CN117229215A

CN117229215A - Biaryl compound, pharmaceutical composition containing biaryl compound, preparation method and application of biaryl compound

Info

Publication number: CN117229215A
Application number: CN202311202216.1A
Authority: CN
Inventors: 刘金明; 唐建川; 任云; 田强; 宋宏梅; 薛彤彤; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2019-09-10
Filing date: 2020-08-31
Publication date: 2023-12-15
Also published as: WO2021047407A1; CN114096525B; CN114096525A

Abstract

The application belongs to the field of pharmaceutical chemistry, and relates to biaryl compounds, a pharmaceutical composition containing the biaryl compounds, a preparation method and application thereof. Specifically, the application provides a compound with a structure shown in a formula I, which has remarkable ROR gamma regulation effect, can be used as a high-efficiency ROR gamma regulator, and has various pharmacological activities such as anti-tumor, anti-autoimmune disease, anti-inflammatory and the like.

Description

Biaryl compound, pharmaceutical composition containing biaryl compound, preparation method and application of biaryl compound

The application relates to a biaryl compound, a pharmaceutical composition containing the biaryl compound, a preparation method and application thereof, which are classified as application nos. 202080050297.6, 2020, 08 and 31.

Technical Field

The application belongs to the field of pharmaceutical chemistry, and relates to a novel compound with ROR gamma regulation activity, a preparation method thereof, a pharmaceutical composition containing the compound and medical application thereof.

Background

The nuclear receptor superfamily is a class of ligand-dependent transcription factors that have a total of 48 family members (ZHANG Y, LUO X Y, WU D H, et al ROR nuclear receptors: structures, related diseases, and drug discovery [ J ], acta Pharmacologica Sinica,2015,36 (1): 71-87). Depending on the ligand type of nuclear receptor, 48 superfamily members can be divided into: steroid hormone receptors, non-steroid hormone receptors, and orphan receptors. Among them, steroid hormone receptors include glucocorticoid receptor (glucocorticoid receptor, GR), mineralocorticoid receptor (mineralcorticoid receptor, MR), androgen receptor (androgen receptor, AR), estrogen Receptor (ER), progestin receptor (progestogen receptor, PR), and the like; non-steroid hormone receptors include thyroid hormone receptor (thyroid hormone receptor, TR), retinoic acid receptor (or tretinoin receptor, retinoic acid receptor) (retinoic acid receptor, RAR), retinoic acid X receptor (retinoid X receptor, RXR), and Vitamin D3 Receptor (VDR), etc.; orphan receptors are named because they have not yet found their endogenous ligands. Orphan receptor family members include retinoic acid receptor-related orphan receptors (retinoic acid receptor-related orphan receptor, ROR), farnesol X receptor (farnesoid X receptor, FXR), peroxisome proliferator-activated receptor (peroxisome proliferator activated receptor, PPAR), liver X Receptor (LXR), and the like.

Members of the ROR superfamily, which include three subtypes ROR alpha, ROR beta and ROR gamma, play a regulatory role in a variety of physiological processes. Recent studies have found that members of the ROR family have a higher affinity for, and are regulated by, oxidized steroid derivatives than retinoic acid. ROR is widely distributed in various tissues of an organism, can directly enter cell nuclei to regulate transcription of target genes, and further participates in different physiological processes, and shows different tissue specificities. Among them, rorα is expressed in various tissues, but is highly expressed in the brain, and plays an important role in cerebellum development and bone formation. The ROR beta has a smaller action range, is mainly expressed in the brain, and plays a role in the development of retina and cerebral cortex. Rory can be expressed in a number of tissues including thymus, liver and skeletal muscle, and plays a key role in the development of secondary lymphoid tissues.

Rory has two subtypes rory 1 and rory 2 (rory t). Rorγ1 is expressed in a variety of tissues, while rorγ2 is specifically expressed on immune cells. Rorγ2 is a key transcription factor for differentiation and maintenance of Th17 and Tc17 effector T cells, regulates secretion of effector IL-17 by Th17 cells, and plays an important role in differentiation of NK cells, γδ T cells, and iNKT cells, which mediate the immune system against cancer cells and pathogenic microorganisms such as bacteria, fungi, etc. In the tumor microenvironment, thl7 cells and IL-17 recruit natural killer cells and cytotoxic cd8+ T cells to attack and kill tumor cells. Several studies have shown that tumor site infiltration Thl7 cell levels and IL-17 expression levels in ovarian cancer patients are positively correlated with good prognosis.

The treatment of cancer, despite extensive research and efforts, remains a major threat to human health. Cancer is the highest mortality disease in both developed and developing countries, and morbidity and mortality continue to increase. Currently, therapeutic drugs against tumors are not effective for all tumor patients, and the development of rorγ modulators has been increasingly emphasized in the pharmaceutical industry, for example, WO2017157332A1, WO2011115892A1, and the like. Therefore, research and development of compounds with high rory modulating activity, few side effects, strong resistance, improved pharmacokinetic properties, etc. may be beneficial for the treatment of tumors, providing more options for the treatment of tumor patients.

Disclosure of Invention

Problems to be solved by the invention

The present invention aims to provide a novel compound having a modulating effect on rory activity, a process for preparing the compound, a pharmaceutical composition comprising the compound, and a medical use of the compound.

Solution for solving the problem

In a first aspect, the present invention provides a compound having the structure of formula I or a pharmaceutically acceptable form thereof,

Wherein,

ring A ¹ Selected from phenyl and 5-6 membered heteroaryl;

ring A ² Selected from phenyl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl;

ring A ³ Selected from phenyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 4-10 membered heterocyclyl;

Z ¹ 、Z ² and Z ³ Each independently selected from CR ⁴ And N;

R ¹ selected from hydrogen and C _1-6 An alkyl group;

each R is ² Each independently selected from halogen, cyano, hydroxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and C _3-6 A cycloalkoxy group;

each R is ³ Each independently selected from halogen, cyano, hydroxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and-S (=o) ₂ -R ⁶ ；

Each R is ⁴ Each independently selected from hydrogen, halogen, cyano, C _1-6 Alkyl and C _1-6 An alkoxy group;

each R is ⁵ Each independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, -C _0-6 alkylene-O-R ^a 、-O-C _1-6 alkylene-O-R ^a 、C _1-6 Haloalkoxy, -C _0-6 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-6 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-C(＝O)-C _1-6 Alkyl, -C _0-6 alkylene-S (=o) ₂ -R ⁶ 、-C _0-6 alkylene-N (R) ^a )(R ^b )、-C _0-6 alkylene-C (=O) -N (R) ^a )(R ^b )、-C _0-6 alkylene-N (R) ^a )-C(＝O)-R ⁶ 、-C _0-6 alkylene-S (=o) ₂ -N(R ^a )(R ^b )、-C _0-6 alkylene-N (R) ^a )-S(＝O) ₂ -R ⁶ 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl; wherein: each R is ^a Each independently selected from hydrogen and C _1-6 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-6 An alkyl group;or R is ^a And R is ^b Forming a 3-7 membered heterocyclic group together with the nitrogen atom to which it is attached;

each R is ⁶ Each independently selected from C _1-6 Alkyl and C _3-6 Cycloalkyl;

m is 1, 2 or 3;

n is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

the pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites and prodrugs.

In a second aspect, the present invention provides a specific compound having the structure of formula I, comprising:

(1) 2- (3- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -1H-pyrazol-1-yl) acetic acid;

(2) N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (2-methoxyethyl) -1H-pyrazol-3-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(3) 2- (3- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide;

(4) N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1-isopropyl-1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(5) N- (3 '- (difluoromethoxy) -4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(6) N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(7) (S) -N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(8) (R) -N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(9) N- (3 '- (difluoromethoxy) -4- (1-ethyl-1H-pyrazol-4-yl) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(10) 2- (4- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -5, 6-dihydropyridin-1 (2H) -yl) acetic acid;

(11) N- (3 '- (difluoromethoxy) -5' -fluoro-4- (thiazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(12) N- (4- (4- (cyclopropyloxy) piperazin-1-yl) -3'- (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(13) 4- (4- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperazin-1-yl) -4-oxobutanoic acid;

(14) 1- (4- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperazine-1-carbonyl) cyclopropanecarboxylic acid;

(15) N- (3 '- (difluoromethoxy) -5' -fluoro-4-morpholinylbiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(16) 1- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidine-4-carboxylic acid methyl ester;

(17) 1- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidine-4-carboxylic acid;

(18) 2- (1- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid;

(19) N- (3 '- (difluoromethoxy) -5' -fluoro-4- (4-hydroxy-4-methylpiperidin-1-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(20) N- (3 '- (difluoromethoxy) -5' -fluoro-4- (4- (methylsulfonyl) piperidin-1-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(21) N- (3 '- (difluoromethoxy) -5' -fluoro-4- (4- (2-methoxyethoxy) piperidin-1-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide;

(22) 2- (1- (3 '-chloro-5' -methoxy-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid;

(23) 2- (1- (3 '-fluoro-5' -methoxy-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid;

(24) 2- (1- (3 '-methoxy-5' -methyl-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid;

(25) 2- (1- (3 '-chloro-5' - (difluoromethoxy) -3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid;

(26) 2- (1- (3 '-chloro-5' -ethoxy-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid;

(27) 2- (1- (3 '-chloro-5' - (trifluoromethoxy) -3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid.

In a third aspect, the present invention provides a method for preparing the above compound having the structure of formula I, comprising the steps of:

(1) Reacting the compound A with the compound B to obtain a compound C;

(2) Carrying out substitution reaction on the compound C to obtain a compound D;

(3) The compound D undergoes a reduction reaction and an optional N-alkylation reaction to obtain a compound E;

(4) Reacting the compound E with a compound F to obtain a compound G;

(5) Reacting a compound G with a compound H to obtain a compound shown in a formula I;

wherein ring A ¹ Ring A ² Ring A ³ 、Z ¹ 、Z ² 、Z ³ 、R ¹ 、R ² 、R ³ 、R ⁵ M, n and q are as defined in formula I; x represents a leaving group including, but not limited to, a halogen atom, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group;

Or comprises the following steps:

(1 ') reacting compound A' with compound B 'to obtain compound C';

(2 ') reducing the compound C ' and optionally N-alkylating to obtain a compound D ';

(3 ') reacting the compound D ' with the compound F to obtain a compound F ';

(4 ') reacting compound F' with compound B to give a compound of formula I;

wherein ring A ¹ Ring A ² Ring A ³ 、Z ¹ 、Z ² 、Z ³ 、R ¹ 、R ² 、R ³ 、R ⁵ M, n and q are as defined in formula I; x represents a leaving group including, but not limited to, a halogen atom, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group; hal represents a halogen atom including, but not limited to, F, cl, br and I, preferably F and Cl.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound having the structure of formula I, or a pharmaceutically acceptable form thereof, as described above, and a pharmaceutically acceptable carrier.

In a fifth aspect, the present invention provides a compound having the structure of formula I as described above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above, for use as a rory modulator.

In a sixth aspect, the present invention provides the use of a compound having the structure of formula I as described above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above, as a rory modulator. Preferably, the rory modulators are used for the prevention and/or treatment of diseases mediated at least in part by rory.

In a seventh aspect, the present application provides the use of a compound having the structure of formula I as described above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by rorγ. Preferably, the disease mediated at least in part by rorγ is selected from cancer, inflammation and autoimmune diseases.

In an eighth aspect, the present application provides a method for preventing and/or treating a disease mediated at least in part by rorγ, comprising the steps of: a therapeutically effective amount of a compound having the structure of formula I as described above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above, is administered to a patient in need thereof.

In a ninth aspect, the present application provides a pharmaceutical combination composition comprising a compound having the structure of formula I or a pharmaceutically acceptable form thereof as described above or a pharmaceutical composition as described above, together with at least one other co-directional rory modulator.

In a tenth aspect, the present application provides a method for preventing and/or treating cancer, comprising the steps of: a therapeutically effective amount of a compound having the structure of formula I as described above or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above or a pharmaceutical combination composition as described above, and as a rory agonist, is administered to a patient in need thereof.

In an eleventh aspect, the present invention provides a method for preventing and/or treating inflammation, comprising the steps of: a therapeutically effective amount of a compound having the structure of formula I as described above or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above or a pharmaceutical combination composition as described above, and as a rory antagonist, is administered to a patient in need thereof.

In a twelfth aspect, the present invention provides a method for preventing and/or treating autoimmune diseases, comprising the steps of: a therapeutically effective amount of a compound having the structure of formula I as described above or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above or a pharmaceutical combination composition as described above, and as a rory antagonist, is administered to a patient in need thereof.

ADVANTAGEOUS EFFECTS OF INVENTION

The invention provides a compound of a formula I with a novel structure, which can be used as an efficient ROR gamma regulator, has various pharmacological activities such as anti-tumor, anti-autoimmune disease, anti-inflammatory and the like, has few side effects, strong drug resistance, and effectively improves the properties such as pharmacokinetics and the like. The synthesis method is mild, the operation is simple and easy, and the method is suitable for industrial mass production.

Detailed Description

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[ definition of terms ]

Unless otherwise indicated, the following terms have the following meanings in the present invention.

The terms "comprising," "including," "having," or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to only those elements explicitly listed, but may also include other elements not explicitly listed or inherent to such composition, method, or apparatus.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention that is substantially non-toxic to an organism. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed from the compounds of the present invention by reaction with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases, such salts also being referred to as acid addition salts or base addition salts.

The term "isomer" refers to a compound that has the same molecular weight due to the same number and type of atoms, but differs in the spatial arrangement or configuration of the atoms.

The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular plane of asymmetry due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby enabling rotation of plane polarized light. The present invention also includes stereoisomers and mixtures thereof, due to the presence of asymmetric centers and other chemical structures which may lead to stereoisomers. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, mixtures of enantiomers and diastereomers. In general, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity. Gtoreq.98%,. Gtoreq.95%,. Gtoreq.93%,. Gtoreq.90%,. Gtoreq.88%,. Gtoreq.85% or. Gtoreq.80%). As described below, individual stereoisomers of the compounds are prepared synthetically from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds having specific stereochemistry are either commercially available or prepared according to the methods described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-overlapping mirror images of each other. The term "diastereoisomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal portions of individual enantiomers. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerisation, imine-enamine isomerisation, amide-imine alcohol isomerisation, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "cis-trans isomer" refers to stereoisomers formed by atoms (or groups) located on either side of a double bond or ring system due to different positions relative to a reference plane; in the cis isomer the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer the atoms (or groups) are on the opposite side of the double bond or ring system. All cis and trans isomeric forms of the compounds of the present invention are within the scope of the present invention unless otherwise indicated.

The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. The polymorphs of a molecule can be obtained by a number of known methods by a person skilled in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, gas phase diffusion, and sublimation. In addition, polymorphs can be detected, classified and identified using well known techniques including, but not limited to, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid state Nuclear Magnetic Resonance (NMR), infrared spectroscopy (IR), raman spectroscopy, scanning Electron Microscopy (SEM), and the like.

The term "solvate" refers to a substance formed by the association of a compound of the invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule by non-covalent intermolecular forces.

The term "N-oxide" refers to compounds formed by oxidation of a nitrogen atom in the structure of tertiary amines or nitrogen-containing (aromatic) heterocycles. Common N-oxides include, but are not limited to, trimethylamine-N-oxide, 4-methylmorpholine-N-oxide, pyridine-N-oxide, and the like. The 1a position in the parent nucleus of the compound of the formula I is tertiary amine nitrogen atom, and corresponding N-oxide can be formed; in addition, when the group directly attached to the nitrogen atom at the 3-position in the parent nucleus is not a (sulfonyl) group, the 3-position is also a tertiary amine nitrogen atom, and the corresponding N-oxide can be formed as well.

The term "isotopic label" refers to a derivative compound from which a specific atom in a compound of the present invention is replaced by its isotopic atom. Unless otherwise indicated, the compounds of the invention include various isotopes of H, C, N, O, F, P, S, cl, e.g ² H(D)、 ³ H(T)、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ S and ³⁷ Cl。

the term "metabolite" refers to a derivative compound of the present invention which is formed after metabolism. For further information on metabolism see Goodman and Gilman's The Pharmacological Basis of Therapeutics (9 ^th ed.)[M],McGraw-Hill International Editions,1996。

The term "prodrug" refers to a derivative compound that is capable of providing a compound of the invention directly or indirectly after administration to a patient. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a patient, may increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood) or promote delivery of the parent compound to the site of action (e.g., the lymphatic system). All prodrug forms of the compounds of the invention are within the scope of the invention unless otherwise indicated, and the various prodrug forms are well known in the art.

The term "independently" means that at least two groups (or ring systems) present in the structure that are the same or similar in value range may have the same or different meanings in the particular case. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, then when substituent X is hydrogen, substituent Y may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

The term "alkyl" refers to a monovalent straight or branched chain alkane group consisting of carbon and hydrogen atoms, free of unsaturation, and linked to other groups by a single bond, e.g., C _1-6 Alkyl means alkyl having 1 to 6 carbon atoms, C _1-4 Alkyl refers to alkyl groups containing 1 to 4 carbon atoms; common alkyl groups include, but are not limited to, methyl (-CH) ₃ ) Ethyl (-CH) ₂ CH ₃ ) N-propyl (-CH) ₂ CH ₂ CH ₃ ) Isopropyl (-CH (CH) ₃ ) ₂ ) N-butyl (-CH) ₂ CH ₂ CH ₂ CH ₃ ) Sec-butyl (-CH (CH) ₃ )CH ₂ CH ₃ ) Isobutyl (-CH) ₂ CH(CH ₃ ) ₂ ) Tert-butyl (-C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) Neopentyl (-CH) ₂ C(CH ₃ ) ₃ ) Etc.

The term "alkylene" refers to a divalent straight or branched chainAn alkane group consisting of carbon and hydrogen atoms, free of unsaturation, and attached to one group by one single bond and to the other group (or ring system) by another single bond, "C" as used herein _0-6 Alkylene "means an alkylene group containing 0 to 6 carbon atoms, 0 carbon atom alkylene representing a covalent bond, e.g. C _1-6 Alkylene means alkylene having 1 to 6 carbon atoms, C _1-4 Alkylene refers to an alkylene group containing 1 to 4 carbon atoms; common alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1, 2-ethylene (-CH) ₂ CH ₂ (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1-methyl-1, 2-ethylene (-CH (CH) ₃ )CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), 1-methyl-1, 3-propylene (-CH (CH) ₃ )CH ₂ CH ₂ (-), 1-dimethyl-1, 2-ethylene (-C (CH) ₃ ) ₂ CH ₂ (-), 1, 2-dimethyl-1, 2-ethylene (-CH (CH) ₃ )CH(CH ₃ ) (-), etc.

The term "haloalkyl" refers to a monovalent straight or branched alkyl group substituted with at least one atom selected from fluorine, chlorine, bromine and iodine, free of unsaturation, and linked to other groups by a single bond, such as C _1-6 Haloalkyl means C substituted with at least one atom selected from fluorine, chlorine, bromine and iodine _1-6 Alkyl, C _1-4 Haloalkyl means C substituted with at least one atom selected from fluorine, chlorine, bromine and iodine _1-4 An alkyl group; common haloalkyl groups include, but are not limited to, fluoromethyl (-CH) ₂ F) Difluoromethyl (-CHF) ₂ ) Trifluoromethyl (-CF) ₃ ) 1-fluoroethyl (-CHFCH) ₃ ) 2-fluoroethyl (-CH) ₂ CH ₂ F) 1, 2-difluoroethyl (-CHFCH) ₂ F) 2, 2-difluoroethyl (-CH) ₂ CHF ₂ ) 1, 2-trifluoroethyl (-CHFCHF) ₂ ) 2, 2-trifluoroethyl group (-CH) ₂ CF ₃ ) Etc.

The term "cycloalkyl" refers to a monovalent, monocyclic or polycyclic (including bridged and spiro forms) non-aromatic cyclic hydrocarbon group consisting of only carbon and hydrogen atoms, and is notContaining unsaturation and being bound to other groups by a single bond, e.g. C _3-10 Cycloalkyl means cycloalkyl having 3 to 10 carbon atoms, C _3-6 Cycloalkyl refers to cycloalkyl groups containing 3 to 6 carbon atoms; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin (also known as decalin, decalin), adamantyl, and the like. Other suitable cycloalkyl groups include, but are not limited to, spiro-pentyl, bicyclo [2.1.0 ]]Amyl, bicyclo [3.1.0 ]]Hexyl, spiro [2.4 ]]Heptyl, spiro [2.5 ]]Octyl, bicyclo [5.1.0]Octyl, spiro [2.6 ]]Nonyl, bicyclo [2.2.0]Hexyl, spiro [3.3 ]]Heptyl, bicyclo [4.2.0]Octyl, and spiro [3.5 ]]And (3) nonyl. Cycloalkyl groups are optionally substituted with one or more substituents described herein.

The term "cycloalkylene" refers to a divalent monocyclic or polycyclic (including bridged and spiro forms) non-aromatic cyclic hydrocarbon group consisting of only carbon and hydrogen atoms, free of unsaturation, and linked by one single bond to one group and by another single bond to another group, such as C _3-10 Cycloalkylene radicals having 3 to 10 carbon atoms, C _3-6 Cycloalkylene contains cycloalkylene of 3-6 carbon atoms; common cycloalkylene groups include, but are not limited to, cyclopropane-1, 1-subunit, cyclopropane-1, 2-subunit, cyclobutane-1, 1-subunit, cyclobutane-1, 2-subunit, cyclobutane-1, 3-subunit, and the like.

The term "heterocyclyl" refers to a monovalent, monocyclic or polycyclic (including bridged and spiro forms) non-aromatic ring system having ring atoms made up of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus and arsenic, and linked to other groups by a single bond, for example, a 3-10 membered heterocyclyl, a 3-7 membered heterocyclyl or a 4-10 membered heterocyclyl; common heterocyclyl groups include, but are not limited to, oxiranyl, oxetan-3-yl, azetidin-3-yl, tetrahydrofuranyl-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidin-4-yl, tetrahydropyridinyl, and the like. The heterocyclyl is optionally substituted with one or more substituents described herein.

The term "heterocyclylene" refers to a divalent monocyclic or polycyclic (including bridged and spiro forms) non-aromatic ring system, the ring atoms of which are made up of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus and arsenic, and which are linked by one single bond to one group and by another single bond to another group (or ring system), such as a 3-10 membered heterocyclylene, 3-7 membered heterocyclylene or 4-10 membered heterocyclylene; common heterocycloalkylene groups include, but are not limited to, oxetan-2, 2-subunit, oxetan-2, 3-subunit, azetidine-2, 2-subunit, azetidine-2, 3-subunit, azetidine-2, 4-subunit, tetrahydrofuran-2, 5-subunit, tetrahydro-2H-pyran-2, 3-subunit, tetrahydro-2H-pyran-2, 4-subunit, tetrahydro-2H-pyran-2, 5-subunit, tetrahydro-2H-pyran-2, 6-subunit, pyrrolidin-1, 2-subunit, pyrrolidin-1, 3-subunit, pyrrolidin-2, 5-subunit, piperidin-1, 2-subunit, piperidin-1, 3-subunit, piperidin-1, 4-subunit, piperidin-2, 3-subunit, piperidin-2, 4-subunit, piperidin-2, 5-subunit, piperidine-6-subunit, and the like.

The term "aryl" refers to a monovalent, monocyclic or polycyclic (including fused forms) all-carbon aromatic ring system having ring atoms consisting of only carbon atoms and attached to other groups, e.g., C, by a single bond _6-10 An aryl group; common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like. Aryl groups are optionally substituted with one or more substituents described herein.

The term "heteroaryl" refers to a monovalent, monocyclic or polycyclic (including fused forms) aromatic ring system having ring atoms made up of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus and arsenic, and linked to other groups by a single bond, e.g. "5-10 membered heteroaryl" as used herein refers to a monocyclic or polycyclic (including fused forms) aromatic ring system having a total number of ring atoms of 5-10; common heterocyclic groups include, but are not limited to, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, acridinyl, carbazolyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indolizinyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phenazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, triazolyl, tetrazolyl, and the like. Heteroaryl groups are optionally substituted with one or more substituents described herein.

The term "alkoxy" refers to a monovalent, linear or branched alkyl-O-group consisting of only carbon, hydrogen and oxygen atoms, which may contain unsaturation, and which is attached to other groups by a single bond to the oxygen atom, e.g., C _1-6 Alkoxy, C _1-4 An alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH) ₃ ) Ethoxy (-OCH) ₂ CH ₃ ) N-propoxy (-OCH) ₂ CH ₂ CH ₃ ) Isopropoxy (-OCH (CH) ₃ ) ₂ ) N-butoxy (-OCH) ₂ CH ₂ CH ₂ CH ₃ ) Sec-butoxy (-OCH (CH) ₃ )CH ₂ CH ₃ ) Isobutoxy (-OCH) ₂ CH(CH ₃ ) ₂ ) T-butoxy (-OC (CH) ₃ ) ₃ ) N-pentyloxy (-OCH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) Neopentyloxy (-OCH) ₂ C(CH ₃ ) ₃ ) Etc.

The term "haloalkoxy" refers to a monovalent linear or branched haloalkyl-O-group substituted with at least one atom selected from fluorine, chlorine, bromine and iodine, which may contain unsaturation, and which is linked to other groups by a single bond to an oxygen atom, e.g., C _1-6 Haloalkoxy, C _1-4 Haloalkoxy groups; common haloalkoxy groups include, but are not limited to, fluoromethoxy (-OCH) ₂ F) Difluoromethoxy (-OCHF) ₂ ) Trifluoromethoxy (-OCF) ₃ ) 1-fluoroethoxy (-OCHFCH) ₃ ) 2-fluoroethoxy (-OCH) ₂ CH ₂ F) 1, 2-difluoroethoxy (-OCHFCH) ₂ F) 2, 2-difluoroethoxy (-OCH) ₂ CHF ₂ ) 1, 2-trifluoroethoxy (-OCHFCHF) ₂ ) 2, 2-trifluoroethoxy (-OCH) ₂ CF ₃ ) Etc.

The term "cycloalkoxy" refers to a monovalent group consisting of a cycloalkyl group and an oxygen atom, and is attached to other groups, e.g., C, by a single bond to the oxygen atom _3-6 A cycloalkoxy group; common cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, decahydronaphthyloxy, adamantyloxy, and the like.

[ Compounds of the general formula ]

The present invention provides a compound of formula I or a pharmaceutically acceptable form thereof,

wherein,

ring A ¹ Selected from phenyl and 5-6 membered heteroaryl;

Z ¹ 、Z ² and Z ³ Each independently selected from CR ⁴ And N;

R ¹ selected from hydrogen and C _1-6 An alkyl group;

each R is ⁵ Each independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, -C _0-6 alkylene-O-R ^a 、-O-C _1-6 alkylene-O-R ^a 、C _1-6 Haloalkoxy, -C _0-6 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-6 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-C(＝O)-R ⁶ 、-C _0-6 alkylene-S (=o) ₂ -R ⁶ 、-C _0-6 alkylene-N (R) ^a )(R ^b )、-C _0-6 alkylene-C (=O) -N (R) ^a )(R ^b )、-C _0-6 alkylene-N (R) ^a )-C(＝O)-R ⁶ 、-C _0-6 alkylene-S (=o) ₂ -N(R ^a )(R ^b )、-C _0-6 alkylene-N (R) ^a )-S(＝O) ₂ -R ⁶ 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl; wherein: each R is ^a Each independently selected from hydrogen and C _1-6 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-6 An alkyl group; or R is ^a And R is ^b Forming a 3-7 membered heterocyclic group together with the nitrogen atom to which it is attached;

m is 1, 2 or 3;

n is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

In some embodiments of the invention, the compound of formula I or a pharmaceutically acceptable form thereof described above is a compound of formula I-A or a pharmaceutically acceptable form thereof,

Wherein ring A ¹ Ring A ² Ring A ³ 、R ² 、R ³ 、R ⁵ M, n and q are as defined above.

In some embodiments of the invention, m is 1 or 2, preferably 2.

In some embodiments of the invention, n is 1 or 2, preferably 1.

In some embodiments of the invention, q is 0, 1 or 2.

In some embodiments of the invention, q is 1 or 2.

In some embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ¹ Selected from phenyl and pyridyl.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ¹ Is phenyl.

In some embodiments of the invention, each R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Each independently selected from halogen, cyano, hydroxy, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and C _3-6 A cycloalkoxy group.

In some preferred embodiments of the invention, each R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy and C _1-4 Haloalkoxy groups.

In some more preferred embodiments of the invention, each R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Each independently selected from halogen, cyano, C _1-3 Haloalkyl, C _3-6 Cycloalkyl, C _1-3 Alkoxy and C _1-3 Haloalkoxy groups.

In some particularly preferred embodiments of the invention, each R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Each independently selected from fluorine, chlorine, cyano, methoxy and difluoromethoxy.

In some embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ¹ Selected from phenyl and pyridyl, each R ² Each independently selected from halogen, cyano, hydroxy, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and C _3-6 A cycloalkoxy group.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ¹ Selected from phenyl groups, each R ² Each independently selected from halogen, cyano, C _1-3 Haloalkyl, C _3-6 Cycloalkyl, C _1-3 Alkoxy and C _1-3 Haloalkoxy groups.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ¹ Selected from phenyl groups, each R ² Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-3 Alkoxy and C _1-3 Haloalkoxy groups.

In some particularly preferred embodiments of the invention, the compound of formula I or formula I-A above, or a pharmaceutically acceptable form thereof, is ring A ¹ Is phenyl; each R is ² Each independently selected from fluorine, chlorine, cyano, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.

In some particularly preferred embodiments of the invention, the compound of formula I or formula I-A above, or a pharmaceutically acceptable form thereof, is ring A ¹ Is phenyl; each R is ² Each independently selected from fluorine, chlorine, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.

In some of the inventionIn a particularly preferred embodiment, ring A in the compounds of formula I or formula I-A above or in pharmaceutically acceptable forms thereof ¹ Is phenyl; each R is ² Each independently selected from fluorine, chlorine, cyano, methoxy and difluoromethoxy.

In some more particularly preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ¹ Is phenyl, each R ² Each independently selected from fluorine and difluoromethoxy.

In some more particularly preferred embodiments of the invention, the compound of formula I or formula I-A as described above, or a pharmaceutically acceptable form thereofSelected from the group consisting of

In some more particularly preferred embodiments of the invention, the compound of formula I or formula I-A as described above, or a pharmaceutically acceptable form thereof

In some embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Selected from phenyl and 5-6 membered heteroaryl.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Selected from phenyl and pyridyl.

In some particularly preferred embodiments of the invention, the compound of formula I or formula I-A above, or a pharmaceutically acceptable form thereof, is ring A ² Is phenyl.

In some embodiments of the invention, each R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ³ Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 NaphtheneRadical, C _1-4 Alkoxy, C _1-4 Haloalkoxy and-S (=o) ₂ -C _1-4 An alkyl group.

In some preferred embodiments of the invention, each R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ³ Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Haloalkoxy and-S (=o) ₂ -C _1-4 An alkyl group.

In some preferred embodiments of the invention, R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ³ Is C _1-4 Haloalkyl, preferably R ³ Is trifluoromethyl.

In some particularly preferred embodiments of the invention, each R in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ³ Each independently selected from fluoro, cyano, methyl, trifluoromethyl and methanesulfonyl.

In some particularly preferred embodiments of the invention, R in the above-mentioned compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ³ Is trifluoromethyl.

In some embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Selected from phenyl and 5-6 membered heteroaryl; each R is ³ Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and-S (=o) ₂ -C _1-4 An alkyl group.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Selected from phenyl and pyridyl, each R ³ Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Haloalkoxy and-S (=o) ₂ -C _1-4 An alkyl group.

In some preferred embodiments of the invention, the above formulaRing A in a compound of formula I or I-A or a pharmaceutically acceptable form thereof ² Selected from phenyl and pyridyl, R ³ Is C _1-4 A haloalkyl group.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Selected from phenyl groups, each R ³ Each independently selected from fluoro, cyano, methyl, trifluoromethyl and methanesulfonyl.

In some more particularly preferred embodiments of the invention, ring A in the above-described compounds of formula I or formula I-A or a pharmaceutically acceptable form thereof ² Is phenyl; r is R ³ Is trifluoromethyl.

In some more particularly preferred embodiments of the invention, the compound of formula I or formula I-A as described above, or a pharmaceutically acceptable form thereofIs->

In some embodiments of the invention, the compounds of formula I or formula I-A described above, or pharmaceutically acceptable forms thereof,

ring A ¹ Phenyl and 5-6 membered heteroaryl;

each R is ² Each independently selected from halogen, cyano, hydroxy, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and C _3-6 A cycloalkoxy group;

ring A ² Selected from phenyl and 5-6 membered heteroaryl;

each R is ³ Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and-S (=o) ₂ -C _1-4 An alkyl group;

ring A ³ Selected from phenyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl;

each R is ⁵ Each independently selected from hydrogen, hydroxy, C _1-3 Alkyl, -C _1-3 alkylene-O-R ^a 、-O-C _1-3 alkylene-O-R ^a 、-C _0-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-S(＝O) ₂ -C _1-3 Alkyl, -C _1-3 alkylene-N (R) ^a )(R ^b )、-C _1-3 alkylene-C (=O) -N (R) ^a )(R ^b ) And 4-6 membered heterocyclyl; wherein: each R is ^a Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-3 An alkyl group;

q is 0, 1 or 2;

m is 1 or 2;

n is 1 or 2.

ring A ¹ Is phenyl;

each R is ² Each independently selected from fluorine, chlorine, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy;

ring A ² Selected from phenyl and 5-6 membered heteroaryl;

R ³ is trifluoromethyl;

Ring A ³ Selected from pyrazolyl, tetrahydropyridinyl, thiazolyl, piperazinyl, morpholinyl, and piperidinyl;

each R is ⁵ Each independently selected from hydrogen, hydroxy, -CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、-CH ₂ COOH、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ C(＝O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₂ CH ₂ COOH、-COOCH ₃ 、-COOH、-S(＝O) ₂ -CH ₃ and-OCH ₂ CH ₂ OCH ₃ ；

q is 0, 1 or 2;

m is 2;

n is 1.

In some embodiments of the invention, the compound of formula I or formula I-A or a pharmaceutically acceptable form thereof described above is a compound of formula I-B1 or a pharmaceutically acceptable form thereof,

wherein ring A ³ 、R ² 、R ⁵ M and q are as defined above.

In some embodiments of the invention, each R in the above-described compounds of formula I, formula I-A or formula I-B1, or a pharmaceutically acceptable form thereof ² Each independently selected from fluorine, chlorine, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.

In some embodiments of the invention, in the compounds of formula I, formula I-A or formula I-B1 above or in pharmaceutically acceptable forms thereof,

q is 0, 1 or 2;

m is 1 or 2.

each R is ² Each independently selected from halogen, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 Haloalkoxy groups;

ring A ³ Selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

q is 0, 1 or 2;

m is 2.

each R is ⁵ Each independently selected from hydrogen, -OH, -CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、-CH ₂ COOH、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ C(＝O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₂ CH ₂ COOH、-COOCH ₃ 、-COOH、-S(＝O) ₂ -CH ₃ and-OCH ₂ CH ₂ OCH ₃ ；

q is 0, 1 or 2;

m is 2.

In some embodiments of the invention, the compound of formula I, formula I-A or formula I-B1 above, or a pharmaceutically acceptable form thereof, is a compound of formula I-B, or a pharmaceutically acceptable form thereof,

wherein ring A ³ 、R ⁵ And q is as defined above.

In some embodiments of the invention, ring A in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ³ Selected from phenyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl.

In some embodiments of the invention, a compound of formula I, formula I-A, formula I-B1 or formula I-B described above, or a pharmaceutically acceptable form thereofRing A of (2) ³ Selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ³ Selected from pyrazolyl, tetrahydropyridinyl, thiazolyl, piperazinyl, morpholinyl, and piperidinyl.

In some particularly preferred embodiments of the invention, ring A in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ³ Selected from the group consisting of

In some embodiments of the invention, each R in the above-described compounds of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof ⁵ Each independently selected from hydrogen, halogen, cyano, hydroxy, C _1-3 Alkyl, C _1-3 Haloalkyl, C _3-6 Cycloalkyl, -C _0-3 alkylene-O-R ^a 、-O-C _1-3 alkylene-O-R ^a 、C _1-3 Haloalkoxy, -C _0-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-C(＝O)-R ⁶ 、-C _0-3 alkylene-S (=o) ₂ -R ⁶ 、-C _0-3 alkylene-N (R) ^a )(R ^b )、-C _0-3 alkylene-C (=O) -N (R) ^a )(R ^b )、-C _0-3 alkylene-N (R) ^a )-C(＝O)-R ⁶ 、-C _0-3 alkylene-S (=o) ₂ -N(R ^a )(R ^b )、-C _0-3 alkylene-N (R) ^a )-S(＝O) ₂ -R ⁶ 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; wherein: each R is ^a Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ⁶ Each independently selected from C _1-3 Alkyl and C _3-6 Cycloalkyl groups.

In some embodiments of the invention, each R in the above-described compounds of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof ⁵ Each independently selected from hydrogen, halogen, cyano, hydroxy, C _1-3 Alkyl, C _1-3 Haloalkyl, C _3-6 Cycloalkyl, -C _0-3 alkylene-O-R ^a 、-O-C _1-3 alkylene-O-R ^a 、C _1-3 Haloalkoxy, -C _0-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 cycloalkylene-C (=o) -O-R ^a 、-C(＝O)-C _1-6 Alkyl, -C _0-3 alkylene-S (=o) ₂ -R ⁶ 、-C _0-3 alkylene-N (R) ^a )(R ^b )、-C _0-3 alkylene-C (=O) -N (R) ^a )(R ^b )、-C _0-3 alkylene-N (R) ^a )-C(＝O)-R ⁶ 、-C _0-3 alkylene-S (=o) ₂ -N(R ^a )(R ^b )、-C _0-3 alkylene-N (R) ^a )-S(＝O) ₂ -R ⁶ 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; wherein: each R is ^a Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ⁶ Each independently selected from C _1-3 Alkyl and C _3-6 Cycloalkyl groups.

In some preferred embodiments of the invention, each R in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ⁵ Each independently selected from hydrogen, hydroxy, C _1-3 Alkyl, -C _1-3 alkylene-O-R ^a 、-O-C _1-3 alkylene-O-R ^a 、-C(＝O)-O-R ^a 、-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-S(＝O) ₂ -C _1-3 Alkyl, -C _1-3 alkylene-N (R) ^a )(R ^b )、-C _1-3 alkylene-C (=O) -N (R) ^a )(R ^b ) And 4-6 membered heterocyclyl; wherein: each R is ^a Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-3 An alkyl group.

In some particularly preferred embodiments of the invention, each R in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ⁵ Each independently selected from hydrogen, hydroxy, methyl, ethyl, isopropyl, -CH ₂ CH ₂ -O-CH ₃ 、-O-CH ₂ CH ₂ -O-CH ₃ 、-C(＝O)-O-H、-C(＝O)-O-CH ₃ 、-CH ₂ -C(＝O)-O-H、-C(＝O)-CH ₂ CH ₂ -C(＝O)-O-H、 -S(＝O) ₂ -CH ₃ 、-CH ₂ CH ₂ -N(CH ₃ ) ₂ 、-CH ₂ -C(＝O)-N(CH ₃ ) ₂ And->

In some embodiments of the invention, ring A in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ³ Selected from phenyl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl; each R is ⁵ Each independently selected from hydrogen, halogen, cyano, hydroxy, C _1-3 Alkyl, C _1-3 Haloalkyl, C _3-6 Cycloalkyl, -C _0-3 alkylene-O-R ^a 、-O-C _1-3 alkylene-O-R ^a 、C _1-3 Haloalkoxy, -C _0-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-C(＝O)-R ⁶ 、-C _0-3 alkylene-S (=o) ₂ -R ⁶ 、-C _0-3 alkylene-N (R) ^a )(R ^b )、-C _0-3 alkylene-C (=O) -N (R) ^a )(R ^b )、-C _0-3 alkylene-N (R) ^a )-C(＝O)-R ⁶ 、-C _0-3 alkylene-S (=o) ₂ -N(R ^a )(R ^b )、-C _0-3 alkylene-N (R) ^a )-S(＝O) ₂ -R ⁶ 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; wherein: each R is ^a Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ⁶ Each independently selected from C _1-3 Alkyl and C _3-6 Cycloalkyl groups.

In some preferred embodiments of the invention, ring A in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ³ Selected from pyrazolyl, tetrahydropyridinyl, thiazolyl, piperazinyl, morpholinyl, and piperidinyl; each R is ⁵ Each independently selected from hydrogen, hydroxy, C _1-3 Alkyl, -C _1-3 alkylene-O-R ^a 、-O-C _1-3 alkylene-O-R ^a 、-C(＝O)-O-R ^a 、-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-3 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-S(＝O) ₂ -C _1-3 Alkyl, -C _1-3 alkylene-N (R) ^a )(R ^b )、-C _1-3 alkylene-C (=O) -N (R) ^a )(R ^b ) And 4-6 membered heterocyclyl; wherein: each R is ^a Each independently selected from hydrogen and C _1-3 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-3 An alkyl group.

In some particularly preferred embodiments of the invention, ring A in the above-described compounds of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof ³ Selected from the group consisting ofEach R is ⁵ Each independently selected from hydrogen, hydroxy, methyl, ethyl, isopropyl, -CH ₂ CH ₂ -O-CH ₃ 、-O-CH ₂ CH ₂ -O-CH ₃ 、-C(＝O)-O-H、-C(＝O)-O-CH ₃ 、-CH ₂ -C(＝O)-O-H、-C(＝O)-CH ₂ CH ₂ -C(＝O)-O-H、/>-S(＝O) ₂ -CH ₃ 、-CH ₂ CH ₂ -N(CH ₃ ) ₂ 、-CH ₂ -C(＝O)-N(CH ₃ ) ₂ And->

In some more particularly preferred embodiments of the invention, the compounds of formula I, formula I-A, formula I-B1 or formula I-B described above, or a pharmaceutically acceptable form thereofSelected from the group consisting of

In addition, the invention also provides the following compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, solvates, N-oxides, isotopic labels, metabolites or prodrugs thereof, the structures and names of which are shown in the following table:

/>

[ preparation method ]

The invention provides a preparation method of the compound shown in the formula I, which comprises the following steps:

(1) Reacting the compound A with the compound B to obtain a compound C;

(4) Reacting the compound E with a compound F to obtain a compound G;

or comprises the following steps:

(1 ') reacting compound A' with compound B 'to obtain compound C';

(3 ') reacting the compound D ' with the compound F to obtain a compound F ';

(4 ') reacting compound F' with compound B to give a compound of formula I;

In some embodiments of the present invention, step (1) of the above-described preparation process is performed in a suitable solvent, including, but not limited to, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), toluene, ethanol, ethylene glycol dimethyl ether, water, 1, 4-dioxane, and any combination thereof, preferably a mixed solvent of 1, 4-dioxane and water. In some embodiments of the invention, step (1) of the above-described preparation process is carried out in the presence of a suitable catalyst, the catalyst used being a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium, palladium acetate, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex. In some embodiments of the present invention, step (1) of the above-described preparation process is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include, but are not limited to, potassium phosphate, potassium acetate, sodium bicarbonate, sodium carbonate, and potassium carbonate, preferably potassium carbonate. In some embodiments of the present invention, a suitable reaction temperature for step (1) of the above-described preparation process is 60-120 ℃. In some embodiments of the invention, a suitable reaction time for step (1) of the above described preparation method is 2-8 hours.

In some embodiments of the present invention, step (2) of the above-described preparation process is performed in a suitable organic solvent, including, but not limited to, acetonitrile, dichloromethane, chloroform, N-dimethylformamide, and any combination thereof, preferably acetonitrile. In some embodiments of the present invention, step (2) of the above-described preparation process is performed in the presence of a suitable nitrite, including, but not limited to, isoamyl nitrite and t-butyl nitrite. In some embodiments of the present invention, step (2) of the above-described preparation process is performed in the presence of a suitable brominating reagent including, but not limited to, cuprous bromide, cupric bromide and N-bromosuccinimide, preferably cuprous bromide. In some embodiments of the present invention, a suitable reaction temperature for step (2) of the above-described preparation process is from-10 to 80 ℃. In some embodiments of the invention, a suitable reaction time for step (2) of the above described preparation method is 2-8 hours.

In some embodiments of the present invention, the reduction reaction in step (3) of the above-described preparation method is performed in a suitable solvent, including, but not limited to, methanol, ethanol, tetrahydrofuran, water, and any combination thereof, preferably a mixed solvent of ethanol and water. In some embodiments of the present invention, the reduction reaction in step (3) of the above-described preparation method is carried out in the presence of suitable reducing agents including, but not limited to, iron powder, zinc powder, sodium dithionite, stannous chloride and hydrazine hydrate, preferably iron powder. In some embodiments of the present invention, the reduction reaction in step (3) of the above-described preparation method is carried out in the presence of suitable inorganic salts including, but not limited to, ammonium chloride and ammonium formate, preferably ammonium chloride. In some embodiments of the invention, a suitable reaction temperature for the reduction reaction in step (3) of the above described preparation method is 20-100 ℃. In some embodiments of the invention, a suitable reaction time for the reduction reaction in step (3) of the above described preparation method is 2-8 hours. In some embodiments of the present invention, the N-alkylation reaction in step (3) of the above-described preparation process is carried out in the presence of suitable alkylating agents including, but not limited to, haloalkanes, alcohols and alkyl sulfates, preferably haloalkanes. In some embodiments of the present invention, the N-alkylation reaction in step (3) of the above-described preparation process is carried out in an alkaline environment, and suitable reagents for providing an alkaline environment include, but are not limited to, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, and potassium carbonate, preferably potassium carbonate.

In some embodiments of the present invention, step (4) of the above-described preparation process is performed in a suitable organic solvent, including, but not limited to, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and any combination thereof, preferably dichloromethane. In some embodiments of the present invention, step (4) of the above-described preparation process is performed in a basic environment, and suitable reagents that provide a basic environment include, but are not limited to, triethylamine, N-dimethylethylamine, pyridine, sodium bicarbonate, sodium carbonate, and potassium carbonate, preferably pyridine. In some embodiments of the invention, a suitable reaction temperature for step (4) of the above described preparation process is 20-80 ℃. In some embodiments of the invention, a suitable reaction time for step (4) of the above described preparation method is 2-8 hours.

In some embodiments of the present invention, step (5) of the above-described preparation process is performed in a suitable solvent, including, but not limited to, N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1, 4-dioxane, and any combination thereof, preferably a mixed solvent of 1, 4-dioxane and water. In some embodiments of the invention, step (5) of the above-described preparation process is carried out in the presence of a suitable catalyst, the catalyst used being a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium, palladium acetate, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex. In some embodiments of the present invention, step (5) of the above-described preparation process is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include, but are not limited to, potassium phosphate, potassium acetate, sodium bicarbonate, sodium carbonate, and potassium carbonate, preferably potassium carbonate. In some embodiments of the invention, a suitable reaction temperature for step (5) of the above described preparation process is 60-120 ℃. In some embodiments of the invention, a suitable reaction time for step (5) of the above described preparation method is 2-8 hours.

In some embodiments of the present invention, step (1') of the above-described preparation process is performed in a suitable organic solvent, including, but not limited to, acetonitrile, N-dimethylformamide, dimethylsulfoxide, 1, 4-dioxane, and any combination thereof, preferably N, N-dimethylformamide. In some embodiments of the present invention, step (1') of the above-described preparation process is performed in a basic environment, and suitable reagents for providing a basic environment include, but are not limited to, diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate. In some embodiments of the invention, a suitable reaction temperature for step (1') of the above described preparation process is 40-80 ℃. In some embodiments of the invention, a suitable reaction time for step (1') of the above described preparation method is 2-24 hours.

In some embodiments of the present invention, the reduction reaction in step (2') of the above-described preparation method is performed in a suitable organic solvent, including, but not limited to, alcoholic protic solvents, tetrahydrofuran, ethyl acetate, and any combination thereof. In some embodiments of the present invention, the reduction reaction in step (2') of the above-described preparation process is carried out in the presence of suitable metal reagents including, but not limited to, raney nickel, palladium on carbon, iron powder and zinc powder, preferably iron powder, and an acid including, but not limited to, hydrochloric acid, formic acid and acetic acid, preferably acetic acid. In some embodiments of the invention, a suitable reaction temperature for the reduction reaction in step (2') of the above described preparation method is 40-80 ℃. In some embodiments of the invention, a suitable reaction time for the reduction reaction in step (2') of the above described preparation method is 2-12 hours. In some embodiments of the present invention, the N-alkylation reaction in step (2') of the above-described preparation process is carried out in the presence of a suitable alkylating agent, including, but not limited to, haloalkanes, alcohols and alkyl sulfates, preferably haloalkanes. In some embodiments of the present invention, the N-alkylation reaction in step (2') of the above-described preparation process is carried out in an alkaline environment, and suitable reagents for providing an alkaline environment include, but are not limited to, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, and potassium carbonate, preferably potassium carbonate.

In some embodiments of the present invention, step (3') of the above-described preparation process is performed in a suitable organic solvent including, but not limited to, triethylamine, N-diisopropylethylamine, pyridine, and any combination thereof, preferably pyridine. In some embodiments of the invention, a suitable reaction temperature for step (3') of the above described preparation process is 40-80 ℃. In some embodiments of the invention, a suitable reaction time for step (3') of the above described preparation method is 2-8 hours.

In some embodiments of the present invention, step (4') of the above-described preparation process is performed in a suitable solvent, including, but not limited to, a mixed solvent of N, N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1, 4-dioxane, and any combination thereof, preferably 1, 4-dioxane, and water. In some embodiments of the invention, step (4 ') of the above-described preparation process is carried out in the presence of a suitable catalyst, the catalyst used being a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex. In some embodiments of the present invention, step (4') of the above-described preparation process is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include, but are not limited to, potassium phosphate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate, preferably potassium carbonate. In some embodiments of the invention, a suitable reaction temperature for step (4') of the above described preparation process is 60-100 ℃. In some embodiments of the invention, a suitable reaction time for step (4') of the above described preparation method is 2-8 hours.

In some preferred embodiments of the present invention, the process for the preparation of the above-described compounds of formula I-A comprises the steps of:

(1) Reacting the compound se:Sub>A-se:Sub>A with se:Sub>A compound B to obtain se:Sub>A compound C-A;

(2) The compound C-A undergoes substitution reaction to obtain se:Sub>A compound D-A;

(3) The compound D-A undergoes a reduction reaction to obtain a compound E-A;

(4) Ext> reactingext> theext> compoundext> Eext> -ext> Aext> withext> theext> compoundext> Fext> toext> obtainext> aext> compoundext> Gext> -ext> Aext>;ext>

(5) Ext> reactingext> aext> compoundext> Gext> -ext> Aext> withext> aext> compoundext> Hext> toext> obtainext> aext> compoundext> ofext> formulaext> Iext> -ext> Aext>;ext>

Wherein ring A ¹ Ring A ² Ring A ³ 、R ² 、R ³ 、R ⁵ M, n and q are as defined in formula I; x represents a leaving group including, but not limited to, a halogen atom, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group;

or comprises the following steps:

(1 ') reacting the compound A' -A with the compound B '-A to obtain a compound C' -A;

(2 ') carrying out reduction reaction on the compound C ' -A to obtain a compound D ' -A;

(3 ') reacting the compound D ' -A with the compound F to obtain the compound F ' -A;

(4 ') reacting compound F' -A with compound B to obtain a compound of formula I-A;

wherein ring A ¹ Ring A ² Ring A ³ 、R ² 、R ³ 、R ⁵ M, n and q are as followsDefined in formula I; x represents a leaving group including, but not limited to, a halogen atom, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group; hal represents a halogen atom including, but not limited to, F, cl, br and I, preferably F and Cl.

In some embodiments of the present invention, step (3) of the above-described preparation process is performed in a suitable solvent, including, but not limited to, methanol, ethanol, tetrahydrofuran, water, and any combination thereof, preferably a mixed solvent of ethanol and water. In some embodiments of the present invention, step (3) of the above-described preparation process is performed in the presence of a suitable reducing agent, including, but not limited to, iron powder, zinc powder, sodium dithionite, stannous chloride and hydrazine hydrate, preferably iron powder. In some embodiments of the present invention, step (3) of the above-described preparation process is performed in the presence of suitable inorganic salts including, but not limited to, ammonium chloride and ammonium formate, preferably ammonium chloride. In some embodiments of the invention, a suitable reaction temperature for step (3) of the above described preparation process is 20-100 ℃. In some embodiments of the invention, a suitable reaction time for step (3) of the above described preparation method is 2-8 hours.

In some embodiments of the present invention, step (2') of the above-described preparation process is performed in a suitable organic solvent, including, but not limited to, alcoholic protic solvents, tetrahydrofuran, ethyl acetate, and any combination thereof. In some embodiments of the present invention, step (2') of the above-described preparation process is performed in the presence of a suitable metal reagent including, but not limited to, raney nickel, palladium on carbon, iron powder and zinc powder, preferably iron powder, and an acid including, but not limited to, hydrochloric acid, formic acid and acetic acid, preferably acetic acid. In some embodiments of the invention, a suitable reaction temperature for step (2') of the above described preparation process is 40-80 ℃. In some embodiments of the invention, a suitable reaction time for step (2') of the above described preparation method is 2-12 hours.

[ pharmaceutical composition ]

The term "pharmaceutical composition" refers to a composition that can be used as a medicament comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to pharmaceutical excipients that are compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, preservatives, antioxidants, pH adjusting agents, solvents, co-solvents, surfactants, and the like.

The present invention provides a pharmaceutical composition comprising a compound of formula I above or a pharmaceutically acceptable form thereof.

In some embodiments of the invention, the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[ medical use ]

Whether a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition, exhibits a modulating effect (especially agonistic activity) on rory, EC against rory ₅₀ Values of 110nM or less, and individual even 10nM or less, can be used as ROR gamma modulators. Accordingly, the present invention provides the use of a compound of formula I as defined above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as defined above, as a rory modulator. In the present invention, the rory modulators are useful for the prevention and/or treatment of diseases mediated at least in part by rory.

In addition, the application also provides the use of a compound of formula I or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above for the preparation of a medicament for the prophylaxis and/or treatment of diseases which are at least partially mediated by ROR gamma.

The term "disease mediated at least in part by rorγ" refers to a disease in which the pathogenesis includes at least a portion of the factors associated with rorγ, including, but not limited to, cancer (e.g., leukemia, lymphoma, myeloma, breast, ovarian, cervical, prostate, bladder, colon, rectal, colorectal, stomach, esophageal, oral, pancreatic, liver, lung, kidney, skin, bone, brain, glioma, melanoma, etc.), inflammation (e.g., ankylosing spondylitis, chronic obstructive pulmonary disease, chronic bronchitis, asthma, mesangial capillary glomerulonephritis, allergic dermatitis, myocarditis, ulcerative colitis, crohn's disease, etc.), and autoimmune diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, etc.). In the present application, the disease mediated at least in part by rorγ is selected from cancer, inflammation and autoimmune diseases.

[ method of treatment ]

The present invention provides a method for preventing and/or treating a disease mediated at least in part by rorγ, comprising the steps of: a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above is administered to a patient in need thereof.

The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient capable of eliciting a biological or medical response in a cell, tissue, organ or organism (e.g., a patient).

The term "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the present invention) to a patient or a cell, tissue, organ, biological fluid, etc. thereof, such that the pharmaceutically active ingredient or pharmaceutical composition is in contact with the patient or a cell, tissue, organ, biological fluid, etc. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.

The term "in need thereof" refers to a judgment of a physician or other caregiver that the patient needs or will benefit from the prevention and/or treatment process based on various factors of the physician or other caregiver in their expertise.

The term "patient" (or subject) refers to a human or non-human animal (e.g., mammal).

[ Combined drug administration ]

The present invention provides a pharmaceutical combination composition comprising a compound of formula I as described above or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above, together with at least one other co-directional rory modulator.

The term "co-directional" means that when at least two modulators are administered to a target, their modulation directions should be substantially the same, either simultaneously exhibiting agonism, or simultaneously exhibiting antagonism. In particular, when the above pharmaceutical combination composition comprises a compound of formula I or a pharmaceutically acceptable form thereof or a pharmaceutical composition as a rory agonist, it further comprises at least one other rory agonist, which pharmaceutical combination composition is suitable for the prevention and/or treatment of cancer; similarly, when the above pharmaceutical combination composition comprises a compound of formula I or a pharmaceutically acceptable form thereof or a pharmaceutical composition as a rory antagonist, it further comprises at least one other rory antagonist, which pharmaceutical combination composition is suitable for use in the prevention and/or treatment of inflammation and/or autoimmune diseases.

The present invention provides a method for preventing and/or treating cancer, inflammation or autoimmune disease, comprising the steps of: a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable form thereof, or a pharmaceutical composition above or a pharmaceutical combination composition above, is administered to a patient in need thereof.

The present invention provides a method for preventing and/or treating cancer, comprising the steps of: a therapeutically effective amount of a compound of formula I as described above or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above or a pharmaceutical combination composition as described above, and as a rory agonist, is administered to a patient in need thereof.

The present invention provides a method for preventing and/or treating inflammation, comprising the steps of: a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable form thereof, or a pharmaceutical composition or a pharmaceutical combination composition as described above, and as a rory antagonist, is administered to a patient in need thereof.

The present invention provides a method for preventing and/or treating autoimmune diseases, comprising the steps of: a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable form thereof, or a pharmaceutical composition or a pharmaceutical combination composition as described above, and as a rory antagonist, is administered to a patient in need thereof.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention. If the experimental methods in the following examples do not specify specific conditions, the conditions are generally conventional or recommended by the manufacturer (e.g., room temperature of 20 to 30 ℃). The reagents used were purchased from Acros Organics, aldrich Chemical Company, shanghai Tebert chemical technologies Co., ltd. The percentages and parts appearing in the following examples are by weight unless otherwise indicated.

Abbreviations in the context of the present invention have the following meanings:

abbreviations (abbreviations)	Meaning of
		TLC	Thin layer chromatography
CC	Column chromatography
		PHPLC	High performance liquid chromatography
LC-MS	Liquid chromatography-mass spectrometry combination
		Pd(dppf)Cl ₂	[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
CD ₃ OD	Deuterated methanol
		CDCl ₃	Deuterated chloroform
DMSO-d ₆	Hexadeuterated dimethyl sulfoxide
		TMS	Tetramethylsilane
NMR	Nuclear magnetic resonance
		MS	Mass spectrometry
s	Singlet
		d	Double peak
t	Triplet peak
		q	Quadruple peak
dd	Double peak
		m	Multiple peaks
br	Broad peak
		J	Coupling constant
Hz	Hertz device
		h	Hours of
min	Minute (min)

When chemical names and structural formulae of compounds in the following examples are not identical, the structural formulae should be taken as reference unless it can be inferred that the chemical names are correct depending on the context. The structural formula of the compound described in the following examples is shown by ¹ H-NMR or MS. ¹ The H-NMR measuring instrument is Bruker 400MHz nuclear magnetic resonance instrument, and the measuring solvent is CD ₃ OD、CDCl ₃ Or DMSO-d ₆ The internal standard substance is TMS, and all delta values are expressed in ppm. The MS measuring instrument is an Agilent 6120B mass spectrometer, and the ion source is ESI.

The reaction progress is monitored by TLC or LC-MS, the developing agent system comprises a methylene dichloride and methanol system, an n-hexane and ethyl acetate system, a petroleum ether and ethyl acetate system, and the volume ratio between the solvents can be adjusted according to the polarity difference of the compounds. To obtain a suitable specific shift value (Rf) or Retention Time (RT), a suitable amount of triethylamine or the like may be added to the developing agent. TLC was performed using an aluminum plate (20X 20 cm) manufactured by Merck, and GF254 silica gel (0.4-0.5 mm) for thin layer chromatography manufactured by Qingdao ocean chemical industry.

The separation and purification of the reaction products are carried out by CC or PHPLC. CC uses 200-300 mesh silica gel as carrier. The system of the eluent comprises: the volume ratio of the solvent in the methylene dichloride and methanol system and the petroleum ether and ethyl acetate system is adjusted according to the polarity of the compound, and a small amount of triethylamine can be added for adjustment. PHPLC uses two conditions: 1) Instrument model: agilent 1260, chromatographic column: waters XBridge Prep C ₁₈ OBD (19 mm. Times.150 mm. Times.5.0 μm); chromatographic column temperature: 25 ℃; flow rate: 20.0mL/min; detection wavelength: 214nm; mobile phase a:100% acetonitrile; mobile phase B:0.05% ammonium bicarbonate aqueous solution; elution gradient: 0min:10% A,90% B;16.0min:90% A,10% B; 2) Instrument model: agilent 1260, chromatographic column: waters SunFire Prep C ₁₈ OBD (19 mm. Times.150 mm. Times.5.0 μm); chromatographic column temperature: 25 ℃; flow rate: 20.0mL/min; detection wavelength: 214nm; mobile phase a:100% acetonitrile; mobile phase B:100% water (0.05% formic acid); elution gradient: 0min:10% A,90% B;16.0min:90% A,10% B.

[ preparation of intermediate ]

Intermediate preparation example 1: preparation of N- (4-bromo-3 '- (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide.

The first step: preparation of 3'- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl-4-amine.

4-bromo-2-nitroaniline (2.00 g,9.22 mmol) and 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (3.72 g,12.90 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (20 mL) and water (5 mL), and potassium carbonate (2.54 g,18.43 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (376 mg,0.46 mmol) were added, and after nitrogen substitution, heated to 80℃for 2h. The reaction solution was poured into water (150 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound of this step (2.42 g, yield: 88.1%).

MS(ESI):m/z 297.1[M-H] ^- 。

And a second step of: preparation of 4-bromo-3 '- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl.

3'- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl-4-amine (2.50 g,8.38 mmol) and cuprous bromide (1.20 g,8.38 mmol) were added to acetonitrile (20 mL), stirred at 0deg.C for 0.5h, and tert-butyl nitrite (2.59 g,25.15 mmol) was slowly added dropwise and reacted at 25deg.C for 3h. The reaction solution was poured into water (100 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.8 g, yield: 92.2%) of the present step.

And a third step of: preparation of 4-bromo-3 '- (difluoromethoxy) -5' -fluorobiphenyl-3-amine.

4-bromo-3 '- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl (2.40 g,6.63 mmol), iron powder (3.70 g,66.3 mmol) and ammonium chloride (3.55 g,66.3 mmol) were added to a mixed solvent of ethanol (20 mL) and water (10 mL), and the mixture was heated to 80℃for 2h. The reaction solution was poured into water (150 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.0 g, yield: 90.9%) of the present step.

MS(ESI):m/z 332.0[M+H] ⁺ 。

Fourth step: preparation of N- (4-bromo-3 '- (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide.

4-bromo-3 '- (difluoromethoxy) -5' -fluorobiphenyl-3-amine (2.0 g,6.02 mmol) was completely dissolved in dichloromethane (50 mL), pyridine (2.38 g,30.11 mmol) and 3- (trifluoromethyl) benzenesulfonyl chloride (2.95 g,12.04 mmol) were added sequentially at room temperature and the reaction was maintained at room temperature for 2h. After concentrating under reduced pressure, the residue was poured into water (150 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound of this step (2.4 g, yield: 73.8%).

MS(ESI):m/z 538.0[M-H] ^- 。

Intermediate preparation example 2: preparation of methyl 4-oxo-4- (piperazin-1-yl) butyrate.

The first step: preparation of tert-butyl 4- (4-methoxy-4-oxobutanoyl) piperazine-1-carboxylate.

Piperazine-1-carboxylic acid tert-butyl ester (0.5 g,2.69 mmol) and triethylamine (0.82 g,8.06 mmol) were dissolved in dichloromethane (5 mL), and monomethyl succinate chloride (0.61 g,4.04 mmol) was added dropwise under ice-bath and reacted at room temperature for 2h. The reaction solution was poured into water (30 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound of this step (0.6 g, yield: 74.1%).

MS(ESI):m/z 301.0[M+H] ⁺ 。

And a second step of: preparation of methyl 4-oxo-4- (piperazin-1-yl) butyrate.

Tert-butyl 4- (4-methoxy-4-oxobutanoyl) piperazine-1-carboxylate (0.6 g,1.99 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.27 g,19.9 mmol) was added dropwise under ice-bath and reacted at room temperature for 2h. The reaction solution was concentrated, diluted with aqueous sodium hydrogencarbonate, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.3 g, yield: 75.3%).

MS(ESI):m/z 201.1[M+H] ⁺ 。

Intermediate preparation example 3: preparation of methyl 1-piperazine-1-carbonyl cyclopropylcarboxylate.

Using a synthesis method similar to intermediate preparation 2, the starting material in the first step was replaced with methyl 1- (chloroformyl) cyclopropanecarboxylate from monomethyl succinate to give the title compound (0.25 g, yield: 73.5%).

MS(ESI):m/z 213.1[M+H] ⁺ 。

[ preparation of Compounds ]

Example 1: preparation of 2- (3- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -1H-pyrazol-1-yl) acetic acid (compound 1).

The first step: preparation of ethyl 2- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetate.

1H-pyrazole-3-boronic acid pinacol ester (1.5 g,7.73 mmol) was completely dissolved in acetonitrile (5 mL), potassium carbonate (3.20 g,23.19 mmol) and ethyl bromoacetate (1.55 g,9.28 mmol) were added sequentially with stirring at room temperature, and the reaction was maintained at room temperature for 2H. The reaction solution was poured into water (100 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.0 g, yield: 92.4%) of the present step.

MS(ESI):m/z 281.1[M+H] ⁺ 。

And a second step of: preparation of ethyl 2- (3- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -1H-pyrazol-1-yl) acetate.

N- (4-bromo-3 ' - (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (200 mg,0.37 mmol) and ethyl 2- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetate (207.4 mg,0.74 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (8 mL) and water (2 mL), and potassium carbonate (102.2 mg,0.74 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (14 mg,0.018 mmol) were added, and after nitrogen substitution, heated to 80℃for 2H. The reaction solution was poured into water (100 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatograph (condition 1) to give the title compound of the present step (82 mg, yield: 36.1%).

MS(ESI):m/z 614.1[M+H] ⁺ 。

And a third step of: preparation of 2- (3- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -1H-pyrazol-1-yl) acetic acid.

Ethyl 2- (3- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -1H-pyrazol-1-yl) acetate (70 mg,0.11 mmol) was dissolved in a mixed solvent of ethanol (5 mL) and water (1 mL), sodium hydroxide (10 mg,0.23 mmol) was added, and the reaction was continued under stirring at 60℃for 1H. The reaction solution was poured into water (50 mL), pH was adjusted with 2N diluted hydrochloric acid=2, extraction was performed three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatograph (condition 2) to give the title compound (10 mg, yield: 15.0%).

MS(ESI):m/z 586.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ7.97-7.95(m,1H),7.88-7.86(m,2H),7.81-7.80(m,1H),7.77-7.74(m,2H),7.62-7.60(m,1H),7.52-7.50(m,1H),7.42(t,J＝2.8Hz,1H),7.37-7.35(m,1H),7.26-7.17(m,2H),6.73-6.71(m,1H),4.90(s,2H)。

Example 2: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (2-methoxyethyl) -1H-pyrazol-3-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 2).

Using a synthesis method similar to example 1, the starting material in the first step was replaced with 2-bromoethyl methyl ether from ethyl bromoacetate to give the title compound (30 mg, yield: 21.5%).

MS(ESI):m/z 586.1[M+H] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ ):δ11.23(s,1H),7.89-7.77(m,3H),7.64(d,J＝7.2Hz,1H),7.54-7.48(m,2H),7.39(t,J＝8.0Hz,1H),7.31-7.29(m,1H),7.17-7.13(m,2H),6.87(d,J＝9.2Hz,1H),6.76-6.58(m,1H),6.39(d,J＝2.8Hz,1H),4.37(t,J＝5.2Hz,2H),3.85(t,J＝4.8Hz,2H),3.40(s,3H)。

Example 3: preparation of 2- (3- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -1H-pyrazol-1-yl) -N, N-dimethylacetamide (compound 3).

Using a synthesis method similar to example 1, the starting material in the first step was replaced with ethyl bromoacetate to 2-bromo-N, N-dimethylacetamide to give the title compound (15 mg, yield: 21.2%).

MS(ESI):m/z 613.1[M+H] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ ):δ10.98(s,1H),7.90-7.87(m,2H),7.77(d,J＝7.6Hz,1H),7.64(d,J＝7.6Hz,1H),7.55-7.53(m,2H),7.45-7.41(m,1H),7.31-7.29(m,1H),7.17-7.12(m,2H),6.89-6.86(m,1H),6.76-6.57(m,1H),6.46-6.39(m,1H),5.07(s,2H),3.22(s,3H),3.06(s,3H)。

Example 4: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1-isopropyl-1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 4).

N- (4-bromo-3 ' - (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (100 mg,0.18 mmol) and 1-isopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (87.4 mg,0.37 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (4 mL) and water (1 mL), and potassium carbonate (51 mg,0.37 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (7 mg,0.009 mmol) were added, and after nitrogen substitution, heated to 80℃for 2H. The reaction solution was poured into water (20 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and purified by TLC (eluent: petroleum ether/ethyl acetate (V/V) =1/1) to give the title compound (20 mg, yield: 18.6%).

MS(ESI):m/z 570.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ10.11(s,1H),8.12(s,1H),8.01-7.99(m,1H),7.93(d,J＝8.0Hz,1H),7.83(s,1H),7.78-7.74(m,2H),7.67-7.62(m,2H),7.56-7.38(s,1H),7.23-7.10(m,3H),7.08(s,1H),4.44-4.41(m,1H),1.42(d,J＝6.8Hz,6H)。

Example 5: preparation of N- (3 '- (difluoromethoxy) -4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 5).

The first step: preparation of N, N-dimethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethylamine.

4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g,7.73 mmol) was completely dissolved in acetonitrile (5 mL), and potassium carbonate (3.20 g,23.19 mmol) and 2-chloro-N, N-dimethylethylamine (998 mg,9.28 mmol) were added sequentially with stirring at room temperature, and reacted at 80℃for 6H. The reaction solution was poured into water (100 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound of this step (1.8 g, yield: 88.2%).

MS(ESI):m/z 266.0[M+H] ⁺ 。

And a second step of: preparation of N- (3 '- (difluoromethoxy) -4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide.

N- (4-bromo-3 ' - (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (200 mg,0.37 mmol) and N, N-dimethyl-2- (4, 5-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethylamine (196.1 mg,0.74 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (8 mL) and water (2 mL), and potassium carbonate (102.2 mg,0.74 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (14 mg,0.018 mmol) were added, followed by nitrogen substitution and heating to 80℃for 2 hours. The reaction solution was poured into water (50 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatograph (condition 1) to give the title compound (8 mg, yield: 5.9%).

MS(ESI):m/z 599.2[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ8.19(s,1H),7.96(d,J＝7.6Hz,2H),7.89(s,1H),7.84(s,1H),7.76-7.73(m,1H),7.59-7.52(m,2H),7.52-7.18(m,1H),7.15-7.07(m,3H),7.03(s,1H),4.21(t,J＝6.4Hz,2H),2.76(t,J＝6.4Hz,2H),2.26(s,6H)。

Example 6: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 6).

Using a synthesis method similar to example 5, substituting starting material 2-chloro-N, N-dimethylethylamine with 2-bromoethyl methyl ether gave the title compound (30 mg, yield: 21.5%).

MS(ESI):m/z 586.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ10.14(s,1H),8.11(s,1H),8.03-7.95(m,2H),7.89(s,1H),7.84-7.74(m,2H),7.66-7.61(m,2H),7.56-7.20(m,1H),7.16-7.13(m,2H),7.10-7.02(m,2H),4.26(t,J＝5.2Hz,2H),3.72(t,J＝5.2Hz,2H),3.28(s,3H)。

Example 7: preparation of (S) -N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 7).

Using a method of synthesis similar to example 5, substituting starting material 2-chloro-N, N-dimethylethylamine with (S) -3-bromotetrahydrofuran, the title compound was obtained (12 mg, yield: 39.1%).

MS(ESI):m/z 598.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ10.13(s,1H),8.15(s,1H),8.02-7.92(m,2H),7.82-7.74(m,3H),7.72-7.60(m,2H),7.56-7.38(s,1H),7.23-7.11(m,3H),7.08(s,1H),5.01-4.96(m,1H),4.00-3.96(m,2H),3.93-3.80(m,2H),2.46-2.34(m,1H),2.28-2.21(m,1H)。

Example 8: preparation of (R) -N- (3 '- (difluoromethoxy) -5' -fluoro-4- (1- (tetrahydrofuran-3-yl) -1H-pyrazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 8).

Using a synthesis method similar to example 5, substituting starting material 2-chloro-N, N-dimethylethylamine with (R) -3-bromotetrahydrofuran, the title compound was obtained (42 mg, yield: 41.2%).

MS(ESI):m/z 598.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ10.14(s,1H),8.23(s,1H),7.97-7.82(m,4H),7.77-7.57(m,3H),7.55-7.36(s,1H),7.23-7.09(m,3H),7.06(s,1H),5.01-4.96(m,1H),4.08-3.93(m,2H),3.93 -3.77(m,2H),2.45-2.33(m,1H),2.28-2.20(m,1H)。

Example 9: preparation of N- (3 '- (difluoromethoxy) -4- (1-ethyl-1H-pyrazol-4-yl) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 9).

Using a method similar to the synthesis of example 4, starting material 1-isopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was replaced with 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester to give the title compound (30 mg, yield: 25.6%).

MS(ESI):m/z 556.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ10.10(s,1H),8.08-7.98(m,2H),7.93(d,J＝7.6Hz,1H),7.85(s,1H),7.79-7.76(m,2H),7.69-7.67(m,1H),7.61-7.59(m,1H),7.56-7.38(m,1H),7.19-7.12(m,3H),7.07(s,1H),4.11(d,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H)。

Example 10: preparation of 2- (4- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -5, 6-dihydropyridin-1 (2H) -yl) acetic acid (compound 10).

Using a synthesis similar to example 1, starting material in the first step was replaced with 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole from 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine to give the title compound (8 mg, yield: 7.0%).

MS(ESI):m/z 599.0[M-H] ^- 。

¹ H-NMR(400MHz,CDCl ₃ ):δ8.15-7.98(m,3H),7.83-7.80(m,1H),7.55-7.36(m,2H),7.23-7.12(m,4H),7.06(s,1H),5.38(s,1H),3.66-3.41(m,4H),2.87-2.84(m,2H),2.35-2.33(m,2H)。

Example 11: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4- (thiazol-4-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 11).

N- (4-bromo-3 '- (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (210 mg,0.37 mmol), tributyl (thiazol-4-yl) stannane (210 mg,0.56 mmol) and lithium chloride (71 mg,1.66 mmol) were added to a 1, 4-dioxane (6 mL) solvent and dissolved under stirring at room temperature. Tetrakis (triphenylphosphine) palladium (46 mg,0.04 mmol) was added, and after nitrogen substitution, stirred at 100℃for 4h. The reaction mixture was concentrated, extracted with ethyl acetate, and the organic phase was dried and purified by preparative high performance liquid chromatography (condition 1) to give the title compound (125 mg, yield: 63.7%).

MS(ESI):m/z 545.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ11.36(s,1H),9.37(s,1H),8.17(s,1H),7.94-7.87(m,2H),7.78(d,J＝8.0Hz,1H),7.74-7.60(m,4H),7.44-7.41(m,1H),7.41(d,J＝9.6Hz,1H),7.30(s,1H),7.21-7.19(m,1H)。

Example 12: preparation of N- (4- (4- (cyclopropyloxy) piperazin-1-yl) -3'- (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 12).

The first step: preparation of (4- (4-bromo-2-nitrophenyl) piperazin-1-yl) (cyclopropyl) methanone.

4-bromo-1-fluoro-2-nitrobenzene (0.50 g,2.27 mmol), 1-cyclopropylpiperazine (0.49 g,3.18 mmol) and cesium carbonate (1.56 g,4.55 mmol) were dissolved in N, N-dimethylformamide (5 mL), and after stirring at 60℃for 12 hours, the reaction solution was poured into water (60 mL), extracted with ethyl acetate (50 mL. Times.3), washed with water, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was dried to give the title compound (0.65 g, yield: 81.2%) of the present step.

MS(ESI):m/z 354.1[M+H] ⁺ 。

And a second step of: preparation of (4- (2-amino-4-bromophenyl) piperazin-1-yl) (cyclopropyl) methanone.

(4- (4-bromo-2-nitrophenyl) piperazin-1-yl) (cyclopropyl) methanone (0.65 g,1.84 mmol) was dissolved in ethanol (8 mL) and water (2 mL), iron powder (0.31 g,5.52 mmol) and ammonium chloride (0.31 g,5.52 mmol) were added, stirred at 80 ℃ for 2h, then filtered, concentrated, diluted with ethyl acetate, washed with water, separated, dried, filtered, concentrated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (V/V) =3/1) to give the title compound of this step (0.29 mg, yield: 48.8%).

MS(ESI):m/z 324.0[M+H] ⁺ 。

And a third step of: preparation of N- (5-bromo-2- (4-cyclopropanecarbonyl) piperazin-1-yl) phenyl) -3- (trifluoromethyl) benzenesulfonamide.

(4- (2-amino-4-bromophenyl) piperazin-1-yl) (cyclopropyl) methanone (0.29 g,0.89 mmol) was dissolved in pyridine (5 mL), 3- (trifluoromethyl) benzenesulfonyl chloride (0.28 g,1.13 mmol) was slowly added and reacted at 60℃for 4 hours, an appropriate amount of ethyl acetate and water were added to the reaction solution, the organic phase was separated, washed once with 1N hydrochloric acid solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was dried to give the title compound of this step (0.42 g, yield: 88.2%).

MS(ESI):m/z 532.1[M+H] ⁺ 。

Fourth step: preparation of N- (4- (4- (cyclopropyloxy) piperazin-1-yl) -3'- (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide.

N- (5-bromo-2- (4-cyclopropylyl) piperazin-1-yl) phenyl) -3- (trifluoromethyl) benzenesulfonamide (180 mg,0.32 mmol), 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (108 mg,0.35 mmol) and potassium carbonate (93.8 mg,0.64 mmol) were dissolved in 1, 4-dioxane (4 mL) and water (1 mL), and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (13.8 mg,0.16 mmol) was added and reacted at 80℃under nitrogen protection, insoluble matter in the reaction solution was removed by filtration, concentrated, ethyl acetate and saturated brine were added, the organic phase was dried over anhydrous sodium sulfate, filtered, and the spin-dried solvent was purified by preparative high performance liquid chromatograph (condition 1) to give the title compound (17 mg, yield of the present step: 8.2%).

MS(ESI):m/z 614.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.77(s,1H),8.09-8.03(m,3H),7.85-7.81(m,1H),7.58-7.39(m,3H),7.27-7.20(m,2H),7.15-7.11(m,2H),3.67(br,2H),3.45(br,2H),2.67(t,J＝2.0Hz,1H),2.52-2.50(m,2H),1.99-1.96(m,1H),0.74-0.69(m,4H)。

Example 13: preparation of 4- (4- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperazin-1-yl) -4-oxobutanoic acid (compound 13).

The first step: preparation of methyl 4- (4- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperazin-1-yl) -4-oxobutanoate.

Using a method of synthesis analogous to example 12, substituting methyl 4-oxo-4- (piperazin-1-yl) butanoate for 1-cyclopropylpiperazine, the title compound of this step (350 mg, yield: 60.9%).

MS(ESI):m/z 659.7[M+H] ⁺ 。

And a second step of: preparation of 4- (4- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperazin-1-yl) -4-oxobutanoic acid.

Methyl 4- (4- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) -4-oxobutanoate (350 mg,0.50 mmol) was dissolved in a mixed solvent of methanol (5 mL) and water (1 mL), sodium hydroxide (61.7 mg,1.50 mmol) was added, and the mixture was stirred at room temperature for 2h. The reaction solution was poured into water (30 mL), ph=4 was adjusted with 2N hydrochloric acid, extraction was performed three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatograph (condition 2) to give the title compound (138 mg, yield: 40.3%).

MS(ESI):m/z 645.8[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ11.96(br,1H),9.66(br,1H),8.09-8.04(m,3H),7.86-7.82(m,1H),7.58-7.39(m,3H),7.27-7.11(m,4H),3.47-3.44(m,4H),3.34-3.28(m,4H),2.67-2.63(m,2H),2.67-2.42(m,2H)。

Example 14: preparation of 1- (4- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperazine-1-carbonyl) cyclopropanecarboxylic acid (compound 14).

Using a method of synthesis similar to example 13, methyl 4-oxo-4- (piperazin-1-yl) butyrate was replaced with methyl 1- (piperazine-1-carbonyl) cyclopropanecarboxylate to give the title compound (16 mg, yield: 5.2%).

MS(ESI):m/z 658.0[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ8.07-8.05(m,2H),7.95-7.93(m,1H),7.77-7.75(m,1H),7.55-7.37(m,2H),7.32-7.29(m,1H),7.19-7.16(m,1H),7.09-7.02(m,3H),3.50-3.38(m,4H),2.77-2.67(m,4H),1.24(d,J＝2.8Hz,2H),1.10(d,J＝2.8Hz,2H)。

Example 15: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4-morpholinylbiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 15).

Using a synthesis method similar to example 12, substituting morpholine for 1-cyclopropylpiperazine, the title compound was obtained (17 mg, yield: 9.1%).

MS(ESI):m/z 545.0[M-H] ^- 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.65(s,1H),8.07-8.04(m,3H),7.84(d,J＝8.0Hz,1H),7.58-7.54(m,1H),7.45-7.44(m,1H),7.39-7.21(m,3H),7.14-7.11(m,2H),3.56-3.54(m,4H),2.62-2.59(m,4H)。

Example 16: preparation of methyl 1- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidine-4-carboxylate (compound 16).

Using a method of synthesis analogous to example 12, substituting 1-cyclopropylpiperazine for methyl piperidine-4-carboxylate gives the title compound (219 mg, yield: 77.2%).

MS(ESI):m/z 601.0[M-H] ^- 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.62(s,1H),8.10-8.03(m,3H),7.84-7.79(m,1H),7.57-7.39(m,3H),7.24-7.10(m,4H),3.63(s,3H),2.75-2.72(m,2H),2.55-2.52(m,2H),2.41-2.34(m,1H),1.77-1.62(m,4H)。

Example 17: preparation of 1- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidine-4-carboxylic acid (compound 17).

Methyl 1- (3 '- (difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-carboxylate (162.1 mg,0.26 mmol) was dissolved in a mixed solvent of methanol (5 mL) and water (1 mL), sodium hydroxide (43.1 mg,1.04 mmol) was added, and the mixture was stirred at 60℃for 1h. The reaction solution was poured into water (10 mL), ph=4 was adjusted with 2N hydrochloric acid, extraction was performed three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatograph (condition 2) to give the title compound (79 mg, yield: 49.9%).

MS(ESI):m/z 587.0[M-H] ^- 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.67(br,1H),9.60(br,1H),8.09-8.02(m,3H),7.83-7.79(m,1H),7.57-7.39(m,3H),7.23-7.10(m,4H),2.75-2.72(m,2H),2.54-2.52(m,2H),2.27-2.23(m,1H),1.77-1.62(m,4H)。

Example 18: preparation of 2- (1- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid (compound 18).

The first step: preparation of methyl 2- (1- (4-bromo-2-nitrophenyl) piperidin-4-yl) acetate.

4-bromo-1-fluoro-2-nitrobenzene (0.50 g,2.27 mmol), methyl 2- (4-piperidinyl) acetate (0.43 g,2.73 mmol) and cesium carbonate (1.11 g,3.41 mmol) were dissolved in N, N-dimethylformamide (5 mL), and after stirring at 60℃for 12h, the reaction mixture was poured into water (60 mL), extracted with ethyl acetate (50 mL. Times.3), washed with water, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was dried to give the title compound of this step (0.60 g, yield: 75.0%).

MS(ESI):m/z 357.0[M+H] ⁺ 。

And a second step of: preparation of methyl 2- (1- (2-amino-4-bromophenyl) piperidin-4-yl) acetate.

Methyl 2- (1- (4-bromo-2-nitrophenyl) piperidin-4-yl) acetate (0.60 g,1.68 mmol) was dissolved in ethanol (8 mL) and water (2 mL), iron powder (0.47 g,8.40 mmol) and ammonium chloride (0.45 g,8.40 mmol) were added, stirred at 80 ℃ for 2h, then filtered, concentrated, diluted with ethyl acetate, washed with water, separated, dried, filtered, concentrated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (V/V) =2/1) to give the title compound of this step (0.38 g, yield: 69.1%).

MS(ESI):m/z 327.1[M+H] ⁺ 。

And a third step of: preparation of methyl 2- (1- (4-bromo-2- (3- (trifluoromethyl) benzenesulfonyl) phenyl) piperidin-4-yl) acetate.

Methyl 2- (1- (2-amino-4-bromophenyl) piperidin-4-yl) acetate (0.38 g,1.16 mmol) was dissolved in pyridine (5 mL), 3- (trifluoromethyl) benzenesulfonyl chloride (0.30 g,1.22 mmol) was slowly added, reacted at 60℃for 4 hours, an appropriate amount of ethyl acetate and water were added to the reaction solution, the organic phase was separated, washed once with 1N hydrochloric acid solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was dried to give the title compound (0.60 g, yield: 96.8%) of the present step.

MS(ESI):m/z 535.0[M+H] ⁺ 。

Fourth step: preparation of methyl 2- (1- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetate.

Methyl 2- (1- (4-bromo-2- (3- (trifluoromethyl) benzenesulfonyl) piperidin-4-yl) acetate (600 mg,1.12 mmol), 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (387 mg,1.34 mmol) and potassium carbonate (310 mg,2.24 mmol) were dissolved in 1, 4-dioxane (10 mL) and water (2 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (91 mg,0.11 mmol) was added and reacted at 80℃with nitrogen protection, insoluble matter was removed by filtration, concentrated, ethyl acetate and saturated brine were added, the extracted organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was dried, and the residue was purified by preparative high performance liquid chromatograph (condition 1) to give the title compound (200 mg, 28.9%) of the present step.

MS(ESI):m/z 617.2[M+H] ⁺ 。

Fifth step: preparation of 2- (1- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid.

Methyl 2- (1- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetate (200 mg,0.32 mmol) was dissolved in a mixed solvent of methanol (5 mL) and water (1 mL), sodium hydroxide (51.2 mg,1.28 mmol) was added, and the mixture was stirred at room temperature for 2h. The reaction solution was concentrated, and then water (15 mL) was added to the concentrate to adjust ph=2 with 4N hydrochloric acid, and the filter cake was filtered and dried to give the title compound (150 mg, yield: 76.9%).

MS(ESI):m/z 603.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.09(s,1H),9.44(s,1H),8.12-8.01(m,3H),7.83(t,J＝7.6Hz,1H),7.59-7.38(m,3H),7.25(d,J＝9.6Hz,1H),7.20(d,J＝8.4Hz,1H),7.16-7.07(m,2H),2.70(d,J＝11.6Hz,2H),2.50-2.45(m,2H),2.15(d,J＝7.2Hz,2H),1.69-1.66(m,1H),1.58(d,J＝11.6Hz,2H),1.16-1.24(m,2H)。

Example 19: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4- (4-hydroxy-4-methylpiperidin-1-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 19).

Using a synthesis method similar to example 12, the starting material in the first step was replaced with 4-methyl-4-hydroxypiperidine from 1-cyclopropylpiperazine to give the title compound (26 mg, yield: 23.7%).

MS(ESI):m/z 575.2[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.40(s,1H),8.08-8.01(m,3H),7.80(t,J＝7.6Hz,1H),7.64-7.54(m,1H),7.46-7.38(m,3H),7.28-6.99(m,4H),4.19(s,1H),2.79(t,J＝9.6Hz,2H),2.60-2.53(m,2H),1.59-1.35(m,4H),1.12(s,3H)。

Example 20: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4- (4- (methylsulfonyl) piperidin-1-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 20).

Using a synthesis method similar to example 12, the starting material in the first step was replaced with 4-methanesulfonylpiperidine from 1-cyclopropylpiperazine, to give the title compound (20 mg, yield: 22.8%).

MS(ESI):m/z 623.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.70(s,1H),8.16-8.02(m,3H),7.84(t,J＝7.6Hz,1H),7.58-7.37(m,3H),7.24-7.08(m,4H),3.15-3.09(m,1H),2.96(s,3H),2.88-2.81(m,2H),2.62-2.54(m,2H),1.95-1.78(m,4H)。

Example 21: preparation of N- (3 '- (difluoromethoxy) -5' -fluoro-4- (4- (2-methoxyethoxy) piperidin-1-yl) biphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 21).

Using a synthesis method similar to example 12, the starting material in the first step was replaced with 4- (2-methoxyethoxy) piperidine from 1-cyclopropylpiperazine to give the title compound (48 mg, yield: 10.1%).

MS(ESI):m/z 619.2[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ9.51(br,1H),8.11-8.04(m,3H),7.85-7.81(m,1H),7.57-7.39(m,3H),7.24-7.17(m,2H),7.13-7.10(m,2H),3.54-3.51(m,2H),3.45-3.43(m,2H),3.38-3.36(m,1H),3.26(s,3H),2.74-2.71(m,2H),2.53-2.51(m,2H),1.80-1.78(m,2H),1.55-1.51(m,2H)。

Example 22: preparation of 2- (1- (3 '-chloro-5' -methoxy-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid (compound 22).

Using a synthesis method similar to example 18, the starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan to 3-chloro-5-methoxyphenylboronic acid, affording the title compound (68 mg, yield: 91.4%).

MS(ESI):m/z 583.3[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.08(s,1H),9.40(s,1H),8.08-8.04(m,3H),7.83(t,J＝8.0Hz,1H),7.48-7.46(m,1H),7.42-7.39(m,1H),7.18(d,J＝4.0Hz,1H),7.07-6.98(m,3H),3.83(s,3H),2.69-2.66(m,2H),2.50-2.46(m,2H),2.15(d,J＝8.8Hz,2H),1.74-1.57(m,3H),1.27-1.17(m,2H)。

Example 23: preparation of 2- (1- (3 '-fluoro-5' -methoxy-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid (compound 23).

Using a synthesis method similar to example 18, starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan to 3-fluoro-5-methoxyphenylboronic acid, affording the title compound (92 mg, yield: 74.5%).

MS(ESI):m/z 567.2[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.10(s,1H),9.40(s,1H),8.08-8.04(m,3H),7.83(t,J＝8.0Hz,1H),7.48-7.45(m,1H),7.42-7.40(m,1H),7.18(d,J＝8.4Hz,1H),6.89-6.80(m,3H),3.82(s,3H),2.68-2.65(m,2H),2.50-2.46(m,2H),2.15(d,J＝7.2Hz,2H),1.71-1.56(m,3H),1.27-1.17(m,2H)。

Example 24: preparation of 2- (1- (3 '-methoxy-5' -methyl-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid (compound 24).

Using a synthesis method similar to example 18, the starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan to 3-methoxy-5-methylphenylboronic acid, affording the title compound (25 mg, yield: 32.5%).

MS(ESI):m/z 563.2[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.04(s,1H),9.33(s,1H),8.09-8.05(m,3H),7.83(t,J＝7.6Hz,1H),7.48-7.39(m,2H),7.17(d,J＝8.0Hz,1H),6.84-6.75(m,3H),3.78(s,3H),2.68-2.65(m,2H),2.50-2.46(m,2H),2.33(s,3H),2.15(d,J＝6.8Hz,2H),1.71-1.58(m,3H),1.28-1.20(m,2H)。

Example 25: preparation of 2- (1- (3 '-chloro-5' - (difluoromethoxy) -3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid (compound 25).

Using a synthesis method similar to example 18, starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan to 3-chloro-5- (difluoromethoxy) phenylboronic acid, affording the title compound (60 mg, yield: 53.8%).

MS(ESI):m/z 619.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.04(s,1H),9.45(s,1H),8.07-8.05(m,3H),7.81(t,J＝8.0Hz,1H),7.58-7.40(m,4H),7.30-7.17(m,3H),2.73-2.67(m,2H),2.50-2.46(m,2H),2.14(d,J＝7.2Hz,2H),1.69-1.56(m,3H),1.23-1.15(m,2H)。

Example 26: preparation of 2- (1- (3 '-chloro-5' -ethoxy-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid (compound 26).

Using a synthesis method similar to example 18, starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan to 3-chloro-5-ethoxyphenylboronic acid, affording the title compound (25 mg, yield: 45.8%).

MS(ESI):m/z 597.0[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.04(s,1H),9.40(s,1H),8.07-8.04(m,3H),7.85-7.81(m,1H),7.64-7.54(m,1H),7.47-7.38(m,2H),7.17-7.14(m,1H),7.05-6.95(m,3H),4.12-4.07(m,2H),2.68(d,J＝9.6Hz,2H),2.49-2.45(m,1H),2.15(d,J＝7.2Hz,2H),1.69-1.56(m,3H),1.35(t,J＝7.2Hz,3H),1.26-1.17(m,2H)。

Example 27: preparation of 2- (1- (3 '-chloro-5' - (trifluoromethoxy) -3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperidin-4-yl) acetic acid (compound 27).

Using a synthesis method similar to example 18, the starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan to 3-chloro-5-trifluoromethoxyphenylboronic acid, affording the title compound (67 mg, yield: 48.6%).

MS(ESI):m/z 637.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ ):δ12.08(s,1H),9.47(s,1H),8.08-8.05(m,3H),7.83(t,J＝8.0Hz,1H),7.64-7.60(m,1H),7.56-7.53(m,2H),7.41-7.39(m,2H),7.20(d,J＝8.8Hz,1H),2.76-2.73(m,2H),2.50-2.48(m,2H),2.15(d,J＝7.2Hz,2H),1.70-1.57(m,3H),1.25-1.19(m,2H)。

[ biological evaluation ]

Experimental example 1: time resolved fluorescence resonance energy transfer (TR-FRET) experiments with RORgamma-LBD.

1. Experimental materials and instruments:

rorγ -LBD (glow-source organism);

biotin-SRC 1 (Perkin Elmer);

LANCE Eu-anti-6 XHis antibody (Perkin Elmer);

Allophycocyanin-Streptavidin(Perkin Elmer)；

microplate reader (B MG Labtech).

2. The experimental method comprises the following steps:

preparing a solution: reaction buffer (25 mM hepes, ph=7.0, 100mM nacl,0.01% Tween 20,0.2% BSA,5mM DTT) was formulated. A solution A1 containing 1nM LANCE Eu-anti-6 XHis antibody, a solution A2 containing 1nM LANCE Eu-anti-6 XHis antibody and 15nM ROR gamma-LBD, and a solution B containing 200nM biotin-SRC 1 and 15nM Allophycocyanin-strepitavidine were prepared with a reaction buffer, and placed on ice for use.

The test compound was diluted with DMSO and at a starting concentration of 5 μm, 4-fold dilution was used to take 10 concentration points. The test compound well in 384 well plate was added with 0.25 μl of diluted test compound, 15 μl of solution A2, and 10 μl of solution B; negative control wells were added with 0.25 μl of LDMSO, 15 μl of solution A1, and 10 μl of solution B; solvent control wells were added 0.25 μl DMSO, 15 μl solution A2, and 10 μl solution B. Sealing the tape sealing plate, vibrating for 2min, and uniformly mixing the reaction solution. After the 384-well plate was left at 4℃overnight, the 384-well plate was taken out to equilibrate to room temperature, centrifuged, and the plate was read with an ELISA reader (detection wavelength 665nm/615 nm).

3. And (3) data processing:

activation rate of compound= (FI ratio) _{Compounds of formula (I)} -FI ratio _{Solvent control} ) /(FI ratio) _{Solvent control} -FI ratio _{Negative control} )×100％；

FI ratio represents the ratio of the microplate reader read fluorescence value (665 nm) to the microplate reader read fluorescence value (615 nm);

calculation of EC by GraphPad Prism software ₅₀ Values.

Maximum activation rate: the activation rate of the corresponding concentration point when the curve obtained by the activation rate formula is in the upper plateau phase; and when the maximum activation rate is greater than 0, the compound to be tested has an agonistic effect on ROR gamma.

4. Results:

the results of the agonist activity of the test compounds of the present invention on rorγ are shown in table 1.

TABLE 1 agonistic Activity of the Compounds of the invention on ROR gamma

Numbering of compounds	EC ₅₀ (nM)	Maximum activation rate (%)
			1	2.1	70.7％
2	26.3	65.3％
			3	59.1	69.4％
4	109.3	61.2％
			5	87.7	70.7％
6	24.6	76.9％
			7	29.2	92.3％
8	58.1	84.2％
			9	89.8	69.9％
11	7.5	59.5％
			12	12.3	82.1％
13	25.8	63.2％
			15	25.3	51.2％
16	45.4	71.9％
			17	19.0	54.6％
18	18.4	58.8％
			19	8.5	59.5％
20	11.4	77.6％
			21	14.5	61.7％
22	14.9	55.5％
			23	12.6	57.2％
25	29.1	62.6％
			26	66.2	64.1％

It follows that the compounds of the invention have a pronounced agonistic effect on ROR gamma with an EC of, for example, less than 110nM, preferably less than 20nM, more preferably less than 10nM ₅₀ The maximum activation rate is above 50%.

Experimental example 2: rory-luciferase reporter assay.

1. Experimental materials and instruments:

plasmid pcDNA3.1 (GAL 4DBD/RORγLBD), pGL4.35 (luc 2P/9XGAL4 UAS/Hygro) (Nanjac Bai biostructural);

Lipofectamine 3000(Invitrogen)；

Bright-Glo ^TM (Promega)；

ursolic acid (Cayman Chemical);

enzyme labelling instrument (BMG Labtech);

293T cells (purchased from ATCC);

test compounds (formulated as 10mM stock in DMSO).

2. The experimental method comprises the following steps:

293T cells were cultured in a DMEM high-sugar medium (containing 10% FBS) in T25 cell culture flasks, and when the cells were grown to a confluency of about 80%, plasmid-entrapped liposomes were prepared according to Lipofectamine 3000. The liposomes were mixed with a volume of DMEM high sugar medium (containing 10% FBS), medium in the T25 flask was removed, and 293T cells were transfected by adding the mixture of the above liposomes and DMEM high sugar medium. 24h after transfection, cells were digested and counted. Diluting cells with DMEM high sugar medium (containing 10% FBS,2 μm ursolic acid) to a certain concentration, and spreading to 96-well culture plate with cells of about 10 per well ⁵ And each. Stock solutions of test compounds and solvent controls (DMSO) were diluted in DMEM high-sugar medium (10% FBS,2 μm ursolic acid) and 10 concentration points were taken at 3-fold dilution starting at 100 μm. The diluted test compound and solvent control are added to the experimental wells and solvent control wells of a 96-well cell culture plate, respectively. Shaking the cell culture plate for 2min to thoroughly mix the compound to be tested with the culture medium, and mixing with 5% CO at 37deg.C ₂ Culturing in incubator for 24 hr. The 96-well cell culture plate was removed to room temperature and equilibrated for 10min, and Bright-Glo was added according to the instructions ^TM And (5) fully and uniformly mixing. And rapidly transferring the mixed solution to a detection plate, and detecting the luminous intensity by adopting an enzyme-labeled instrument.

3. And (3) data processing:

activation rate = experimental well luminescence value/solvent control well mean luminescence value x 100%.

Solvent control wells mean luminescence values were defined as 100% and data analysis and mapping were performed using Graphpad Prism 5 software to calculate EC as log activation rate versus compound concentration via a four parameter fitted curve ₅₀ A value; the maximum activation rate is the activation rate of the corresponding concentration point when the fitted curve is in the upper plateau phase; when the maximum activation rate is greater than 100%, the compound to be tested has an agonistic effect on ROR gamma.

4. Results:

the results of the agonist activity of the compounds of the application on rorγ in cells are shown in table 2.

TABLE 2 agonistic Activity of the Compounds of the application on ROR gamma

Numbering of compounds	EC ₅₀ (nM)	Maximum activation rate (%)
			4	930	302.0％
8	566	370.1％
			11	1295	330.2％
12	517	489.7％
			15	1184	312.8％
16	1368	354.2％
			18	1075	488.3％
19	1260	388.7％
			20	1245	412.3％
21	1528	342.2％
			22	381	628.0％
23	1347	847.8％
			24	768	694.1％
25	854	534.3％
			26	1485	454.9％
27	929	653.8％

It can be seen that the compounds of the application have a pronounced agonistic effect on rorγ in cells, with an EC of, for example, less than 2000nM ₅₀ And a maximum activation rate greater than 300%.

Various modifications of the application, 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 disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims

1. A compound having the structure of formula I or a pharmaceutically acceptable form thereof,

wherein,

ring A ¹ Selected from phenyl;

ring A ² Selected from phenyl;

Z ¹ 、Z ² and Z ³ Each independently selected from CR ⁴ And N;

R ¹ selected from hydrogen and C _1-6 An alkyl group;

each R is ³ Each independently selected from halogen, cyano, hydroxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy group、C _1-6 Haloalkoxy and-S (=o) ₂ -R ⁶ ；

each R is ⁵ Each independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, -C _0-6 alkylene-O-R ^a 、-O-C _1-6 alkylene-O-R ^a 、C _1-6 Haloalkoxy, -C _0-6 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _1-6 alkylene-C (=O) -O-R ^a 、-C(＝O)-C _3-6 Cycloalkyl, -C (=o) -C _3-6 cycloalkylene-C (=o) -O-R ^a 、-C(＝O)-C _1-6 Alkyl, -C _0-6 alkylene-S (=o) ₂ -R ⁶ 、-C _0-6 alkylene-N (R) ^a )(R ^b )、-C _0-6 alkylene-C (=O) -N (R) ^a )(R ^b )、-C _0-6 alkylene-N (R) ^a )-C(＝O)-R ⁶ 、-C _0-6 alkylene-S (=o) ₂ -N(R ^a )(R ^b )、-C _0-6 alkylene-N (R) ^a )-S(＝O) ₂ -R ⁶ 4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl; wherein: each R is ^a Each independently selected from hydrogen and C _1-6 An alkyl group; each R is ^b Each independently selected from hydrogen and C _1-6 An alkyl group; or R is ^a And R is ^b Forming a 3-7 membered heterocyclic group together with the nitrogen atom to which it is attached;

m is 1, 2 or 3;

n is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

2. The compound or pharmaceutically acceptable form thereof according to claim 1, which is a compound having the structure of formula I-A or a pharmaceutically acceptable form thereof,

wherein ring A ¹ Ring A ² Ring A ³ 、R ² 、R ³ 、R ⁵ M, n and q are as defined in claim 1.

3. The compound or pharmaceutically acceptable form thereof according to claim 2, wherein,

ring A ¹ Selected from phenyl and pyridyl; each R is ² Each independently selected from halogen, cyano, hydroxy, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and C _3-6 A cycloalkoxy group.

4. A compound or pharmaceutically acceptable form thereof according to claim 2 or 3, wherein,

Ring A ² Selected from phenyl and 5-6 membered heteroaryl; each R is ³ Each independently selected from halogen, cyano, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and-S (=o) ₂ -C _1-4 An alkyl group.

5. The compound or pharmaceutically acceptable form thereof according to claim 2, which is a compound having the structure of formula I-B1 or a pharmaceutically acceptable form thereof,

wherein ring A ³ 、R ² 、R ⁵ M and q are as defined in claim 2.

6. The compound or pharmaceutically acceptable form thereof according to claim 5,

wherein each R ² Each independently selected from halogen, cyano, hydroxy, C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy and C _3-6 A cycloalkoxy group;

q is 0, 1 or 2;

m is 1 or 2.

7. The compound or pharmaceutically acceptable form thereof according to claim 6,

wherein,

ring A ³ Selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

q is 0, 1 or 2;

m is 2.

8. The compound or pharmaceutically acceptable form thereof according to claim 7,

wherein,

each R is ⁵ Each independently selected from hydrogen, -OH, -CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、-CH ₂ COOH、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ C(＝O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₂ CH ₂ COOH、/>-COOCH ₃ 、-COOH、-S(＝O) ₂ -CH ₃ and-OCH ₂ CH ₂ OCH ₃ ；

q is 0, 1 or 2;

m is 2;

preferably, ring A ³ Selected from the group consisting ofEach R is ⁵ Each independently selected from hydrogen, hydroxy, methyl, ethyl, isopropyl, -CH ₂ CH ₂ -O-CH ₃ 、-O-CH ₂ CH ₂ -O-CH ₃ 、-C(＝O)-O-H、-C(＝O)-O-CH ₃ 、-CH ₂ -C(＝O)-O-H、-C(＝O)-CH ₂ CH ₂ -C(＝O)-O-H、/>-S(＝O) ₂ -CH ₃ 、-CH ₂ CH ₂ -N(CH ₃ ) ₂ 、-CH ₂ -C(＝O)-N(CH ₃ ) ₂ And->

More preferably, the process is carried out,selected from->

9. The compound or pharmaceutically acceptable form thereof according to any one of claim 5 to 8, which is a compound having the structure of formula I-B or a pharmaceutically acceptable form thereof,

wherein ring A ³ 、R ⁵ And q is as defined in any one of claims 5 to 8.

10. The compound of claim 1, or a pharmaceutically acceptable form thereof, wherein the compound is selected from the group consisting of:

11. A process for the preparation of a compound having the structure of formula I according to claim 1, comprising the steps of:

(1) Reacting the compound A with the compound B to obtain a compound C;

(4) Reacting the compound E with a compound F to obtain a compound G;

wherein ring A ¹ Ring A ² Ring A ³ 、Z ¹ 、Z ² 、Z ³ 、R ¹ 、R ² 、R ³ 、R ⁵ M, n and q are as defined in claim 1; x represents a leaving group selected from the group consisting of a halogen atom, a methanesulfonyloxy group and a trifluoromethanesulfonyloxy group;

or comprises the following steps:

(1 ') reacting compound A' with compound B 'to obtain compound C';

(3 ') reacting the compound D ' with the compound F to obtain a compound F ';

(4 ') reacting compound F' with compound B to give a compound of formula I;

wherein ring A ¹ Ring A ² Ring A ³ 、Z ¹ 、Z ² 、Z ³ 、R ¹ 、R ² 、R ³ 、R ⁵ M, n and q are as defined in claim 1; x represents a leaving group selected from the group consisting of a halogen atom, a methanesulfonyloxy group and a trifluoromethanesulfonyloxy group; hal represents a halogen atom selected from F, cl, br and I.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier.

13. A pharmaceutical combination composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable form thereof or a pharmaceutical composition according to claim 12, and at least one other co-directional rory modulator.

14. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 12, or a pharmaceutical combination composition according to claim 13, in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by rorγ.