CN110724076A - Para-aryldicarboxamide compound, pharmaceutical composition containing same, preparation method and use thereof - Google Patents

Abstract

The present invention relates to a p-aryldicarboxamide compound of formula (I), a pharmaceutical composition containing the same, a preparation method thereof and a use thereof, and in particular, to the use thereof for preventing or treating diseases or conditions mediated by retinoic acid receptor-related orphan nuclear receptor γ (RORγ).

Description

Para-aryldicarboxamide compound, pharmaceutical composition containing same, and preparation method thereof and its use

technical field

The present invention relates to p-aryldicarboxamides, pharmaceutical compositions containing them, preparation methods thereof, and their use in the prevention or treatment of diseases or conditions mediated by retinoic acid receptor-related orphan nuclear receptor gamma (RORγ) use.

Background technique

Retinoic acid receptor-related orphan nuclear receptors (RORs) include three subtypes, RORα, RORβ and RORγ, which play a regulatory role in various physiological processes. Recent studies have found that ROR has a higher affinity for and is regulated by oxidative steroid derivatives than retinoic acid. ROR is widely distributed in various tissues of the body, can directly enter the nucleus to regulate the transcription of target genes, and then participate in different physiological processes, showing different tissue specificities. Among them, RORα is expressed in various tissues, but is highly expressed in the brain and plays an important role in the development of the cerebellum and bone formation. RORβ has a smaller scope of action, is mainly expressed in the brain, and plays a role in the development of the retina and cerebral cortex. RORγ is expressed in many tissues, including the thymus, liver, and skeletal muscle, and plays a key role in the development of secondary lymphoid tissues.

RORγ has two isoforms, RORγ1 and RORγ2 (RORγt). RORγ1 is expressed in a variety of tissues, while RORγ2 is a subtype specifically expressed on immune cells. RORγ2 is a key transcription factor for the differentiation and maintenance of Th17 and Tc17 effector T cells, regulates Th17 cells to secrete the effector IL-17 and other proinflammatory cytokines, and plays a role in the differentiation of NK cells, γδT cells and iNK T cells and in autoimmune Important in disease and body defense responses, these cells mediate the immune system against cancer cells as well as pathogenic microorganisms such as bacteria and fungi. In the tumor microenvironment, Th17 cells and IL-17 can recruit natural killer cells and cytotoxic CD8 ⁺ T cells to attack and kill tumor cells. Some studies have shown that the level of infiltrating Th17 cells and the expression of IL-17 in the tumor site of ovarian cancer patients are positively correlated with good prognosis. Meanwhile, Th17 cells play a key role in many mouse models of autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. Elevated levels of IL-17 have been detected in human autoimmune diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis (Psoriasis) and inflammatory bowel disease (IBD). In addition, increased numbers of Th17 cells were found in tissue and peripheral blood samples from patients with autoimmune diseases.

The treatment of cancer, despite a great deal of research and effort, remains a major threat to human health. Cancer is the leading cause of death in both developed and developing countries, and both morbidity and mortality continue to increase. However, cancer-targeted drugs are not effective for all cancer patients.

For the treatment of immune system diseases, researchers found that regulating RORγ will effectively regulate the differentiation of Th17 cells, regulate the production and secretion of IL-17 cytokines, and thus regulate the immune system. Therefore, RORγ may serve as a new target for the treatment of immune diseases.

Therefore, it is of great significance to find small molecule modulators of RORγ and use them for the treatment of RORγ-mediated diseases or conditions. At present, the development of ROR modulators has gradually attracted attention in the pharmaceutical industry, and published patent applications include WO2017157332A1, WO2016201225A1, WO2011115892A1, WO2017102784A1, WO2017024018A1, WO2015180614A1 and the like.

SUMMARY OF THE INVENTION

The present invention provides compounds useful as modulators of retinoic acid receptor-related orphan nuclear receptor gamma (RORγ), which have good modulating activity on RORγ, good physicochemical properties (eg, solubility, physical and/or chemical stability) ), good pharmacokinetic properties (e.g. good bioavailability, suitable plasma concentration, half-life and duration of action), good safety profile (lower toxicity and/or fewer side effects, wider treatment window) and other excellent properties.

One aspect of the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro- medicine, wherein the compound has the structure of formula (I):

X ¹ is selected from CR ⁵ and N;

X ² is selected from CR ⁶ and N;

X ³ is selected from CR ⁷ and N;

X ⁴ is selected from CR ⁸ and N;

X ⁵ is selected from CR ⁹ and N;

Ring A is selected from C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl;

R ^a and R ^b are each independently selected from hydrogen and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy and cyano ;or

R ^a and R ^b together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group, wherein the C _3-6 cycloalkyl group is optionally selected by one or more independently selected from halogen, hydroxy, cyano , C _1-6 alkyl and C _1-6 haloalkyl substitution;

R ^c and R ^d are each independently selected from hydrogen and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy and cyano ;or

R ^c and R ^d together with the carbon atom to which they are attached form a C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl is optionally selected by one or more independently selected from halogen, hydroxy, cyano , C _1-6 alkyl and C _1-6 haloalkyl substitution;

R ¹ is selected from -S(O) ₂ -C _1-6 alkyl, -S(O) ₂ -NH ₂ , -S(O) ₂ -NH-C _1-6 alkyl and -S(O) ₂ -N(C _1-6 alkyl) ₂ , wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and C _3-6 cycloalkyl;

R ² is each independently selected at each occurrence from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and C _1-6 alkoxy wherein the alkyl and alkoxy groups are each optionally substituted with one or more substituents independently selected from halogen, hydroxy, and cyano, and the cycloalkyl and heterocyclyl groups are each optionally substituted with a or more substituents independently selected from halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy;

^R is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally replaced by one or more substituted with substituents independently selected from halogen, hydroxy, cyano, -N(R ¹¹ )(R ¹² ) and C _1-6 alkoxy;

^R4 is selected from hydrogen and _C1-6 alkyl, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

R ⁵ is selected from hydrogen, halogen, cyano and hydroxyl;

R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected at each occurrence from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl and C _1-6 alkoxy, the each of alkyl and alkoxy is optionally substituted with one or more substituents independently selected from halo, hydroxy, and cyano;

R ¹¹ and R ¹² are each independently selected from hydrogen and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

m is 0, 1, 2, or 3; and

n is 1, 2, 3 or 4.

Another aspect of the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate thereof compounds, N-oxides, isotopically labeled compounds, metabolites, or prodrugs, and one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, Use of a metabolite or prodrug or a pharmaceutical composition of the present invention in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by RORγ.

Another aspect of the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, Metabolites or prodrugs or pharmaceutical compositions of the invention for use in the prevention or treatment of RORγ mediated diseases or disorders.

Another aspect of the present invention provides a method of preventing or treating a disease or disorder mediated by RORγ, the method comprising administering to an individual in need thereof an effective amount of a compound or a pharmaceutically acceptable salt, stereoisomer, mutual Variants, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.

Another aspect of the present invention provides methods for the preparation of the compounds of the present invention.

definition

Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations or substitutions of equivalent techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

As used herein, the terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended, and do not Other unlisted elements or method steps are excluded.

As used herein, the term "hydrogen" and hydrogen in each group refers to protium (H), deuterium (D), or tritium (T). In certain preferred embodiments, the hydrogen is H. In certain preferred embodiments, the hydrogen is D.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon optionally substituted with 1 or more (such as 1 to 3) suitable substituents, eg, halogen (in this case the group is referred to as "haloalkyl"), hydroxy (in this case the group is referred to as "alkylene-OH") or cyano (in this case the group is referred to as "alkylene- EN"). In some embodiments, the alkyl group has 1 to 12 carbon atoms, such as 1 to 6 carbon atoms (C _1-6 alkyl) or 1 to 4 carbon atoms (C _1-4 alkyl). For example, as used herein, the term "C _1-6 alkyl" refers to a linear or branched group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl). The term "C _1-6 haloalkyl" refers to a C _1-6 alkyl substituted with 1 or more halogens, such as "C _1-4 haloalkyl", more particularly, such as -CH ₂ F, -CHF ₂ , -CF ₃ , -CCl ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CH ₂ CF ₃ , -CH ₂ Cl or -CH ₂ CH ₂ CF ₃ and the like. The term "C _1-6 alkylene-OH" refers to a C _1-6 alkyl group substituted with hydroxy, such as "C _1-4 alkylene-OH". The term "C _1-6 alkylene-CN" refers to a C _1-6 alkyl group substituted with a cyano group, such as "C _1-4 alkylene-CN".

As used herein, the term "alkoxy" refers to a group having the structure "alkyl-O-" (where alkyl is as defined above), optionally surrounded by 1 or more (such as 1 to 3 ) with a suitable substituent such as halogen (in this case this group is referred to as "haloalkoxy"). As used herein, the term "C _1-6 alkoxy" refers to a group having the structure "C _1-6 alkyl-O-" (wherein C _1-6 alkyl is as defined above), eg, C _{1 -4} alkoxy, C _1-2 alkoxy, C ₁ alkoxy, C ₂ alkoxy, C ₃ alkoxy, C ₄ alkoxy, C ₅ alkoxy or C ₆ alkoxy, Preferred is C _1-4 alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, Hexyloxy, etc.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens. As used herein, the term "C _1-6 haloalkoxy" refers to C _1-6 alkoxy substituted with 1 or more halogens, such as but not limited to -OCH ₂ F, -OCH ₂ Cl, - _OCH2CH2F , _-OCH2CH2Cl , _{-OCH2CH2CH2Cl} , _-OCH2CH2CH2F , _{-OC ( CH2 ) 2Cl} , _{-OC ( CH2 ) 2F} .

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) , cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbons For example, the term "C _3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, cyclopropyl, cyclobutyl, cyclopentane) having 3 to 6 ring carbon atoms or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, eg, methyl substituted cyclopropyl.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms in the ring and One or more (eg one, two, three or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O) ₂ and ^NRx group, wherein R ^x represents a hydrogen atom or a C _1-6 alkyl or C _1-6 haloalkyl group; the heterocyclyl group can be bonded to the rest of the molecule through any of the carbon atoms or a nitrogen atom (if present) Partial connection. In particular, a 3-10 membered heterocyclyl group is a group having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridine Alanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi electron system. For example, as used herein, the term " _C6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, _-NO2 , _C1-6 alkyl, etc.).

As used herein, the term "aralkyl" preferably refers to an aryl-substituted alkyl group, wherein said aryl group and said alkyl group are as defined herein. Typically, the aryl group can have 6-10 carbon atoms, and the alkyl group can have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

As used herein, the term "5-10 membered heteroaryl" refers to a monocyclic or polycyclic aromatic group containing 5-10 ring members, including 1-4 (eg, 1 , 2, 3, or 4) heteroatoms selected from N, O, and S, eg, 5-membered heteroaryl, 6-membered heteroaryl, and the like. Specific examples thereof include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3 ,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3- Triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl and the like. As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

As used herein, the term "substituted" means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than The designated atom has the normal valence in the present case and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

If a substituent is described as "optionally substituted", the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Selected optional substituents are substituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional substitution of substituents.

If substituents are described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.

Unless otherwise indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.

When the bond of a substituent is shown as a bond connecting two atoms in a ring, such substituent may be bonded to any ring-forming atom in the substitutable ring.

The present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass number. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of ^hydrogen (eg, deuterium (2H), tritium ( ^3H )); isotopes of carbon (eg, ^11C , ^13C , ^and14C ) ; isotopes of chlorine (eg ³⁶ Cl); isotopes of fluorine (eg ¹⁸ F); isotopes of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O) , ¹⁷ O and ¹⁸ O); isotopes of phosphorus (eg ³² P); and isotopes of sulfur (eg ³⁵ S). Certain isotopically-labeled compounds of the invention (eg, those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (eg, assays). The radioisotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly useful for this purpose due to their ease of incorporation and ease of detection. Substitution with positron emitting isotopes such ^as11C , ^18F , ^15O , ^and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically-labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the previously employed non-labeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, _D2O , acetone-d6, or _{DMSO -} d6.

The term "stereoisomer" refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, one, two, three or four) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual of diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of this application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% %) of isomers or mixtures thereof.

)或虚楔形(

)描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。In this paper, solid lines (—), solid wedges (

) or imaginary wedge (

) depict the chemical bonds of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, racemic mixture, etc.). The use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists. When present in a racemic mixture, real and imaginary wedges are used to define relative, rather than absolute, stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

It will also be appreciated that certain compounds of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs after their administration to a patient in need thereof , capable of directly or indirectly providing the compounds of the invention or their metabolites or residues. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.

The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other components that make up the formulation and/or the mammal to be treated with it.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, glucoheptonate, gluconate, orotate, palmitate and other similar salts.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, magnesium, and other similar salts.

For a review of suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

The compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; Nitrogen-containing heterocycles. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W.H. Cheeseman and E.S.G.Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety" (eg as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)' Prepared by substituting appropriate functional groups present in the compounds of the present invention.

The present invention also encompasses compounds of the present invention that contain protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

Compounds and methods for their preparation

A first aspect of the present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A prodrug, wherein the compound has the structure of formula (I):

X ¹ is selected from CR ⁵ and N;

X ² is selected from CR ⁶ and N;

X ³ is selected from CR ⁷ and N;

X ⁴ is selected from CR ⁸ and N;

X ⁵ is selected from CR ⁹ and N;

Ring A is selected from C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl;

R ^a and R ^b are each independently selected from hydrogen and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy and cyano ;or

R ^a and R ^b together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group, wherein the C _3-6 cycloalkyl group is optionally selected by one or more independently selected from halogen, hydroxy, cyano , C _1-6 alkyl and C _1-6 haloalkyl substitution;

R ^c and R ^d are each independently selected from hydrogen and C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy and cyano ;or

R ^c and R ^d together with the carbon atom to which they are attached form a C _3-6 cycloalkyl, wherein the C _3-6 cycloalkyl is optionally selected by one or more independently selected from halogen, hydroxy, cyano , C _1-6 alkyl and C _1-6 haloalkyl substitution;

R ¹ is selected from -S(O) ₂ -C _1-6 alkyl, -S(O) ₂ -NH ₂ , -S(O) ₂ -NH-C _1-6 alkyl and -S(O) ₂ -N(C _1-6 alkyl) ₂ , wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, and C _3-6 cycloalkyl;

R ² is each independently selected at each occurrence from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and C _1-6 alkoxy wherein the alkyl and alkoxy groups are each optionally substituted with one or more substituents independently selected from halogen, hydroxy, and cyano, and the cycloalkyl and heterocyclyl groups are each optionally substituted with a or more substituents independently selected from halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy;

^R is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally replaced by one or more substituted with substituents independently selected from halogen, hydroxy, cyano, -N(R ¹¹ )(R ¹² ) and C _1-6 alkoxy;

^R4 is selected from hydrogen and _C1-6 alkyl, wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

R ⁵ is selected from hydrogen, halogen, cyano and hydroxyl;

R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected at each occurrence from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl and C _1-6 alkoxy, the each of alkyl and alkoxy is optionally substituted with one or more substituents independently selected from halo, hydroxy, and cyano;

R ¹¹ and R ¹² are each independently selected from hydrogen and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

m is 0, 1, 2, or 3; and

n is 1, 2, 3 or 4.

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. A labeled compound, metabolite or prodrug, wherein the compound has the structure of formula (II):

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. A labeled compound, metabolite or prodrug, wherein:

R ^a and R ^b are each independently selected from hydrogen and C _1-6 alkyl; or

R ^a and R ^b together with the carbon atom to which they are attached form a C _3-6 cycloalkyl;

R ^c and R ^d are each independently selected from hydrogen and C _1-6 alkyl; or

R ^c and R ^d together with the carbon atom to which they are attached form a C _3-6 cycloalkyl;

R ¹ is selected from -S(O) ₂ -C _1-6 alkyl, -S(O) ₂ -NH ₂ , -S(O) ₂ -NH-C _1-6 alkyl, -S(O) ₂ -N(C _1-6 alkyl) ₂ and -S(O) ₂ -C _1-6 alkylene-C _3-6 cycloalkyl;

R ² at each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl , C _1-6 alkoxy and C _1-6 haloalkoxy;

^R is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally replaced by one or more substituted with substituents independently selected from halogen, hydroxy, cyano, -N(R ¹¹ )(R ¹² ) and C _1-6 alkoxy;

R ⁴ is selected from hydrogen and C _1-6 alkyl;

R ⁵ is selected from hydrogen and halogen, and

R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ at each occurrence are each independently selected from hydrogen, halogen, cyano, hydroxy, and C _1-6 alkoxy;

R ¹¹ and R ¹² are each independently selected from hydrogen and C _1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano.

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. A labeled compound, metabolite or prodrug, wherein: Ring A is selected from C _3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl. In a preferred embodiment, Ring A is selected from the group consisting of phenyl, pyridyl, piperidinyl and cyclohexyl. In a more preferred embodiment, Ring A is phenyl.

在更优选的实施方案中，R¹选自-S(O)₂-CH₂CH₃、-S(O)₂-NH-CH₃、-S(O)₂-N(CH₃)₂和

在甚至更优选的实施方案中，R¹选自-S(O)₂-CH₂CH₃。In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. A labeled compound, metabolite or prodrug, wherein: R ¹ is selected from -S(O) ₂ -C _1-4 alkyl, -S(O) ₂ -NH ₂ , -S(O) ₂ -NH-C _1-4 alkyl, -S(O) ₂ -N(C _1-4 alkyl) ₂ and -S(O) ₂ -C _1-4 alkylene-C _3-6 cycloalkyl. In a preferred embodiment, R ¹ is selected from -S(O) ₂ -CH ₃ , -S(O) ₂ -CH ₂ CH ₃ , -S(O) ₂ -NH ₂ , -S(O) ₂ - NH-CH ₃ , -S(O) ₂ -NH-CH ₂ CH ₃ , -S(O) ₂ -N(CH ₃ ) ₂ , -S(O) ₂ -N(CH ₂ CH ₃ ) ₂ and

In a more preferred embodiment, R ¹ is selected from the group consisting of -S(O) ₂ -CH ₂ CH ₃ , -S(O) ₂ -NH-CH ₃ , -S(O) ₂ -N(CH ₃ ) ₂ and

In an even more preferred embodiment, R1 is selected from -S(O ₎ ² _{- CH2CH3} .

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. A labeled compound, metabolite or prodrug wherein: R2 is each independently selected at each occurrence from ^hydrogen , halogen, cyano, hydroxy, _C1-4 alkyl, _C1-4 haloalkyl, _{C3- 6} -cycloalkyl, 3-6 membered heterocyclyl, C _1-4 alkoxy and C _1-4 haloalkoxy. ^In preferred embodiments, each occurrence of R2 is independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, hydroxy, methyl, ethyl, isopropyl, _-CH2F , - _CHF2 , _-CF3 , _-CH2CH2F , _cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy. In a more preferred embodiment, each occurrence of R2 is independently selected from ^hydrogen , fluoro, chloro, cyano, methyl, ethyl, _-CF3 , cyclopropyl, methoxy, difluoromethyl oxy and trifluoromethoxy. ^In an even more preferred embodiment, each occurrence of R2 is independently selected from fluoro, _-CF3 , methoxy.

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. Labeled compound, metabolite or prodrug, wherein: ^R is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each optionally optionally selected by one or more independently selected from halogen, hydroxy, cyano, _-NH2 , -NH( _C1-4alkyl ), -N( _C1-4alkyl ) ₂ , -NH(C _1-4 haloalkyl), -N(C _1-4 alkyl) (C _1-4 haloalkyl) and C _1-4 alkoxy substituents. In a preferred embodiment, ^R3 is selected from hydrogen, _C1-4 alkyl and _C3-6 cycloalkyl, wherein each of said alkyl and cycloalkyl is optionally selected by one or more independently selected from Halogen, hydroxyl, cyano, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -NH(C _1-4 haloalkyl), -N(C _{1 -4} alkyl) (C _1-4 haloalkyl) and C _1-4 alkoxy substituents. In a more preferred embodiment, ^R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, _-CH2CH2F , _-CH2C ( _{CH3 ) 2F} , _-CH2C ( _CH3 ) ₂ -OH, -CH2CH2-O- _CH3 , _-CH2C ( _{CH3 ) 2} -CN, _{-CH2 -} NH _{- CH2CH2F} . In an even more preferred embodiment, ^R3 is selected from _hydrogen , _-CH2CH2F .

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. ^A labeled compound, metabolite or prodrug wherein: R6, ^R7 , ^R8 , ^R9 and ^R10 are each independently selected at each occurrence from hydrogen, halogen and _C1-4alkoxy . In preferred embodiments, R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected at each occurrence from hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, n- Propoxy and isopropoxy. In a more preferred embodiment, R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are selected from hydrogen.

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. A labeled compound, metabolite or prodrug, wherein the compound has the structure of formula (III):

In a preferred embodiment, the compound has the structure of formula (IV):

In a more preferred embodiment, the compound has the structure of formula (V):

The present invention encompasses compounds resulting from any combination of the various embodiments.

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof, or a pharmaceutically acceptable salt thereof. A labeled compound, metabolite or prodrug, wherein the compound is selected from:

The compounds of the present invention are RORγ modulators. In some embodiments, the compounds of the present invention are RORγ agonists. In other embodiments, the compounds of the present invention are RORγ inhibitors.

A second aspect of the present invention provides a process for the preparation of a compound of formula (I), said process comprising the steps of:

wherein Rings A, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ , R ¹⁰ , R ^a , R ^b , R ^c , R ^d , m and n as defined above;

(1) reacting compound IN-1 with compound IN-2 to obtain compound IN-3;

The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from tetrahydrofuran, dimethylformamide, dimethylacetamide, 1,4-dioxane and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out in the presence of a suitable condensing agent. The condensing agent can be selected from dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-benzotriazole oxide) )-N,N,N',N'-tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, hexafluorophosphate benzotriazol-1-yl- Oxytripyrrolidinophosphorus, preferably 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. The reaction is preferably carried out in the presence of a suitable organic base. The organic base can be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably 20-50°C, especially room temperature. The reaction is preferably carried out for a suitable time, preferably 2-8 hours, eg 3, 4, 5, 6 or 7 hours.

(2) oxidizing compound IN-3 to obtain compound IN-4;

The oxidation reaction is preferably carried out in a suitable solvent. The solvent can be selected from acetone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water and any combination thereof, preferably acetone. The reaction is preferably carried out in the presence of a suitable oxidizing agent. The oxidant can be selected from m-chloroperoxybenzoic acid, potassium peroxymonosulfate complex salt, hydrogen peroxide, potassium permanganate, preferably potassium permanganate. The reaction is preferably carried out at a suitable temperature, preferably 20-50°C, especially room temperature. The reaction is preferably carried out for a suitable time, preferably 2-5 hours, eg 3 or 4 hours.

(3) Compound IN-4 is reacted with compound IN-5 to obtain the compound of formula (I).

The reaction is preferably carried out in a suitable organic solvent. The organic solvent can be selected from tetrahydrofuran, dimethylformamide, dimethylacetamide, 1,4-dioxane and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out in the presence of a suitable condensing agent. The condensing agent can be selected from dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-benzotriazole oxide) )-N,N,N',N'-tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, hexafluorophosphate benzotriazol-1-yl- Oxytripyrrolidinophosphorus, preferably 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. The reaction is preferably carried out in the presence of a suitable organic base. The organic base can be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably 20-50°C, especially room temperature. The reaction is preferably carried out for a suitable time, preferably 2-8 hours, eg 3, 4, 5, 6 or 7 hours.

Pharmaceutical compositions and methods of treatment

A third aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate thereof compounds, N-oxides, isotopically labeled compounds, metabolites, or prodrugs, and one or more pharmaceutically acceptable carriers.

A fourth aspect of the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, Use of a metabolite or prodrug or a pharmaceutical composition of the present invention in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by RORγ. In preferred embodiments, the drug is a drug administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.

A fifth aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, Metabolites or prodrugs or pharmaceutical compositions of the invention for use in the prevention or treatment of RORγ mediated diseases or disorders.

A sixth aspect of the present invention provides a method of preventing or treating a RORγ-mediated disease or disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomeric Conformers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.

In preferred embodiments, the RORγ-mediated disease or disorder is an inflammatory or autoimmune disease or disorder. In a more preferred embodiment, the inflammatory or autoimmune disease or disorder is selected from the group consisting of: psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis , asthma, osteoarthritis, Crohn's disease and Kawasaki disease.

In a preferred embodiment, the RORγ-mediated disease or disorder is cancer. In a more preferred embodiment, the cancer is selected from the group consisting of: non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, Oral cancer, brain cancer, stomach cancer, liver cancer, rectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, solid tumor, glioma , glioblastoma, papillary malignancies, head and neck tumors, leukemia, lymphoma and myeloma. In preferred embodiments, the medicament further comprises other antineoplastic agents or other medicaments for the treatment or prevention of inflammatory or autoimmune diseases or disorders.

In the present invention "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene glycol, water, Ethanol etc. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose they may be administered by a suitable route, for example by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasal, transmucosal, topical, in ophthalmic formulations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , injectable solutions, elixirs, syrups.

The term "effective amount" as used herein refers to the amount of a compound which, when administered, will alleviate to some extent one or more symptoms of the condition being treated.

Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.

The amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, an effective dose will range from about 0.0001 to about 50 mg per kg of body weight per day, eg, from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, eg, about 0.7 mg/day to about 700 mg/day. In some cases, dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first The dose is divided into several smaller doses to be administered throughout the day.

The content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg, 25mg, etc.

Unless otherwise specified, the term "treating" as used herein means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.

An "individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein). "Non-human animals" in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).

Detailed ways

In order to make the purpose and technical solutions of the present invention clearer, the present invention is further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, the specific experimental methods not mentioned in the following examples were all carried out according to the conventional experimental methods.

Abbreviations in this document have the following meanings:

The structures of the compounds described in the following examples were confirmed by nuclear magnetic resonance spectroscopy ( ¹ H-NMR) or mass spectrometry (MS).

The measuring instrument of ¹ H-NMR is Bruker 400MHz nuclear magnetic resonance instrument, and the measuring solvent is deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or hexadeuterated dimethyl sulfoxide (DMSO-d ₆ ). Designated as tetramethylsilane (TMS). Chemical shifts (δ) are given in parts per million (ppm).

The measuring instrument for mass spectrometry (MS) was an Agilent (ESI) mass spectrometer, model Agilent 6120B.

Thin-layer chromatography (TLC) was performed using aluminum plates (20×20 cm) produced by Merck, and preparative thin-layer chromatography was performed using GF254 (0.4-0.5 mm) silica gel plates.

The reaction was monitored by thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and the developing solvent systems used included dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and acetic acid Ethyl ester system. The developing agent system is adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

Initiator+(400W,RT～300℃)微波反应器进行。microwave reaction use

Initiator+ (400W, RT~300°C) microwave reactor.

Column chromatography generally uses 200-300 mesh silica gel as the stationary phase. The eluent systems include dichloromethane and methanol systems and petroleum ether and ethyl acetate systems. Adjust the eluent system according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.)

Instrument model used for preparative high performance liquid chromatography: Agilent 1260, chromatographic column: Waters XBridgePrep C ₁₈ OBD (19mm×150mm×5.0μm); Column temperature: 25°C; Flow rate: 20.0mL/min; Detection wavelength: 214nm ; Elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); Mobile phase A: 100% acetonitrile; Mobile phase B: 0.05% aqueous ammonium bicarbonate.

Unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., and the like.

Example

Preparation of intermediates

Intermediate Preparation Example 1: Preparation of 4-((4-(ethylsulfonyl)benzyl)carbamoyl)benzoic acid

The first step: the preparation of 4-((4-(ethylsulfonyl)benzyl)carbamoyl)benzaldehyde

4-Formylbenzoic acid (1.0 g, 6.7 mmol), HATU (3.8 g, 10.0 mmol) and DIPEA (2.6 g, 20.0 mmol) were dissolved in tetrahydrofuran (20 mL), and after stirring at room temperature for 0.5 hours, 4- Ethylsulfonylbenzylamine (1.3 g, 6.7 mmol) was reacted at room temperature for 4 hours, an appropriate amount of water was added, extracted with ethyl acetate three times, the organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated to give the title compound of this step (1.7 g, yield: 77%).

The second step: preparation of 4-((4-(ethylsulfonyl)benzyl)carbamoyl)benzoic acid

4-((4-(Ethylsulfonyl)benzyl)carbamoyl)benzaldehyde (1.7 g, 5.1 mmol) was dissolved in acetone (20 mL), 10% aqueous potassium permanganate (10 mL) was added, and the solution was heated to room temperature. After reacting for 3 hours, the reaction solution was concentrated, an appropriate amount of ethanol was added to the concentrate to wash, filtered, and the filtrate was concentrated to obtain the title compound (1.5 g, yield: 84%).

Intermediate Preparation Example 2: Preparation of N-(4-chloro-2-trifluoromethylbenzyl)-2-fluoroethylamine

4-Chloro-2-trifluoromethylbenzylamine (100.0 mg, 0.5 mmol), 1-bromo-2-fluoroethane (78.7 mg, 0.6 mmol) and potassium carbonate (138.2 mg, 1.0 mmol) were dissolved in acetonitrile (5 mL), heated to 80°C for 4 hours, the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the concentrate was subjected to preparative thin layer chromatography (eluent: petroleum ether: ethyl acetate = 4:1 (v:v) ) was purified to give the title compound (40.0 mg, yield: 30%).

Intermediate Preparation Example 3: Preparation of N-(2-fluorobenzyl)-2-fluoroethylamine

2-Fluorobenzylamine (200.0 mg, 1.6 mmol), 1-bromo-2-fluoroethane (608.7 mg, 4.8 mmol) and potassium carbonate (883.5 mg, 6.4 mmol) were dissolved in acetonitrile (10 mL) and heated to The reaction was carried out at 80°C for 10 hours, the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the concentrate was purified by preparative thin layer chromatography (eluent: petroleum ether:ethyl acetate=2:1 (v:v)) to obtain the title compound (180.0 mg, yield: 66%).

Intermediate Preparation Example 4: Preparation of N-(3-fluorobenzyl)-2-fluoroethylamine

3-Fluorobenzylamine (200.0 mg, 1.6 mmol), 1-bromo-2-fluoroethane (608.7 mg, 4.8 mmol) and potassium carbonate (883.5 mg, 6.4 mmol) were dissolved in acetonitrile (10 mL) and heated to The reaction was carried out at 80°C for 10 hours, the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the concentrate was purified by preparative thin layer chromatography (eluent: petroleum ether:ethyl acetate=2:1 (v:v)) to obtain the title compound (190.0 mg, yield: 69%).

Intermediate Preparation Example 5: Preparation of N-(4-fluorobenzyl)-2-fluoroethylamine

4-Fluorobenzylamine (200.0 mg, 1.6 mmol), 1-bromo-2-fluoroethane (608.7 mg, 4.8 mmol) and potassium carbonate (883.5 mg, 6.4 mmol) were dissolved in acetonitrile (10 mL) and heated to The reaction was carried out at 80°C for 10 hours, the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the concentrate was purified by preparative thin layer chromatography (eluent: petroleum ether:ethyl acetate=2:1 (v:v)) to obtain the title compound (150.0 mg, yield: 55%).

Intermediate Preparation Example 6: Preparation of N-(4-methoxybenzyl)-2-fluoroethylamine

4-Methoxybenzylamine (219.2 mg, 1.6 mmol), 1-bromo-2-fluoroethane (608.7 mg, 4.8 mmol) and potassium carbonate (883.5 mg, 6.4 mmol) were dissolved in acetonitrile (10 mL), The reaction was heated to 80°C for 12 hours, the reaction solution was cooled to room temperature, the reaction solution was concentrated, and the concentrate was purified by preparative thin layer chromatography (eluent: petroleum ether: ethyl acetate=2:1 (v:v)) to obtain the title compound (153.0 mg, yield: 51%).

Example 1: Preparation of N1-( ⁴ -chloro- ² -trifluoromethylbenzyl)-N4-(4-(ethylsulfonyl)benzyl)terephthalamide

4-((4-(Ethylsulfonyl)benzyl)carbamoyl)benzoic acid (100.0 mg, 0.29 mmol), HATU (164.2 mg, 0.43 mmol) and DIPEA (185.7 mg, 1.44 mmol) were dissolved in tetrahydrofuran ( 5mL), stirred at room temperature for 0.5 hours, added 4-chloro-2-trifluoromethylbenzylamine (60.6mg, 0.29mmol), reacted at room temperature for 4 hours, then added an appropriate amount of water, extracted with ethyl acetate 3 times. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by preparative high performance liquid chromatography to obtain the title compound (80.0 mg, yield: 51%).

MS m/z (ESI): 539.1 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ: 7.79-7.76(m, 6H), 7.60(s, 1H), 7.54(d, J=8.0Hz, 1H), 7.46-7.44(m, 3H), 6.79 (s, 1H), 6.54 (s, 1H), 4.73-4.67 (m, 4H), 3.03 (q, J=8.0 Hz, 2H), 1.20 (t, J=8.0 Hz, 3H).

Example 2: N1-( ⁴ -Chloro-2-trifluoromethylbenzyl)-N4-(4-(ethanesulfonyl)benzyl) ^-N1- ( ² -fluoroethyl)terephthalene Preparation of formamide

4-((4-(Ethylsulfonyl)benzyl)carbamoyl)benzoic acid (150.0 mg, 0.43 mmol), HATU (246.3 mg, 0.65 mmol) and DIPEA (278.6 mg, 2.16 mmol) were dissolved in tetrahydrofuran ( 5 mL), stirred at room temperature for 0.5 hours, added N-(4-chloro-2-trifluoromethylbenzyl)-2-fluoroethanamine (112.2 mg, 0.44 mmol), and reacted at room temperature for 4 hours, Then an appropriate amount of water was added and extracted with ethyl acetate 3 times. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by preparative high performance liquid chromatography to obtain the title compound (115.0 mg, yield: 45%).

MS m/z (ESI): 585.1 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ: 7.80-7.76(m, 6H), 7.60(s, 1H), 7.46-7.44(m, 3H), 6.79(s, 1H), 6.54(s, 1H) ,4.73-4.67(m,4H),3.56(t,J＝8.0Hz,2H),3.27(t,J＝8.0Hz,2H),3.03(q,J＝8.0Hz,2H),1.20(t, J=8.0Hz, 3H).

Example 3: Preparation of N1-( ^4- (ethylsulfonyl)benzyl)-N4-( ² -fluorobenzyl)-N4-( ² -fluoroethyl)terephthalamide

4-((4-(Ethylsulfonyl)benzyl)carbamoyl)benzoic acid (220.0 mg, 0.63 mmol), HATU (359.4 mg, 0.95 mmol) and DIPEA (122.8 mg, 0.95 mmol) were dissolved in tetrahydrofuran ( 5 mL), after stirring at room temperature for 0.5 hours, N-(2-fluorobenzyl)-2-fluoroethylamine (130.2 mg, 0.76 mmol) was added, and the mixture was reacted at room temperature for 4 hours, then an appropriate amount of water was added, and acetic acid was used. Ethyl ester extraction 3 times. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the concentrate was purified by preparative high performance liquid chromatography to obtain the title compound (85.0 mg, yield: 27%).

MS m/z (ESI): 501.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.89-7.87 (m, 4H), 7.57-7.55 (m, 4H), 7.35-6.91 (m, 4H), 4.95-4.54 (m, 6H), 3.84-3.50 (m, 2H), 3.14 (q, J=8.0 Hz, 2H), 1.31 (t, J=8.0 Hz, 3H).

Example 4: Preparation of N1-(4-(ethylsulfonyl)benzyl)-N4-( ³ -fluorobenzyl)-N4-( ² -fluoroethyl) ^{-terephthalamide}

将4-((4-(乙磺酰基)苄基)氨基甲酰基)苯甲酸(220.0mg,0.63mmol)、HATU(359.4mg,0.95mmol)和DIPEA(122.8mg,0.95mmol)溶于四氢呋喃(5mL)中，在室温下搅拌0.5小时后，加入N-(3-氟苄基)-2-氟乙胺(130.2mg,0.76mmol)，在室温下反应4小时，然后加入适量水，用乙酸乙酯萃取3次。合并有机相并用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过滤，浓缩滤液，浓缩物经制备高效液相色谱仪纯化得到标题化合物(62.0mg，收率：20％)。

4-((4-(Ethylsulfonyl)benzyl)carbamoyl)benzoic acid (220.0 mg, 0.63 mmol), HATU (359.4 mg, 0.95 mmol) and DIPEA (122.8 mg, 0.95 mmol) were dissolved in tetrahydrofuran ( 5 mL), after stirring at room temperature for 0.5 hours, N-(3-fluorobenzyl)-2-fluoroethylamine (130.2 mg, 0.76 mmol) was added, and reacted at room temperature for 4 hours, then an appropriate amount of water was added, and acetic acid was used. Ethyl ester extraction 3 times. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the concentrate was purified by preparative high performance liquid chromatography to obtain the title compound (62.0 mg, yield: 20%).

MS m/z (ESI): 501.2 [M+H] ⁺ .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.78-7.74 (m, 4H), 7.43-7.26 (m, 4H), 7.02-6.80 (m, 4H), 4.71-4.27 (m, 6H), 3.73- 3.36 (m, 2H), 3.03 (q, J=8.0 Hz, 2H), 1.20 (t, J=8.0 Hz, 3H).

Example ⁵ : Preparation of N1-(4-(ethylsulfonyl)benzyl)-N4-( ⁴ -fluorobenzyl)-N4-( ² -fluoroethyl)-terephthalamide

4-((4-(Ethylsulfonyl)benzyl)carbamoyl)benzoic acid (220.0 mg, 0.63 mmol), HATU (359.4 mg, 0.95 mmol) and DIPEA (122.8 mg, 0.95 mmol) were dissolved in tetrahydrofuran ( 5 mL), after stirring at room temperature for 0.5 hours, N-(4-fluorobenzyl)-2-fluoroethylamine (140.9 mg, 0.82 mmol) was added, and the mixture was reacted at room temperature for 4 hours, and then an appropriate amount of water was added, followed by acetic acid. Ethyl ester extraction 3 times. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the concentrate was purified by preparative high performance liquid chromatography to obtain the title compound (74.0 mg, yield: 24%).

MS m/z (ESI): 501.2 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ: 7.79-7.75(m, 4H), 7.45-7.26(m, 4H), 7.00-6.79(m, 4H), 4.72-4.27(m, 6H), 3.71- 3.35 (m, 2H), 3.02 (q, J=8.0 Hz, 2H), 1.19 (t, J=8.0 Hz, 3H).

Example 6: Preparation of N1-(4-(ethylsulfonyl)benzyl)-N4-( ² -fluoroethyl) ^-N4- ( ⁴ -methoxybenzyl)-terephthalamide

4-((4-(Ethylsulfonyl)benzyl)carbamoyl)benzoic acid (220.0 mg, 0.63 mmol), HATU (359.4 mg, 0.95 mmol) and DIPEA (122.8 mg, 0.95 mmol) were dissolved in tetrahydrofuran ( 5 mL), stirred at room temperature for 0.5 hours, added N-(4-methoxybenzyl)-2-fluoroethylamine (150.8 mg, 0.83 mmol), reacted at room temperature for 4 hours, and then added an appropriate amount of water, Extracted 3 times with ethyl acetate. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was purified by preparative high performance liquid chromatography to obtain the title compound (81.0 mg, yield: 26%).

MS m/z (ESI): 513.2 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ: 7.89-7.87(m, 4H), 7.57-7.55(m, 4H), 7.10-6.93(m, 4H), 4.79-4.37(m, 6H), 3.86( s, 3H), 3.75-3.43 (m, 2H), 3.12 (q, J=8.0 Hz, 2H), 1.31 (t, J=8.0 Hz, 3H).

Biological evaluation

Test Example 1. RORγ-LBD TR-FRET experiment

Reaction buffer was prepared (25 mM HEPES, pH 7.0, 100 mM NaCl, 0.01% Tween 20, 0.2% BSA, 5 mM DTT). Solution A1 containing 1nM LANCE Eu-anti-6xHis antibody (PerkinElmer), solution A2 containing 1nMLANCE Eu-anti-6xHis antibody (PerkinElmer) and 15nM RORγ-LBD (HDB), and 200nM in buffer were prepared Solution B of biotin-SRC1 (PerkinElmer) and 15 nM Allophycocyanin-Streptavidin (PerkinElmer), both kept on ice until use.

Dilute the test compound with DMSO (starting from 5 μM, 4-fold dilution, set 10 concentration points), transfer the diluted test compound to a 384-well plate, and set up duplicate wells; transfer DMSO to solvent control wells and negative control wells . 15 μl of solution A1 was added to the negative control well, and 15 μl of solution A2 was added to the solvent control well and the test compound well. Add 10 μl of solution B to each well, seal the plate with sealing tape, and shake for 2 minutes to mix the reaction solution. The 384-well plate was placed at 4°C overnight. On the second day, the 384-well plate was taken out to equilibrate at room temperature for 1 hour, and centrifuged for 1 minute. Read the plate with a microplate reader (detection wavelength 665nm/615nm).

Data processing: compound inhibition rate (%)=(FI compound-FI solvent control)/(FI solvent control-FI negative control)*100. FI represents the fluorescence value read by the microplate reader. _IC50 values were calculated by GraphPad Prism software. The results are shown in Table 1.

Table 1. _IC50 of compounds of the invention for RORγ modulating activity

Example number IC₅₀(nM) 2 5.6 3 48.0 5 151.9 6 131.2

From the above results, it can be seen that the compounds of the examples have obvious inhibitory effect on RORγ.

Test Example 2. GAL4-RORγ luciferase reporter gene assay

1. Experimental materials

pcDNA3.1 (GAL4DBD/RORγLBD); pGL4.35 (Promega); Lipofectamine 3000 (ThermoFisher Scientific)

2. Experimental method

When the 293T cells grew to about 80% confluence, the plasmid liposome complex was prepared according to the instructions of Lipofectamine 3000, and the medium was added. Twenty-four hours after the cells were transfected, they were evenly spread into a 96-well plate, the compounds to be tested were added, and the culture plate was placed in a 37°C, 5% CO ₂ incubator for 24 hours. On the second day, take out the culture plate, add Bright-Glo (Promega), shake for 5 minutes, pipette a certain volume of the mixture to the detection plate, and read with a microplate reader (BMG).

Data processing: compound inhibition rate (%)=(1-luminescence value of test group/luminescence value of solvent control group)*100. _IC50 values were calculated by fitting with GraphPad Prism software.

3. Results

Table 2. _IC50 of compounds of the invention for RORγ modulating activity

Example number IC₅₀(nM) 2 344.2

It can be seen from the above results that the compound of Example 2 has a significant inhibitory effect on RORγ.

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is incorporated by reference in its entirety.

Claims (15)

1. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (I):

X¹selected from the group consisting of CR⁵And N;

X²selected from the group consisting of CR⁶And N;

X³selected from the group consisting of CR⁷And N;

X⁴selected from the group consisting of CR⁸And N;

X⁵selected from the group consisting of CR⁹And N;

ring A is selected from C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_6-10Aryl and 5-10 membered heteroaryl;

R^aand R^bEach independently selected from hydrogen and C_1-6Alkyl radical, wherein said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano; or

R^aAnd R^bTogether with the carbon atom to which they are attached form C_3-6Cycloalkyl, wherein said C_3-6Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, C_1-6Alkyl and C_1-6Substituted with a haloalkyl;

R^cand R^dEach independently selected from hydrogen and C_1-6Alkyl radical, wherein said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano; or

R^cAnd R^dTogether with the carbon atom to which they are attached form C_3-6Cycloalkyl, wherein said C_3-6Cycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxy, cyano, C_1-6Alkyl and C_1-6Substituted with a haloalkyl;

R¹selected from-S (O)₂-C_1-6Alkyl, -S (O)₂-NH₂、-S(O)₂-NH-C_1-6Alkyl and-S (O)₂-N(C_1-6Alkyl radical)₂Wherein said alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and C_3-6Cycloalkyl substituents;

R²independently at each occurrence, selected from hydrogen, halogen, cyano, hydroxy, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl and C_1-6Alkoxy, wherein the alkyl and alkoxy are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano, and the cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_1-6Substituted with a halo alkoxy group;

R³selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, -N (R)¹¹)(R¹²) And C_1-6Substituent substitution of alkoxy;

R⁴selected from hydrogen and C_1-6Alkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and cyano;

R⁵selected from hydrogen, halogen, cyano and hydroxy;

R⁶、R⁷、R⁸、R⁹and R¹⁰Each occurrence is independently selected from hydrogen, halogen, cyano, hydroxy, C_1-6Alkyl and C_1-6Alkoxy, each of said alkyl and alkoxy being optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy andsubstituent substitution of cyano;

R¹¹and R¹²Each independently selected from hydrogen and C_1-6Alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano;

m is 0, 1,2 or 3; and is

n is 1,2,3 or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (II):

3. the compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:

R^aand R^bEach independently selected from hydrogen and C_1-6An alkyl group; or

R^aAnd R^bTogether with the carbon atom to which they are attached form C_3-6A cycloalkyl group;

R^cand R^dEach independently selected from hydrogen and C_1-6An alkyl group; or

R^cAnd R^dTogether with the carbon atom to which they are attached form C_3-6A cycloalkyl group;

R¹selected from-S (O)₂-C_1-6Alkyl, -S (O)₂-NH₂、-S(O)₂-NH-C_1-6Alkyl, -S (O)₂-N(C_1-6Alkyl radical)₂and-S (O)₂-C_1-6alkylene-C_3-6A cycloalkyl group;

R²independently at each occurrence, selected from hydrogen, haloElement, cyano group, hydroxy group, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_1-6Alkoxy and C_1-6A haloalkoxy group;

R³selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, -N (R)¹¹)(R¹²) And C_1-6Substituent substitution of alkoxy;

R⁴selected from hydrogen and C_1-6An alkyl group;

R⁵is selected from hydrogen and halogen, and

R⁶、R⁷、R⁸、R⁹and R¹⁰Each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy and C_1-6An alkoxy group;

R¹¹and R¹²Each independently selected from hydrogen and C_1-4Alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and cyano.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, wherein:

ring A is selected from C_3-6Cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl;

preferably, ring a is selected from phenyl, pyridyl, piperidinyl and cyclohexyl;

more preferably, ring a is phenyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein:

R¹selected from-S (O)₂-C_1-4Alkyl, -S (O)₂-NH₂、-S(O)₂-NH-C_1-4Alkyl, -S (O)₂-N(C_1-4Alkyl radical)₂and-S (O)₂-C_1-4alkylene-C_3-6A cycloalkyl group;

preferably, R¹Selected from-S (O)₂-CH₃、-S(O)₂-CH₂CH₃、-S(O)₂-NH₂、-S(O)₂-NH-CH₃、-S(O)₂-NH-CH₂CH₃、-S(O)₂-N(CH₃)₂、-S(O)₂-N(CH₂CH₃)₂And

more preferably, R¹Selected from-S (O)₂-CH₂CH₃、-S(O)₂-NH-CH₃、-S(O)₂-N(CH₃)₂And

even more preferably, R¹Selected from-S (O)₂-CH₂CH₃。

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein:

R²independently at each occurrence, selected from hydrogen, halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_1-4Alkoxy and C_1-4A haloalkoxy group;

preferably, R²Independently at each occurrence, is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, hydroxy, methyl, ethyl, isopropyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, difluoromethoxy, and trifluoromethoxy;

more preferably, R²Independently at each occurrence, is selected from hydrogen, fluoro, chloro, cyano, methyl, ethyl, -CF₃Cyclopropyl, methoxy, difluoromethoxy and trifluoromethoxy;

even more preferably, R²Independently at each occurrence, selected from fluoro, -CF₃And a methoxy group.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein:

R³selected from hydrogen, C_1-4Alkyl radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NH(C_1-4Haloalkyl), -N (C)_1-4Alkyl) (C_1-4Haloalkyl) and C_1-4Substituted by a substituent of alkoxy;

preferably, R³Selected from hydrogen, C_1-4Alkyl and C_3-6Cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, -NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、-NH(C_1-4Haloalkyl), -N (C)_1-4Alkyl) (C_1-4Haloalkyl) and C_1-4Substituted by a substituent of alkoxy;

more preferably, R³Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH₂CH₂F、-CH₂C(CH₃)₂F、-CH₂C(CH₃)₂-OH、-CH₂CH₂-O-CH₃、-CH₂C(CH₃)₂-CN、-CH₂-NH-CH₂CH₂F；

Even more preferably, R³Selected from hydrogen, -CH₂CH₂F。

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein:

R⁶、R⁷、R⁸、R⁹and R¹⁰Each independently at each occurrence is selected from the group consisting of hydrogen, halogen and C_1-4An alkoxy group;

preferably, R⁶、R⁷、R⁸、R⁹And R¹⁰Each occurrence is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methoxy, ethoxy, n-propoxy, and isopropoxy;

more preferably, R⁶、R⁷、R⁸、R⁹And R¹⁰Selected from hydrogen.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (III):

preferably, the compound has the structure of formula (IV):

more preferably, the compound has the structure of formula (V):

10. a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, wherein said compound is selected from:

11. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

12. Use of a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of claim 11, for the manufacture of a medicament for the prevention or treatment of a rory-mediated disease or disorder.

13. The use of claim 12, wherein:

the medicament is a medicament administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or transdermal route; and/or

The ROR γ -mediated disease or disorder is an inflammatory or autoimmune disease or disorder;

preferably, the inflammatory or autoimmune disease or disorder is selected from: psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis, asthma, osteoarthritis, crohn's disease, and kawasaki disease; or

The ROR γ -mediated disease or disorder is cancer;

preferably, the cancer is selected from: non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, oral cancer, brain cancer, stomach cancer, liver cancer, rectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, papillary carcinoma, head and neck tumor, leukemia, lymphoma, and myeloma.

14. The use of claim 12 or 13, wherein the medicament further comprises an additional anti-neoplastic agent or other medicament for treating or preventing an inflammatory or autoimmune disease or disorder.

15. A process for the preparation of a compound of formula (I) according to claim 1, comprising the steps of:

wherein, ring A, X¹、X²、X³、X⁴、X⁵、R¹、R²、R³、R⁴、R¹⁰、R^a、R^b、R^c、R^dM and n are as defined in claim 1;

(1) reacting compound IN-1 with compound IN-2 to give compound IN-3;

(2) oxidizing the compound IN-3 to obtain a compound IN-4;

(3) reacting compound IN-4 with compound IN-5 to obtain the compound of formula (I).