(m, 1H), 2.22–2.15(m, 1H).MS-ESI(m / z)=338[M+H] + .

[0313] Example 42 3-(1-(3-chloro-5-fluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0314]

[0315] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-chloro-5-fluoroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 24%.

[0316] 1 H NMR (400MHz, MeOD) δ7.86–7.67 (m, 1H), 7.62–7.49 (m, 1H), 7.22 (t, J=7.7Hz, 1H), 6.40-6.35 (m, 2H), 6.28-6.24 (m, 1H), 3 .93–3.80(m, 1H), 3.79–3.65(m, 1H), 3.50–3.31(m, 3H), 2.48-2.41(m, 1H), 2.25-2.16(m, 1H).MS-ESI(m / z)=338.1[M+H] + .

[0317] Example 43 3-(1-(3-chloro-2-fluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0318]

[0319] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-fluoro-3-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 25%.

[0320] 1H NMR (400MHz, CDCl3) δ7.93-7.89 (m, 1H), 7.55-7.52 (m, 1H), 7.23-7.19 (m, 1H), 6.93 -6.89(m, 1H), 6.77-6.73(m, 1H), 6.59-6.55(m, 1H), 3.86-3.81(m, 2H), 3.62 -3.50(m, 3H), 2.43-2.39(m, 1H), 2.17-2.08(m, 1H).MS-ESI(m / z)=338[M+H] + .

[0321] Example 44 3-(1-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0322]

[0323] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-fluoro-4-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 32%.

[0324] 1 H NMR (400MHz, MeOD) δ7.77–7.62 (m, 1H), 7.49 (t, J=7.0Hz, 1H), 7.36 (dd, J=13.7, 8.2Hz, 1H), 7.26–7.01 (m, 1H), 6.9 5-6.90m, 1H), 6.66-6.62(m, 1H), 3.93-3.12(m, 5H), 2.36-2.25(m, 1H), 2.07-1.98(m, 1H).MS-ESI(m / z)=338[M+H] + .

[0325] Example 45 3-(1-(5-chloro-2-fluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0326]

[0327] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-fluoro-5-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 29%.

[0328] 1H NMR (400MHz, CDCl3) δ7.90 -7.87 (m, 1H), 7.51 -7.49(m, 1H), 7.21-7.15(m, 1H), 6.92–6.87(m, 1H), 6.67–6.53(m, 2H), 3.88–3.70(m, 2H), 3.68–3.28(m, 3H), 2.47–2.30(m, 1H), 2.18–2.03(m, 1H).MS-ESI(m / z)=338[M+H] + .

[0329] Example 46 3-(1-(5-chloro-2-methylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0330]

[0331] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-iodo-4-chlorotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 32%.

[0332] 1 H NMR (400MHz, MeOD) δ7.83–7.72 (m, 1H), 7.66 -7.62 (m, 1H), 7.24-7.20 (m, 1H), 7.05 -7.03(m, 1H), 6.89-6.88(m, 1H), 6.80-6.77(m, 1H), 3.85-3.77(m, 1H), 3.58–3.47(m, 1H), 3.45-3.39 (m, 1H), 3.36–3.23 (m, 3H), 2.47–2.37 (m, 1H), 2.27 (s, 3H), 2.16–2.06 (m, 1H).MS-ESI (m / z)=334[M+H] + .

[0333] Example 47 3-(1-(3-chloro-2-methylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0334]

[0335] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-iodo-6-chlorotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 30%.

[0336] 1H NMR (400MHz, CDCl3) δ7.90-7.87(m, 1H), 7.63-7.60(m, 1H), 7.22-7.17(m, 1H), 7.07–7.01(m, 2H), 6.89 -6.87(m, 1H), 3.89–3.78(m, 1H), 3.52-3.48(m, 1H), 3.35–3.25(m, 3H), 2 .45-2.38(m, 1H), 2.37(s, 3H), 2.12–2.04(m, 1H).MS-ESI(m / z)=334[M+H] + .

[0337] Example 48 3-(1-(3,4-dichlorophenyl)piperidin-3-yl)-2-fluorobenzoic acid

[0338]

[0339] Step 1) Methyl 2-fluoro-3-(pyridin-3-yl)benzoate

[0340]

[0341] 3-Bromopyridine (10mmol, 1.57g), 2-fluoro-3-methoxycarbonylphenylboronic acid pinacol ester (10mmol, 2.8g) were dissolved in 50mL of ethylene glycol dimethyl ether: water mixed solvent (v:v=4:1), bistriphenylphosphine palladium dichloride (Pd(dppf)Cl2) (1mmol, 700mg), sodium carbonate (50mmol, 4.2g) were added, nitrogen was protected, the reaction was carried out at 80°C for 4 hours, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=200:1) to obtain the title compound as a white solid (1.9g, 82%). It was identified as the target compound by mass spectrometry: MS-ESI (m / z)=232[M+H] + .

[0342] Step 2) Methyl 2-fluoro-3-(piperidin-3-yl)benzoate

[0343]

[0344] Methyl 2-fluoro-3-(pyridin-3-yl)benzoate (1mmol, 0.23g) was dissolved in 2mL of methanol, and 10.6mg of 5% palladium on carbon was added to 2mL, and the mixture was reacted at 90°C for 24 hours under a hydrogen pressure of 5 bar. The palladium on carbon was filtered off, and the solvent was removed by concentration under reduced pressure to obtain a crude product of methyl 2-fluoro-3-(piperidin-3-yl)benzoate, which was used directly in the next step without further purification.

[0345] Step 3) Methyl 3-(1-(3,4-dichlorophenyl)piperidin-3-yl)-2-fluorobenzoate

[0346]

[0347] Dissolve methyl 2-fluoro-3-(piperidin-3-yl)benzoate (0.2mmol, 47mg) in 5mL toluene, add 3,4-dichloroiodobenzene (0.25mmol, 68mg), palladium acetate (0.02mmol, 4.5mg), BINAP (1.0mmol, 622mg), cesium carbonate (0.6mmol, 194mg), protect with nitrogen, react at 100℃ for 4 hours, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the product methyl 3-(1-(3,4-dichlorophenyl)piperidin-3-yl)-2-fluorobenzoate as a white solid (17mg, 22%). MS-ESI (m / z) = 382 [M+H] + .

[0348] Step 4) 3-(1-(3,4-dichlorophenyl)piperidin-3-yl)-2-fluorobenzoic acid

[0349]

[0350] Methyl 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoate (0.044mmol, 17mg) was dissolved in 2mL of tetrahydrofuran, 0.5mL of 1M sodium hydroxide aqueous solution was added, methanol was added dropwise until the reaction solution was clear, and stirred at 20°C overnight. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 3-(1-(3,4-dichlorophenyl)piperidin-3-yl)-2-fluorobenzoic acid as a white solid (13mg, 79%).

[0351] 1 H NMR (400MHz, MeOD) δ7.86–7.69 (m, 1H), 7.66–7.55 (m, 1H), 7.30 -7.28 (m, 1H), 7.24 -7.20(m, 1H), 7.07-7.06(m, 1H), 6.91-6.88(m, 1H), 3.79–3.62(m, 2H), 3.31–3.23(m, 1H), 2.97–2.76(m, 2H), 1.99 -1.96(m, 1H), 1.90 -1.78(m,3H).MS-ESI(m / z)=368[M+H] + .

[0352] Example 49 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoic acid

[0353]

[0354] Step 1: Methyl 3-bromo-2,6-difluorobenzoate

[0355] 3-Bromo-2,6-difluorobenzoic acid (200 mg, 0.84 mmol) was dissolved in DMF (5 mL) at 20°C. Anhydrous potassium carbonate (582 mg, 4.2 mmol) and iodomethane (179 mg, 1.26 mmol) were added, and the resulting mixture was reacted at 20°C for 4 h. After the reaction, water (50 mL) was added, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the target product (204 mg, 96.8%).

[0356] Step 2: tert-Butyl 3-(2,4-difluoro-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0357] At 20°C, methyl 3-bromo-2,6-difluorobenzoate (204 mg, 0.81 mmol) was dissolved in ethylene glycol dimethyl ether / water (4 / 1.5 mL). Anhydrous sodium carbonate (172.3 mg, 1.6 mmol), tetrakistriphenylphosphine palladium (184.9 mg, 0.16 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (286.9 mg, 0.97 mmol) were added in sequence, and the resulting mixture was reacted at 80°C for 2 hours. TLC was used to monitor the reaction. After the reaction was completed, the reaction solution was cooled to 20°C, water (50 mL) was added, and ethyl acetate was extracted (50 mL×3). The organic phases were combined and washed with saturated brine (50 mL). Drying was performed over anhydrous sodium sulfate, filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the desired product (222 mg, 80.8%).

[0358] Step 3: tert-Butyl 3-(2,4-difluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

[0359] At 20°C, tert-butyl 3-(2,4-difluoro-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (222 mg, 0.65 mmol) was dissolved in methanol (5 mL). Pd\C (22.2 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was reacted at 20°C overnight. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (191 mg, 85.5%).

[0360] Step 4: Methyl 2,6-difluoro-3-(pyrrolidin-3-yl)benzoate

[0361] At 20°C, tert-butyl 3-(2,4-difluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (191 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added at 20°C, and the resulting mixture was reacted at 20°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the target product (190 mg, 95.5%).

[0362] Step 5: Methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoate

[0363] At 20°C, methyl 2,6-difluoro-3-(pyrrolidin-3-yl)benzoate (190 mg, 0.53 mmol) was dissolved in toluene (3 mL). Cesium carbonate (522.7 mg, 1.6 mmol), 13,4-dichloroiodobenzene (218.3 mg, 0.8 mmol), palladium acetate (23.8 mg, 0.1 mmol), and Xantphos (57.9 mg, 0.1 mmol) were added in sequence, and the resulting mixture was reacted at 100°C overnight. After the reaction was completed, the reaction solution was cooled to 20°C, and water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25:1) to obtain the target product (121 mg, 59.1%).

[0364] Step 6: 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoic acid

[0365] At 20°C, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoate (121 mg, 0.31 mmol) was dissolved in tetrahydrofuran / water (2 / 1, 3 mL). Sodium hydroxide (25 mg, 0.62 mmol) was added at 20°C, and the resulting mixture was reacted at 60°C for 2 hours. The reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain the target product (90 mg, 78.1%).

[0366] 1 H NMR (500MHz, DMSO) δ7.34 -7.33 (m, 1H), 7.14-7.10 (m, 1H), 6.90 -6.87(m, 1H), 6.74-6.73(m, 1H), 6.57-6.54(m, 1H), 3.69–3.60(m, 2H), 3.4 3–3.24(m, 3H), 2.35-2.32(m, 1H), 2.11-2.04(m, 1H).MS(ESI)m / z:372[M+H] + .

[0367] Step 7) Chromatographic separation of methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoate

[0368] Chiral separation was performed on 50 mg of the target product of step 5, 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoic acid methyl ester, under separation conditions (n-hexane:isopropanol=93.5:6.5, flow rate: 4.0 mL / min, peak A retention time: 19 min, peak B retention time: 23 min, Y1 chiral preparative column, 10*250 mm, 1 μm), to obtain 21 mg of peak A and 23 mg of peak B. The chiral preparative chromatogram is shown in the following figure. Figure 2 shown.

[0369] Step 8) 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoic acid 49A, 49B

[0370] Using the above 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoic acid methyl ester peak A and peak B as raw materials, the alkaline hydrolysis method is the same as step 6 to obtain the target compound 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoic acid A (49A) as a white solid 16 mg with a yield of 81%, and 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoic acid B (49B) as a white solid 17 mg with a yield of 80%.

[0371] Example 50 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,4-difluorobenzoic acid

[0372]

[0373] Using 2,4-difluoro-3-bromobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3,4-dichloroiodobenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 11%.

[0374] 1 H NMR (400MHz, DMSO) δ7.90 -7.84 (m, 1H), 7.38 -7.36(m, 1H), 7.26-7.21(m, 1H), 6.77-6.76(m, 1H), 6.59-6.57(m, 1H), 4.01–3.85(m, 1H), 3.66 -3.62(m, 1H), 3.60–3.50(m, 1H), 3.49–3.20(m, 2H), 2.43–2.25(m, 2H).MS-ESI(m / z)=372[M+H] + .

[0375] Example 51 3-(1-(4-chloro-3-methylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0376]

[0377] Using methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate and 2-chloro-5-iodotoluene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 20%.

[0378] 1H NMR (400MHz, MeOD) δ7.81 -7.77 (m, 1H), 7.53-7.50 (m, 1H), 7.23-7.19 (m, 1H), 7.11 (d, J=8.7Hz, 1H), 6.51 -6.50 (m, 1H), 6.43 -6.40(m, 1H), 3.91–3.78(m, 1H), 3.71-3.66(d, J=9.0Hz, 1H), 3.55–3.22(m, 3H), 2.47-2.40(m, 1H), 2.29(s, 3H), 2.22 -2.13(m,1H).MS-ESI(m / z)=334[M+H] + .

[0379] Example 52 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)benzoic acid

[0380]

[0381] Using 3-bromobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3,4-dichloroiodobenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 18% in 5 steps.

[0382] 1 H NMR (400MHz, CDCl3) δ8.08–7.98 (m, 2H), 7.52 -7.44(m, 2H), 7.26-7.23(m, 1H), 6.64(d, J=2.7Hz, 1H), 6.43-6.40(m, 1H), 3.74–3.70(m, 1H), 3.65-3.57(m, 1H), 3. 53–3.48(m, 1H), 3.46–3.40(m, 1H), 3.37-3.33(m, 1H), 2.57–2.41(m, 1H), 2.24-2.14(m, 1H).MS-ESI(m / z)=336[M+H] + .

[0383] Example 53 5-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0384]

[0385] Using 5-fluoro-2-fluorobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3,4-dichloroiodobenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 22% in 5 steps.

[0386] 1H NMR (400MHz, MeOD) δ7.88 -7.86 (m, 1H), 7.56-7.53 (m, 1H), 7.26-7.23 (m, 1H), 7.19-7.12 (m, 1H), 6.69 (d, J=2.7Hz, 1H), 6.54-6.51 (m, 1H), 3.76–3.67 (m, 1H), 3.64 -3.56(m, 1H), 3.51-3.46(m, 1H), 3.44-3.37(m, 1H), 3.31-3.30(m, 1H), 2.49-2.42(m, 1H), 2.21-2.09(m, 1H).MS-ESI(m / z)=354.0[M+H] + .

[0387] Example 54 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-5-fluorobenzoic acid

[0388]

[0389] Using 3-bromo-5-fluorobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3,4-dichloroiodobenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 27% in 5 steps.

[0390] 1 H NMR (400MHz, CDCl3) δ7.71 (s, 1H), 7.56-7.54 (m, 2H), 7.17 (d, J=8.8Hz, 1H), 7.1 1-7.08 (m, 1H), 6.56 (d, J=2.7Hz, 1H), 6.35-6.32 (m, 1H), 3.66-3.59 (m, 1H), 3.55 -3.47(m, 1H), 3.45–3.40(m, 1H), 3.37-3.31(m, 1H), 3.27-3.23(m, 1H), 2.43-2.36(m, 1H), 2.14-2.06(m, 1H).MS-ESI(m / z)=354[M+H] + .

[0391] Example 55 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4-fluorobenzoic acid

[0392]

[0393] Using 3-bromo-4-fluorobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3,4-dichloroiodobenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 19% in 5 steps.

[0394] 1 H NMR (400MHz, DMSO) δ7.76 (s, 1H), 7.55 -7.49 (m, 2H), 7.35 (d, J=8.9Hz, 1H), 6.77 (d, J=2.7Hz, 1H), 6.59-6.56 (m, 1H), 3.80–3.70 (m, 1H), 3.69–3.60 (m, 1H), 3.48-3.43 (m, 1H), 3.39–3.22 (m, 2H), 2.51-2.45 (m, 1H), 2.18–2.02 (m, 1H).MS-ESI (m / z)=354[M+H] + .

[0395] Example 56 N-((4-chlorophenyl)sulfonyl)-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzamide

[0396]

[0397] 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid (0.1mmol, 35mg) was dissolved in 5mL of dichloromethane, 4-chlorobenzenesulfonamide (0.15mmol, 28mg) was added, triethylamine (0.3mmol, 0.4mL), 4-dimethylaminopyridine (0.01mmol, 1.2mg), 2-chloro-1-methylpyridinium iodide (1.7mmol, 43mg) were added, and the mixture was reacted at 20°C for 8 hours. Dichloromethane (20mL) was added to the reaction solution, the organic phase was washed with water (20mL), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain the product as a white solid (35mg, 67%).

[0398] 1 H NMR (400MHz, DMSO) δ7.87 (d, J=8.4Hz, 2H), 7.56 (d, J=8.3Hz, 2H), 7.47-7.43 (m, 1H), 7.35 -7.33(m, 2H), 7.13-7.09(m, 1H), 6.75(d, J=2.6Hz, 1H), 6.58-6.55(m, 1H), 3.74-3.63( m, 2H), 3.47–3.19 (m, 3H), 2.38–2.29 (m, 1H), 2.15-2.07 (m, 1H).MS-ESI (m / z)=527[M+H] + .

[0399] Example 57 2-Chloro-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)benzoic acid

[0400]

[0401] Using 3-bromo-2-chlorobenzoic acid methyl ester, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester and 3,4-dichloroiodobenzene as raw materials, the preparation method was the same as Example 49, and the product was a white solid powder with a total yield of 11% for 5 steps.

[0402] 1 H NMR (400MHz, MeOD) δ7.58-7.55(m, 1H), 7.45-7.42(m, 1H), 7.36-7.32(m, 1H), 7.27 -7.24 (m, 1H), 6.70 (d, J=2.8Hz, 1H), 6.53 (dd, J=8.9, 2.8Hz, 1H), 4.14-4.07 (m, 1H), 3.74-3 .70(m, 1H), 3.53–3.29(m, 3H), 2.50-2.47(m, 1H), 2.22–2.09(m, 1H).MS-ESI(m / z)=370[M+H] + .

[0403] Example 58 3-(1-(3,4-dichlorophenyl)-2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoic acid

[0404]

[0405] Step 1) tert-butyl 2,5-dimethyl-1H-pyrrole-1-carboxylate

[0406] 2,5-Dimethylpyrrole (10.5mmol, 1g) was dissolved in 5mL tetrahydrofuran, 2,5-dimethylpyrrole (3.16mmol, 688mg) was added, 4-dimethylaminopyridine (42mmol, 51mg) was added, and the mixture was reacted at 20°C for 8 hours. Ethyl acetate (20mL) was added to the reaction solution, the organic phase was washed with water (20mL), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (pure petroleum ether) to obtain the product as a white solid (250mg, 62%).

[0407] Step 2) tert-butyl 2,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate

[0408] Dissolve bis(pyrazol)-1-ylpyridinium diboronate (1.38mmol, 351mg), 4,4'-di-tert-butyl-2,2'-bipyridine (0.01mmol, 3.0mg), add methoxy(cyclooctadiene)iridium dimer (0.01mmol, 7.4mg) in 10mL DME, replace with N2 three times, wait until the solution turns red, add tert-butyl 2,5-dimethyl-1H-pyrrole-1-carboxylate (1.38mmol, 270mg) dissolved in 10mL DME, react at 20℃ for 8 hours. Add ethyl acetate (20mL) to the reaction solution, wash the organic phase with water (20mL), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (pure petroleum ether) to obtain the product as a white solid (250mg, 62%).

[0409] Step 3) tert-butyl 3-(2-fluoro-3-(methoxycarbonyl)phenyl)-2,5-dimethyl-1H-pyrrole-1-carboxylate

[0410] Dissolve 2,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (3.0mmol, 964mg), 3-bromo-2-fluorobenzoic acid methyl ester (3.0mmol, 700mg), tetrakistriphenylphosphine palladium (346mg, 0.3mmol), anhydrous sodium carbonate (172.3mg, 1.6mmol) in ethylene glycol dimethyl ether / water (16 / 4mL) in turn, and react the resulting mixture at 100°C for 3 hours under nitrogen protection. Monitor the reaction by TLC. After the reaction is completed, cool the reaction solution to 20°C, add water (50mL), extract with ethyl acetate (50mL×3), combine the organic phases and wash with saturated brine (50mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the desired product (861 mg, 83%).

[0411] Step 4) Methyl 3-(2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoate

[0412] At 20°C, tert-butyl 3-(2-fluoro-3-(methoxycarbonyl)phenyl)-2,5-dimethyl-1H-pyrrole-1-carboxylate (861 mg, 2.4 mmol) was dissolved in methanol (5 mL). Pd\C (22.2 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was reacted overnight at 20°C. The TLC plate detected that the raw material was completely consumed, the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was directly used for the next step reaction.

[0413] The crude product was dissolved in dichloromethane (5 mL) at 20°C. Trifluoroacetic acid (2 mL) was added at 20°C, and the resulting mixture was reacted at 20°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the target product, 3-(2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester (400 mg, two-step yield 63%). MS-ESI (m / z) = 252 [M+H] + .

[0414] Step 5) Methyl 3-(1-(3,4-dichlorophenyl)-2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoate

[0415] Dissolve 3-(2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester (0.4mmol, 100mg) in 5mL toluene, add 1,2-dichloro-4-iodobenzene (130mg, 0.48mmol), palladium acetate (0.08mmol, 18mg), BINAP (0.08mmol, 50mg), cesium carbonate (0.8mmol, 260mg), protect with nitrogen, react overnight at 100℃, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the product 3-(1-(3,4-dichlorophenyl)-2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoic acid methyl ester as a white solid (25mg, 10%). MS-ESI (m / z) = 396 [M+H] + .

[0416] Step 6) 3-(1-(3,4-dichlorophenyl)-2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoic acid

[0417] At 20°C, methyl 3-(1-(3,4-dichlorophenyl)-2,5-dimethylpyrrolidin-3-yl)-2-fluorobenzoate (25 mg, 0.06 mmol) was dissolved in tetrahydrofuran / water (2 / 1, 3 mL). Sodium hydroxide (25 mg, 0.62 mmol) was added at 20°C, and the resulting mixture was reacted at 60°C for 2 hours. The reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain the target product (10 mg, 41%).

[0418] 1H NMR (400MHz, CDCl3) δ7.95 -7.91 (m, 1H), 7.52-7.50 (m, 1H), 7.25–7.22 (m, 2H), 6.69 -6.68 (m, 1H), 6.48 -6.45(m, 1H), 4.23–4.20(m, 1H), 3.88-3.82(m, 1H), 3.66–3.59(m, 1H), 2.55–2.41(m, 1H), 2.30 -2.21(m, 1H), 1.39(d, J=5.8Hz, 3H), 0.86(d, J=6.5Hz, 3H).MS-ESI(m / z)=382[M+H] + .

[0419] Example 59 5-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0420]

[0421] Step 1) 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-6-methoxypicolinic acid methyl ester

[0422] At 20°C, 5-bromo-6-methoxypicolinate (167 mg, 0.68 mmol) was dissolved in ethylene glycol dimethyl ether / water (9 / 1.5 mL). Anhydrous sodium carbonate (144 mg, 1.36 mmol), Pd(dppf)Cl2 . CH2Cl2 (55 mg, 0.068 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (200 mg, 0.68 mmol), the resulting mixture was reacted at 80°C for 2 hours. TLC monitored the reaction. After the reaction was completed, the reaction solution was cooled to 20°C, water (50 mL) was added, and ethyl acetate was extracted (50 mL×3). The organic phases were combined and washed with saturated brine (50 mL). Drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product (130 mg, 57%).

[0423] Step 2) 5-(1-(tert-Butyloxycarbonyl)pyrrolidin-3-yl)-6-methoxypicolinic acid methyl ester

[0424] At 20°C, methyl 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-6-methoxypicolinate (130 mg, 0.38 mmol) was dissolved in methanol (5 mL). Pd\C (10 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was reacted at 20°C overnight. The palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without purification.

[0425] Step 3) 6-methoxy-5-(pyrrolidin-3-yl)picolinic acid methyl ester

[0426] At 20°C, methyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-6-methoxypicolinate (130 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added at 20°C, and the resulting mixture was reacted at 20°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the target product (90 mg, 99%).

[0427] Step 4) 5-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-methoxypicolinic acid methyl ester

[0428] At 20°C, methyl 6-methoxy-5-(pyrrolidin-3-yl)picolinate (90 mg, 0.38 mmol) was dissolved in 1,4-dioxane (10 mL). Cesium carbonate (247 mg, 0.76 mmol), 1,2-dichloro-4-iodobenzene (124 mg, 0.46 mmol), palladium acetate (17 mg, 0.076 mmol), and Xantphos (43 mg, 0.076 mmol) were added in sequence, and the resulting mixture was reacted at 100°C overnight. After the reaction was completed, the reaction solution was cooled to 20°C, and water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25:1) to obtain the target product (40 mg, 28%).

[0429] Step 5) 5-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0430] At 20°C, methyl 5-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-methoxypicolinate (40 mg, 0.1 mmol) was dissolved in 40% HBr. The mixture was reacted at 110°C for 2 hours until the reaction was complete. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the target product (12 mg, 30%).

[0431] 1H NMR (400MHz, DMSO) δ7.40 (d, J=7.1Hz, 1H), 7.34 (d, J=8.9Hz, 1H), 6.87-6.85 (m, 1H), 6.71 (d, J=2.7Hz, 1H), 6.54 (dd, J =8.9, 2.7Hz, 1H), 3.65–3.54(m, 2H), 3.39–3.19(m, 3H), 2.35–2.21(m, 1H), 2.15–1.97(m, 1H).MS-ESI(m / z)=353[M+H] + .

[0432] Example 60 2-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)benzoic acid

[0433]

[0434] Using 2-bromobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3-chloro-4-iodotrifluoromethylbenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 24% in 5 steps.

[0435] 1 H NMR (400MHz, CDCl3) δ8.04-8.02 (m, 1H), 7.68–7.47 (m, 3H), 7.41–7.23 (m, 2H), 6.85 (d, J=8.7Hz, 1H), 4.49 -4.42(m, 1H), 3.89-3.85(m, 1H), 3.70-3.66(m, 3H), 2.47-2.37(m, 1H), 2.20-2.11(m, 1H).MS-ESI(m / z)=370[M+H] + .

[0436] Example 61 4-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)benzoic acid

[0437]

[0438] Using 4-bromobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3-chloro-4-iodotrifluoromethylbenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 33% in 5 steps.

[0439] 1H NMR (400MHz, CDCl3) δ8.09 (d, J=8.1Hz, 2H), 7.55-7.54 (m, 1H), 7.42-7.37 (m, 3H), 6.87-6.84 (m, 1H), 3.85-3.69 (m, 3H), 3.66–3.51 (m, 2H), 2.48 -2.41(m, 1H), 2.19-2.09(m, 1H).MS-ESI(m / z)=370[M+H] + .

[0440] Example 62 2-(2-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)phenyl)acetic acid

[0441]

[0442] Using 2-bromophenylacetic acid methyl ester, 1-Boc-3-pyrroleboronic acid pinacol ester and 3-chloro-4-iodotrifluoromethylbenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 21% in 5 steps.

[0443] 1 H NMR (400MHz, CDCl3) δ7.50 (m, 1H), 7.42-7.38 (m, 1H), 7.33-7.32 (m, 2H), 7.24-7.15 (m, 2H), 6.7 7-6.75(m, 1H), 372-3.56(m, 7H), 2.32-2.24(m, 1H), 2.08-1.99(m, 1H).MS-ESI(m / z)=384[M+H] + .

[0444] Example 63 2-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-fluorobenzoic acid

[0445]

[0446] Using 2-bromo-3-fluorobenzoic acid methyl ester, 1-Boc-3-pyrroleboric acid pinacol ester and 3-chloro-4-iodotrifluoromethylbenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 19% in 5 steps.

[0447] 1H NMR (400MHz, CDCl3) δ7.66-7.64(m, 1H), 7.52(m, 1H), 7.36-7.21(m, 3H), 6.86-6.84(m, 1H), 4.34–4.25(m, 1H), 4.01–3.86(m , 1H), 3.82-3.79(m, 1H), 3.71-3.67(m, 1H), 3.54-3.50(m, 1H), 2.52-2.42(m, 1H), 2.35–2.18(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0448] Example 64 5-Chloro-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0449]

[0450] Using 3-bromo-5-chloro-2-fluorobenzoic acid methyl ester, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester and 3,4-dichloroiodobenzene as raw materials, the preparation method was the same as that in Example 49, and the product was a white solid powder with a two-step yield of 21%.

[0451] 1 H NMR (400MHz, CDCl3) δ7.93-7.90 (m, 1H), 7.48-7.46 (m, 1H), 7.28 -7.27(m, 1H), 6.67-6.66(m, 1H), 6.45-6.4(m, 1H), 3.91-3.83(m, 1H), 3.77–3.73(m, 1H), 3.62 –3.40(m, 2H), 3.36-3.32(m, 1H), 2.57–2.42(m, 1H), 2.25-2.16(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0452] Example 65 2-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3,4-difluorobenzoic acid

[0453]

[0454] Using 2-bromo-3,4-difluorobenzoic acid methyl ester, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester and 3-chloro-4-iodotrifluoromethylbenzene as raw materials, the preparation method was the same as that in Example 49. The product was a white solid powder with a total yield of 14% for 5 steps.

[0455] 1 H NMR (400MHz, MeOD) δ7.77 -7.72 (m, 1H), 7.53 -7.52(m, 1H), 7.50–7.41(m, 2H), 7.03-7.01(m, 1H), 4.42–4.35(m, 1H), 3.82–3.78(m, 1H), 3.69 -3.57(m, 2H), 3.63–3.53(m, 1H), 2.43-2.35(m, 1H), 2.17–2.05(m, 1H).MS-ESI(m / z)=406[M+H] + .

[0456] Example 66 2-(1-(Naphthalen-2-yl)pyrrolidin-3-yl)benzoic acid

[0457]

[0458] Using 2-(pyrrolidin-3-yl)benzoic acid methyl ester, 1-Boc-3-pyrroleboronic acid pinacol ester and 2-iodonaphthalene as raw materials, the preparation method is the same as Example 61, and the product is a white solid powder with a total yield of 17% in 5 steps.

[0459] 1 H NMR (400MHz, CDCl3) δ8.02-8.00 (m, 1H), 7.73-7.62 (m, 3H), 7.53-7.49 (m, 1H), 7.45 -7.43 (m, 1H), 7.37-7.31 (m, 2H), 7.19 -7.15 (m, 1H), 7.04 -7.01(m, 1H), 6.80(m, 1H), 5.19-5.14(m, 1H), 4.60–4.45(m, 1H), 3.93–3.81(m, 1H ), 3.66–3.50(m, 3H), 2.57-2.51(m, 1H), 2.27–2.18(m, 1H).MS-ESI(m / z)=318[M+H] + .

[0460] Example 67 2-Fluoro-3-(1-(naphthalen-2-yl)pyrrolidin-3-yl)benzoic acid

[0461]

[0462] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester, 1-Boc-3-pyrroleboric acid pinacol ester and 2-iodonaphthalene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a two-step yield of 32%.

[0463] 1H NMR (400MHz, DMSO) δ7.81 -7.75(m, 3H), 7.71-7.65(m, 2H), 7.41-7.37(m, 1H), 7.34-7.30(m, 1H), 7.21–7.13(m, 2H), 6.88(m, 1H ), 3.92–3.88(m, 2H), 3.68–3.45(m, 3H), 2.57-2.50(m, 1H), 2.27-2.22(m, 1H).MS-ESI(m / z)=336[M+H] + .

[0464] Example 68 2-(3-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluorophenyl)acetic acid

[0465]

[0466] Using 3-bromo-2-fluorophenylacetic acid methyl ester, 1-Boc-3-pyrroleboric acid pinacol ester and 3-chloro-4-iodotrifluoromethylbenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 18% in 5 steps.

[0467] 1 H NMR (400MHz, CDCl3) δ7.53(m, 1H), 7.37-7.35(m, 1H), 7.29-7.22(m, 1H), 7.19-7.16(m, 1H), 7.12-7.09(m, 1H), 6.85-6.82(m , 1H), 3.91–3.80(m, 1H), 3.78–3.69(m, 2H), 3.69–3.51(m, 2H), 2.50–2.31(m, 1H), 2.19-2.09(m, 1H).MS-ESI(m / z)=402[M+H] + .

[0468] Example 69 2-(1-(Naphthalen-1-yl)pyrrolidin-3-yl)benzoic acid

[0469]

[0470] Using 2-(pyrrolidin-3-yl)benzoic acid methyl ester, 1-Boc-3-pyrroleboronic acid pinacol ester and 1-iodonaphthalene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a two-step yield of 26%.

[0471] 1H NMR (400MHz, CDCl3) δ8.24-8.21(m, 1H), 7.99-7.97(m, 1H), 7.82-7.80(m , 1H), 7.76-7.75(m, 1H), 7.59-7.55(m, 1H), 7.50–7.29(m, 5H), 7.03-7.00 (m, 1H), 4.59–4.42 (m, 1H), 3.81-3.76 (m, 1H), 3.71–3.61 (m, 1H), 3.60–3 .42(m, 2H), 2.62-2.53(m, 1H), 2.23-2.14(m, 1H).MS-ESI(m / z)=318[M+H] + .

[0472] Example 70 2-(1-(2,4-difluorophenyl)pyrrolidin-3-yl)benzoic acid

[0473]

[0474] Using 2-(pyrrolidin-3-yl)benzoic acid methyl ester, 1-Boc-3-pyrroleboric acid pinacol ester and 2,4-difluoro-1-iodobenzene as raw materials, the preparation method is the same as Example 61, and the product is a white solid powder with a two-step yield of 19%.

[0475] 1 H NMR (400MHz, CDCl3) δ7.99-7.97(m, 1H), 7.54-7.53(m, 2H), 7.36-7.30(m, 1H), 6.89–6.72 (m, 2H), 6.67-6.61 (m, 1H), 4.51–4.35 (m, 1H), 3.72-3.68 (m, 1H), 3.59–3.34 (m, 3H), 2.49 -2.41(m, 1H), 2.15-2.06(m, 1H).MS-ESI(m / z)=304[M+H] + .

[0476] Example 71 2-(1-phenylpyrrolidin-3-yl)benzoic acid

[0477]

[0478] Using 2-(pyrrolidin-3-yl)benzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and iodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 33%.

[0479] 1H NMR (400MHz, CDCl3) δ8.00-7.99(m, 1H), 7.56-7.45(m, 1H), 7.43-7.41(m, 1H), 7.28-7.22(m, 2H), 6.71-6.68(m, 1H), 6.62-6.60(m, 2H), 4.53- 4.46 (p, J=7.1Hz, 1H), 3.79–3.64 (m, 1H), 3.55–3.45 (m, 1H), 3.44–3.3 1(m, 2H), 2.51-2.43(m, 1H), 2.20-2.12(m, 1H).MS-ESI(m / z)=268[M+H] + .

[0480] Example 72 2-(1-(2-Chloronaphthalen-1-yl)pyrrolidin-3-yl)benzoic acid

[0481]

[0482] Using 2-(pyrrolidin-3-yl)benzoic acid methyl ester, 1-Boc-3-pyrroleboronic acid pinacol ester and 1-iodo-2-chloronaphthalene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a two-step yield of 42%.

[0483] 1 H NMR (400MHz, CDCl3) δ8.36-8.34(m, 1H), 8.06-7.94(m, 1H), 7.83-7.80(m, 2H), 7.63-7.59 (m, 2H), 7.54-7.51 (m, 1H), 7.48-7.43 (m, 2H), 7.36-7.32 (m, 1H), 4.74-4.66 (m, 1H), 3.94 -3.90(m, 1H), 3.67-3.64(m, 2H), 3.50-3.47(m, 1H), 2.64-2.57(m, 1H), 2.42-2.30(m, 1H).MS-ESI(m / z)=352[M+H] + .

[0484] Example 73 2-(1-(4-chloronaphthalen-1-yl)pyrrolidin-3-yl)benzoic acid

[0485]

[0486] Using 2-(pyrrolidin-3-yl)benzoic acid methyl ester, 1-Boc-3-pyrroleboric acid pinacol ester and 1-chloro-4-iodonaphthalene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a two-step yield of 31%.

[0487] 1H NMR (400MHz, CDCl3) δ8.24 (d, J=8.5Hz, 2H), 7.99 (d, J=7.9Hz, 1H), 7.72 (s, 1H), 7.64–7.52 (m, 2H), 7.50 -7.44 (m, 2H), 7.35 -7.31 (m, 1H), 6.92 (d, J=8.2Hz, 1H), 4.60–4.45 (m, 1H), 3.80–3.68 (m, 1H), 3.63 -3.57(m, 1H), 3.51-3.46(m, 2H), 2.60-2.52(m, 1H), 2.23-2.14(m, 1H).MS-ESI(m / z)=352[M+H] + .

[0488] Example 74 2-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-6-fluorobenzoic acid

[0489]

[0490] Using 2-bromo-6-fluorobenzoic acid methyl ester, 1-Boc-3-pyrroleboric acid pinacol ester and 3-chloro-4-iodotrifluoromethylbenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total yield of 24% in 5 steps.

[0491] 1 H NMR (400MHz, CDCl3) δ7.46(m, 1H), 7.42–7.25(m, 2H), 7.21-7.16(m, 1H), 7.01–6.88(m, 1H), 6.76-6.74(m , 1H), 3.77–3.65(m, 2H), 3.65–3.44(m, 3H), 2.44–2.29(m, 1H), 2.20–1.99(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0492] Example 75 2-Fluoro-6-(1-phenylpyrrolidin-3-yl)benzoic acid

[0493]

[0494] Using 2-bromo-6-fluorobenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and iodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a total yield of 19% in 5 steps.

[0495] 1H NMR (400MHz, CDCl3) δ7.41-7.36(m, 1H), 7.29-7.21(m, 2H), 7.17-7.15(m, 1H), 7.04-7.00(m, 1H), 6.73-6.69(m, 1H), 6.61-6.58(m, 2H), 3 .89–3.78(m, 1H), 3.75–3.67(m, 1H), 3.53-3.48(m, 1H), 3.44-3.38(m, 2H), 2.55–2.40(m, 1H), 2.18-2.11(m, 1H).MS-ESI(m / z)=286[M+H] + .

[0496] Example 76 2-(1-(2,4,5-trifluorobenzyl)pyrrolidin-3-yl)benzoic acid

[0497]

[0498] Step 1) Methyl 2-(1-(2,4,5-trifluorobenzyl)pyrrolidin-3-yl)benzoate

[0499] At 20°C, methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate (0.05mmol, 110mg) and 2,4,5-trifluorobenzaldehyde (0.06mmol, 96mg) were dissolved in 5mL of dichloromethane, and the mixture was reacted at 20°C for 0.5h. Sodium cyanoborohydride (0.10mmol, 62mg) was added, and the solvent was removed by concentration under reduced pressure. A saturated sodium bicarbonate solution (10mL) was added, and the mixture was extracted with ethyl acetate (10mL×3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product (126mg, 72%).

[0500] Step 2) 2-(1-(2,4,5-trifluorobenzyl)pyrrolidin-3-yl)benzoic acid

[0501] At 20°C, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoate (126 mg, 0.36 mmol) was dissolved in tetrahydrofuran / water / methanol (2 / 1 / 2, 5 mL). Sodium hydroxide (40 mg, 1 mmol) was added at 20°C, and the resulting mixture was reacted at 20°C for 2 hours, and the reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, water (10 mL) was added, and ethyl acetate was extracted (10 mL×3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain 97 mg of the target product. The total yield was 79%.

[0502] 1 H NMR (400MHz, CDCl3) δ7.90-7.84(m, 1H), 7.80-7.78(m, 1H), 7.44-7.39(m ,2H),7.34–7.26(m,1H),6.99-6.93(m,1H),4.67–4.45(m,1H),4.39-4.29 (m, 2H), 4.04–3.85 (m, 1H), 3.75–3.53 (m, 1H), 3.35-3.29 (m, 1H), 3.21–2 .94(m, 1H), 2.66–2.42(m, 1H), 2.42–2.16(m, 1H).MS-ESI(m / z)=336[M+H] + .

[0503] Example 77 2-Fluoro-3-(1-(4-nitrophenyl)pyrrolidin-3-yl)benzoic acid

[0504]

[0505] Step 1) Methyl 2-fluoro-3-(1-(4-nitrophenyl)pyrrolidin-3-yl)benzoate

[0506] At 20°C, methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate (0.05mmol, 110mg), 4-fluoronitrobenzene (0.06mmol, 85mg) and anhydrous potassium carbonate (0.1mmol, 138mg) were dissolved in 5mL N,N-dimethylformamide solution, reacted at 100°C overnight, water (10mL) was added, and ethyl acetate was extracted (10mL×3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the target product (45mg, 30%).

[0507] Step 2) 2-Fluoro-3-(1-(4-nitrophenyl)pyrrolidin-3-yl)benzoic acid

[0508] At 20°C, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2,6-difluorobenzoate (45 mg, 0.13 mmol) was dissolved in tetrahydrofuran / water / methanol (2 / 1 / 2, 5 mL). Sodium hydroxide (40 mg, 1 mmol) was added at 20°C, and the resulting mixture was reacted at 20°C for 2 hours, and the reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, water (10 mL) was added, and ethyl acetate was extracted (10 mL×3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain 37 mg of the target product. The yield was 83%.

[0509] 1 H NMR (400MHz, DMSO) δ8.16-8.12(m, 2H), 7.84-7.80(m, 1H), 7.71-7.67(m, 1H), 7.36-7.33(m, 1H), 6.77-6.74(m, 2H), 3 .96–3.86(m, 2H), 3.72–3.67(m, 1H), 3.62-3.50(m, 2H), 2.51–2.47(m, 1H), 2.31–2.14(m, 1H).MS-ESI(m / z)=331[M+H] + .

[0510] Example 78 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-5-methylbenzoic acid

[0511]

[0512] Using 2-bromo-5-methylbenzoic acid methyl ester, 1-Boc-3-pyrrole boronic acid pinacol ester and 3,4-dichloroiodobenzene as raw materials, the preparation method is the same as that in Example 1, and the product is a white solid powder with a total step yield of 19%.

[0513] 1H NMR (400MHz, DMSO) δ7.80 (s, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 7.18 (d, J = 8.9Hz, 1H), 6.69 (d, J = 2.8Hz, 1H), 6.54-6.51 (m, 1H), 3.72–3.68 (m , 1H), 3.62–3.56(m, 1H), 3.52–3.46(m, 1H), 3.44–3.37(m, 1H), 2.48–2.41(m, 1H), 2.39(s, 3H), 2.21–2.11(m, 1H).MS-ESI(m / z)=350[M+H] + .

[0514] Example 79 6-Chloro-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0515]

[0516] Using 3-bromo-6-chloro-2-fluorobenzoic acid methyl ester, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester and 3,4-dichloroiodobenzene as raw materials, the preparation method was the same as Example 50, and the product was a white solid powder with a two-step yield of 27%.

[0517] 1 H NMR (400MHz, DMSO) δ7.39 (d, J=8.9Hz, 1H), 7.34-7.19 (m, 2H), 6.79 (d, J=2.5Hz, 1H), 6.62-6.59 (m, 1H ), 3.78–3.67(m, 2H), 3.48–3.31(m, 3H), 2.50–2.34(m, 1H), 2.20–2.07(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0518] Example 80 3-(1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0519]

[0520] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-fluoro-4-chloroiodobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 23%.

[0521] 1H NMR (400MHz, DMSO) δ7.63-7.59 (m, 1H), 7.46-7.42 (m, 1H), 7.31-7.27 (m, 1H), 7.19-7.16 (m, 1H), 6.59-6.55 (m, 1H), 6.44-6.41 (m, 1H), 3.86–3.71 (m, 1H), 3.70–3.62 (m, 1H), 3.53–3.11 (m, 3H), 2.44–2.34 (m, 1H), 2.17–2.07 (m, 1H).MS-ESI (m / z)=338[M+H] + .

[0522] Example 81 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-N-(methylsulfonyl)benzamide

[0523]

[0524] Using 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid and methanesulfonamide as raw materials, the preparation method is the same as Example 57. The product is a white solid powder with a yield of 83%.

[0525] 1 H NMR (400MHz, DMSO) δ12.27 (s, 1H), 7.63-7.48 (m, 2H), 7.37-7.35 (m, 1H), 7.31-7.27 (m, 1H), 6.76 (m, 1H), 6.59-6.56 (m, 1H), 3.8 3–3.75(m, 1H), 3.75–3.61(m, 1H), 3.49–3.40(m, 1H), 3.38(m, 3H), 2.43–2.29(m, 1H), 2.26–1.96(m, 1H).MS-ESI(m / z)=431[M+H] + .

[0526] Example 82 3-(1-(3-bromophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0527]

[0528] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 3-iodobromobenzene as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 36%.

[0529] 1H NMR (400MHz, CDCl3) δ7.91–7.78 (m, 1H), 7.41-7.38 (m, 1H), 7.15 -7.11(m, 1H), 7.04-7.00(m, 1H), 6.75-6.73(m, 1H), 6.66-6.55(m, 1H), 6.45-6.42(m, 1H), 3.85 -3.77(m, 1H), 3.70–3.65(m, 1H), 3.44-3.37(m, 2H), 3.31-3.28(m, 1H), 2.42 -2.39(m, 1H), 2.15–2.06(m, 1H).MS-ESI(m / z)=364[M+H] + .

[0530] Example 83 3-(1-(4-chloro-3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0531]

[0532] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-chloro-5-iodobenzotrifluoride as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 17%.

[0533] 1 H NMR (400MHz, DMSO-d6) δ7.68-7.64(m, 1H), 7.52-7.49(m, 1H), 7.45-7.43(m, 1H), 7.23-7.19(m, 1H), 6.90–6.7 7(m, 2H), 3.83–3.68(m, 2H), 3.51–3.31(m, 3H), 2.43-2.38(m, 1H), 2.19–2.10(m, 1H).MS-ESI(m / z)=388[M+H] + .

[0534] Example 84 3-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluoro-N-(methylsulfonyl)benzamide

[0535]

[0536] Using 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid and methanesulfonamide as raw materials, the preparation method was the same as Example 56. The product was a white solid powder with a yield of 53%.

[0537] 1H NMR (400MHz, CDCl3) δ8.84 (s, 1H), 8.03-7.99 (m, 1H), 7.64-7.60 (m, 1H), 7.56 (m, 1H), 7.43–7.36 (m, 1H), 7.40 -7.31(m, 1H), 6.88-6.86(m, 1H), 3.91–3.76(m, 2H), 3.74-3.62(m, 3H), 3 .45(s, 3H), 2.48-2.40(m, 1H), 2.19-2.10(m, 1H).MS-ESI(m / z)=465[M+H] + .

[0538] Example 85 3-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluoro-N-(phenylsulfonyl)benzamide

[0539]

[0540] Using 3-(1-(2-chloro-4-trifluoromethylphenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid and benzenesulfonamide as raw materials, the preparation method is the same as Example 56. The product is a white solid powder with a yield of 53%.

[0541] 1 H NMR (400MHz, CDCl3) δ8.99 (s, 1H), 8.22–8.12 (m, 2H), 7.90-7.86 (m, 1H), 7.69 -7.65(m, 1H), 7.60-7.54(m, 4H), 7.42–7.33(m, 1H), 7.29–7.21(m, 1H), 6.87-6.85(m, 1H), 3.88–3.55(m, 5H), 2.46-2.38(m, 1H), 2.17-2.08(m, 1H).MS-ESI(m / z)=527[M+H] + .

[0542] Example 86 3-(1-(4-bromo-3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0543]

[0544] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 2-bromo-5-iodobenzotrifluoride as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 17%.

[0545] 1H NMR (400MHz, CDCl3) δ7.87 -7.83(m, 1H), 7.43-7.37(m, 2H), 7.19–7.09(m, 1H), 6.78(m, 1H), 6.50-6.47(m, 1H), 3.93–3.80(m, 1H ), 3.78–3.62(m, 2H), 3.44-3.29(m, 3H), 2.44-2.39(m, 1H), 2.23–2.07(m, 1H).MS-ESI(m / z)=432[M+H] + .

[0546] Example 87 2-Fluoro-3-(1-(pyridin-4-yl)pyrrolidin-3-yl)benzoic acid

[0547]

[0548] Using 2-fluoro-3-(pyrrolidin-3-yl)benzoic acid methyl ester and 4-bromopyridine as raw materials, the preparation method is the same as Example 1, and the product is a white solid powder with a two-step yield of 36%.

[0549] 1 H NMR (400MHz, DMSO) δ8.28-8.26 (m, 2H), 7.76-7.73 (m, 1H), 7.63-7.60 (m, 1H), 7.32-7.28 (m, 1H), 6 .87-6.86(m, 2H), 4.00-3.45(m, 5H), 2.54–2.39(m, 1H), 2.34–2.15(m, 1H).MS-ESI(m / z)=287[M+H] + .

[0550] Example 88 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiophene-2-carboxylic acid

[0551]

[0552] Step 1: tert-Butyl 3-(5-(methoxycarbonyl)thiophen-3-yl)-2,5-dihydropyrrole-1-carboxylate

[0553] At room temperature, methyl 4-bromothiophene-2-carboxylate (250 mg, 1.13 mmol) was dissolved in ethylene glycol dimethyl ether / water (4 / 1, 5 mL). Anhydrous potassium carbonate (283 mg, 2.05 mmol), tetrakistriphenylphosphine palladium (59 mg, 0.05 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (300 mg, 1.02 mmol) were added in sequence, and the mixture was reacted at 80 ° C overnight under nitrogen protection. TLC was used to monitor the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined and washed with saturated brine (30 mL). Drying was performed over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the desired product (280 mg, 88.5%).

[0554] Step 2: tert-Butyl 3-(5-(methoxycarbonyl)thiophen-3-yl)pyrrolidine-1-carboxylate

[0555] At room temperature, tert-butyl 3-(5-(methoxycarbonyl)thiophene-3-yl)-2,5-dihydropyrrole-1-carboxylate (280 mg, 0.91 mmol) was dissolved in methanol (5 mL). Pd\C (60 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (280 mg, 99.4%), which was directly used in the next step.

[0556] Step 3: Methyl 4-(pyrrolidin-3-yl)thiophene-2-carboxylate

[0557] At room temperature, tert-butyl 3-(5-(methoxycarbonyl)thiophene-3-yl)pyrrolidine-1-carboxylate (280 mg, 0.90 mmol) was dissolved in dichloromethane (3 mL). At room temperature, a hydrochloric acid 1,4-dioxane solution (3 mL) was added and the mixture was reacted at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure, the pH was adjusted to alkaline, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The target product (170 mg, 89.7%) was obtained by purification by silica gel column chromatography.

[0558] Step 4: 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiophene-2-carboxylic acid methyl ester

[0559] At room temperature, methyl 4-(pyrrolidin-3-yl)thiophene-2-carboxylate (170 mg, 0.80 mmol) was dissolved in toluene (5 mL). Cesium carbonate (523 mg, 1.60 mmol), 1,2-dichloro-4-iodobenzene (328 mg, 1.20 mmol), palladium acetate (18 mg, 0.08 mmol), Xphos (76 mg, 0.16 mmol) were added in sequence, and the resulting mixture was reacted at 100°C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 24:1) to obtain the target product (170 mg, 59.3%).

[0560] Step 5: 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiophene-2-carboxylic acid

[0561] At room temperature, methyl 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiophene-2-carboxylate (170 mg, 0.48 mmol) was dissolved in tetrahydrofuran and methanol (1:1, 4 mL). 2 mL of 1M sodium hydroxide aqueous solution was added, and the reaction was carried out at room temperature for 2 h. The reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain the target product (70 mg, 42.9%).

[0562] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=1.6Hz,1H),7.31–7.26(m,1H),7.17(d,J=8.9Hz,1H),6.55(d,J=2.8Hz,1H),6.33(d d,J=8.9,2.8Hz,1H),3.65–3.45(m,2H),3.45–3.25(m,2H),3.28–3.19(m,1H),2.44–2.26(m,1H),2.12–1.98(m,1H).

[0563] MS (ESI) m / z: 342 [M+H] + .

[0564] Example 89 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiazole-2-carboxylic acid

[0565]

[0566] Step 1: 4-(1-tert-Butyloxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)thiazole-2-carboxylic acid

[0567] At room temperature, methyl 4-bromothiazole-2-carboxylate (400 mg, 1.80 mmol) was dissolved in ethylene glycol dimethyl ether / water (4 / 1, 20 mL). Anhydrous potassium carbonate (497.3 mg, 3.6 mmol), tetrakistriphenylphosphine palladium (104.1 mg, 0.09 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (550 mg, 1.86 mmol) were added in sequence, and the resulting mixture was reacted at 80 ° C for 3 h under nitrogen protection. TLC monitored the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and ethyl acetate was extracted (50 mL×3). The organic phases were combined and washed with saturated brine (50 mL). Drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=0%-25%) to obtain the target product (632 mg, 94.5%).

[0568] Step 2: 4-(1-tert-Butyloxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)thiazole-2-carboxylic acid methyl ester

[0569] At room temperature, 4-(1-tert-butyloxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)thiazole-2-carboxylic acid (632 mg, 2.14 mmol) was dissolved in DMF (5 mL). Anhydrous potassium carbonate (589.2 mg, 4.27 mmol) and iodomethane (454.8 mg, 3.20 mmol) were added, and the resulting mixture was reacted at room temperature for 4 h. TLC monitored the reaction. After the reaction was completed, water (50 mL) was added, and ethyl acetate was extracted (50 mL×3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0%-30%) to obtain the target product (402 mg, 65.7%).

[0570] Step 3: 4-(1-(tert-Butyloxycarbonyl)pyrrolidin-3-yl)thiazole-2-carboxylic acid methyl ester

[0571] At room temperature, methyl 4-(1-tert-butyloxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)thiazole-2-carboxylate (402 mg) was dissolved in methanol (5 mL). Pd\C (30.3 mg) was added, hydrogen was introduced to replace the air, and the resulting mixture was reacted at room temperature overnight. TLC monitored the reaction. After the reaction was completed, the reaction solution was filtered, and water (50 mL) was added to the filtrate, and ethyl acetate was extracted (50 mL×3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0%-40%) to obtain the target product (363 mg, 90.0%).

[0572] Step 4: 4-(Pyrrolidin-3-yl)thiazole-2-carboxylic acid methyl ester

[0573] At room temperature, methyl 4-(1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)thiazole-2-carboxylate (363 mg) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added at room temperature, and the resulting mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target product (350 mg, 94.6%).

[0574] Step 5: 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiazole-2-carboxylic acid methyl ester

[0575] At room temperature, methyl 4-(pyrrolidin-3-yl)thiazole-2-carboxylate (175 mg, 0.71 mmol) was dissolved in toluene (5 mL). Cesium carbonate (461.3 mg, 1.42 mmol), 1,2-dichloro-4-iodobenzene (230 mg, 0.85 mmol), palladium acetate (16.0 mg, 0.07 mmol), and Xphos (67.5 mg, 0.14 mmol) were added in sequence, and the resulting mixture was reacted at 100 ° C overnight under nitrogen protection. TLC monitored the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, and water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0%-20%) to obtain the target product (21 mg, 7.1%).

[0576] Step 6: 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiazole-2-carboxylic acid

[0577] At room temperature, methyl 4-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)thiazole-2-carboxylate (21 mg) was dissolved in tetrahydrofuran (2 mL), and 1M sodium hydroxide aqueous solution (2 mL) and methanol (1 mL) were added at room temperature to react for 2 h. The reaction was monitored by TLC. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to 3-4, and water (30 mL) was added. The mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 0%-15%) to obtain the target product (14 mg, 70%).

[0578] MS (ESI) m / z: 343 [M+H] + .

[0579] 1 H NMR (400MHz, DMSO-d6) δ7.46 (s, 1H), 7.33 (d, J = 9.0Hz, 1H), 6.66 (s, 1H), 6.49 (s, 1H),3.74–3.53(m,2H),3.44–3.35(m,3H),2.36–2.31(m,1H),2.24–2.11(m,1H).

[0580] Example 90 3-(1-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)-2-fluorobenzoic acid

[0581]

[0582] Step 1: Methyl 3-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-fluorobenzoate

[0583] At room temperature, methyl 3-bromo-2-fluorobenzoate (1g, 4.29mmol) was dissolved in N,N-dimethylformamide (20mL). Potassium phosphate (1.83g, 8.58mmol), ethyl acrylate (860mg, 8.58mmol), palladium acetate (100mg, 0.86mmol), tri(o-methylphenyl)phosphine (522mg, 1.72mmol) were added, and the resulting mixture was reacted at 80°C overnight under nitrogen protection. After the reaction was completed, it was cooled to room temperature. Water (200mL) was added, and the aqueous phase was extracted with ethyl acetate (150mL×3), the organic phases were combined, concentrated under reduced pressure, and the organic phase was washed with saturated brine (50mL×3). The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (546mg, 54.2%).

[0584] Step 2: Methyl 3-(4-ethoxy-1-nitro-4-oxobutan-2-yl)-2-fluorobenzoate

[0585] At room temperature, methyl 3-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-fluorobenzoate (700 mg, 2.78 mmol) and nitromethane (10 mL) were dissolved in acetonitrile (10 mL). Under nitrogen protection, 1,8-diazabicyclo[5.4.0]undec-7-ene (465 mg, 3.05 mmol) was added at 0°C and stirred for 10 min. The reaction mixture was moved to room temperature and reacted overnight. After the reaction was completed, 1 mol / L hydrochloric acid solution (20 mL) was added and stirred at room temperature for 10 min. The aqueous phase was extracted with ethyl acetate (30 mL×3) and the organic phases were combined. Drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (533 mg, 61.3%).

[0586] Step 3: Methyl 3-(1-amino-4-ethoxy-4-oxobutan-2-yl)-2-fluorobenzoate

[0587] At room temperature, methyl 3-(4-ethoxy-1-nitro-4-oxobutan-2-yl)-2-fluorobenzoate (533 mg, 1.70 mmol), zinc powder (443 mg, 6.79 mmol), ammonium chloride (363 mg, 6.79 mmol) and methanol (10 mL) were mixed evenly. Stir the reaction at room temperature for 30 min. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL), filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (10 mL×2). The filtrate was concentrated under reduced pressure. 520 mg of the target crude product was obtained, which was used directly in the next step without further treatment.

[0588] Step 4: Methyl 3-(1-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)-2-fluorobenzoate

[0589] At room temperature, methyl 3-(1-amino-4-ethoxy-4-oxobutan-2-yl)-2-fluorobenzoate (200 mg, 0.71 mmol) was dissolved in 1,4-dioxane (10 mL). Cesium carbonate (461 mg, 1.42 mmol), 1,2-dichloro-4-iodobenzene (232 mg, 0.85 mmol), palladium acetate (16 mg, 0.07 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (68 mg, 0.14 mmol) were added in sequence, and the resulting mixture was reacted at 80°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (76 mg, 28.3%).

[0590] Step 5: 3-(1-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)-2-fluorobenzoic acid

[0591] At room temperature, methyl 3-chloro-5-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)benzoate (76 mg, 0.20 mmol) was dissolved in tetrahydrofuran (4 mL). 1 mol / L sodium hydroxide solution (4 mL) and methanol (1 mL) were added at room temperature, and the resulting mixture was reacted at room temperature for 2 h, and the reaction was completed. 1 mol / L dilute hydrochloric acid was added to adjust the pH to 5, and the mixture was distilled under reduced pressure. The residue was purified by C18 column (mobile phase: 0.1% formic acid solution / acetonitrile; gradient: 5%-5% 2 min, 5%-67% 15 min, 67% received product) to obtain the target product (20 mg, 27.3%).

[0592] MS (ESI) m / z: 368 [M+H] + .

[0593] 1 H NMR (400MHz, DMSO) δ8.06(d,J=2.4Hz,1H),7.74(dd,J=10.4,4.2Hz,1H),7.69(dt,J=5.4,2.6Hz,2H),7.64(d,J=8.9Hz,1H), 7.29(t,J=7.7Hz,1H), 4.24(t,J=8.3Hz,1H), 3.96(dd,J=19.2,8.5Hz,2H), 2.99–2.92(m,1H), 2.79(dd,J=16.8,8.8Hz,1H).

[0594] Example 91 3-(1-(Benzothiazol-6-yl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0595]

[0596] Step 1: Methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate

[0597] At room temperature, tert-butyl 3-(2-fluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (130 mg, 0.46 mmol) was dissolved in DCM (2 mL). TFA (0.4 ml) was added dropwise, and the resulting mixture was reacted at room temperature for 1 h. After the reaction, the pH was adjusted to 6 with a saturated aqueous solution of NaHCO3, and extracted with DCM three times (10 mL×3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (60 mg, 85%).

[0598] Step 2: Methyl 3-(1-(Benzothiazol-6-yl)pyrrolidin-3-yl)-2-fluorobenzoate

[0599] At room temperature, methyl 2-fluoro-3-(pyrrolidin-3-yl)benzoate (60 mg, 0.34 mmol) and 6-iodobenzothiazole (89 mg, 0.34 mmol) were dissolved in toluene (5 mL). Anhydrous cesium carbonate (175 mg, 0.54 mmol), palladium acetate (6 mg, 0.03 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (56 mg, 0.05 mmol) were added in sequence, and the resulting mixture was reacted at 100°C for 12 h. LCMS monitored the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (50 mL). Drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the desired product (57 mg, 47.1%).

[0600] Step 3: 3-(1-(Benzothiazol-6-yl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0601] At room temperature, methyl 3-(1-(benzothiazol-6-yl)pyrrolidin-3-yl)-2-fluorobenzoate (57 mg, 0.16 mmol) was dissolved in THF (2 mL), 1M / L LiOH aqueous solution (2 ml) was added, and the resulting mixture was reacted at room temperature for 2 h. After the reaction was completed, 1M / L HCl was added to adjust the pH to 6, the organic phase was spin-dried, and extracted with DCM (10 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain the target product (35 mg, 63.9%).

[0602] 1H NMR (400MHz, CDCl3) δ8.63(s,1H),8.18(d,J=8.7Hz,1H),7.92(d,J=8.9Hz,1H),7.86(t ,J=6.6Hz,1H),7.43(t,J=7.3Hz,1H),7.13(d,J=7.8Hz,1H),6.96(d,J=1.9Hz,1H),6.79 (dd,J=8.9,2.3Hz,1H),3.91–3.82(m,1H),3.81–3.74(m,1H),3.50(ddd,J=14.6,9.7,5 .7Hz,2H),3.41(dd,J=9.0,7.2Hz,1H),2.44(td,J=11.8,6.8Hz,1H),2.22–2.13(m,1H).

[0603] MS (ESI) m / z: 343 [M+H] + .

[0604] Example 92 3-(3-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-1-yl)-2-fluorobenzoic acid

[0605]

[0606] Step 1: tert-Butyl 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0607] A 1M toluene solution of diethylzinc was added to ultra-dry DCM (5 mL) at 0°C, TFA (1.16 g, 10.18 mmol) was added dropwise while keeping warm, and the reaction was kept warm for half an hour. Diiodomethane (2.7 g, 10.18 mmol) was added dropwise, and the reaction was kept warm for 1 hour. 1-tert-Butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (500 mg, 1.69 mmol) was dissolved in a small amount of DCM and added dropwise to the system. After the addition was completed, the ice bath was removed, and the temperature was naturally raised to room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and dissolved in THF. DMAP (0.1 eq), TEA (10 eq), and Boc2O (5 eq) were added, stirred for 2 h, poured into water (30 mL), extracted with EA (20 mL×3), the EA phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, dissolved again in THF and water (2:1), NBS (0.7 eq) was added, stirred for half an hour, extracted again with EA, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the target product (270 mg, 51.5%).

[0608] Step 2: Potassium (3-(tert-Butyloxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)trifluoroborate

[0609] At room temperature, 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100 mg) was dissolved in methanol (2 mL). KHF2 (151 mg, 1.94 mmol) was added, and the resulting mixture was reacted at 70°C for 4 h. After the reaction, the reaction solution was concentrated under reduced pressure, the crude product was slurried with ether, the filter cake was dissolved with acetonitrile, hot filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (70 mg, 74.8%).

[0610] Step 3: tert-Butyl 1-(2-fluoro-3-methoxycarbonyl)phenyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0611] At room temperature, methyl 3-bromo-2-fluorobenzoate (85 mg, 0.36 mmol), anhydrous potassium carbonate (66 mg, 0.48 mmol), tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (70 mg, 0.24 mmol) were added to the reaction bottle, and then ethylene glycol dimethyl ether / water (4:1, 5 mL) was added to react at 80°C overnight under nitrogen protection. TLC monitored the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined and washed with saturated brine (30 mL). Drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the desired product (25 mg, 32.8%).

[0612] Step 4: 3-(3-azabicyclo[3.1.0]hexan-1-yl)-2-fluorobenzoic acid methyl ester

[0613] At room temperature, tert-butyl 1-(2-fluoro-3-methoxycarbonyl)phenyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (25 mg, 0.074 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added at room temperature and reacted at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product (25 mg) which was directly used in the next step.

[0614] Step 5: Methyl 3-(3-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-fluorobenzoate

[0615] At room temperature, methyl 3-(3-azabicyclo[3.1.0]hexane-1-yl)-2-fluorobenzoate trifluoroacetate (25 mg, 0.074 mmol) was dissolved in toluene (3 mL). Cesium carbonate (49 mg, 0.149 mmol), 1,2-dichloro-4-iodobenzene (31 mg, 0.111 mmol), palladium acetate (1.7 mg, 0.007 mmol), and Xphos (7.2 mg, 0.015 mmol) were added in sequence, and the resulting mixture was reacted at 100°C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 24:1) to obtain the target product (15 mg, 52.7%).

[0616] Step 6: 3-(3-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hex-1-yl)-2-fluorobenzoic acid

[0617] At room temperature, methyl 3-(3-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2-fluorobenzoate (15 mg, 0.04 mmol) was dissolved in tetrahydrofuran and methanol (1:1, 2 mL). 1 mL of 1M sodium hydroxide aqueous solution was added and the reaction was allowed to react at room temperature for 2 h. The reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 column preparation (H2O:ACN=20-70%) to obtain products 92A (4 mg) and 92B (4 mg), both of which were light yellow solids.

[0618] 92A 1 H NMR(400MHz,Chloroform-d)δ7.33(d,J=37.7Hz,1H),6.93(d,J=8.7Hz,1H),6.84(s,1H),6.47(s,1H),6.24( s,1H),6.02(d,J=9.1Hz,1H),3.30(s,1H),3.19(s,1H),3.02(s,1H),2.71(s,1H),1.51(s,1H),0.56(s,2H).

[0619] MS (ESI) m / z: 366 [M+H] +

[0620] 92B 1H NMR (400MHz, Chloroform-d) δ7.86 (s, 1H), 7.47 (t, J = 7.1Hz, 1H), 7.14 (d, J = 8. 9Hz, 2H), 6.56 (d, J=2.8Hz, 1H), 6.33 (dd, J=8.9, 2.8Hz, 1H), 3.74 (d, J=8.9Hz, 1H),3.57(d,J=9.0Hz,1H),3.45(dd,J=9.0,4.0Hz,1H),3.28(d,J=8.9Hz,1H), 1.94(dt,J=8.4,4.3Hz,1H), 1.08(dd,J=8.2,4.8Hz,1H), 0.97(t,J=4.6Hz,1H).

[0621] MS (ESI) m / z: 366 [M+H] + .

[0622] Example 93 6-Bromo-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0623]

[0624] Step 1: Methyl 6-amino-3-bromo-2-fluorobenzoate

[0625] At room temperature, 6-amino-3-bromo-2-fluorobenzoic acid (500 mg, 2.14 mmol) was suspended in 20 ml of DCM / MeOH (4:1) mixed solvent, stirred evenly, and (trimethylsilyl)diazomethane (2.14 ml 4.28 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3 h, and then 2 mL of 1M HCl was added to quench the reaction. Saturated sodium bicarbonate solution was added to adjust the pH to 8, and DCM was extracted three times, washed with saturated NaCl aqueous solution, dried, and concentrated to obtain 400 mg of a light yellow solid product. The yield was 75%.

[0626] Step 2: tert-Butyl 3-(2-fluoro-3-methoxycarbonyl)-4-amino-2,5-dihydropyrrole-1-carboxylate

[0627] At room temperature, methyl 6-amino-3-bromo-2-fluorobenzoate (400 mg), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (480 mg), Pd(dppf)Cl2CH2Cl2 (133 mg) and sodium carbonate (340 mg) were added to a single-mouth bottle, and 18 mL of a mixed solution of 1,4-dioxane / H2O (5 / 1) was added. The mixture was heated to 80 degrees Celsius under nitrogen protection for 4 hours, cooled, quenched with water, extracted with ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified on a silica gel column to obtain the title compound as a white solid (320 mg, 59%).

[0628] Step 3: tert-Butyl 3-(4-amino-2-fluoro-3-methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

[0629] At room temperature, tert-butyl 3-(2-fluoro-3-methoxycarbonyl)-4-amino-2,5-dihydropyrrole-1-carboxylate (320 mg) was dissolved in MeOH / THF (4 / 1, 10 mL), 100 mg of Pd / C was added, and the mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere. The mixture was filtered through celite and the filtrate was concentrated to obtain 300 mg of an oily product.

[0630] Step 4: tert-Butyl 3-(4-bromo-2-fluoro-3-methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

[0631] At room temperature, isoamyl nitrite (156 mg) and CuBr (190 mg) were suspended in acetonitrile (6 mL) and stirred evenly. The reaction mixture was heated to 50°C, and an acetonitrile solution (3 mL) of tert-butyl 3-(4-amino-2-fluoro-3-methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (300 mg) was added dropwise. After the addition was completed, the reaction was continued at 50°C for 3 hours. After the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting mixture was purified by silica gel column chromatography to obtain 200 mg of an oily product.

[0632] Step 5: Methyl 6-bromo-2-fluoro-3-(pyrrolidin-3-yl)benzoate

[0633] At room temperature, tert-butyl 3-(4-bromo-2-fluoro-3-methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (200 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 1 hour. The pH of the reaction system was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and dichloromethane (30 mL) was added. The liquids were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 130 mg of an oily product.

[0634] Step 6: Methyl 6-bromo-3-(1-(3-chloro-4-nitrophenyl)pyrrolidin-3-yl)-2-fluorobenzoate

[0635] At room temperature, methyl 6-bromo-2-fluoro-3-(pyrrolidin-3-yl)benzoate (130 mg) and 2-chloro-4-fluoronitrobenzene (84 mg) were dissolved in DMF, and potassium carbonate (120 mg) was added. The resulting reaction mixture was heated to 60°C and stirred for 2 hours. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography to obtain 133 mg of the product.

[0636] Step 7: Methyl 3-(1-(4-amino-3-chlorophenyl)pyrrolidin-3-yl)-6-bromo-2-fluorobenzoate

[0637] At room temperature, methyl 6-bromo-3-(1-(3-chloro-4-nitrophenyl)pyrrolidin-3-yl)-2-fluorobenzoate (133 mg) was suspended in 10 mL of ethanol, and ammonium chloride (75 mg) was added, followed by 2 mL of water and iron powder (80 mg). The resulting reaction mixture was heated to 80° C. and stirred for 1 hour. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was concentrated to remove ethanol, and 800 mL of dichloromethane was added, washed with water 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 110 mg of an oily product.

[0638] Step 8: Methyl 6-bromo-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoate

[0639] At room temperature, 46 mg of isoamyl nitrite and 38 mg of cuprous chloride were suspended in 6 mL of acetonitrile, and the resulting mixture was heated to 50°C, and then a solution prepared by dissolving 3-(1-(4-amino-3-chlorophenyl)pyrrolidin-3-yl)-6-bromo-2-fluorobenzoic acid methyl ester (110 mg) in acetonitrile (3 mL) was added dropwise. After the addition was completed, the reaction was continued at 50°C for 3 hours. After the reaction solution was cooled to room temperature, a saturated aqueous sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 20 mg of an oily product.

[0640] Step 9: 6-Bromo-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoic acid

[0641] At room temperature, methyl 6-bromo-3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorobenzoate (20 mg) was dissolved in methanol / tetrahydrofuran (1 / 1, 4 mL), and 1 M NaOH aqueous solution (2 mL) was added. The reaction was stirred at room temperature for 16 hours. The pH of the reaction system was adjusted to about 5 with 1 M HCl, and 20 mL of water was added. The product was extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain a white solid product (10 mg).

[0642] MS (ESI) m / z: 432 [M+H] + .

[0643] Example 94 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methylbenzoic acid

[0644]

[0645] Step 1: 3-Bromo-2-fluoro-6-methylbenzoic acid

[0646] 2,2.6,6-Tetramethylpiperidine (1.069 ml, 6.35 mmol) was added to THF (20 ml) and the temperature was cooled to -10°C. 2.5 M / L n-butyllithium (2.6 ml, 6.35 mmol) was added dropwise to the system under nitrogen atmosphere and reacted at -10°C for 1 h.

[0647] When the reaction time is up, the temperature is lowered to -78°C, 1-bromo-2-fluoro-4-methylbenzene (0.669 mL 5.29 mmol) is added dropwise, and the mixture is stirred at the same temperature for 30 min. 5 g of dry ice solid (931 mg 21.16 mmol) is added, and the reaction is continued for 20 min.

[0648] After the reaction, 5 ml of 1M / L HCl was added dropwise at -78°C and the temperature was naturally raised to room temperature. The organic phase was spin-dried and extracted three times with ethyl acetate (20 ml). The organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 1.1 g (1.1 g 90%) of the target product.

[0649] MS (ESI) m / z: 231 [MH] +

[0650] Step 2: Methyl 3-bromo-2-fluoro-6-methylbenzoate

[0651] At room temperature, 3-bromo-2-fluoro-6-methylbenzoic acid (500 mg, 2.16 mmol) and iodomethane (459 mg, 3.23 mmol) were added to DMF (20 mL). The mixture was reacted at room temperature for 2 h. After the reaction was completed, water (200 mL) was added, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). Drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product (476 mg, 89.5%).

[0652] Step 3: tert-Butyl 3-(2-fluoro-3-methoxycarbonyl)-4-methylphenyl-2,5-dihydropyrrole-1-carboxylate

[0653] At room temperature, methyl 3-bromo-2-fluoro-6-methylbenzoate (476 mg, 1.93 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-ene-1-carboxylate (856 mg 2.90 mmol), tetrakis(triphenylphosphine)palladium (224 mg 0.19 mmol), sodium carbonate (410 mg 3.87 mmol) were dissolved in 12 ml DME and 4 ml water, and the resulting mixture was reacted at 80°C for 2 h. After the reaction was completed, the organic phase was dried by spin drying and extracted with DCM (10 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain the target product (538 mg, 83.2%).

[0654] Step 4: tert-Butyl 3-(2-fluoro-3-methoxycarbonyl)-4-methylphenylpyrrolidine-1-carboxylate

[0655] At room temperature, tert-butyl 3-(2-fluoro-3-methoxycarbonyl)-4-methylphenyl-2,5-dihydropyrrole-1-carboxylate (200 mg 0.59 mmol) and wet palladium carbon (20 mg 10%) were dissolved in MeOH (5 ml) and stirred at room temperature under hydrogen atmosphere for 4 h.

[0656] After the reaction was completed, the product was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain the target product (120 mg, 60.3%).

[0657] Step 5: Methyl 2-fluoro-6-methyl-3-pyrrolidin-3-ylbenzoate

[0658] At room temperature, tert-butyl 3-(2-fluoro-3-methoxycarbonyl)-4-methylphenylpyrrolidine-1-carboxylate (120 mg 0.36 mmol) was dissolved in a TFA:DCM=1:5 solution (5 ml) and stirred at room temperature for 0.5 h.

[0659] After the reaction, adjust the pH to 8 with sodium bicarbonate. Add water (5 ml) and extract with DCM (5 mL x 3). Combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target product (60 mg, 74.7%).

[0660] Step 6: Methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methylbenzoate

[0661] At room temperature, methyl 2-fluoro-6-methyl-3-pyrrolidin-3-ylbenzoate (60 mg, 0.27 mmol), 1,2-dichloro-4-iodobenzene (110 mg 0.40 mmol), palladium acetate (5.7 mg 0.03 mmol), sodium carbonate (410 mg 3.87 mmol) were dissolved in 12 ml DME and 4 ml water, and the resulting mixture was reacted at 80°C for 2 h. After the reaction was completed, the organic phase was spin-dried and extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EA = 10: 1) to obtain the target product (53 mg, 51.5%).

[0662] Step 7: 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methylbenzoic acid

[0663] At room temperature, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methylbenzoate (53 mg, 0.14 mmol) was dissolved in 2 ml of THF, 2 ml of 1 M / L lithium hydroxide aqueous solution was added to the solution, and the resulting mixture was reacted at room temperature overnight. After the reaction, the pH was adjusted to pH = 6 with 1 M / L HCl, the organic phase was spin-dried, and extracted with EA (10 mL × 3). After the organic phases were combined, they were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EA = 10: 1) to obtain the target product (20 mg, 38.9%).

[0664] 1HNMR (400MHz, CDCl3) δ7.12(t,J=7.7Hz,1H),6.92(d,J=7.9Hz,1H),6.55(d,J=2.7Hz,1H ),6.55(d,J=2.7Hz,1H),6.55(d,J=2.7Hz,1H),6.32(dd,J=8.9,2.7Hz,1H),6.32(dd,J=8 .9,2.7Hz,1H),3.70(dd,J=15.1,7.7Hz,1H),3.60(t,J=8.3Hz,1H),3.39–3.29(m,2H),3 .26–3.18(m,1H),2.37(s,3H),2.32(dd,J=11.1,6.8Hz,1H),2.09(dd,J=12.4,8.4Hz,1H)

[0665] MS (ESI) m / z: 368 [M+H] + .

[0666] Example 95 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-trifluoromethylbenzoic acid

[0667]

[0668] Step 1: 3-Bromo-2-fluoro-6-trifluoromethylbenzoic acid

[0669] At room temperature, 1-bromo-2-fluoro-4-trifluoromethylbenzene (300 mg, 1.23 mmol) was dissolved in ultra-dry THF (5 mL), cooled to -78 ° C under nitrogen protection, and lithium diisopropylamide (0.925 mL, 1.85 mmol) was slowly added dropwise. After the addition was completed, the reaction was stirred at -78 ° C for 1 hour, and dry ice (50 g) was added. The reaction was continued for 0.5 hour. Water (20 mL) was added to the reaction system, and the pH was acidified to about 5 with 1M HCl, and then extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (200 mg, 54.5%).

[0670] Step 2: Methyl 3-bromo-2-fluoro-6-trifluoromethylbenzoate

[0671] At room temperature, 3-bromo-2-fluoro-6-trifluoromethylbenzoic acid (200 mg, 0.7 mmol) was dissolved in DMF (5 mL), anhydrous potassium carbonate (193 mg, 1.4 mmol) and iodomethane (149 mg, 1.05 mmol) were added, and the resulting mixture was reacted overnight at room temperature. After the reaction, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (120 mg, 55.4%).

[0672] Step 3: tert-Butyl 3-(2-fluoro-3-(methoxycarbonyl)-4-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0673] At room temperature, methyl 3-bromo-2-fluoro-6-trifluoromethylbenzoate (120 mg, 0.4 mmol) was dissolved in ethylene glycol dimethyl ether / water (4 / 1,5 mL), and anhydrous potassium carbonate (110 mg, 0.8 mmol), tetrakistriphenylphosphine palladium (46 mg, 0.04 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (177 mg, 0.6 mmol) were added in sequence, and the resulting mixture was reacted at 80 ° C for 2 hours. After the reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (75 mg, 48.1%).

[0674] Step 4: tert-Butyl 3-(2-fluoro-3-methoxycarbonyl)-4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate

[0675] At room temperature, tert-butyl 3-(2-fluoro-3-methoxycarbonyl)-4-trifluoromethylphenyl-2,5-dihydropyrrole-1-carboxylate (75 mg, 0.19 mmol) was dissolved in methanol (5 mL). Pd / C (20 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was stirred at room temperature under a hydrogen atmosphere and reacted overnight. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (75 mg), which was directly used in the next step without further purification.

[0676] Step 5: Methyl 2-fluoro-3-(pyrrolidin-3-yl)-6-(trifluoromethyl)benzoate

[0677] At room temperature, tert-butyl 3-(2-fluoro-3-methoxycarbonyl)-4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate (75 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and a 2M hydrochloric acid 1,4-dioxane solution (2 mL) was added at room temperature, and the mixture was reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to about 8. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as an oil (50 mg).

[0678] Step 6: Methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-(trifluoromethyl)benzoate

[0679] At room temperature, methyl 2-fluoro-3-(pyrrolidin-3-yl)-6-(trifluoromethyl)benzoate (50 mg, 0.17 mmol) was dissolved in toluene (5 mL). Cesium carbonate (112 mg, 0.34 mmol), 1,2-dichloro-4-iodobenzene (70 mg, 0.26 mmol), palladium acetate (4 mg, 0.017 mmol), and Xphos (16 mg, 0.034 mmol) were added in sequence, and the resulting mixture was stirred and reacted at 100 ° C overnight under nitrogen protection. After the reaction solution was cooled to room temperature, water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 24:1) to obtain the target product (55 mg, 73.7%).

[0680] Step 7: 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-(trifluoromethyl)benzoic acid,

[0681] At room temperature, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-(trifluoromethyl)benzoate (55 mg, 0.13 mmol) was dissolved in tetrahydrofuran and methanol (1:1, 2 mL), 1 mL of 1 M sodium hydroxide aqueous solution was added, and the resulting mixture was stirred at room temperature for 2 hours, and dilute hydrochloric acid was added to adjust the pH to 3-4, water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to give the target product as a light yellow solid (50 mg, 93.9%).

[0682] 1H NMR (400MHz, CDCl3) δ7.33(d,J=8.2Hz,1H),7.29–7.22(m,1H),7.14(d,J=8.8Hz,1H),6.51(d,J=2.8Hz,1H),6.28(dd,J=8 .9,2.8Hz,1H),3.70(q,J=7.7Hz,1H),3.57(t,J=8.4Hz,1H),3.35–3.16(m,3H),2.33(m,1H),2.07(dq,J=12.2,8.0Hz,1H).

[0683] MS (ESI) m / z: 422 [M+H] + .

[0684] Example 96 Optical Resolution of 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-trifluoromethylbenzoic acid

[0685] 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-(trifluoromethyl)benzoic acid (5 mg) obtained in Example 95 was dissolved in isopropanol (10 mL) to obtain a 0.5 mg / mL solution. 10 μL of the above solution was sampled and analyzed on a polysaccharide-derivative chiral chromatographic column (CHIRALPAK IC 4.6 mm×250 mm, 5 μm), with a mobile phase of n-hexane:ethanol (0.1% trifluoroacetic acid) (98:2), a flow rate of 1.0 mL per minute, a detection wavelength of 263 nm, and a column temperature of 30°C (analysis spectrum); the sample solution was then separated in batches on a polysaccharide-derivative chiral chromatographic column (CHIRALPAK IC 10 mm×250 mm, 5 μm) to obtain two optical isomers as light yellow solids 96A (2 mg, 15.61 min) and 96B (2 mg, 17.95 min).

[0686] Optical resolution spectrum Figure 3 shown.

[0687] 96A: 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.2Hz,1H),7.29–7.22(m,1H),7.14(d,J=8.8Hz,1H),6.53(d,J=2.7Hz,1H),6.30(dd,J=8 .9,2.7Hz,1H),3.70(q,J=7.7Hz,1H),3.59(t,J=8.4Hz,1H),3.38–3.18(m,3H),2.35(m,1H),2.08(dq,J=13.2,8.0Hz,1H).

[0688] MS (ESI) m / z: 422 [M+H] + .

[0689] 96B: 1 H NMR (400MHz, CDCl3) δ7.44–7.29(m,2H),7.15(d,J=8.8Hz,1H),6.54(d,J=2.6Hz,1H),6.32(dd,J=8.8,2.6Hz,1H),3. 82–3.72(m,1H),3.62(t,J=8.4Hz,1H),3.40–3.21(m,3H),2.38(td,J=11.8,6.8Hz,1H),2.10(dq,J=15.9,7.9Hz,1H).

[0690] MS (ESI) m / z: 422 [M+H] + .

[0691] Example 97 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-nitrobenzoic acid

[0692]

[0693] Step 1: 3-Bromo-2-fluoro-6-nitrobenzoic acid

[0694] At room temperature, 1-bromo-2-fluoro-4-nitrobenzene (2.0 g, 9.1 mmol) was dissolved in dry tetrahydrofuran (20 mL). Diisopropyl lithium amide (2 mol / L, 10 ml) was added dropwise at -78 °C under nitrogen protection. After the addition was complete, the mixture was reacted at -78 °C for 30 minutes. 50 g of dry ice washed with dry tetrahydrofuran was added, and the mixture was stirred and reacted at -78 °C for 30 min. After the reaction was completed, the mixture was heated to room temperature and water (50 mL) was added to quench the reaction. The aqueous phase was washed with ethyl acetate (30 mL × 3). The aqueous phase was adjusted to pH 3 with hydrochloric acid solution, extracted with ethyl acetate (60 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the title compound (924.6 mg, 38.5%).

[0695] Step 2: Methyl 3-bromo-2-fluoro-6-nitrobenzoate

[0696] At room temperature, 3-bromo-2-fluoro-6-nitrobenzoic acid (924 mg, 3.5 mmol), potassium carbonate (967 mg, 7.0 mmol) and N, N-dimethylformamide (10 mL) were mixed evenly, iodomethane (993 mg, 7.0 mmol) was added, and the reaction was stirred at room temperature overnight. Water (100 mL) was added to dilute the reaction solution, the aqueous phase was extracted with ethyl acetate (75 mL × 3), the organic phases were combined, concentrated under reduced pressure, and washed with saturated brine (30 mL × 3). Drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (460 mg, 47.0%).

[0697] Step 3: tert-Butyl 3-(2-fluoro-3-(methoxycarbonyl)-4-nitrophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0698] At room temperature, methyl 3-bromo-2-fluoro-6-nitrobenzoate (200 mg, 0.72 mmol) was dissolved in 1,4-dioxane / water (5 / 1, 12 mL). Anhydrous cesium carbonate (470 mg, 1.44 mmol), tetrakistriphenylphosphine palladium (84 mg, 0.07 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (319 mg, 1.08 mmol) were added in sequence, and the resulting mixture was stirred at 80 ° C under nitrogen protection for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound (262 mg, 99.4%).

[0699] Step 4: tert-Butyl 3-(2-fluoro-3-(methoxycarbonyl)-4-nitrophenyl)pyrrolidine-1-carboxylate

[0700] At room temperature, tert-butyl 3-(2-fluoro-3-(methoxycarbonyl)-4-nitrophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (200 mg, 0.55 mmol) was dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (5 mL), tris(triphenylphosphine)rhodium chloride (51 mg, 0.06 mmol) was added, and hydrogen was introduced to replace the air. The resulting mixture was stirred and reacted overnight at room temperature under a hydrogen atmosphere. After the reaction was completed, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (130 mg, 64.6%).

[0701] Step 5: Methyl 2-fluoro-6-nitro-3-(pyrrolidin-3-yl)benzoate

[0702] At room temperature, tert-butyl 3-(2-fluoro-3-(methoxycarbonyl)-4-nitrophenyl)pyrrolidine-1-carboxylate (130 mg, 0.35 mmol) was dissolved in methanol (12 mL). At room temperature, 2M hydrochloric acid (4 mL) was added, and the resulting mixture was reacted at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (30 mL×4), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (72 mg, 76.1%).

[0703] Step 6: Methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-nitrobenzoate

[0704] At room temperature, methyl 2-fluoro-6-nitro-3-(pyrrolidin-3-yl)benzoate (72 mg, 0.27 mmol) was dissolved in toluene (10 mL). Cesium carbonate (176 mg, 0.54 mmol), 1,2-dichloro-4-iodobenzene (110 mg, 0.41 mmol), palladium acetate (6 mg, 0.03 mmol), and Xantphos (26 mg, 0.05 mmol) were added in sequence, and the resulting mixture was stirred at 80 ° C under nitrogen protection overnight. After the reaction solution was cooled to room temperature, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound as a light yellow solid (25 mg, 22.5%).

[0705] Step 7: 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-nitrobenzoic acid

[0706] At room temperature, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-nitrobenzoate (25 mg, 0.06 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (2 mL), and 1 mol / L sodium hydroxide solution (10 mL) was added at room temperature. The resulting mixture was reacted at room temperature overnight. 1 mol / L dilute hydrochloric acid was added to the reaction solution to adjust the pH to 3, and the solution was concentrated under reduced pressure. Dichloromethane (20 mL) was added to the concentrated solution, filtered, and the filtrate was distilled under reduced pressure. The residue was purified by C18 column (mobile phase: 0.1% formic acid solution / acetonitrile; gradient: 5%-5% 1 min, 5%-75% 11 min) to obtain the title compound as a light yellow solid (10 mg, 41.4%).

[0707] 1H NMR (400MHz, DMSO) δ7.88(d,J=8.6Hz,1H),7.51(t,J=7.7Hz,1H),7.36(d,J=8.9Hz,1H),6.76(d,J=2.1Hz,1H),6.58(dd,J=8.5,2.2Hz,1H),3.87– 3.78(m,1H),3.73–3.65(m,1H),3.43(dd,J=10.3,5.7Hz,4H),2.98(t,J= 7.4Hz,1H),2.69(t,J=7.4Hz,1H),2.45–2.37(m,1H),2.19–2.09(m,1H).

[0708] MS (ESI) m / z: 399 [M+H] + .

[0709] Example 98 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methoxybenzoic acid Step 1: 3-Bromo-2-fluoro-6-methoxybenzoic acid

[0710] At room temperature, 1-bromo-2-fluoro-4-methoxybenzene (200 mg, 0.98 mmol) was dissolved in dry tetrahydrofuran (10 mL). Diisopropylamide lithium (2 mol / L, 0.6 ml) was added dropwise at -78 °C under nitrogen protection. After the addition was complete, the mixture was reacted at -78 °C for 30 minutes. 50 g of dry ice washed with dry tetrahydrofuran was added and the mixture was reacted at -78 °C for 30 minutes. After the reaction was completed, the mixture was heated to room temperature and water (30 mL) was added to quench the reaction. The aqueous phase was washed with ethyl acetate (20 mL × 3). The aqueous phase was adjusted to pH 5 with 2M hydrochloric acid solution, extracted with ethyl acetate (30 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the title compound (155 mg, 63.8%).

[0711] Step 2: Methyl 3-bromo-2-fluoro-6-methoxybenzoate

[0712] At room temperature, 3-bromo-2-fluoro-6-methoxybenzoic acid (150 mg, 0.60 mmol), potassium carbonate (167 mg, 1.20 mmol) and N, N-dimethylformamide were mixed evenly. Iodomethane (94 mg, 0.66 mmol) was added and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, water (50 mL) was added to dilute the reaction solution, the aqueous phase was extracted with ethyl acetate (75 mL × 3), the organic phases were combined, concentrated under reduced pressure, and washed with saturated brine (30 mL × 3). Drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (130 mg, 82.0%).

[0713] Step 3: tert-Butyl 3-(2-fluoro-4-methoxy-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0714] At room temperature, methyl 3-bromo-2-fluoro-6-methoxybenzoate (120 mg, 0.46 mmol) was dissolved in 1,4-dioxane / water (5 / 1, 12 mL). Anhydrous cesium carbonate (298 mg, 0.92 mmol), tetrakistriphenylphosphine palladium (53 mg, 0.05 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (148 mg, 0.51 mmol) were added in sequence, and the resulting mixture was stirred at 80°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (102 mg, 63.6%).

[0715] Step 4: tert-Butyl 3-(2-fluoro-4-methoxy-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

[0716] At room temperature, tert-butyl 3-(2-fluoro-4-methoxy-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (102mg, 0.29mmol) was dissolved in methanol (10mL). Pd\C (100mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was stirred and reacted overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (76mg, 74.1%).

[0717] Step 5: Methyl 2-fluoro-6-methoxy-3-(pyrrolidin-3-yl)benzoate

[0718] At room temperature, tert-butyl 3-(2-fluoro-4-methoxy-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (76 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added at room temperature, and the resulting mixture was reacted at room temperature for 2 hours. After the reaction, the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (30 mL×4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (50 mg, 91.8%).

[0719] Step 6: Methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methoxybenzoate

[0720] At room temperature, methyl 2-fluoro-6-methoxy-3-(pyrrolidin-3-yl)benzoate (50 mg, 0.20 mmol) was dissolved in toluene (10 mL). Cesium carbonate (129 mg, 0.40 mmol), 1,2-dichloro-4-iodobenzene (65 mg, 0.24 mmol), palladium acetate (5 mg, 0.02 mmol), and Xantphos (19 mg, 0.04 mmol) were added in sequence, and the resulting mixture was stirred at 80°C under nitrogen protection overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (26 mg, 33%).

[0721] Step 7: 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methoxybenzoic acid

[0722] At room temperature, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluoro-6-methoxybenzoate (26 mg, 0.07 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (2 mL). 1 mol / L sodium hydroxide solution (10 mL) was added at room temperature, and the resulting mixture was stirred and reacted at room temperature overnight. 1 mol / L dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5, and the solution was concentrated under reduced pressure. Dichloromethane (20 mL) was added to the concentrate, filtered, and the filtrate was distilled under reduced pressure. The residue was purified by C18 column (mobile phase: 0.1% formic acid solution / acetonitrile; gradient: 5%-5% 1 min, 5%-75% 11 min) to obtain the target product (16 mg, 63.8%).

[0723] 1 H NMR (400MHz, DMSO) δ7.42–7.31(m,2H),6.92(d,J=8.7Hz,1H),6.75(d,J=2.8Hz,1H),6.57(dd,J=8.9,2. 8Hz,1H),3.80(s,3H),3.69–3.61(m,2H),3.24(d,J=12.0Hz,3H),2.39–2.29(m,1H),2.17–1.99(m,1H).

[0724] MS (ESI) m / z: 364 [M+H] + .

[0725] Example 99 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-ethyl-2-fluorobenzoic acid

[0726]

[0727] Step 1: 1-Bromo-4-ethyl-2-fluorobenzene

[0728] At room temperature, 3-fluoro-4-bromoacetophenone (1.0 g, 4.6 mmol) was dissolved in tetrahydrofuran (10 mL), triethylsilane (1.1 g, 9.2 mmol) was added at 0°C, and the reaction was stirred overnight at room temperature. The reaction solution was cooled to 0°C, and then petroleum ether (100 mL) was added to dilute the reaction solution, and the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the organic phase was removed by vacuum distillation. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and vacuum distilled to obtain the target product (320 mg, 34%).

[0729] Step 2: 3-Bromo-6-ethyl-2-fluorobenzoic acid

[0730] At room temperature, 1-bromo-4-ethyl-2-fluorobenzene (1 g, 4.92 mmol) was dissolved in dry tetrahydrofuran (20 mL). Diisopropyl lithium amide (2 mol / L, 3 mL) was added dropwise at -78 °C under nitrogen protection. After the addition was complete, the mixture was reacted at -78 °C for 30 min. Dry ice washed with dry tetrahydrofuran was added and the mixture was reacted at -78 °C for 30 min. After the reaction was completed, the mixture was heated to room temperature and water (30 mL) was added to quench the reaction. The aqueous phase was washed with ethyl acetate (20 mL × 3). The aqueous phase was adjusted to pH 3 with hydrochloric acid solution, extracted with ethyl acetate (30 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the title compound (400 mg, 32.9%).

[0731] Step 3: Methyl 3-bromo-6-ethyl-2-fluorobenzoate

[0732] At room temperature, 3-bromo-6-ethyl-2-fluorobenzoic acid (400 mg, 1.62 mmol), potassium carbonate (448 mg, 3.24 mmol) and N, N-dimethylformamide (5 mL) were mixed evenly. Iodomethane (460 mg, 3.24 mmol) was added and the reaction was allowed to react overnight at room temperature. After the reaction was completed, water (50 mL) was added to dilute the reaction solution, the aqueous phase was extracted with ethyl acetate (75 mL × 3), the organic phases were combined, concentrated under reduced pressure, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (200 mg, 47.3%).

[0733] Step 4: tert-Butyl 3-(4-ethyl-2-fluoro-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0734] At room temperature, methyl 3-bromo-6-ethyl-2-fluorobenzoate (200 mg, 0.77 mmol) was dissolved in 1,4-dioxane / water (5 / 1, 12 mL). Anhydrous cesium carbonate (502 mg, 1.54 mmol), tetrakistriphenylphosphine palladium (89 mg, 0.08 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (339 mg, 1.15 mmol) were added in sequence, and the resulting mixture was reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product (86 mg, 32.1%).

[0735] Step 5: tert-Butyl 3-(4-ethyl-2-fluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

[0736] At room temperature, tert-butyl 3-(4-ethyl-2-fluoro-3-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (86 mg, 0.25 mmol) was dissolved in methanol (10 mL). Pd\C (100 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was stirred at room temperature under a hydrogen atmosphere and reacted overnight. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (86 mg, 99.4%).

[0737] Step 6: Methyl 6-ethyl-2-fluoro-3-(pyrrolidin-3-yl)benzoate

[0738] At room temperature, tert-butyl 3-(4-ethyl-2-fluoro-3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (86 mg, 0.25 mmol) was dissolved in methanol (12 mL). At room temperature, hydrochloric acid (4 mL) was added, and the resulting mixture was reacted at room temperature for 30 minutes. After the reaction, the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (30 mL×4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product (60 mg, 97.6%).

[0739] Step 7: Methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-ethyl-2-fluorobenzoate

[0740] At room temperature, methyl 6-ethyl-2-fluoro-3-(pyrrolidin-3-yl)benzoate (60 mg, 0.24 mmol) was dissolved in toluene (10 mL). Cesium carbonate (169 mg, 0.48 mmol), 1,2-dichloro-4-iodobenzene (85 mg, 0.29 mmol), palladium acetate (7 mg, 0.03 mmol), and Xantphos (25 mg, 0.05 mmol) were added in sequence, and the resulting mixture was stirred at 80 ° C under nitrogen protection overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (52 mg, 55.0%).

[0741] Step 8: 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-ethyl-2-fluorobenzoic acid

[0742] At room temperature, methyl 3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-6-ethyl-2-fluorobenzoate (52 mg, 0.07 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL). 1 mol / L sodium hydroxide solution (10 mL) was added at room temperature, and the resulting mixture was reacted overnight at room temperature until the reaction was complete. 1 mol / L dilute hydrochloric acid was added to adjust the pH value to 3, and the mixture was concentrated under reduced pressure. Dichloromethane (20 mL) was added to the concentrate, filtered, and the filtrate was distilled under reduced pressure. The residue was purified by C18 column (mobile phase: 0.1% formic acid solution / acetonitrile; gradient: 5%-5% 1 min, 5%-90% 17 min, 90% received product) to obtain the title compound as a light yellow solid (5 mg, 10.0%).

[0743] 1 H NMR (400MHz, DMSO) δ7.65(t,J=7.7Hz,1H),7.35(dd,J=8.9,2.6Hz,1H),7.14(d,J=8.0Hz,1H),6.75(d,J=2.7Hz,1H),6.57(dd,J=8.9,2.8H z,1H),3.84(dd,J=18.5,9.1Hz,1H),3.60–3.51(m,2H),3.25–3.18(m,2H),2.79(q,J=7.5Hz,2H),2.37–2.25(m,2H),1.17(t,J=7.5Hz,3H).

[0744] MS (ESI) m / z: 382 [M+H] + .

[0745] Example 100 2-(3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorophenyl)acetic acid

[0746]

[0747] Step 1: tert-Butyl 3-(2-fluoro-3-(2-methoxy-2-oxoethyl)phenyl)-2,5-dihydropyrrole-1-carboxylate

[0748] At room temperature, methyl 2-(3-bromo-2-fluorophenyl)acetate (500 mg, 2.02 mmol) was dissolved in ethylene glycol dimethyl ether / water (4 / 1, 10 mL), and anhydrous potassium carbonate (559 mg, 4.05 mmol), tetrakistriphenylphosphine palladium (117 mg, 0.101 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (716 mg, 2.42 mmol) were added in sequence. The mixture was stirred at 80 °C under nitrogen protection overnight. After the reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give the title compound (250 mg, 36.7%).

[0749] Step 2: tert-Butyl 3-(2-fluoro-3-(2-methoxy-2-oxoethyl)phenyl)pyrrolidine-1-carboxylate

[0750] At room temperature, tert-butyl 3-(2-fluoro-3-(2-methoxy-2-oxoethyl)phenyl)-2,5-dihydropyrrole-1-carboxylate (250 mg, 0.74 mmol) was dissolved in methanol (5 mL). Pd\C (50 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was stirred at room temperature under a hydrogen atmosphere and reacted overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (250 mg) which was directly used in the next step.

[0751] Step 3: Methyl 2-(2-fluoro-3-(pyrrolidin-3-yl)phenyl)acetate

[0752] At room temperature, tert-butyl 3-(2-fluoro-3-(2-methoxy-2-oxoethyl)phenyl)pyrrolidine-1-carboxylate (250 mg, 0.74 mmol) was dissolved in dichloromethane (3 mL). At room temperature, a hydrochloric acid 1,4-dioxane solution (3 mL) was added and the mixture was reacted at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure, the pH was adjusted to alkaline, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (170 mg, 97.3%).

[0753] Step 4: Methyl 2-(3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorophenyl)acetate

[0754] At room temperature, methyl 2-(2-fluoro-3-(pyrrolidin-3-yl)phenyl)acetate (170 mg, 0.72 mmol) was dissolved in toluene (5 mL). Cesium carbonate (490 mg, 1.44 mmol), 1,2-dichloro-4-iodobenzene (310 mg, 10.8 mmol), palladium acetate (17 mg, 0.07 mmol), and Xphos (72 mg, 0.14 mmol) were added in sequence, and the resulting mixture was stirred and reacted overnight at 100 ° C under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and water (30 mL) was added, and ethyl acetate was extracted (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 24:1) to obtain the title compound (130 mg, 47.6%).

[0755] Step 5: 2-(3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorophenyl)acetic acid

[0756] At room temperature, methyl 2-(3-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-2-fluorophenyl)acetate (130 mg, 0.34 mmol) was dissolved in tetrahydrofuran and methanol (1:1, 4 mL). 2 mL of 1M sodium hydroxide aqueous solution was added, and the reaction was carried out at room temperature for 2 h. The reaction was completed. Dilute hydrochloric acid was added to adjust the pH to 3-4, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain the title compound as a light yellow solid (120 mg, 95.8%).

[0757] 1H NMR(400MHz,Chloroform-d)δ7.16(d,J=8.8Hz,1H),7.10(t,J=7.3Hz,2H),7.01(d d,J=8.5,6.7Hz,1H),6.55(d,J=2.8Hz,1H),6.33(dd,J=8.9,2.8Hz,1H),3.78–3.6 8(m,1H),3.66(d,J=1.5Hz,2H),3.61(dd,J=9.0,7.7Hz,1H),3.42–3.30(m,2H),3. 29–3.20(m,1H),2.34(dtd,J=11.1,6.9,4.1Hz,1H),2.11(dq,J=12.3,8.3Hz,1H).

[0758] MS (ESI) m / z: 368 [M+H] + .

[0759] Example 101 Methyl 2-fluoro-6-methoxy-3-(pyrrolidin-3-yl)benzoate

[0760]

[0761] Step 1: tert-Butyl 3-(4,5-difluoro-2-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0762] At room temperature, methyl 2-bromo-4,5-difluorobenzoate (200 mg, 0.80 mmol) was dissolved in 1,4-dioxane / water (5 / 1, 12 mL). Anhydrous cesium carbonate (522 mg, 1.60 mmol), tetrakistriphenylphosphine palladium (93 mg, 0.08 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (260 mg, 0.88 mmol) were added in sequence, and the resulting mixture was reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (204 mg, 75.5%).

[0763] Step 2: tert-Butyl 3-(4,5-difluoro-2-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate

[0764] At room temperature, tert-butyl 3-(4,5-difluoro-2-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (204 mg, 0.60 mmol) was dissolved in methanol (10 mL), Pd\C (200 mg) was added, and hydrogen was introduced to replace the air. The resulting mixture was reacted at room temperature overnight. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (200 mg, 97.5%).

[0765] Step 3: Methyl 4,5-difluoro-2-(pyrrolidin-3-yl)benzoate

[0766] At room temperature, tert-butyl 3-(4,5-difluoro-2-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (200 mg, 0.22 mmol) was dissolved in methanol (15 mL). At room temperature, 2M hydrochloric acid (5 mL) was added, and the resulting mixture was reacted at room temperature for 30 minutes. After the reaction, the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (50 mL×4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (140 mg, 99.0%).

[0767] Step 4: Methyl 2-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4,5-difluorobenzoate

[0768] At room temperature, methyl 4,5-difluoro-2-(pyrrolidin-3-yl)benzoate (140 mg, 0.60 mmol) was dissolved in toluene (10 mL). Cesium carbonate (391 mg, 1.20 mmol), 1,2-dichloro-4-iodobenzene (197 mg, 0.72 mmol), palladium acetate (14 mg, 0.06 mmol), Xantphos (58 mg, 0.12 mmol) were added in sequence, and the resulting mixture was stirred at 80 ° C under nitrogen protection overnight. After the reaction solution was cooled to room temperature, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the title compound (32 mg, 14.3%).

[0769] Step 5: Methyl 2-fluoro-6-methoxy-3-(pyrrolidin-3-yl)benzoate

[0770] At room temperature, methyl 2-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-4,5-difluorobenzoate (32 mg, 0.08 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL). 1 mol / L sodium hydroxide solution (10 mL) was added at room temperature, and the resulting mixture was reacted at room temperature for 2 h, and the reaction was completed. 1 mol / L dilute hydrochloric acid was added to adjust the pH to 3, and the solution was concentrated under reduced pressure. Dichloromethane (20 mL) was added to the concentrate, filtered, and the filtrate was distilled under reduced pressure. The residue was purified by C18 column (mobile phase: 0.1% formic acid solution / acetonitrile; gradient: 5%-5% 1 min, 5%-85% 22 min, 85% received product) to obtain the title compound as a light yellow solid (5 mg, 16.2%).

[0771] 1 H NMR (400MHz, DMSO) δ7.79(dd,J=11.3,8.5Hz,1H),7.56(dd,J=12.4,7.9Hz,1H),7.35(d,J=8.9Hz,1H),6.73(d,J=2.7Hz,1H),6.55(dd,J= 8.9,2.8Hz,1H),4.36–4.23(m,1H),3.63(dd,J=9.4,7.7Hz,1H),3.47(d,J=3.3Hz,2H),3.26(s,2H),2.36–2.29(m,1H),2.20–2.07(m,1H).

[0772] MS (ESI) m / z: 372 [M+H] + .

[0773] Effect test:

[0774] MRGPRX4 is a G protein-coupled receptor that generates downstream signals upon stimulation, releasing IP1, TGFα, and Ca 2+ Ions. The Cal-520AM calcium flow method was used to detect IP1, TGFα, and Ca 2+ The inhibitory effect of the above compounds on the activity of MRGPRX4 was tested by the method of measuring the intensity of downstream signals such as ions.

[0775] The experimental procedures and test results are as follows:

[0776] Engineered Cell Screening System:

[0777] The human MRGPRX4 overexpression plasmid hu-Mrgprx4-pCDH was used to transfect the HEK293T cell line to construct the MRGPRX4 receptor overexpression HEK293 cell line. Select the stable cell line with mRNA transcription increased by more than 100 times for WB verification. Select the stable cell line with protein expression increased by more than 10 times for flow cytometry verification and monoclonal selection. The candidate positive clones and wild-type cell lines were labeled with MRGPRX4 flow cytometry antibodies, and the expression level of MRGPRX4 on the membrane was compared according to the flow cytometry results. Select the stable cell line with membrane surface protein expression increased by more than 5 times for screening experiments and monoclonal selection.

[0778] After the above cell system is verified, calcium flow / HTRF and other detection methods are used to screen and verify the test compounds.

[0779] Natural agonist potency testing

[0780] Each compound was designed with 6 to 8 concentrations (3 to 5-fold gradient), and the relative response rate was calculated using the calcium flux method with the formula: (signal value of each concentration - negative control detection) / (maximum signal value - negative control value) × 100%, and the IC 50 .

[0781] Select appropriate concentration of agonist as screening system and use control drug (1-55) to test adjustment

[0782] Table 1 Agonist concentration

[0783]

[0784] Screening experiment: Cal-520AM calcium flow method (cells without GFP / EGFP labeling)

[0785] HEK293-MRGPRX4 cells were plated at 30,000 / well in a 384-well plate. After the cells adhered to the wall and grew to confluence, 40 μL of HHBS + 2% low serum medium (1:1) containing 2 μM Cal-520AM was added to load the Cal-520AM probe for 2 hours. The supernatant was discarded and 40 μL of drug-containing HHBS was added and incubated for 15 minutes. Agonists were added dropwise at 10 μL / well in single-well mode using an automatic sampler (see Table 1 for the concentrations of each agonist), and the fluorescence intensity was immediately read at 0.5 seconds / time for a total of 8 seconds using EX490 / EM530. The inhibition curve was obtained by calculation and fitting. The slope EC was obtained by subtracting the lowest fluorescence value RFUmin (fluorescence value at T0) from the highest fluorescence value RFUmax of each well within 8 seconds, divided by the time RUFtmax to reach the highest fluorescence value. Calculate according to the following formula:

[0786] Inhibition rate (%) = 1-slope of drug experimental group / slope of control group x 100%

[0787] Calculate the activity inhibition rate of each well and fit the IC of each test compound and positive control. 50 All data were completed using SPSS / Graphpad Prism software, including IC 50 The grade is divided into 5 levels: 0.1μΜ <A<0.5μΜ;0.5μΜ<B<1μΜ;1μΜ<C<5μΜ,;5μΜ<D<10μΜ;E> 10μΜ), and the activity results are shown in Table 2-4 below.

[0788] Table 2. Activity test results of the compounds of the present application (DCA)

[0789]

[0790]

[0791]

[0792]

[0793] Table 3 Activity of some compounds of this application (DCA, OCA, Nateglinide, UDCA)

[0794]

[0795] Table 4 Activity of some compounds of this application (DCA)

[0796] Example <![CDATA[IC 50 (25μM DCA)μM]]> 20 0.54 20B 0.26 49 0.37 49A 0.46 49B 0.21 14 0.45 15 1.40 23 1.83 32 1.44 34 0.74 37 0.84 42 0.63 53 1.09 50 1.41 57 0.79 79 0.35 82 0.72 1-55 0.37 93 0.39 94 1.66 95 0.31 96A 0.42 96B 0.15 97 0.26 98 0.82 100 0.95 101 0.98

[0797] Among the above compounds, 1-55 is a compound in patent (WO2020198537 A1), and the synthesis method refers to the above patent. From the above results, it can be seen that the small molecule inhibitor of MRGPRX4 provided in this application has a good inhibitory effect on MRGPRX4.

[0798] Stability evaluation in rat and human liver microsomes:

[0799] The stability of the compounds of the present application (20, 20B, 49B) and the control compounds (Midazolam, 1-55) in rat and human liver microsomes was evaluated. The test compounds were co-incubated with human and rat liver microsomes at 37°C and pH = 7.4. The concentration of the samples at different incubation times was measured, and the rate constant was obtained by plotting Log [drug concentration] against the incubation time. The drug half-life and in vivo clearance rate Cl were calculated. in vivoThe stability of the drug in liver microsomes was evaluated by drug half-life and in vivo clearance. The composition of the specific experimental incubation system is shown in Table 5. The stability data of the compounds of the present application in liver microsomes are shown in Table 6.

[0800] Table 5 Composition of experimental incubation system

[0801]

[0802] Table 6 Stability data of the compounds of the present application in liver microsomes

[0803]

[0804] Note: When the final residual amount (%) is greater than 75%, T1 / 2 is reported as >120min; R2: linear correlation coefficient; T1 / 2: half-life; CL: intrinsic clearance; The control group (midazolam) showed significant metabolism in liver microsomes, indicating that the liver microsomes used in this study are active.

[0805] It can be seen from the test data that the compound of the present application has good stability in human liver microsomes.

[0806] The pharmacokinetic parameter testing method is as follows

[0807] The pharmacokinetic study of the compounds of the present application in SD rats, dogs or monkeys was evaluated. The compounds of the present application were administered in a physiological saline solution of 5% DMSO + 5% Solutol + 90% PBS. For intravenous (iv) administration, animals were given a dose of 5 mg / kg, and blood (0.2 mL) was taken at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 24 hours, placed in EDTA-2K anticoagulant tubes, and centrifuged at 4000 rpm for 10 minutes. For oral (po) administration, animals were given a dose of 5 mg / kg, and blood (0.2 mL) was taken at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours, placed in EDTA-2K anticoagulant tubes, and centrifuged at 4000 rpm for 10 minutes. The plasma solution was collected and stored at -70°C until the above-mentioned LC / MS / MS analysis was performed.

[0808] Tissue distribution in ICR mice

[0809] The corresponding compound in the example was dissolved in a mixed solvent of DMSO / 15-hydroxystearic acid polyethylene glycol (HS-15) / normal saline (Saline) (5:5:90, v / v / v) to prepare a 0.5 mg / mL solution. The above solution was administered orally to 6-8 week old male ICR mice at 10 mL / kg, and the plasma and skin tissue were taken at 0.5, 1, 4, and 24 hours after administration to determine the content of the test substance therein. The specific operation is as follows:

[0810] Plasma: Satellite blood sampling method was used. Three animals were alternately collected intravenously at each time point for anticoagulation (EDTA-K2 was used as anticoagulant, and blood samples were placed in an ice bath after collection). Plasma was separated by centrifugation at 6000 g for 5 min at 4°C, and the concentration of the test substance in plasma was determined.

[0811] Skin tissue: After blood was collected from three animals at each time point, the animals were killed and back skin tissue was collected (hair was shaved, and the same part of each animal was collected as much as possible, and subcutaneous fat was removed). The skin tissue samples were homogenized at a ratio of 1:6 (the homogenate was 50% methanol-water), vortexed and mixed, and the concentration of the test substance was determined.

[0812] The main pharmacokinetic parameters were calculated using Winnolin 8.3 non-compartmental model based on the plasma and skin concentration data of the test substance at all time points.

[0813] Table 7 Distribution of the compounds of the present application in plasma / skin of ICR mice

[0814]

[0815]

[0816] It can be seen from the test data that the compound of the present application has good distribution characteristics in ICR mice and has a higher concentration in the skin tissue.

[0817] The applicant declares that the present invention illustrates the compounds having Mrgpr X4 receptor inhibitory effects and their applications through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0818] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0819] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A compound having Mrgpr X4 receptor inhibitory effect or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or an isotope-labeled substance thereof, characterized in that: The compound structural formula is shown in the following formula I: wherein n is selected from 0, 1, 2 or 3, m is selected from 0, 1, 2 or 3, k is selected from 0, 1, 2, 3 or 4, p is selected from 0, 1, 2, 3 or 4, and when n, m, k, p are each 0, the group does not exist; R 1 Selected from hydrogen, halogen, carbonyl, hydroxyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, cyano, ester, nitro, amino, C 6-12 Aryl, C 6-12 Aromatic or C 4-7 Heterocycle, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms; R 1 independently selected from m identical or different substitutions above; when m is 2 or 3, two adjacent R 1 Stand alone or together with their connected rings, form C 3-8 Aliphatic ring, C 3-8 Heterocyclic or C 6-10 Aromatic rings, wherein the above groups are unsubstituted or substituted with 1 to 5 halogen atoms; Cy1 is selected from C 3-7 Cycloalkyl, C 6-10 Aromatic ring, C 8-14 Fused heterobicyclic group, C 6-10 Aromatic heterocyclic group or C 5-7 Monocyclic heterocyclyl; R 2 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, acyl, cyano, ester, nitro, amino, C 6-12 Aryl, C 6-12 Aryloxy, C 6-12 Aromatic or C 4-7 Heterocycle, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms; R 2 independently selected from k identical or different substitutions above; when k is 2, 3 or 4, two adjacent R 2 Stand alone or together with their connected rings, form C 3-8 Aliphatic ring, C 3-8 Heterocyclic or C 6-10 Aromatic ring groups, wherein the above groups are unsubstituted or substituted with 1 to 5 halogen atoms; R 3 Selected from C 1-6 Alkylcarboxyl, -C(=O)OR 5 , C 2-6 Alkyl, amino, C 1-6 Alkylamino, C 1-6 Alkylamide, imidazole, triazolyl, tetrazolyl, cyano, nitro or -C(=O)NH-SO2-R 7 , where R 5 Selected from hydrogen, R 6 Substituted C 1-6 Alkyl, C 6-10 Aromatic ring group, C 6-10 Aromatic or C 4-7 Heterocyclic ring, wherein the C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur; R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl or C 1-6 Alkoxy, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms; R 7 Selected from hydrogen, R 8 Substituted C 1-6 Alkyl, C 3-7 Cycloalkyl, benzyl, phenyl, naphthyl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, in which C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur; R 8 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms; Cy2 is selected from C 3-8 Cycloalkyl, C 6-10 Aryl, C 8-14 Fused heterobicyclic group, C 6-10 Aromatic heterocyclic group or C 5-7 Monocyclic heterocyclyl; R 4 is selected from hydrogen, halogen, hydroxyl, cyano, ester, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkoxy, C 6-12 Aryl, C 6-12 Aryloxy or C 4-7 Heterocycle; wherein the above groups are unsubstituted or substituted by 1-5 halogen atoms; R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Stand alone or together with their connected rings, form C 3-7 Aliphatic ring, C 3-8 Heterocyclic or C 6-10 Aromatic rings, wherein the above groups are unsubstituted or substituted by 1 to 5 halogen atoms.

2. The compound having Mrgpr X4 receptor inhibitory effect according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotope-labeled substance thereof, characterized in that: R 1 Selected from hydrogen, fluorine, chlorine, bromine, iodine, carbonyl, hydroxyl, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, cyano, ester, nitro, amino, C 6-12 Aryl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms; Preferably, R 1 independently selected from m identical or different substitutions above; when m is 2 or 3, two adjacent R 1 Independently or together with the rings they are connected to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-8 Heterocyclic or C 6-10 Aromatic rings, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms; Preferably, the Cy1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridinyl, benzofuran, benzimidazole, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrimidinyl, purinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl or piperazinyl; Preferably, R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, acyl, cyano, ester, nitro, amino, phenyl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms; Preferably, R 2 independently selected from k identical or different substitutions above; when k is 2, 3 or 4, two adjacent R 2 Independently or together with the rings they are connected to form cyclopropyl, cyclobutyl, cyclopentyl, C 3-8 Heterocyclic or C 6-10 Aromatic ring groups, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms; Preferably, R 3 Selected from formate, acetate, propionate, -C(=O)OR 5 , acetate, propionate, acetonitrile, cyano, nitro, amino, formamide, acetamide, propionamide, imidazole, triazolyl, tetrazolyl or -C(=O)NH-SO2-R 7 ; Preferably, R 5 Selected from hydrogen, R 6 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, C 6-10 Aromatic or C 4-7 Heterocyclic ring, wherein the C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur; Preferably, R 6 Selected from hydrogen, fluorine, chlorine, C 1-3 Alkyl, C 3-7 Cycloalkyl or C 1-3 Alkoxy, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms; Preferably, R 7 Selected from hydrogen, R 8 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, C 6-12 Aromatic or C 4-7 Heterocyclic ring, in which C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur; Preferably, R 8 Selected from hydrogen, fluorine, chlorine, C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms; Preferably, Cy2 is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl, furanyl, pyrrolyl, thiazolyl, thienyl, oxazolyl, pyridinyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrimidinyl, purinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl or piperazinyl; Preferably, R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, ester, nitro, amino, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy or C 4-7 Heterocycle; wherein the above groups are unsubstituted or substituted by 1-5 fluorine atoms or chlorine atoms; Preferably, R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Independently or together with the rings they are connected to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-8 Heterocyclic or C 6-10 An aromatic ring wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms.

3. The compound having Mrgpr X4 receptor inhibitory effect according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotope-labeled substance thereof, characterized in that: The structural formula of the compound is shown in Formula II below: Wherein, n is selected from 1 or 2, m is selected from 0, 1 or 2, k is selected from 0, 1, 2 or 3, p is selected from 0, 1, 2, 3 or 4, and when m, k, p are each 0, the group does not exist; Ar1 is selected from phenyl, naphthyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridinyl, benzofuran, benzimidazole, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrimidinyl or purinyl; R 1 , R 2 , R 3 , R 4 , Cy2 has the same scope as claim 1; Preferably, R 1 Selected from hydrogen, fluorine, chlorine, bromine, carbonyl, hydroxyl or substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyloxy, cyano, ester, nitro, amino, phenyl, naphthyl, anthracenyl, phenanthrenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, morpholinyl, piperidinyl or piperazinyl, wherein the substituted group is fluorine or chlorine, and the number of substitutions is 1-5; Preferably, when m is 2, two adjacent R 1 Together with the ring to which they are attached, they form cyclopropyl, cyclobutyl, cyclopentyl, epoxypropyl, epoxybutyl, epoxypentyl, pyrrolidinyl, tetrahydrofuranyl, phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl or quinolyl, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine or chlorine atoms; Preferably, R 2 is selected from hydrogen, fluorine, chlorine, bromine, carbonyl, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyloxy, acetyl, cyano, ester, nitro, amino, phenyl, C 6-12 Aromatic or C 4-7 Heterocyclic rings, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine or chlorine atoms; Preferably, R 3 Selected from formate, acetate, -C(=O)OR 5 , acetate, acetonitrile, cyano, nitro, amino, formamide, acetamide, imidazole, triazolyl, tetrazolyl or -C(=O)NH-SO2-R 7 ; Preferably, R 5 Selected from hydrogen, R 6 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl or C 4-7 Heterocyclic ring, wherein the C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur; Preferably, R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms; Preferably, R 7 Selected from hydrogen, R 8 Substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl, phenyl or C 4-7 Heterocyclic ring, in which C 4-7 The heterocyclic ring contains 1-2 atoms selected from nitrogen, oxygen or sulfur; Preferably, R 8 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine atoms or chlorine atoms; Preferably, Cy2 is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, naphthyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, benzofuran, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinolyl, indolyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl; Preferably, R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, ester, nitro, amino, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, phenoxy, benzyloxy or C 4-7 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms; Preferably, R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Independently or together with the rings to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl or C 3-8 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms.

4. The compound having Mrgpr X4 receptor inhibitory effect according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotope-labeled substance thereof, characterized in that: Ar1 is selected from phenyl, naphthyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl or quinolyl; Preferably, R 1 Selected from hydrogen, fluorine, chlorine, carbonyl, hydroxyl or substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, cyclopropyloxy, cyano, ester, nitro, amino, phenyl, naphthyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, benzofuran, benzoxazolyl, morpholinyl, piperidinyl or piperazinyl, wherein the substituted group is fluorine or chlorine, and the number of substitutions is 1-5; Preferably, when m is 2, two adjacent R 1 Together with the ring to which they are attached, they form cyclopropyl, cyclobutyl, glycidyl, glycidyl, pyrrolidinyl, phenyl, oxazolyl, thiazolyl, pyrrolyl or pyridyl, wherein the above groups are unsubstituted or substituted with 1 to 5 fluorine or chlorine atoms; Preferably, R 2 is selected from hydrogen, fluorine, chlorine, bromine, carbonyl, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, cyclopropyloxy, acetyl, cyano, ester, nitro, amino, pyrrolidinyl, phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl or pyridyl, wherein the above groups are unsubstituted or substituted by 1-5 fluorine or chlorine atoms; Preferably, R 3 Selected from formate, acetate, -C(=O)OR 5 , methyl acetate, cyano, amino, formamide, imidazole, triazolyl, tetrazolyl or -C(=O)NH-SO2-R 7 ; Preferably, R 5 Selected from hydrogen, R 6 substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl or phenyl; Preferably, R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl or propyl, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms; Preferably, R 7 Selected from hydrogen, R 8 substituted methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzyl or phenyl; Preferably, R 8 is selected from hydrogen, fluorine, chlorine, methyl, ethyl or propyl, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms or chlorine atoms; Preferably, Cy2 is selected from cyclobutane, cyclopentane, cyclohexane, phenyl, naphthyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, benzofuran, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinolyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl; Preferably, R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, ester, nitro, amino, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, phenoxy, benzyloxy or C 4-7 Heterocyclic ring, wherein the above groups are unsubstituted or substituted by 1 to 5 fluorine atoms; Preferably, R 4 independently selected from p identical or different substitutions above; when p is 2, 3 or 4, two adjacent R 4 Independently or together with the rings to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, epoxypropyl, epoxybutyl, epoxypentyl, pyrrolidinyl, phenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl or pyridyl, wherein the above groups are unsubstituted or substituted with 1-5 fluorine atoms or chlorine atoms.

5. The compound having Mrgpr X4 receptor inhibitory effect according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotope-labeled substance thereof, characterized in that: The structural formulas of the compounds are shown in the following formulas III, IV and V: wherein Ar1 is selected from phenyl, naphthyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, benzofuran, benzothienyl, benzothiazolyl, benzoxazolyl or quinolyl; Cy2 is selected from cyclobutane, cyclopentane, cyclohexane, benzyl, phenyl, naphthyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, benzofuran, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinolyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl; q is independently selected from 0, 1 or 2, and when q is 0, it means that the group does not exist; R 1 , R 2 , R 4 The limited ranges of Cy2, m, n, p, and k are the same as those in claim 1.

6. The compound having Mrgpr X4 receptor inhibitory effect according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an isotope-labeled substance thereof, characterized in that: The compound is selected from the following structures:

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a compound having Mrgpr X4 receptor inhibitory effect according to any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant, wherein the adjuvant comprises any one or a combination of at least two of a carrier, an excipient, a diluent, a binder, a wetting agent, a disintegrant, an emulsifier, a solubilizer, a solubilizing agent, an osmotic pressure regulator, a surfactant, a colorant, a pH regulator, an antioxidant, an antibacterial agent or a buffer.

8. Use of the compound having Mrgpr X4 receptor inhibitory effect according to any one of claims 1 to 6 or its pharmaceutically acceptable salt or stereoisomer or isotope-labeled substance or the pharmaceutical composition according to claim 7 in the preparation of Mrgpr X4 receptor inhibitor.

9. Use of the compound having Mrgpr X4 receptor inhibitory effect according to any one of claims 1 to 6 or its pharmaceutically acceptable salt or stereoisomer or isotope-labeled substance or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating skin itching caused by a disease, characterized in that: The diseases include neurodermatitis, pain, liver and biliary diseases, chronic nephritis, chronic pyelonephritis, diabetes, thyroid disease, drug allergy, vitamin deficiency, external genital infection, autoimmune disease, multiple sclerosis, chickenpox, measles, flat warts, bacterial skin diseases, herpes, folliculitis, fungal skin diseases, tinea capitis, tinea manuum, tinea pedis, tinea corporis, tinea cruris, tinea versicolor, parasitic and animal skin diseases, hookworm dermatitis, schistosoma dermatitis, creeping eruption, lice, mosquito bites, Mite dermatitis, mulberry caterpillar dermatitis, scabies, prickly heat, polymorphic light eruption, solar dermatitis, chilblain, frictional lichenoid eruption, herpetic dermatosis, dermatitis herpetiformis, bullous pemphigoid, herpes gestationis, cirrhosis of the liver, cholelithiasis, bile duct tumor disease, neurological dysfunction skin disease, pruritus, prurigo, nodular prurigo, prurigo gestationis, exudative discoid and lichen dermatitis, diabetes, iron deficiency anemia, high bile acid concentration, lymphatic system tumors, cholecystitis, Hodgkin's disease or myeloproliferation.

10. Use of the compound having Mrgpr X4 receptor inhibitory effect according to any one of claims 1 to 6 or its pharmaceutically acceptable salt or stereoisomer or isotope-labeled substance or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating cholestatic pruritus.

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