Phenyl-3-azabicyclo [3.1. 0] hexane ROR gamma regulator and application thereof

Abstract

The invention relates to a compound with a structure shown as a formula (I) or a stereoisomer, a tautomer or pharmaceutically acceptable salt or a solvate or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the modulators and application of the pharmaceutical composition in treatment of ROR gamma-mediated inflammatory, metabolic and autoimmune diseases, # imgabs0 #.

Description

Technical Field

[0001] The present invention relates to novel regulators of retinoic acid-related orphan receptor γ (RORγ), methods for their preparation, pharmaceutical compositions containing these regulators, and their use in the treatment of RORγ-mediated inflammatory, metabolic, and autoimmune diseases. Background Art

[0002] Retinoic acid receptor-related orphan receptors (RORs) are a class of ligand-dependent transcription factors that play important roles in a series of physiological and pathological processes such as reproductive development, regulation of circadian rhythm, metabolic disorders, inflammation, and immune system regulation. RORs are members of the nuclear receptor superfamily, including RORα, RORβ, and RORγ. RORα is mainly distributed in the liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain, and blood, and is related to physiological and pathological processes such as hepatic glycogenolysis, lipid metabolism, and atherosclerosis. RORβ is mainly distributed in the central nervous system, including the brain, retina, and pineal gland, and is mainly related to the processing of sensitive information in the spinal cord, thalamus, and cerebellar cortex. RORγ is highly expressed in the thymus and is also distributed in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas, and is related to autoimmune diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis.

[0003] RORγ includes two subtypes, RORγ1 and RORγ2 (RORγt). RORγ1 is expressed in a variety of tissues including the thymus, muscle, kidney, and liver; RORγt is uniquely expressed only in immune system cells and plays a key role in thymopoiesis, the development of several secondary lymphoid tissues, and Th17 lineage differentiation. Studies have shown that RORγt is a key regulator of Th17 cell differentiation. Th17 cells are a subtype of T helper cells that produce IL-17 and other pro-inflammatory cytokines. Th17 cells play a key role in several murine autoimmune disease models, including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, studies have shown that Th17 cells or their products are related to the pathology of various human inflammatory and autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, and asthma. The main cause of autoimmune diseases is the intolerance to autoantigens and the development of autoreactive effector T cells that infiltrate tissues. Th17 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity. During the development of the disease, Th17 cells are activated and are responsible for recruiting other inflammatory cells (neutrophils), thereby mediating the lesions of target tissues.

[0004] It is reported that RORγt is a key regulator of Th17 cell differentiation. Recently, Th17 cells have been found to be a subset of T helper cells that preferentially produce cytokines IL-17A, IL-17F, IL-21, and IL-22. RORγt induces the transcription of genes encoding IL-17A and IL-17F in naive CD4+ T helper cells. Mice deficient in RORγt show very few Th17 cells. Inhibition or deletion of RORγt improves EAE.

[0005] In asthma patients, increased levels of RORγt and IL-17A expression have been shown in saliva, lung, bronchoalveolar lavage (BAL) fluid, and peripheral blood, and the levels are directly correlated with disease severity. In addition to IL-17A, recent studies have shown that another cytokine of the IL-17 family, IL-17F, can play an important role in allergic airway inflammation and thus have an important impact on airway diseases such as asthma. Overexpression of the IL-17F gene in the mouse airway is associated with airway neutrophilia, cytokine induction, increased airway hyperresponsiveness, and mucus hypersecretion.

[0006] Given the role of RORγ in the pathogenesis of diseases, it is desirable to prepare compounds that modulate the activity of RORγ and are thus useful for treating RORγ-mediated inflammatory, metabolic, and autoimmune diseases, such as respiratory diseases asthma, chronic obstructive pulmonary disease (COPD), and bronchitis, allergic diseases including allergic rhinitis and atopic dermatitis, cystic fibrosis, and lung allograft rejection. Summary of the Invention

[0007] According to the present invention, there are provided novel retinoic acid-related orphan receptor γ (RORγ) modulators, methods for their preparation, pharmaceutical compositions containing these modulators, and their use in the treatment of RORγ-mediated inflammatory, metabolic, autoimmune, and other diseases.

[0008] More specifically, on the one hand, the present invention relates to compounds of the structure shown in formula (I) or their stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates, or prodrugs thereof: Formula (I) Wherein, R 1 、R 2 are independently selected from hydrogen, halogen, alkyl, haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, alkoxy; X, Y are independently selected from N or CR3 ; R 3 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy; Ring A is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, and the 5- to 10-membered heteroaryl and 6- to 10-membered aryl may be further substituted with halogen, cyano, alkyl, haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, alkoxy; Ring B is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, and the 5- to 10-membered heteroaryl and 6- to 10-membered aryl may be further substituted with halogen, alkyl, haloalkyl, C 3 -C 8 (substituted) cycloalkyl, C 2 -C 8 heterocycloalkyl, 5- to 10-membered (substituted) heteroaryl, 6- to 10-membered aryl, alkoxy;

[0009] Further, R 1 , R 2 are selected from hydrogen, F atom.

[0010] Further, Ring A is selected from: , and may be further substituted with C 1 -C 8 short-chain alkane;

[0011] Further, Ring B is selected from: , and may be further substituted with C 1 -C 8 short-chain alkane, cyclopropyl, , or one or more of the groups;

[0012] Further, the ring containing X and Y is a benzene ring or a pyridine ring.

[0013] Further, the compound is selected from: .

[0014] The present invention discloses the above-mentioned compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug, and its use in the preparation of a drug for treating RORγ-mediated diseases.

[0015] Further, the disease is an inflammatory, metabolic or autoimmune disease.

[0016] Further, the inflammatory, metabolic or autoimmune disease is asthma, chronic obstructive pulmonary disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, inflammatory bowel syndrome, Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Guillain-Barré syndrome, psoriatic arthritis, Graves' disease or scleritis.

[0017] The terms in the specification and claims of the present invention have the following meanings.

[0018] "Alkyl" refers to a saturated aliphatic hydrocarbon group. It includes straight-chain or branched-chain groups having 1 to 20 carbon atoms. C 1-6 Alkyl refers to a medium-sized alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. Preferred is a lower alkyl having 1 to 4 carbon atoms, more preferably a lower alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc. The alkyl may be substituted or unsubstituted. When substituted, preferred groups are: halogen, C 2 -C 6 alkenyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, halo C 1 -C 6 alkyl, a 4- to 8-membered heteroalicyclic group, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy.

[0019] "Alkylamino" refers to a group in which one or two hydrogen atoms in the amino group are replaced by an alkyl group. It includes amino groups substituted by straight-chain, branched-chain or cyclic alkyl groups, such as methylamino, dimethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, cyclopropylamino, cyclobutylamino, pentylamino, etc. Preferred is an amino group substituted by a lower straight-chain, branched-chain or cyclic alkyl having 1 to 4 carbon atoms.

[0020] "Cycloalkyl" refers to a 3- to 8-membered all-carbon monocyclic, all-carbon 5 / 6- or 6 / 6-fused or polycyclic-fused ring group ("fused" rings mean that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), where one or more rings have a fully conjugated π-electron system. Examples of cycloalkyl (but not limited to) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane or cycloheptatriene. Cycloalkyl can be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups each independently selected from the following, including: hydrogen, hydroxy, mercapto, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino.

[0021] "Aryl" means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a fully conjugated π-electron system. "Aryl" includes: Six-membered carbon aromatic rings, such as benzene; Bicyclics, where at least one ring is a carbon aromatic ring, such as naphthalene, indene or 1,2,3,4-tetrahydroquinoline; and Tricyclics, where at least one ring is a carbon aromatic ring, such as fluorene.

[0022] For example, aryl includes a six-membered carbon aromatic ring and a six-membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbon aromatic ring. However, aryl does not include and is not in any way overlapping with heteroaryl as defined separately below. Thus, as defined herein, if one or more carbon aromatic rings are fused to a heteroaromatic ring, the resulting ring system is heteroaryl, not aryl. Non-limiting examples of aryl are phenyl, naphthyl. Aryl can be substituted or unsubstituted. When substituted, the preferred groups are: hydrogen, hydroxy, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino.

[0023] "Heteroaryl" means a monocyclic or fused ring group having 5 to 14 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and further having a fully conjugated π electron system. Heteroaryl refers to: A 5- to 8-membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as 1 to 4 heteroatoms, and in some embodiments, 1 to 3 heteroatoms, with the other atoms on the ring being carbon atoms; An 8- to 12-membered bicyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as 1 to 4 heteroatoms, and in some embodiments, 1 to 3 heteroatoms, with the other atoms on the ring being carbon atoms; wherein at least one ring is an aromatic ring; and An 11- to 14-membered tricyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as 1 to 4 heteroatoms, and in some embodiments, 1 to 3 heteroatoms, with the other atoms on the ring being carbon atoms; wherein at least one ring is an aromatic ring.

[0024] For example, heteroaryl includes a 5- to 6-membered heteroaromatic ring fused to a 5- to 6-membered cycloalkyl group. For such a bicyclic fused heteroaryl, only one of the rings contains one or more heteroatoms, and the attachment site is on the heteroaromatic ring.

[0025] When the total number of sulfur and oxygen atoms on the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl does not exceed 2. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl does not exceed 1.

[0026] Examples of heteroaryl include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, midine, pyrazine, pyridazine, indole, azaindole, benzimidazole, benzotriazole, indoline, indolinone, quinoline, isoquinoline, quinazoline, thiophenopyridine, thiophenopyrimidine, etc. Preferred embodiments of such groups are benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, pyrrole, pyrazole, imidazole, thiophene, thiazole, furan or oxazole. One or all of the hydrogen atoms in the heteroaryl can be substituted by the following groups: hydrogen, hydroxyl, nitro, cyano, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino.

[0027] "Heterocycloalkyl" means a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings (including spiro ring systems), each ring having 3 to 8 atoms, which is bonded to one or more ring heteroatoms (selected from N, O or S(O) 0-2 ) and which may optionally and independently be substituted by one or more, preferably 1 or 2 substituents selected from: hydrogen, hydroxy, mercapto, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heterocycloalkyl, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heterocycloalkylalkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino. Unless otherwise indicated.

[0028] Examples of heterocycloalkyl include but are not limited to oxirane, aziridine, pyridine, morpholin-3-one, thiomorpholine 1,1-dioxide, morpholino, piperazino, piperidino, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydro-2H-pyranyl, thiomorpholino, quinuclidinyl and imidazolinyl, preferably 、 、 , W is selected from O, S or NR 12 , each group as described above, and the examples may also be bicyclic, such as, for example, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane or octahydro-pyrazino[2,1-c][1,4]oxazine; preferably oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, aziridine, azetidine, pyrrolidine, piperidine, morpholine, pyridine, morpholin-3-one or thiomorpholine 1,1-dioxide; and its heterocycloalkyl (and derivatives) include its ionic forms.

[0029] "Alkoxy" means -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include but are not limited to methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.

[0030] "Aryloxy" means -O-aryl and -O-heteroaryl. Representative examples include but are not limited to phenoxy, pyridyloxy, furanyloxy, thiophenyloxy, pyrimidyloxy, pyrazinyloxy, etc. and their derivatives.

[0031] "Arylalkylene" means an alkyl group, preferably a lower alkyl as defined above, which is substituted by an aryl group as described above, e.g. -CH2 phenyl, -(CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, CH 3 CH(CH 3 )CH 2 phenyl and its derivatives.

[0032] "heteroarylalkylene" means an alkylene group, preferably a lower alkylene group as defined above, which is substituted by a heteroaryl group as described above, e.g. -CH 2 pyridyl, -(CH 2 ) 2 pyrimidinyl, -(CH 2 ) 3 imidazolyl and the like and their derivatives.

[0033] "oxo group" means the =O group.

[0034] "hydroxy group" means the -OH group.

[0035] "mercapto group" means the -SH group.

[0036] "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0037] "haloalkyl" means an alkyl group substituted by halogen, preferably a lower alkyl group as defined above, which is substituted by one or more identical or different halogen atoms, e.g. -CH 2 Cl, -CF 3 , -CCl 3 , -CH 2 CF 3 , -CH 2 CCl 3 etc.

[0038] "cyano group" means the -CN group.

[0039] "amino group" means the -NH 2 group.

[0040] "nitro group" means the -NO 2 group.

[0041] "tetrahydro-2H-pyran" means .

[0042] "alkylsulfonyl" means -S(O 2 )C 1-6 alkyl, wherein the alkyl is defined as above.

[0043] "Optionally substituted" includes both the cases where one or more substituents are present and the unsubstituted case. For example, optionally substituted alkyl includes unsubstituted alkyl and alkyl substituted by one or more substituents.

[0044] The term "optionally" means that the subsequent described event or circumstance may or may not occur, and this description includes both the case where the thing or circumstance may occur and the case where it may not occur.

[0045] In some embodiments, "substituted by one or more groups" means that one, two, three, or four hydrogen atoms in the specified atom or group are respectively replaced by the same or different groups selected from the groups within the specified range.

[0046] The wavy line represents the bonding site; "Pharmaceutically acceptable salts" refer to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include: (1) Salts formed by reacting the free base of the parent compound with inorganic acids or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.; organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D)- or (L)-malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, etc.

[0047] (2) Salts formed by replacing the acidic proton present in the parent compound with a metal ion or by coordinating with an organic base. Metal ions such as alkali metal ions, alkaline earth metal ions, or aluminum ions; organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.

[0048] "Pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs with one or more pharmaceutically acceptable excipients. Among them, "excipients" are usually other chemical components other than the compounds described in the present invention, such as pharmaceutically acceptable pharmaceutical carriers, or mixtures with other compounds having drug effects, etc. The purpose of the pharmaceutical composition can be to facilitate the administration process to animals or to achieve drug synergistic effects.

[0049] "Pharmaceutical carrier" refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as but not limited to: calcium carbonate, calcium phosphate, various sugars (such as lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.

[0050] In the aforementioned pharmaceutical composition, in addition to including a pharmaceutically acceptable carrier, etc., pharmaceutically common adjuvants can also be included, such as: antibacterial agents, antifungal agents, antimicrobial agents, preservatives, colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or their combinations, etc.

[0051] The compound of formula (I) described in the present invention has an obvious inhibitory effect on RORγt, and RORγt plays a very important role in inflammatory, metabolic and autoimmune diseases. Inhibiting RORγt will relieve or effectively treat these diseases. Detailed implementation mode

[0052] The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

[0053] Example 1: 3-(3-(2-Cyclopropyl-5-methyl-4-(1-(trifluoromethyl)cyclopropyl)-1H-imidazol-1-yl)-2,4-difluorophenyl)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane CMP 1 Preparation 1) Preparation of compound C Compound A (3.19 g, 10 mmol, 1 eq), Na 2 CO 3 (5.30 g, 50 mmol, 5 eq), compound B (2.76 g, 12 mmol, 1.2 eq), and 80 mL of toluene were added to a 100 ml single-necked flask. The flask was purged with nitrogen three times, heated to 100 °C, and reacted for 3 hours. The reaction was monitored by TLC and determined to be complete. After the reaction, toluene was removed by concentration. EA (200 ml) * 3 and ice water (30 ml) were added, and the organic phase was separated. The organic phase was washed with saturated brine (50 ml), dried over magnesium sulfate, and concentrated by rotary evaporation to obtain a crude product. The crude product was purified by Prep-HPLC to obtain 3.37 g of a white solid compound C with a yield of 80%. LC-MS [M+1] +: 421.2; 1 H NMR (400 MHz, CDCl 3 ): 7.12 (m, 2H), 2.23 (m, 5H), 0.84 - 1.24 (m, 8H).

[0054] 2) CMP 1 Preparation Compound C (2.10 g, 5 mmol, 1 eq), compound D (0.90 g, 6.0 mmol, 1.2 eq), Pd(dppf)Cl2 (570 mg, 0.78 mmol, 0.16 eq), and potassium phosphate (4.97 g, 23.4 mmol, 4.7 eq) were added to a 100 ml single-necked flask. Dioxane (50 ml) and water (2 ml) were added. The flask was purged with nitrogen three times, heated to 100 °C, and reacted for 3 hours. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and EA (300 ml) * 3 and water (30 ml) were added. The organic phase was separated, washed with saturated brine (50 ml), dried over magnesium sulfate, concentrated by rotary evaporation, and purified by Prep-HPLC to obtain 11.47 g of off-white solid CMP with a yield of 60%. LC-MS [M + 1]+: 491.2; 1H NMR (400 MHz, CDCl3): 8.64 (s, 2H), 6.70 (m, 2H), 2.95 - 3.17 (m, 4H), 2.23 (m, 5H), 0.90 - 1.12 (m, 10H).

[0055] Example 2: 3-(3-(4-Cyclopropyl-6-methyl-2-(1-(trifluoromethyl)cyclopropyl)pyrimidin-5-yl)-2,4-difluorophenyl)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane CMP 2 Preparation Referring to the method of Example 1, 21.25 g of off-white solid compound CMP was obtained with a yield of 58%. LC-MS [M + 1] + : 503.20. 1 H NMR (400 MHz, CDCl 3 ): 8.65 (s, 2H), 6.95 (t, 1H), 6.80 (t, 1H), 2.96 - 3.17 (m, 5H), 2.23 (m, 2H), 0.82 - 1.02 (m, 10H).

[0056] Example 3: 3-(4-(2-Cyclopropyl-5-methyl-4-(1-(trifluoromethyl)cyclopropyl)-1H-imidazol-1-yl)-3,5-difluoropyridin-2-yl)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane CMP 3 Preparation Referring to the method of Example 1, 1.37 g of a white solid compound CMP was obtained, with a yield of 64%. LC-MS [M+1] + : 492.5. 1 H NMR (400 MHz, CDCl 3 ): 8.55(s, 2H),7.35(d, 1H), 2.92-3.15(m, 4H),2.23(m,5H), 0.85-1.04(m,10H).

[0057] Example 4: 5-(tert-Butyl)-3-(3-(3-(2-Cyclopropyl-5-methyl-4-(1-(trifluoromethyl)cyclopropyl)-1H-imidazol-1-yl)-2,4-difluorophenyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1,2,4-oxadiazole CMP 4 Preparation Referring to the method of Example 1, 1.87 g of a white solid compound CMP was obtained, with a yield of 78%. LC-MS [M+1] + : 548.6. 1 H-NMR (400MHz, CDCl 3 ): 6.78(m,1H),6.70(m,1H),2.96-3.12(m, 4H), 2.22(m,4H),2.10(s,1H), 1.36(s,9H),1.28(m,2H), 0.86-1.05(m,8H).

[0058] Example 5: 3-(2,4-Difluoro-3-(4-methyl-6-(5-methylfuran-2-yl)-2-(1-(trifluoromethyl)cyclopropyl)pyrimidin-5-yl)phenyl)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane CMP 5 Preparation Referring to the method of Example 1, 1.38 g of a white solid compound CMP was obtained, with a yield of 52%. LC-MS [M+1] 5 1.38 g, yield 52%. LC-MS [M+1] +: 543.5。 1 H-NMR (400MHz, CDCl 3 ): δ 8.66(s,2H),6.95 - 6.98(m,1H),6.79(m,1H), 6.12(d,1H),2.93 - 3.10(m, 7H), 2.27(m,4H), 0.82 - 1.03(m,6H)。

[0059] Example 6: 2-(tert-Butyl)-4-(3-(3-(2-Cyclopropyl-5-methyl-4-(1-(trifluoromethyl)cyclopropyl)-1H-imidazol-1-yl)-2,4-difluorophenyl)-3-azabicyclo[3.1.0]hex-6-yl)oxazole CMP 6 Preparation Referring to the method of Example 1, a white solid compound CMP was prepared 6 1.28 g, yield 52%. LC-MS [M+1] + : 547.6。 1 H-NMR (400MHz, CDCl 3 ): δ 7.69(s,1H),6.80(m,1H),6.68(m,1H),2.95 - 3.10(m, 4H), 2.23(m,4H),2.13(m,1H), 1.38(s,9H), 1.27(m,2H), 0.86 - 0.98(m,8H)。

[0060] Example 7: 3-(5-(2-Cyclopropyl-5-methyl-4-(1-(trifluoromethyl)cyclopropyl)-1H-imidazol-1-yl)-4-fluoropyridin-3-yl)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane CMP 7 Preparation Referring to the method of Example 1, a white solid compound CMP was prepared 7 0.28 g, yield 32%. LC-MS [M+1] + : 474.50。 1 H-NMR (400MHz, CDCl 3 ): δ 8.70(s, 2H),7.95 - 8.02(m, 2H), 2.95 - 3.11(m,4H), 2.25(m,5H), 0.90 - 1.04(m,10H)。

[0061] Example 8: 3-(5-(4-Cyclopropyl-6-methyl-2-(1-(trifluoromethyl)cyclopropyl)pyrimidin-5-yl)-4-fluoropyridin-3-yl)-6-(4H-1,2,4-triazol-4-yl)-3-azabicyclo[3.1.0]hexane CMP 8 Preparation Referring to the method of Example 1, a white solid compound CMP was prepared 8 0.68 g, yield 42%. LC-MS [M+1] + : 486.5 1 H-NMR (400 MHz, CDCl 3 ): 8.85 (d, 1H), 8.66 (s, 2H), 8.15 (d, 1H), 2.98 - 3.17 (m, 7H), 2.23 (m, 2H), 0.82 - 1.02 (m, 10H).

[0062] Example 9: 2-(tert-Butyl)-4-(3-(3-(2-Cyclopropyl-5-methyl-4-(1-(trifluoromethyl)cyclopropyl)-1H-imidazol-1-yl)-2,4-difluorophenyl)-3-azabicyclo[3.1.0]hex-6-yl)thiazole CMP 9 Preparation Referring to the method of Example 1, a white solid compound CMP was prepared 9 0.78 g, yield 52%. LC-MS [M+1] + : 563.7 1 H-NMR (400 MHz, CDCl 3 ): 6.70 (s, 1H), 6.78 - 6.80 (m, 2H), 2.96 - 3.10 (m, 4H), 2.25 (m, 4H), 2.15 (m, 1H), 1.48 (s, 9H), 1.29 (m, 2H), 0.86 - 1.08 (m, 8H).

[0063] Example 10 RORγt Inhibitor luciferase reporter gene experiment Experimental materials and instruments: Among them, SR1001 is an inverse agonist of RORγt and is used as a positive reference. Its structure is: .

[0064] Experimental procedure: 1. Seed the cells on the first day. Add 1 mL of trypsin to the adherent 293T cells and incubate for about 5 minutes. Aspirate the digested cells with a pipette and transfer them to a 15 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes. Discard the old medium, resuspend the cells in fresh medium and dilute to the desired density.

[0065] 2. Cell counting. Prepare a cell suspension at a cell density of 15,000 cells / well. Seed the cells, 100 μL per well. To prevent edge effects, only seed the middle 60 wells of a 96-well cell culture plate, and fill the surrounding 36 wells with 100 μL of PBS per well. Incubate the cells in a 37 ºC, 5% CO 2 incubator.

[0066] 3. Perform the cell transient transfection experiment 24 hours after seeding the cells. Prepare the transient transfection plasmids (i.e., Gal4-RORγ-LBD: 25 ng / well; PgL4.3-luc: 25 ng / well) and the transfection reagent (the concentration of Lipofectamine 2000 is 3 times that of DNA).

[0067] 4. After the transfection reagent is diluted, incubate for 5 minutes. Mix the transfection reagent and the plasmid and incubate for 20 minutes, then add 10 μL per well. Small molecule compounds (SR1001 or compounds of Exp1-Exp34) can be added more than 5 hours after transient transfection.

[0068] 5. If needed, first serially dilute the compound to be tested 3-fold with DMEM cell culture medium containing 10% fetal bovine serum (100 - 0.195 μM). Then aspirate the existing medium in the cell culture plate, and then add the prepared compound to be tested and fresh medium.

[0069] 6. Then place it in a 37 ºC, 5% CO 2 incubator to culture the cells. Take out the cells after about 24 hours, observe the cell growth under the microscope, and take the cell culture plate out of the cell room. Then perform the luciferase dual reporter gene detection experiment.

[0070] 7. First, aspirate and discard the cell medium, then add about 100 μL of PBS to wash the residual medium. Dilute the 5× cell lysis buffer to 1× and add 20 μL per well, then shake for about 20 minutes to lyse the cells.

[0071] 8. Transfer the cells to a white opaque 96-well detection plate. Then use the En Spire Alpha 2390 homogeneous luminescence immunoassay system to test the experimental results: add the prepared firefly luciferin substrate to detect the cell activity after compound interference.

[0072] 9. Calculation of inhibitory activity: 10. Experimental results: ++++ indicates IC 50 < 10 nM; +++ indicates IC 50 range is 10 - 100 nM; ++ indicates IC 50 range is 100 - 1000 nM; + indicates IC 50 > 1000 nM.

[0073] Example 11 RORγt Binding experiment 1. Reagents and consumables: 2. Compound management: 2.1 Compound storage: Dissolve the compound in DMSO to make a 10 mM stock solution.

[0074] 2.2 Compound preservation: All compounds dissolved in DMSO are stored in a desiccator in the short term at room temperature for no more than 3 months. For long term, they are stored at -20 °C.

[0075] 2.3 Prepare compounds: a) Dilute all compounds 3-fold serially in DMSO with 10 dilution gradients, starting from a concentration of 500 μM.

[0076] b) Dilute the positive control compound 3-fold serially in DMSO with 10 dilution gradients, starting from a concentration of 25 μM.

[0077] c) Prepare 50x positive control (25 μM positive control compound) and 50x negative control (100% DMSO).

[0078] d) Seal and shake the compound plate for 5 minutes.

[0079] 3. Experimental procedure: 3.1 Prepare reaction buffer: Dissolve DTT and KF in 1x buffer D. Final concentration: DTT 5 mM, KF 50 mM.

[0080] 3.2 Detect compounds: a) Prepare 2-fold serially diluted compounds in buffer (see step 2.3).

[0081] b) Add 10 μl of 2-fold serially diluted compounds (see step a) to a 384-well reaction plate.

[0082] c) Prepare 2x reactants with chilled buffer: RORγ-LBD (40 nM), SRC (100 nM), anti-GST Eu (1:200), and streptavidin-D2 (25 nM).

[0083] d) Add 10 μl of 2x reactants (see step c) to a 384-well reaction plate (see step b).

[0084] e) Centrifuge the 384-well reaction plate at 1000 g for 1 min.

[0085] f) Incubate for 1 hour at room temperature in the dark.

[0086] g) Detect the plate: wavelengths 665 nm and 615 nm; instrument: multimode microplate reader.

[0087] 4. Data Analysis 4.1 Relative Ratio (RR): Calculate the relative ratio for each well [(response value at 665 nm / response value at 615 nm - blank background response value) * 1000].[[]]END]]

[0088] 4.2 Calculate the percent inhibition (%) as follows: 4.3 Calculate the IC 50 of the compound and the dose-response curve: Using the inhibition rate of the compound and the log value of the compound concentration obtained by calculation, and with Graphpad 5.0, obtain the IC50 of the compound and the dose-response curve.

[0089] 4.4 Inspection Report: 4.4.1 One experimenter completes the report, and another experimenter checks the report again to ensure the accuracy of the data.

[0090] 4.4.1.1 Export the data from the detection instrument and analyze it manually.

[0091] 4.4.1.2 Convert the ratio to percent inhibition. Use Graphpad 5.0 software and the percent inhibition to first calculate the IC 50 of the compound.

[0092] 4.4.1.3 Calculate the IC 50 of the compound using the ratio, and use the current IC 50 to check the accuracy of the data.

[0093] 4.4.2 Determine whether the names of all compounds are correct.

[0094] 4.5 Data standard: Z factor > 0.5; S / B > 3; IC of the positive control compound 50 Within 3 times the historical average value.

[0095] 5. Data results: Compound <![CDATA[Half maximal inhibitory concentration of RORγt activity (IC 50 )]]> 5nM 19nM 1nM 150nM 177nM 295nM It can be seen from the above experimental results that the compound of formula (I) has an obvious inhibitory effect on RORγt, and RORγt plays a very important role in inflammatory, metabolic and autoimmune diseases. Inhibiting RORγt will relieve or effectively treat these diseases. In particular, the use of RORγt inhibitors for the treatment of respiratory diseases (such as asthma, COPD), autoimmune diseases (such as rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease) has been deeply studied and recognized.

Claims

1. A compound having a structure as shown in formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate or a prodrug thereof: Formula (I) in, R1, R2 are selected from hydrogen, halogen, alkyl, haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, alkoxy; X and Y are independently selected from N or CR3; R3 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy; Ring A is a 5-10 membered heteroaryl or a 6-10 membered aryl, and the 5-10 membered heteroaryl or the 6-10 membered aryl may be further substituted by halogen, cyano, alkyl, haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, or alkoxy; Ring B is a 5-10 membered heteroaryl or a 6-10 membered aryl, and the 5-10 membered heteroaryl or 6-10 membered aryl may be further substituted by halogen, alkyl, haloalkyl, C3-C8 (substituted) cycloalkyl, C2-C8 heterocycloalkyl, 5-10 membered (substituted) heteroaryl, 6-10 membered aryl, or alkoxy.

2. The compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug according to claim 1, characterized in that: R1 and R2 are selected from hydrogen and F atoms.

3. The compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug according to claim 1, characterized in that: The ring A is selected from: , which can be further substituted by C1-C8 short chain alkanes.

4. The compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug according to claim 1, characterized in that The ring B is selected from: , can be further replaced by C1-C8 short chain alkanes, cyclopropyl, , One or more groups are substituted.

5. The compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug according to claim 1, characterized in that: The ring containing X and Y is a benzene ring or a pyridine ring.

6. The compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug according to any one of claims 1 to 5, characterized in that: The compound is selected from: 。 7. A compound of formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt or a solvate or a prodrug according to any one of claims 1 to 6, and its use in the preparation of a medicament for treating RORγ-mediated diseases.

8. The use according to claim 7, characterized in that: The disease is an inflammatory, metabolic or autoimmune disease.

9. The use according to claim 8, characterized in that The inflammatory, metabolic or autoimmune disease is asthma, chronic obstructive pulmonary disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, inflammatory bowel syndrome, Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Guillain-Barré syndrome, psoriatic arthritis, Graves' disease or scleritis.

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