CN110724076A

CN110724076A - Para-aryl dicarboxamide compound, pharmaceutical composition containing same, preparation method and application thereof

Info

Publication number: CN110724076A
Application number: CN201810776287.5A
Authority: CN
Inventors: 刘春池; 刘金明; 蔡家强; 王利春; 王晶翼
Original assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Current assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Priority date: 2018-07-16
Filing date: 2018-07-16
Publication date: 2020-01-24
Anticipated expiration: 2038-07-16
Also published as: CN117024318A; CN110724076B

Description

Para-aryl dicarboxamide compound, pharmaceutical composition containing same, preparation method and application thereof

Technical Field

The present invention relates to para-aryldicarboxamides, pharmaceutical compositions comprising the same, processes for their preparation and their use for the prevention or treatment of diseases or disorders mediated by retinoic acid receptor-related orphan nuclear receptor gamma (ROR γ).

Background

Retinoic acid receptor-associated orphan nuclear receptors (RORs) include three subtypes, ROR α, ROR β and ROR γ, which play a regulatory role in a variety of physiological processes. Recent studies have found that ROR has a higher affinity for, and is regulated by, oxidized steroid derivatives than tretinoin. ROR is widely distributed in each tissue of an organism, can directly enter a cell nucleus to regulate the transcription of a target gene, further participate in different physiological processes, and show different tissue specificities. Among them, ROR α is expressed in various tissues, but is highly expressed in the brain, and plays an important role in cerebellar development and bone formation. ROR β has a small range of action, is mainly expressed in the brain, and plays a role in the development of the retina and cerebral cortex. ROR γ is expressed in many tissues, including thymus, liver and skeletal muscle, and plays a key role in secondary lymphoid tissue development.

ROR γ has two subtypes, ROR γ 1 and ROR γ 2(ROR γ t). ROR γ 1 is expressed in various tissues, while ROR γ 2 is a subtype specifically expressed on immune cells. ROR gamma 2 is a key transcription factor for the differentiation and maintenance of Th17 and Tc17 effector T cells, regulates Th17 cells to secrete effector IL-17 andother proinflammatory cytokines and have important implications in the differentiation of NK cells, γ δ T cells and inkt cells, as well as in autoimmune diseases and in body defense responses, which mediate the immune system against cancer cells and pathogenic microorganisms such as bacteria, fungi, etc. In the tumor microenvironment, Th17 cells and IL-17 can recruit natural killer cells and cytotoxic CD8⁺T cells attack and kill tumor cells. Some studies have shown that infiltration of Th17 cells and IL-17 expression levels at tumor sites in patients with ovarian cancer are positively correlated with good prognosis. Meanwhile, Th17 cells play a key role in many mouse autoimmune disease models, such as Experimental Allergic Encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. Elevated IL-17 levels are detectable in human autoimmune diseases including Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Psoriasis (Psoriasisis) and Inflammatory Bowel Disease (IBD). In addition, an increase in the number of Th17 cells was found in tissue and peripheral blood samples from patients with autoimmune diseases.

The treatment of cancer, despite the extensive research and extensive efforts, remains a significant threat to human health. Cancer is the most mortality disease, both in developed and developing countries, and morbidity and mortality continue to increase. However, therapeutic drugs against tumors are not effective in all tumor patients.

Aiming at the treatment of body immune system diseases, researchers find that the regulation of ROR gamma can effectively regulate the cell differentiation of Th17 and the generation and secretion level of IL-17 cytokines, thereby regulating the body immune system. Therefore, ROR γ can be a new target for the treatment of immune diseases.

Therefore, it would be of great interest to find small molecule modulators of ROR γ and to use them in the treatment of ROR γ mediated diseases or disorders. Currently, the development of ROR modulators has been gaining attention in the pharmaceutical industry, and published patent applications include WO2017157332a1, WO2016201225a1, WO2011115892a1, WO2017102784a1, WO2017024018a1, WO2015180614a1, and the like.

Disclosure of Invention

The present invention provides compounds useful as modulators of retinoic acid receptor-related orphan nuclear receptor gamma (ROR γ) having excellent properties such as good modulating activity on ROR γ, good physicochemical properties (e.g., solubility, physical and/or chemical stability), good pharmacokinetic properties (e.g., good bioavailability, suitable blood drug concentration, half-life and duration of action), good safety (less toxicity and/or less side effects, wider therapeutic window), and the like.

One aspect of the present invention provides 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 which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and 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.

Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, 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.

Another aspect of the present invention provides a use of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for the manufacture of a medicament for the prevention or treatment of a ROR γ -mediated disease or disorder.

Another 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, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of a ROR γ -mediated disease or disorder.

Another aspect of the present invention provides a method of preventing or treating a ROR γ -mediated disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

Another aspect of the invention provides a process for the preparation of the compounds of the invention.

Definition of

Unless defined otherwise 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. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those 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 "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

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, for example, halogen (when the group is referred to as "haloalkyl"), hydroxy (when the group is referred to as "alkylene-OH"), or cyano (when the group is referred to as "alkylene-CN"). In some embodiments, the alkyl group has 1 to 12 carbon atoms, e.g., 1 to 6 carbon atoms (C)_1-6Alkyl) or 1 to 4 carbon atoms (C)_1-4Alkyl groups). For example, as used herein, the term "C_1-6Alkyl "refers to a linear or branched group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl). The term "C_1-4Alkyl group meansA linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). The term "C_1-6Haloalkyl "means C substituted with 1 or more halogens_1-6Alkyl radicals, e.g. "C_1-4Haloalkyl ", more particularly, for example, -CH₂F、-CHF₂、-CF₃、-CCl₃、-C₂F₅、-C₂Cl₅、-CH₂CF₃、-CH₂Cl or-CH₂CH₂CF₃And the like. The term "C_1-6alkylene-OH "refers to C substituted by hydroxy_1-6Alkyl radicals, e.g. "C_1-4alkylene-OH ". The term "C_1-6alkylene-CN "means C substituted by cyano_1-6Alkyl radicals, e.g. "C_1-4alkylene-CN ".

As used herein, the term "alkoxy" refers to a group having the structure "alkyl-O-" (wherein alkyl is as defined above) which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example, halogen (in which case the group is referred to as "haloalkoxy"). As used herein, the term "C_1-6Alkoxy "means having" C_1-6alkyl-O- "structure (wherein C_1-6Alkyl is as defined above), e.g. C_1-4Alkoxy radical, C_1-2Alkoxy radical, C₁Alkoxy radical, C₂Alkoxy radical, C₃Alkoxy radical, C₄Alkoxy radical, C₅Alkoxy or C₆Alkoxy, preferably C_1-4An alkoxy group. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, hexyloxy, and the like.

The term "haloalkoxy" refers to an alkoxy group substituted with 1 or more halogens. As used herein, the term "C_1-6Haloalkoxy "means C substituted with 1 or more halogens_1-6Alkoxy radicals such as but not limited to-OCH₂F、-OCH₂Cl、-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 (e.g., 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 carbon atoms. For example, the term "C_3-6Cycloalkyl "refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) having 3 to 6 ring carbon atoms, which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example, 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 (e.g., one, two, three or four) selected from C (═ O), O, S, S (═ O), S (═ O)₂And NR^xWherein R is^xRepresents a hydrogen atom or C_1-6Alkyl or C_1-6A haloalkyl group; the heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, a 3-to 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, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

As herein describedAs 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 "C_6-10Aryl "means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)₂、C_1-6Alkyl, etc.).

As used herein, the term "aralkyl" preferably denotes an aryl substituted alkyl, wherein said aryl and said alkyl are as defined herein. Typically, the aryl group can have 6 to 10 carbon atoms and the alkyl group can have 1 to 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, and which ring members contain 1-4 (e.g., 1,2,3, or 4) heteroatoms selected from N, O and S, e.g., 5-membered heteroaryl, 6-membered heteroaryl, and the like. Specific examples thereof include, but are not limited to, furyl, 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-pyridonyl, 4-pyridonyl, 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-tetrazinyl, 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 (e.g., one, two, three, or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency at the present time is not exceeded and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted with …," the substituent may 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 replaced individually and/or together with an independently selected optional substituent. If the 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 any hydrogen is present) may each be replaced with an independently selected optional substituent.

If a substituent is 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.

As used herein, unless otherwise indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

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

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (g), (b), (c), (d), (²H) Tritium (a)³H) ); isotopes of carbon (e.g. of¹¹C、¹³C and¹⁴C) (ii) a Isotopes of chlorine (e.g. of chlorine)³⁶Cl); isotopes of fluorine (e.g. of fluorine)¹⁸F) (ii) a Isotopes of iodine (e.g. of iodine)¹²³I and¹²⁵I) (ii) a Isotopes of nitrogen (e.g. of¹³N and¹⁵n); isotopes of oxygen(e.g. in¹⁵O、¹⁷O and¹⁸o); isotopes of phosphorus (e.g. of phosphorus)³²P); and isotopes of sulfur (e.g. of³⁵S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in drug and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) Are particularly useful for this purpose because of their ease of incorporation and ease of detection. Using positron-emitting isotopes (e.g. of the type¹¹C、¹⁸F、¹⁵O and¹³n) can be used to examine substrate receptor occupancy in Positron Emission Tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent employed previously. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D₂O, acetone-d₆Or DMSO-d₆。

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

Solid line (-), solid wedge shape (may be used herein) (i.e.)

) Or virtual wedge shape (

) Chemical bonds of the compounds of the present invention are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown are present. When present in a racemic mixture, solid and dotted wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

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

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other components comprising the formulation and/or the mammal being treated therewith.

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 salts, arginine salts, choline salts, magnesium salts, 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 invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, since the available lone pair is required for oxidation of the nitrogen to the oxide; one skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-750; a.r.katitzky and a.j.boulton, eds., Academic Press; and G.W.H.Cheeseman and E.S.G.Werstuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite 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 which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (t.higuchi and v.stella). Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. 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 of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved 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. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

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

Compound and preparation method thereof

A first aspect of the invention provides 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;

R^cAnd R^dIn conjunction withThe carbon atoms to which they are attached together 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;

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, said alkyl and alkoxyEach 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.

In some embodiments, the present invention provides a compound as described above, 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 (II):

in some embodiments, the present invention provides a compound as described above, 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, halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_1-6Alkoxy and C_1-6A haloalkoxy group;

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.

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: ring A is selected from C_3-6Cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl. In a preferred embodiment, ring a is selected from phenyl, pyridyl, piperidinyl and cyclohexyl. In a more preferred embodiment, ring a is phenyl.

In some embodiments, the present invention provides a compound as described above, 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. In a preferred embodiment, 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

in a more preferred embodiment, R¹Selected from-S (O)₂-CH₂CH₃、-S(O)₂-NH-CH₃、-S(O)₂-N(CH₃)₂And

in an even more preferred embodiment, R¹Selected 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, 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. In a preferred embodiment, 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. In a more preferred embodiment, R²Independently at each occurrence, is selected from hydrogenFluoro, chloro, cyano, methyl, ethyl, -CF₃Cyclopropyl, methoxy, difluoromethoxy and trifluoromethoxy. In an even more preferred embodiment, R²Independently at each occurrence, selected from fluoro, -CF₃And a methoxy group.

In some embodiments, the present invention provides a compound as described above, 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. In a preferred embodiment, 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. In a more preferred embodiment, 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. In an even more preferred embodiment, R³Selected from hydrogen, -CH₂CH₂F。

In some embodiments, the present invention provides a compound as described above, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereofA variant, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, 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. In a preferred embodiment, 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. In a more preferred embodiment, R⁶、R⁷、R⁸、R⁹And R¹⁰Selected 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, isotopically labeled compound, metabolite, or prodrug thereof, 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, isotopically labeled compound, metabolite or prodrug thereof, wherein said compound is selected from the group consisting of:

the compounds of the invention are ROR γ modulators. In some embodiments, the compounds of the invention are ROR γ agonists. In other embodiments, the compounds of the present invention are ROR γ inhibitors.

A second aspect of the invention provides a process for the preparation of a compound of formula (I), said process 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 above;

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

the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of 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, benzotriazole-1-yl-oxy tripyrrolidinyl phosphorus hexafluorophosphate, and preferably 2- (7-benzotriazole oxide) -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 and diisopropylethylamine, and preferably is diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably from 20 to 50 c, in particular room temperature. The reaction is preferably carried out for a suitable time, preferably 2 to 8 hours, for example 3,4, 5, 6 or 7 hours.

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

the oxidation reaction is preferably carried out in a suitable solvent. The solvent may be selected from the group consisting of 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 and potassium permanganate, and potassium permanganate is preferred. The reaction is preferably carried out at a suitable temperature, preferably from 20 to 50 c, in particular room temperature. The reaction is preferably carried out for a suitable time, preferably 2 to 5 hours, for example 3 or 4 hours.

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

Pharmaceutical compositions and methods of treatment

A third aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, 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.

A fourth aspect of the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a ROR γ -mediated disease or disorder. In a preferred embodiment, the medicament is a medicament administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.

A fifth aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a ROR γ -mediated disease or disorder.

A sixth aspect of the present invention provides a method for preventing or treating a ROR γ -mediated disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

In a preferred embodiment, the rory 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's disease.

In a preferred embodiment, the rory mediated disease or disorder is cancer. In a more preferred embodiment, 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. In preferred embodiments, the medicament further comprises an additional anti-neoplastic agent or other agent for treating or preventing an inflammatory or autoimmune disease or disorder.

By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be employed 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 and the like. 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, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, 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 (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations 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 an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.

The dosing regimen may be adjusted to provide the best 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 being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject 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. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

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

As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Detailed Description

In order to make the objects and technical solutions of the present invention clearer, the present invention is further illustrated below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, specific experimental methods not mentioned in the following examples were carried out according to the usual experimental methods.

The abbreviations herein have the following meanings:

the structures of the compounds described in the following examples were measured by nuclear magnetic resonance spectroscopy (¹H-NMR) or Mass Spectrometry (MS).

¹The H-NMR analyzer is Bruker 400MHz NMR spectrometer, and the solvent is deuterated methanol (CD)₃OD), deuterated chloroform (CDCl)₃) Or hexadeutero dimethyl sulfoxide (DMSO-d)₆) Internal standard is Tetramethylsilane (TMS). Chemical shifts (δ) are given in parts per million (ppm).

The Mass Spectrometer (MS) was an Agilent (ESI) mass spectrometer model Agilent 6120B.

Thin Layer Chromatography (TLC) was carried out using an aluminum plate (20X 20cm) from Merck, and thin layer preparative chromatography was carried out using a GF254(0.4 to 0.5mm) silica gel plate.

The reaction was monitored by Thin Layer Chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS) using a developing reagent system including dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems. The developer system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine or the like).

Use of microwave reaction

Initiator + (400W, RT-300 ℃) microwave reactor.

The column chromatography generally uses 200-300 mesh silica gel as a stationary phase. The system of eluent comprises a dichloromethane and methanol system and a petroleum ether and ethyl acetate system. The eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine or the like)

The instrument model used for preparing the high performance liquid chromatography is as follows: agilent 1260, column: waters XBridgePrep C₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; 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 solution.

Unless otherwise stated, 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 Teber Chemical science and technology, Inc., and the like.

Examples

Preparation of intermediates

Intermediate preparation example 1: preparation of 4- ((4- (ethylsulfonyl) benzyl) carbamoyl) benzoic acid

The first step is as follows: preparation of 4- ((4- (ethylsulfonyl) benzyl) carbamoyl) benzaldehyde

4-formylbenzoic acid (1.0g,6.7mmol), HATU (3.8g,10.0mmol) and DIPEA (2.6g,20.0mmol) were dissolved in tetrahydrofuran (20mL), and after stirring at room temperature for 0.5 hour, 4-ethylsulfonylbenzylamine (1.3g,6.7mmol) was added, reacted at room temperature for 4 hours, appropriate water was added, ethyl acetate was extracted 3 times, the organic phase was combined and washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (1.7g, yield: 77%).

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

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

Intermediate preparation example 2: preparation of N- (4-chloro-2-trifluoromethylbenzyl) -2-fluoroethylamine

4-chloro-2-trifluoromethylbenzylamine (100.0mg,0.5mmol), 1-bromo-2-fluoroethane (78.7mg,0.6mmol) and potassium carbonate (138.2mg,1.0mmol) were dissolved in acetonitrile (5mL), heated to 80 ℃ for reaction for 4 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 ═ 4:1(v: v)) to give the title compound (40.0mg, yield: 30%).

Intermediate preparation example 3: preparation of N- (2-fluorobenzyl) -2-fluoroethylamine

2-fluorobenzylamine (200.0mg,1.6mmol), 1-bromo-2-fluoroethane (608.7mg,4.8mmol) and potassium carbonate (883.5mg,6.4mmol) were dissolved in acetonitrile (10mL), heated to 80 ℃ 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 give the title compound (180.0mg, yield: 66%).

Intermediate preparation example 4: preparation of N- (3-fluorobenzyl) -2-fluoroethylamine

3-fluorobenzylamine (200.0mg,1.6mmol), 1-bromo-2-fluoroethane (608.7mg,4.8mmol) and potassium carbonate (883.5mg,6.4mmol) were dissolved in acetonitrile (10mL), heated to 80 ℃ 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 give the title compound (190.0mg, yield: 69%).

Intermediate preparation example 5: preparation of N- (4-fluorobenzyl) -2-fluoroethylamine

4-fluorobenzylamine (200.0mg,1.6mmol), 1-bromo-2-fluoroethane (608.7mg,4.8mmol) and potassium carbonate (883.5mg,6.4mmol) were dissolved in acetonitrile (10mL), heated to 80 ℃ 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 give the title compound (150.0mg, yield: 55%).

Intermediate preparation example 6: preparation of N- (4-methoxybenzyl) -2-fluoroethylamine

4-methoxybenzylamine (219.2mg,1.6mmol), 1-bromo-2-fluoroethane (608.7mg,4.8mmol) and potassium carbonate (883.5mg,6.4mmol) were dissolved in acetonitrile (10mL), heated to 80 ℃ 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 give the title compound (153.0mg, yield: 51%).

Example 1: n is a radical of¹- (4-chloro-2-trifluoromethylbenzyl) -N⁴Preparation of (4- (ethylsulfonyl) benzyl) terephthalamide

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

MS m/z(ESI):539.1[M+H]⁺。

¹H-NMR(400MHz,CDCl₃)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＝8.0Hz,2H),1.20(t,J＝8.0Hz,3H)。

Example 2: n is a radical of¹- (4-chloro-2-trifluoromethylbenzyl) -N⁴- (4- (ethylsulfonyl) benzyl) -N¹Preparation of (2-fluoroethyl) terephthalamide

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

MS m/z(ESI):585.1[M+H]⁺。

¹H-NMR(400MHz,CDCl₃)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: n is a radical of¹- (4- (ethylsulfonyl) benzyl) -N⁴- (2-fluorobenzyl) -N⁴Preparation of (2-fluoroethyl) terephthalamide

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

MS m/z(ESI):501.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃)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＝8.0Hz,2H),1.31(t,J＝8.0Hz,3H)。

Example 4: n is a radical of¹- (4- (ethylsulfonyl) benzyl) -N⁴- (3-fluorobenzyl) -N⁴Preparation of (2-fluoroethyl) -terephthalamide

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

MS m/z(ESI):501.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃)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＝8.0Hz,2H),1.20(t,J＝8.0Hz,3H)。

Example 5: n is a radical of¹- (4- (ethylsulfonyl) benzyl) -N⁴- (4-fluorobenzyl) -N⁴Preparation of (2-fluoroethyl) -terephthalamide

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

MS m/z(ESI):501.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃)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＝8.0Hz,2H),1.19(t,J＝8.0Hz,3H)。

Example 6: n is a radical of¹- (4- (ethylsulfonyl) benzyl) -N⁴- (2-fluoroethyl) -N⁴Preparation of (4-methoxybenzyl) -terephthalamide

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

MS m/z(ESI):513.2[M+H]⁺。

¹H-NMR(400MHz,CDCl₃)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＝8.0Hz,2H),1.31(t,J＝8.0Hz,3H)。

Biological evaluation

Experimental example 1 ROR γ -LBD TR-FRET experiment

Reaction buffer (25mM HEPES, pH 7.0, 100mM NaCl, 0.01% Tween 20, 0.2% BSA, 5mM DTT) was prepared. A solution A1 containing 1nM of LANCE Eu-anti-6 XHis antibody (PerkinElmer), a solution A2 containing 1 nMALCE Eu-anti-6 XHis antibody (PerkinElmer) and 15nM ROR γ -LBD (HDB), and a solution B containing 200nM biotin-1 (PerkinElmer) and 15nM allophycy-streptovidin (PerkinElmer) were prepared in buffer, all on ice for use.

Diluting a compound to be tested (starting from 5 mu M, diluting by 4 times and setting 10 concentration points) by DMSO, transferring the diluted compound to be tested to a 384-pore plate, and setting a plurality of pores; DMSO was transferred to solvent control wells and negative control wells. Mu.l of solution A1 was added to the negative control wells, and 15. mu.l of solution A2 was added to the solvent control wells and the test compound wells. Add 10. mu.l of solution B to each well, seal the plate with sealing tape, shake for 2 minutes to mix the reaction solution. The 384 well plates were placed at 4 ℃ overnight. On day 2, the 384 well plates were removed to room temperature for 1 hour and centrifuged for 1 minute. And reading the plate by a microplate reader (detection wavelength is 665nm/615 nm).

Data processing: compound inhibition (%) (FI compound-FI solvent control)/(FI solvent control-FI negative control) × 100. FI represents the fluorescence value read by the microplate reader. IC calculation by GraphPad Prism software₅₀The value is obtained. The results are shown in Table 1.

TABLE 1 IC of compounds of the invention for ROR gamma modulating activity₅₀

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

As can be seen from the above results, each example compound had a significant inhibitory effect on ROR γ.

Experimental example 2 GAL4-ROR gamma luciferase reporter Gene experiment

1. Experimental Material

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

2. Experimental methods

When 293T cells grow to about 80% confluence, plasmid liposome complex is prepared according to Lipofectamine 3000 specification, and culture medium is added. After 24 hours of cell transfection, the cells were spread evenly in a 96-well plate, the test compound was added, and the plate was incubated at 37 ℃ with 5% CO₂Incubate in incubator for 24 hours. The plate was removed on day 2, Bright-glo (promega) was added, shaken for 5 minutes, and a volume of the mixture was transferred to the detection plate and read with a microplate reader (BMG).

Data processing: compound inhibition (%) (1-test group luminescence/solvent control group luminescence) 100. IC was calculated by GraphPad Prism software fitting₅₀The value is obtained.

3. Results

TABLE 2 IC of compounds of the invention for ROR gamma modulating activity₅₀

Example numbering	IC₅₀(nM)
		2	344.2

As can be seen from the above results, the compound of example 2 has a significant inhibitory effect on ROR γ.

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, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

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;

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;

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

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;

R⁴selected from hydrogen and C_1-6An alkyl group;

R⁵is selected from hydrogen and halogen, and

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;