CN120136849A - A class of phenyl-3-azabicyclo[3.1.0]hexane RORγ modulators and their uses - Google Patents

Abstract

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

Description

Phenyl-3-azabicyclo [3.1.0] hexane ROR gamma regulator and application thereof

Technical Field

The present invention relates to novel modulators of tretinoin related orphan receptors gamma (rory), processes for their preparation, pharmaceutical compositions containing these modulators and their use in the treatment of rory-mediated inflammatory, metabolic and autoimmune diseases.

Background

Retinoic acid receptor-related orphan receptors (retinoic acid receptor-related orphan receptors, RORs) are ligand-dependent transcription factors that play an important role in a range of physiological and pathological processes such as reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, immune system regulation, etc. RORs is a member of the superfamily of nuclear receptors, including rorα, rorβ, rorγ. Rorα is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood, and is involved in physiological and pathological processes such as liver gluconeogenesis, lipid metabolism, atherosclerosis, etc. Rorβ is mainly distributed in the central nervous system, including brain, retina and pineal gland, and is mainly involved in the processing of sensitive information by spinal cord, thalamus, cerebellar cortex. Rorγ is highly expressed in thymus and is also distributed in kidneys, liver, heart, skeletal muscle, adipose tissue, testis, prostate and pancreas, and is involved in autoimmune diseases such as rheumatoid arthritis, psoriasis and multiple sclerosis.

Rory includes two subtypes rory 1 and rory 2 (rory t). Rorγ1 is expressed in a variety of tissues including thymus, muscle, kidney and liver, rorγt is expressed exclusively in immune system cells and plays a key role in thymic production, development of several secondary lymphoid tissues and Th17 lineage differentiation. Studies have shown that roryt 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 have a key role in several mouse autoimmune disease models, including encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, studies have shown that Th17 cells or products thereof are associated with the pathology of a variety of human inflammatory and autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, crohn's disease, asthma. The main cause of autoimmune disease onset is intolerance to autoantigens and development of autoinvasive effector T cells that infiltrate tissues. Th17 cells are one of the important drivers in inflammatory processes in tissue-specific autoimmunity, and during disease progression Th17 cells are activated and responsible for recruiting other inflammatory cells (neutrophils) to mediate lesions of the target tissue.

Rorγt has been reported to be a key regulator of Th17 cell differentiation, and Th17 cells have recently 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 transcription of genes encoding IL-17A and IL-17F in naive cd4+ T helper cells. Roryt deficient mice show very few Th17 cells. Inhibition and deletion of roryt results in improved EAE.

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

In view of the role of rory in the pathogenesis of 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, it is desirable to prepare compounds which modulate rory activity and which are therefore useful in the treatment of rory mediated inflammatory, metabolic and autoimmune diseases.

Disclosure of Invention

In accordance with the present invention, novel modulators of tretinoin-related orphan receptors gamma (ROR gamma), methods of preparing the same, pharmaceutical compositions comprising these modulators, and their use in the treatment of ROR gamma-mediated inflammatory, metabolic, and autoimmune diseases are provided.

More specifically, in one aspect, the present invention relates to a compound having the structure shown in formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof:

formula (I)

Wherein,

R ₁、R₂ is selected from hydrogen, halogen, alkyl, haloalkyl, C ₃-C₈ cycloalkyl, C ₂-C₈ heterocycloalkyl, alkoxy;

X, Y are independently selected from N or CR ₃;

R ₃ is selected from hydrogen, halogen, alkyl, haloalkyl, and alkoxy;

Ring a is a 5-10 membered heteroaryl or a 6-10 membered aryl, which 5-10 membered heteroaryl, 6-10 membered aryl may be further substituted by halogen, cyano, alkyl, haloalkyl, C ₃-C₈ cycloalkyl, C ₂-C₈ heterocycloalkyl, alkoxy;

Ring B is a 5-10 membered heteroaryl or a 6-10 membered aryl, which 5-10 membered heteroaryl, 6-10 membered aryl may be further substituted by halogen, alkyl, haloalkyl, C ₃-C₈ (substituted) cycloalkyl, C ₂-C₈ heterocycloalkyl, 5-10 membered (substituted) heteroaryl, 6-10 membered aryl, alkoxy.

Further, R ₁、R₂ is selected from hydrogen, F atoms.

Further, the ring a is selected from: may be further substituted with C ₁-C₈ short-chain alkanes.

Further, the ring B is selected from:

Can be further substituted with C ₁-C₈ short-chain alkane, cyclopropyl, 、Substituted with one or more groups.

Further, the ring containing X, Y is a benzene ring or a pyridine ring.

Further, the compound is selected from:

。

The invention discloses the application of the compound or stereoisomer, tautomer or pharmaceutically acceptable salt or solvate or prodrug thereof in preparing medicaments for treating ROR gamma mediated diseases.

Further, the disease is an inflammatory, metabolic or autoimmune disease.

Still 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 ocular disease, ulcerative colitis, crohn's disease, inflammatory bowel syndrome, sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, green-barre syndrome, psoriatic arthritis, grave's disease, or scleritis.

The terms used in the specification and claims of the present invention have the following meanings.

"Alkyl" refers to a saturated aliphatic hydrocarbon group. A linear or branched group comprising 1 to 20 carbon atoms. C _1-6 alkyl refers to medium size alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. Preferred are lower alkyl groups having 1 to 4 carbon atoms, more preferred are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, preferred groups are halogen, C ₂-C₆ alkenyl, C ₆-C₁₀ aryl, C ₅-C₁₀ heteroaryl, halogenated C ₁-C₆ alkyl, 4 to 8 membered heteroalicyclic, hydroxy, C ₁-C₆ alkoxy, C ₆-C₁₀ aryloxy.

"Alkylamino" refers to a group in which one or two hydrogen atoms in the amino group are replaced with an alkyl group. Including amino groups substituted with linear, branched, or cyclic alkyl groups such as methylamino, dimethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, t-butylamino, cyclopropylamino, cyclobutylamino, pentylamino, and the like. Preferred are lower straight, branched or cyclic alkyl substituted amino groups containing 1 to 4 carbon atoms.

"Cycloalkyl" refers to a3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 membered fused ring or polycyclic fused ring ("fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system), wherein one or more rings have a fully attached pi-electron system, examples of cycloalkyl being, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane or cycloheptatriene. Cycloalkyl groups are substituted and unsubstituted. When substituted, the substituent is preferably one or more groups each selected from the group consisting of 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.

"Aryl" means an all-carbon monocyclic or fused multicyclic group of 6 to 14 carbon atoms having a fully conjugated pi-electron system. "aryl" includes:

Six-membered carbon aromatic rings, such as benzene;

Bicyclic rings in which at least one ring is a carbon aromatic ring, e.g. naphthalene, indene or 1, 2, 3, 4-tetrahydroquinoline, and

Tricyclic, wherein at least one of the rings is a carbon aromatic ring, such as fluorene.

For example, aryl groups include six-membered carbon aromatic rings and a six-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbon aromatic ring. But the aryl group does not contain, nor in any way overlap, the heteroaryl group defined below, respectively. Thus, as defined herein, if one or more carbon aromatic rings are fused to a heteroaromatic ring, the resulting ring system is heteroaryl, rather than aryl. Non-limiting examples of aryl groups are phenyl, naphthyl. Aryl groups may be substituted or unsubstituted. When substituted, 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.

"Heteroaryl" means a monocyclic or fused ring radical of 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, with the addition of a fully conjugated pi-electron system. Heteroaryl refers to:

a 5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, in some embodiments 1-3 heteroatoms, the other atoms on the ring being carbon atoms;

8-12 membered bicyclic aromatic hydrocarbons containing one or more heteroatoms selected from N, O and S, e.g. 1-4 heteroatoms, in some embodiments 1-3 heteroatoms, the other atoms on the ring being carbon atoms, wherein at least one ring is aromatic, and

The 11-14 membered tricyclic aromatic hydrocarbon contains one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, in some embodiments 1-3 heteroatoms, the other atoms on the ring being carbon atoms, wherein at least one ring is aromatic.

For example, heteroaryl groups include a 5-6 membered heteroaromatic ring and a 5-6 membered cycloalkyl. For such bicyclic and fused heteroaryl groups, only one ring contains one or more heteroatoms, and the attachment site is on the heteroaromatic ring.

When the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one to another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group is no more than 1.

Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, imidate, pyrazine, pyridazine, indole, azaindole, benzimidazole, benzotriazol, indoline, indolone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like. Preferred examples of such groups are benzene rings, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, pyrrole, pyrazole, imidazole, thiophene, thiazole, furan or oxazole. One or all of the hydrogen atoms in the heteroaryl group may be substituted with 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.

"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 be independently substituted with 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 heterocycloalkyl alkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminoculfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino. Unless otherwise indicated.

Examples of heterocycloalkyl groups include, but are not limited to, oxetan, aziridine, pyridine, morpholin-3-one, thiomorpholin 1, 1-dioxide, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydro-2H-pyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, preferably、、W is selected from O, S or NR ¹², each of which as previously described, 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, heterocycloalkyl (and derivatives) including ionic forms thereof.

"Alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

"Aryloxy" means-O-aryl and-O-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanyloxy, thiophenyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.

"Arylalkylene" means an alkyl group, preferably a lower alkyl group as defined above, which is substituted with an aryl group as defined above, for example-CH ₂ phenyl, - (CH ₂)₂ phenyl, - (CH ₂)₃ phenyl, CH ₃CH (CH₃) CH₂ phenyl and derivatives thereof.

"Heteroarylalkylene" means an alkyl group, preferably a lower alkyl group as defined above, which is substituted with a heteroaryl group as defined above, for example, -CH ₂ pyridyl, - (CH ₂)₂ pyrimidinyl, - (CH ₂)₃ imidazolyl, and the like, and derivatives thereof.

"Oxo" means an =o group.

"Hydroxy" means an-OH group.

"Mercapto" means a-SH group.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"Haloalkyl" means an alkyl substituted with halogen, preferably lower alkyl as defined above, which is substituted with one or more halogen atoms, which may be the same or different, for example, -CH ₂Cl、-CF₃、-CCl₃、-CH₂CF₃、-CH₂CCl₃, etc.

"Cyano" means a-CN group.

"Amino" means the-NH ₂ group.

"Nitro" means a-NO ₂ group.

"Tetrahydro-2H-pyran" means。

"Alkylsulfonyl" means-S (O ₂) C_1-6 alkyl, where alkyl is as defined above).

"Optionally substituted" includes both the case of substitution with one or more substituents and the case of unsubstituted, such as optionally substituted alkyl includes both unsubstituted alkyl and alkyl substituted with one or more substituents.

By "optionally" is meant that the event or circumstance described subsequently may or may not occur, and that the description includes that the event or circumstance occurs and that it does not.

In some embodiments, "substituted with one or more groups" means that one, two, three, or four hydrogen atoms in a given atom or group, respectively, are replaced with the same or different groups selected from the given range of groups.

Wavy lines indicate ligation sites;

"pharmaceutically acceptable salts" means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:

(1) Salified with acids obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or with organic acids including 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, and the like.

(2) The acidic proton present in the parent compound is replaced by a metal ion or a salt formed by complexation with an organic base such as alkali metal ion, alkaline earth metal ion or aluminum ion, and an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

"Pharmaceutical composition" refers to a combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, with one or more pharmaceutically acceptable excipients. Wherein "excipients" are typically selected from other chemical components than the compounds of the present invention, such as a pharmaceutically acceptable carrier, or other pharmaceutically effective compound, and the like. The purpose of the pharmaceutical composition may be to facilitate the process of administration to an animal, or may be a pharmaceutical synergy.

"Pharmaceutically acceptable 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 compound being administered, such as, but not limited to, calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.

The pharmaceutical compositions may include pharmaceutically acceptable carriers and the like, and may further include pharmaceutically acceptable adjuvants such as antibacterial agents, antifungal agents, antimicrobial agents, shelf-life agents, toners, solubilizing agents, thickening agents, surfactants, complexing agents, proteins, amino acids, fats, carbohydrates, vitamins, minerals, trace elements, sweeteners, pigments, fragrances, combinations thereof, and the like.

The compounds of formula (I) of the present invention have a significant inhibitory effect on RORγt, which is very important in inflammatory, metabolic and autoimmune diseases, which would result in the alleviation or effective treatment of these diseases.

Detailed Description

The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

EXAMPLE 1 preparation of 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

1) Preparation of Compound C

Compound A (3.19 g,10mmol,1 eq), na ₂CO₃ (5.30 g,50mmol,5 eq), compound B (2,76 g, 12mmol, 1.2 eq), toluene 80mL are added to a 100mL single-necked flask, replaced 3 times with nitrogen, warmed to 100℃and reacted for 3 hours, and the reaction is terminated by TLC. After completion of the reaction, toluene was removed by concentration, EA (200 ml) 3 was added, ice water (30 ml), and the organic phase was separated, washed with saturated brine (50 ml), dried over magnesium sulfate, and concentrated by spin-drying to obtain a crude product. Prep-HPLC preparation gave off-white solid compound C3.37g, yield 80%.LC-MS [M+1]⁺：421.2;¹H NMR (400 MHz, CDCl₃): 7.12(m, 2H), 2.23(m, 5H),0.84-1.24(m,8H).

2) CMP1 preparation

Compound C (2.10 g,5mmol,1 eq), compound D (0.90 g,6.0mmol,1.2 eq), pd (dppf) Cl2 (570 mg, 0.78mmol, 0.16 eq), potassium phosphate (4.97 g,23.4mmol,4.7 eq) were added to a 100ml single-necked flask, dioxane (50 ml) was added, water (2 ml) was replaced 3 times with nitrogen, the temperature was raised to 100℃and the reaction was completed by TLC. The reaction solution was cooled to room temperature, EA (300 ml) 3, water (30 ml) and the organic phase was separated, washed with saturated brine (50 ml), dried over magnesium sulfate, dried by spin-drying and prepared by Prep-HPLC to give an off-white solid CMP 11.47g, yield 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).

EXAMPLE 2 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP21.25g was prepared in yield 58%.LC-MS [M+1]⁺：503.20.¹H NMR (400 MHz, CDCl₃): 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).

EXAMPLE 3 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP31.37g was prepared in yield 64%.LC-MS [M+1]⁺：492.5.¹H NMR (400 MHz, CDCl₃): 8.55(s, 2H),7.35(d, 1H), 2.92-3.15(m, 4H), 2.23(m,5H), 0.85-1.04(m,10H).

EXAMPLE 4 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP41.87g was prepared in yield 78%.LC-MS [M+1]⁺：548.6.¹H-NMR (400MHz, CDCl₃): 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).

EXAMPLE 5 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP51.38g was prepared in yield 52%.LC-MS [M+1]⁺：543.5.¹H-NMR (400MHz, CDCl₃): 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).

EXAMPLE 6 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP61.28g was prepared in yield 52%.LC-MS [M+1]⁺：547.6.¹H-NMR (400MHz, CDCl₃): 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).

EXAMPLE 7 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP70.28g was prepared in yield 32%.LC-MS [M+1]⁺：474.50.¹H-NMR (400MHz, CDCl₃): 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).

EXAMPLE 8 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP80.68g was prepared in yield 42%.LC-MS [M+1]⁺：486.5.¹H-NMR (400MHz, CDCl₃): 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).

EXAMPLE 9 preparation of 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

Referring to the procedure of example 1, an off-white solid compound CMP90.78g was prepared in yield 52%.LC-MS [M+1]⁺：563.7.¹H-NMR (400MHz, CDCl₃): 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).

Example 10 ROR gamma t inhibitor luciferase reporter Gene experiment

Experimental materials and instruments:

wherein SR1001 is an inverse agonist of roryt, as a positive reference, its structure is:

。

the experimental steps are as follows:

1. Cell plating on day one. The 293T adherent cells were digested with 1 mL pancreatin to about 5min, the digested cells were pipetted and transferred to a 15 mL centrifuge tube, and centrifuged at 1000 rpm for 5min. The old medium was discarded and the cells were resuspended in fresh medium and diluted to the desired density.

2. Cell count. Cell suspensions were prepared at a cell density of 1.5 ten thousand cells/well. Plates, 100 μl cells per well. To prevent edge effects, 96-well cell culture plates were filled with 60 wells in the middle of the plate, 36 wells around with 100 μl PBS per well. 37 The cells were cultured in an oC,5% CO ₂ incubator.

3. Cell transient transfection experiments were performed 24 hours after cell plating. Transient plasmids (i.e., gal 4-RORgamma-LBD: 25 ng/well; pgL4.3-luc:25 ng/well), transfection reagents (liposome 2000 concentration 3-fold over DNA) were formulated.

4. After dilution of the transfection reagent, incubation was 5min, the transfection reagent and plasmid were mixed and incubated 20 min, and then 10 μl was added per well. The small molecule compound (SR 1001 or Exp1-Exp34 compound) can be added after transient transfection of more than 5 h.

5. According to the requirement, the compound to be detected is diluted by 3 times of DMEM cell culture medium containing 10% of fetal bovine serum (100-0.195 mu M), then the existing culture medium in the cell culture plate is sucked out, and then the prepared compound to be detected and fresh culture medium are added.

6. The cells were then cultured in a 37℃5% CO ₂ incubator. After about 24 h hours, the cells were removed, the growth observed under a microscope, and the cell culture plates were removed from the cells. And then carrying out a luciferase dual-reporter gene detection experiment.

7. The cell culture medium was first aspirated and then the residual medium was washed by adding approximately 100. Mu.L of PBS. After diluting the mother liquor 5X cell lysate to 1X, 20. Mu.L was added to each well, and then the cells were lysed by shaking about 20 min.

8. Cells were transferred to a white opaque 96-well assay plate. And then testing the experimental result by using EN SPIRE ALPHA 2390 homogeneous phase luminescence immunoassay system, namely adding the prepared firefly luciferin substrate to detect the cell activity after the compound is interfered.

9. Calculation of inhibitory Activity:

10. Experimental results:

++ + + and representing IC ₅₀ <10 nM; +++ represents IC ₅₀ the range is 10-100 nM; ++ means IC ₅₀ is 100-1000 nM, and +means IC ₅₀ >1000nM.

Example 11 ROR γt binding assay

1. Reagent and consumable:

2. compound management:

2.1 Compound storage compound was dissolved in DMSO to make 10mM stock solution.

2.2 The compound is preserved, all the compound dissolved in DMSO is stored in a desiccator for a short period of time, and the room temperature is not more than 3 months. Long-term storage at-20deg.C.

2.3 Preparing a compound:

a) All compounds were diluted 3-fold in DMSO, 10 dilution gradients, starting at 500uM.

B) Positive control compounds were diluted 3-fold in DMSO, 10 dilution gradients, starting at 25uM.

C) A positive control of 50x (25 uM positive control compound) and a negative control of 50x (100% dmso) were prepared.

D) The compound plates were blocked and shaken for 5 minutes.

3. The experimental process comprises the following steps:

3.1 Reaction buffer was prepared by dissolving DTT and KF in 1x buffer D. Final concentration was DTT 5mM, KF 50mM.

3.2 Detection of compounds:

a) Prepare 2x gradient diluted compound in buffer (see step 2.3).

B) 10ul of 2x gradient diluted compound was added to 384 well reaction plates (see step a).

C) The frozen buffer was used to prepare 2X reactants, RORgamma-LBD (40 nM), SRC (100 nM), anti-GST Eu (1:200) and streptavidin-D2 (25 nM).

D) 10ul of 2x reactant (see step c) was added to 384 well reaction plates (see step b).

E) The 384-well reaction plate was centrifuged, 1000g, 1min.

F) Incubate for 1 hour at room temperature in the dark.

G) The detection plate has wavelength of 665nm and 615nm, and the instrument is a multi-mark microplate detector.

4. Data analysis

4.1 Relative Ratio (RR) the relative ratio of each well was calculated [ (665 nm response value/615 nm response value-blank background response value). ] 1000.

4.2 The percent Inhibition (% Inhibition) is calculated as follows:

4.3 Calculating IC ₅₀ and dose-response curve of the compound, namely obtaining the IC50 and dose-response curve of the compound by using Graphpad 5.0 according to the calculated inhibition rate of the compound and the log value of the compound concentration.

4.4 Inspection report:

4.4.1 One experimenter completed the report and the other was again checked to ensure accuracy of the data.

4.4.1.1 The data is derived from the test instrument and analyzed manually.

4.4.1.2 The ratio was converted to percent inhibition. IC ₅₀ for the compound was calculated for the first time using graphpad5.0 software and percent inhibition.

4.4.1.3 The IC ₅₀ of the compound was calculated using the ratio and the accuracy of the data was checked using this IC ₅₀.

4.4.2 It was determined whether the names of all compounds were correct.

4.5 The data standard is Z factor >0.5, S/B >3;

IC ₅₀ for positive control compounds was within 3-fold of the historical average.

5. Data results:

Compounds of formula (I)	Half inhibition concentration of rorγt activity (IC 50)
		CMP 1	5nM
CMP 2	19nM
		CMP 5	1nM
CMP 6	150nM
		CMP 8	177nM
SR1001	295nM

From the above experimental results, it can be seen that the compounds of formula (I) have a significant inhibitory effect on roryt, which plays a very important role in inflammatory, metabolic and autoimmune diseases, and that inhibition of roryt will lead to alleviation or effective treatment of these diseases. In particular, the use of roryt inhibitors for the treatment of respiratory diseases (e.g. asthma, COPD), autoimmune diseases (e.g. rheumatoid arthritis, psoriasis, ulcerative colitis, crohn's disease) is intensively studied and accepted.

Claims (9)

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, R ₁ and R ₂ are selected from hydrogen, halogen, alkyl, haloalkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, and alkoxy; X and Y are independently selected from N or CR ₃ ; _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, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ heterocycloalkyl, or alkoxy; Ring B is a 5-10 membered heteroaryl or a 6-10 membered aryl, and the 5-10 membered heteroaryl and the 6-10 membered aryl may be further substituted by halogen, alkyl, haloalkyl, C ₃ -C ₈ (substituted) cycloalkyl, C ₂ -C ₈ 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 may be further substituted by C ₁ -C ₈ 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 C ₁ -C ₈ 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 of 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, Sjögren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Guillain-Barré syndrome, psoriatic arthritis, Grave's disease or scleritis.