CN114096525A

CN114096525A - Biaryl compounds, pharmaceutical compositions containing them, processes for their preparation and their use

Info

Publication number: CN114096525A
Application number: CN202080050297.6A
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: 2022-02-25
Anticipated expiration: 2040-08-31
Also published as: CN117229215A; CN114096525B; WO2021047407A1

Abstract

Biaryl compounds, and pharmaceutical compositions, preparation methods and uses thereof. The compound has a structure shown in a formula I, has a remarkable ROR gamma regulation effect, can be used as a high-efficiency ROR gamma regulator, and has various pharmacological activities such as tumor resistance, autoimmune disease resistance, inflammation resistance and the like.

Description

Biaryl compounds, pharmaceutical compositions containing them, processes for their preparation and their use

Reference to related applications

The present invention claims priority of the invention patent application with application number 201910853525.2, filed in china on 9/10/2019, entitled "biaryl based compounds, pharmaceutical compositions comprising the same, methods for the preparation thereof and uses thereof", which is incorporated herein by reference in its entirety.

Technical Field

The invention 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 same, and medical application thereof.

Background

The nuclear receptor superfamily is a class of ligand-dependent transcription factors, and there are 48 family members (ZHANG Y, LUO X Y, WU D H, et al, ROR nuclear receptors: structures, related diseases, and drug discovery [ J ], Acta Pharmacological Sinica,2015,36(1): 71-87). Depending on the ligand type of the nuclear receptor, 48 superfamily members can be classified: steroid hormone receptors, non-steroid hormone receptors and orphan receptors. Wherein, the steroid hormone receptor includes Glucocorticoid Receptor (GR), Mineralocorticoid Receptor (MR), Androgen Receptor (AR), Estrogen Receptor (ER), Progestogen Receptor (PR), etc.; the nonsteroidal hormone receptors include thyroid hormone receptors (TR), retinoic acid receptors (or retinoic acid receptors, Retinoic Acid Receptors) (RAR), retinoic acid X receptors (RXR), Vitamin D3 Receptors (VDR), and the like; orphan receptors are so named because their endogenous ligands have not been discovered so far. The orphan receptor family members include retinoic acid receptor-Related Orphan Receptors (RORs), Farnesoid X Receptors (FXRs), Peroxisome Proliferator Activated Receptors (PPARs), Liver X Receptors (LXRs), and the like.

The members of the ROR superfamily include three subtypes, namely ROR alpha, ROR beta and ROR gamma, and play a role in regulation in various 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 tretinoin. RORs are widely distributed in various tissues of an organism, can directly enter cell nuclei to regulate the transcription of target genes, further participate in different physiological processes, and show different tissue specificities. Among them, ROR α is expressed in various tissues, but highly expressed in the brain, and plays an important role in cerebellar development and bone formation. ROR β has a small range of action, is mainly expressed in the brain, and plays a role in the development of the retina and cerebral cortex. ROR γ can be expressed in many tissues, including thymus, liver, skeletal muscle, etc., and plays a key role in secondary lymphoid tissue development.

ROR γ has two subtypes, ROR γ 1 and ROR γ 2(ROR γ t). ROR γ 1 is expressed in various tissues, while ROR γ 2 is specifically expressed on immune cells. ROR gamma 2 is a key transcription factor for differentiation and maintenance of Th17 and Tc17 effector T cells, regulates Th17 cells to secrete effector IL-17, plays an important role in the differentiation of NK cells, gamma delta T cells and iNKT cells, and can mediate the immune system to resist cancer cells and pathogenic microorganisms such as bacteria, fungi and the like. In the tumor microenvironment, Thl7 cells and IL-17 can recruit natural killer cells and cytotoxic CD8+ T cells to attack and kill tumor cells. Some studies have shown that levels of infiltrating Thl7 cells and IL-17 expression levels at tumor sites in patients with ovarian cancer are positively correlated with good prognosis.

The treatment of cancer, despite the extensive research and great efforts, remains a major threat to human health. Cancer is the most mortality disease, both in developed and developing countries, and morbidity and mortality continue to increase. At present, therapeutic drugs against tumors are not effective for all tumor patients, and the development of ROR γ modulators has been gradually emphasized in the pharmaceutical industry, for example, WO2017157332a1, WO2011115892a1, and the like. Therefore, research and development of compounds with high ROR gamma regulation activity, less side effect, strong drug resistance, improved pharmacokinetics and other properties can be beneficial to treatment of tumors, and more choices are provided for 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 ROR γ activity, a process for the preparation of the compound, a pharmaceutical composition comprising the compound, and a medical use of the compound.

Means for solving the problems

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

wherein the content of the first and second substances,

ring A¹Selected from phenyl and 5-6 membered heteroaryl;

ring A²Selected from phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl;

ring A³Selected from phenyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 4-10 membered heterocyclyl;

Z ¹、Z ²and Z³Each independently selected from CR⁴And N;

R ¹selected from hydrogen and C_1-6An alkyl group;

each R²Each independently selected from halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_3-6A cycloalkoxy group;

each R³Each independently selected from halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy and-S (═ O)₂-R ⁶；

Each R⁴Each independently selected from hydrogen, halogen, cyano, C_1-6Alkyl and C_1-6An alkoxy group;

each R⁵Each independently selected from hydrogen, halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, -C_0-6alkylene-O-R^a、-O-C _1-6alkylene-O-R^a、C _1-6Haloalkoxy, -C_0-6alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-6alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ C)O)-C _3-6cycloalkylene-C (═ O) -O-R^a、-C(＝O)-C _1-6Alkyl, -C_0-6alkylene-S (═ O)₂-R ⁶、-C _0-6alkylene-N (R)^a)(R ^b)、-C _0-6alkylene-C (═ O) -N (R)^a)(R ^b)、-C _0-6alkylene-N (R)^a)-C(＝O)-R ⁶、-C _0-6alkylene-S (═ O)₂-N(R ^a)(R ^b)、-C _0-6alkylene-N (R)^a)-S(＝O) ₂-R ⁶4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl; wherein: each R^aEach independently selected from hydrogen and C_1-6An alkyl group; each R^bEach independently selected from hydrogen and C_1-6An alkyl group; or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;

each R⁶Each independently selected from C_1-6Alkyl and C_3-6A cycloalkyl group;

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 specific compounds 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- (cyclopropylformyl) 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-formyl) 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 process for the preparation of a compound having the structure of formula I as described above, 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) carrying out reduction reaction and optional N-alkylation reaction on the compound D to obtain a compound E;

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

(5) reacting the compound G with a compound H to obtain a compound of a formula I;

wherein, ring A¹Ring A²Ring A³、Z ¹、Z ²、Z ³、R ¹、R ²、R ³、R ⁵M, 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' with the compound B 'to obtain a compound C';

(2 ') subjecting the compound C ' to a reduction reaction and an optional N-alkylation reaction to obtain a compound D ';

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

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

wherein, ring A¹Ring A²Ring A³、Z ¹、Z ²、Z ³、R ¹、R ²、R ³、R ⁵M, 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 ROR γ modulator.

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

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 rory. Preferably, the disease mediated at least in part by ROR γ is selected from cancer, inflammation and autoimmune disease.

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

In a ninth aspect, the present invention provides a pharmaceutical combination composition comprising a compound having the structure of formula I as described above or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above, and at least one other modulator of homeotropic ROR γ.

In a tenth aspect, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof 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 ROR γ agonist.

In an eleventh aspect, the present invention provides a method for preventing and/or treating inflammation, comprising the steps of: administering to a patient in need thereof 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 ROR γ antagonist.

In a twelfth aspect, the present invention provides a method for preventing and/or treating an autoimmune disease, comprising the steps of: administering to a patient in need thereof 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 ROR γ antagonist.

ADVANTAGEOUS EFFECTS OF INVENTION

The invention provides a compound of formula I with a novel structure, which can be used as a high-efficiency ROR gamma regulator, has various pharmacological activities such as anti-tumor, anti-autoimmune disease and anti-inflammation, and has the characteristics of less side effect, strong anti-drug resistance, effectively improved pharmacokinetics and the like. The synthesis method is mild, simple and feasible in operation and 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 ]

The following terms have the following meanings in the present invention unless otherwise specified.

The terms "comprises," "comprising," "includes," "including," "has," "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 include other elements not explicitly listed or inherent to such composition, method, or apparatus.

"pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, such salts also being referred to as acid addition salts or base addition salts.

The term "isomers" refers to compounds having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms, due to the same number and type of atoms.

The term "stereoisomer" (or "optical isomer") refers to a stable isomer having a perpendicular plane of asymmetry due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) that enables rotation of plane polarized light. Since the compounds of the present invention have asymmetric centers as well as other chemical structures that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds may 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 hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral center, 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 the enantiomers on chiral chromatographic columns. The starting compounds of a particular stereochemistry are either commercially available or may be prepared according to the methods described hereinafter and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" 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 parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, 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 a stereoisomer of an atom (or group) located on both sides of a double bond or ring system, as a result of differing positions relative to a reference plane; in the cis isomer the atom (or group) is located on the same side of the double bond or ring system, and in the trans isomer the atom (or group) is located on the opposite side of the double bond or ring system. Unless otherwise indicated, all cis-trans isomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of a molecule can be obtained by a number of known methods by those skilled in the art. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor 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, and Scanning Electron Microscopy (SEM), among others.

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

The term "N-oxide" refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or nitrogen (aryl) containing heterocyclic compound. 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 shown in the formula I is a tertiary amine nitrogen atom, and a corresponding N-oxide can be formed; in addition, when the group directly linked to the nitrogen atom at the 3-position of the parent nucleus is not a (sulfonyl) acyl group, then the 3-position is also a tertiary amine nitrogen atom, and the corresponding N-oxide can likewise be formed.

The term "isotopic label" refers to a derivatized compound formed by replacing a particular atom in a compound of the invention with its isotopic atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as²H(D)、 ³H(T)、 ¹³C、 ¹⁴C、 ¹⁵N、 ¹⁷O、 ¹⁸O、 ¹⁸F、 ³¹P、 ³²P、 ³⁵S、 ³⁶S and³⁷Cl。

the term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized. Further information on metabolism can be found in Goodman and Gilman's: The pharmaceutical 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, directly or indirectly, a compound of the invention upon administration to a patient. Particularly preferred derivative compounds or prodrugs are those which, when administered to a patient, increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

The term "independently of each other" means that at least two groups (or ring systems) present in the structure in the same or similar range of values may have the same or different meaning in a particular case. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when substituent X is hydrogen, substituent Y may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be hydrogen, or may be 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 attached to other groups by a single bond, e.g., C_1-6Alkyl means an alkyl group containing 1 to 6 carbon atoms, C_1-4Alkyl refers to alkyl groups containing 1 to 4 carbon atoms; common alkyl groups include, but are not limited to, methyl (-CH)₃) Ethyl (-CH)₂CH ₃) N-propyl (-CH)₂CH ₂CH ₃) Isopropyl (-CH (CH)₃) ₂) N-butyl (-CH)₂CH ₂CH ₂CH ₃) Sec-butyl (-CH (CH)₃)CH ₂CH ₃) Isobutyl (-CH)₂CH(CH ₃) ₂) T-butyl (-C (CH))₃) ₃) N-pentyl (-CH)₂CH ₂CH ₂CH ₂CH ₃) Neopentyl (-CH)₂C(CH ₃) ₃) And the like.

The term "alkylene" refers to a divalent straight or branched chain alkane group consisting of carbon and hydrogen atoms, free of unsaturation, and attached to one group by one single bond and to other groups (or ring systems) by another single bond, "C" as used herein_0-6Alkylene "means an alkylene group containing from 0 to 6 carbon atoms, 0 carbon atom representing a covalent bond, e.g. C_1-6Alkylene means a radical containing from 1 to 6 carbon atomsAlkyl radical, C_1-4Alkylene means 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)₂CH ₂-), 1, 3-propylene (-CH)₂CH ₂CH ₂-), 1-methyl-1, 2-ethylene (-CH (CH)₃)CH ₂-) 1, 4-butylene (-CH₂CH ₂CH ₂CH ₂-), 1-methyl-1, 3-propylene (-CH (CH)₃)CH ₂CH ₂-), 1-dimethyl-1, 2-ethylene (-C (CH)₃) ₂CH ₂-), 1, 2-dimethyl-1, 2-ethylene (-CH (CH)₃)CH(CH ₃) -) and the like.

The term "haloalkyl" refers to a monovalent straight or branched chain alkyl group substituted with at least one atom selected from fluorine, chlorine, bromine and iodine, free of unsaturation, and attached to other groups by a single bond, e.g., C_1-6Haloalkyl means C substituted by at least one atom selected from fluorine, chlorine, bromine and iodine_1-6Alkyl radical, C_1-4Haloalkyl means C substituted by at least one atom selected from fluorine, chlorine, bromine and iodine_1-4An alkyl group; common haloalkyl groups include, but are not limited to, fluoromethyl (-CH)₂F) Difluoromethyl (-CHF)₂) Trifluoromethyl (-CF)₃) 1-fluoroethyl (-CHFCH)₃) 2-fluoroethyl (-CH)₂CH ₂F) 1, 2-difluoroethyl (-CHFCH)₂F) 2, 2-difluoroethyl (-CH)₂CHF ₂)1, 2, 2-trifluoroethyl (-CHFCHF)₂)2, 2, 2-trifluoroethyl (-CH)₂CF ₃) And the like.

The term "cycloalkyl" refers to a monovalent monocyclic or polycyclic (including bridged and spiro forms) non-aromatic cyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, containing no unsaturation, and being linked to other groups by a single bond, e.g. C_3-10Cycloalkyl means a cycloalkane containing from 3 to 10 carbon atomsBase, C_3-6Cycloalkyl means cycloalkyl containing from 3 to 6 carbon atoms; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl (also known as decahydronaphthyl, naphthylalkyl), adamantyl, and the like. Other suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo [2.1.0 ]]Pentyl, 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 ]]Nonyl radical. 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 radical consisting only of carbon and hydrogen atoms, containing no unsaturation, and being linked to one group by one single bond and to other groups by another single bond, e.g. C_3-10Cycloalkylene radicals containing 3 to 10 carbon atoms, C_3-6Cycloalkylene radicals containing from 3 to 6 carbon atoms; common cycloalkylene groups include, but are not limited to, cyclopropane-1, 1-ylidene, cyclopropane-1, 2-ylidene, cyclobutane-1, 1-ylidene, cyclobutane-1, 2-ylidene, cyclobutane-1, 3-ylidene, and the like.

The term "heterocyclyl" refers to a monovalent monocyclic or polycyclic (including bridged and spiro forms) non-aromatic ring system whose ring atoms are composed of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus, and arsenic, and which is linked to other groups by a single bond, e.g., 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, tetrahydrofuran-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, mono-or polycyclic (including bridged and spiro forms) non-aromatic ring system whose ring atoms are composed of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus, and arsenic, and are connected to one group by one single bond and to other groups (or ring systems) by another single bond, such as 3-10 membered heterocyclylene, 3-7 membered heterocyclylene, or 4-10 membered heterocyclylene; common heterocyclylene groups include, but are not limited to, oxetan-2, 2-ylidene, oxetan-2, 3-ylidene, azetidin-2, 2-ylidene, azetidin-2, 3-ylidene, azetidin-2, 4-ylidene, tetrahydrofuran-2, 5-ylidene, tetrahydro-2H-pyran-2, 3-ylidene, tetrahydro-2H-pyran-2, 4-ylidene, tetrahydro-2H-pyran-2, 5-ylidene, tetrahydro-2H-pyran-2, 6-ylidene, pyrrolidine-1, 2-ylidene, pyrrolidine-1, 3-ylidene, pyrrolidine-2, 3-ylidene, oxetane-2, 3-ylidene, Pyrrolidine-2, 4-subunit, pyrrolidine-2, 5-subunit, piperidine-1, 2-subunit, piperidine-1, 3-subunit, piperidine-1, 4-subunit, piperidine-2, 3-subunit, piperidine-2, 4-subunit, piperidine-2, 5-subunit, piperidine-2, 6-subunit and the like.

The term "aryl" refers to a monovalent, mono-or polycyclic (including fused forms) all-carbon aromatic ring system whose ring atoms are composed of carbon atoms only and which is linked to other groups by a single bond, e.g. C_6-10An aryl group; common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, 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 whose ring atoms are composed of carbon atoms and heteroatoms selected from boron, nitrogen, oxygen, sulfur, phosphorus, and arsenic, and which are 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 heterocyclyl groups include, but are not limited to, benzopyrolyl, 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, pyridyl, triazolyl, tetrazolyl, and the like. Heteroaryl groups are optionally substituted with one or more substituents described herein.

The term "alkoxy" refers to a monovalent straight or branched chain alkyl-O-group consisting of only carbon, hydrogen and oxygen atoms, which may contain unsaturation, and which is attached to another group, e.g. C, by a single bond to the oxygen atom_1-6Alkoxy radical, C_1-4An alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH)₃) Ethoxy (-OCH)₂CH ₃) N-propoxy group (-OCH)₂CH ₂CH ₃) I-propoxy (-OCH (CH)₃) ₂) N-butoxy (-OCH)₂CH ₂CH ₂CH ₃) Sec-butoxy (-OCH (CH)₃)CH ₂CH ₃) Isobutoxy (-OCH)₂CH(CH ₃) ₂) T-butoxy (-OC (CH))₃) ₃) N-pentyloxy (-OCH)₂CH ₂CH ₂CH ₂CH ₃) Neopentyloxy (-OCH)₂C(CH ₃) ₃) And the like.

The term "haloalkoxy" refers to a monovalent straight or branched chain haloalkyl-O-group which is substituted with at least one atom selected from fluorine, chlorine, bromine and iodine, may contain unsaturation, and is attached to another group, such as C, by a single bond to an oxygen atom_1-6Haloalkoxy, C_1-4A haloalkoxy group; common haloalkoxy groups include, but are not limited to, fluoromethoxy (-OCH)₂F) Difluoromethoxy (-OCHF)₂) Trifluoromethoxy (-OCF)₃) 1-fluoroethoxy (-OCHFCH)₃) 2-fluoroethoxy (-OCH)₂CH ₂F) 1, 2-Difluoroethoxy (-OCHFCH)₂F) 2, 2-difluoroethoxy (-OCH) ₂CHF ₂)1, 2, 2-trifluoroethoxy (-OCHFCHF)₂)2, 2, 2-trifluoroethoxy (-OCH)₂CF ₃) And the like.

The term "cycloalkoxy" refers to a monovalent group consisting of a cycloalkyl group and an oxygen atom, and is linked to other groups by a single bond to the oxygen atom, e.g. C_3-6A cycloalkoxy group; common cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, decahydronaphthoxy, adamantyloxy, and the like.

[ Compound of the general formula ]

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

wherein the content of the first and second substances,

ring A¹Selected from phenyl and 5-6 membered heteroaryl;

Z ¹、Z ²and Z³Each independently selected from CR⁴And N;

R ¹selected from hydrogen and C_1-6An alkyl group;

each R⁵Each independently selected from hydrogen, halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, -C_0-6alkylene-O-R^a、-O-C _1-6alkylene-O-R^a、C _1-6Haloalkoxy, -C_0-6alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-6alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-C(＝O)-R ⁶、-C _0-6alkylene-S (═ O)₂-R ⁶、-C _0-6alkylene-N (R)^a)(R ^b)、-C _0-6alkylene-C (═ O) -N (R)^a)(R ^b)、-C _0-6alkylene-N (R)^a)-C(＝O)-R ⁶、-C _0-6alkylene-S (═ O)₂-N(R ^a)(R ^b)、-C _0-6alkylene-N (R)^a)-S(＝O) ₂-R ⁶4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl; wherein: each R^aEach independently selected from hydrogen and C_1-6An alkyl group; each R^bEach independently selected from hydrogen and C_1-6An alkyl group; or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;

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 A¹Ring A²Ring A³、R ²、R ³、R ⁵M, 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 compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Selected from phenyl and pyridyl.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Is phenyl.

In some embodiments of the invention, each R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Each independently selected from halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4HalogenatedAlkyl radical, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_3-6A cycloalkoxy group.

In some preferred embodiments of the invention, each R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy and C_1-4A haloalkoxy group.

In some more preferred embodiments of the invention, each R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Each independently selected from halogen, cyano, C_1-3Haloalkyl, C_3-6Cycloalkyl radical, C_1-3Alkoxy and C_1-3A haloalkoxy group.

In some particularly preferred embodiments of the invention, each R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Each independently selected from fluoro, chloro, cyano, methoxy and difluoromethoxy.

In some embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Selected from phenyl and pyridyl, each R²Each independently selected from halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_3-6A cycloalkoxy group.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Selected from phenyl, each R²Each independently selected from halogen, cyano, C_1-3Haloalkyl, C_3-6Cycloalkyl radical, C_1-3Alkoxy and C_1-3A haloalkoxy group.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Selected from phenyl, each R²Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-3Alkoxy and C_1-3A haloalkoxy group.

In some particularly preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Is phenyl; each R²Each independently selected from fluoro, chloro, cyano, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.

In some particularly preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Is phenyl; each R²Each independently selected from the group consisting of fluoro, chloro, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.

In some particularly preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Is phenyl; each R²Each independently selected from fluoro, chloro, cyano, methoxy and difluoromethoxy.

In some more particularly preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof¹Is phenyl, each R²Each independently selected from fluoro and difluoromethoxy.

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

Is selected from

Is composed of

In some embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Selected from phenyl and 5-6 membered heteroaryl.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Selected from phenyl and pyridyl.

In some particularly preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Is phenyl.

In some embodiments of the invention, each R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof³Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and-S (═ O)₂-C _1-4An alkyl group.

In some preferred embodiments of the invention, each R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof³Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy and-S (═ O)₂-C _1-4An alkyl group.

In some preferred embodiments of the invention, R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof³Is C_1- ₄Haloalkyl, preferably, R³Is trifluoromethyl.

In some particularly preferred embodiments of the invention, each R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof³Each independently selected from fluoro, cyano, methyl, trifluoromethyl and methylsulfonyl.

In some particularly preferred embodiments of the invention, R in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof³Is trifluoromethyl.

In some embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Selected from phenyl and 5-6 membered heteroaryl; each R³Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and-S (═ O)₂-C _1-4An alkyl group.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Selected from phenyl and pyridyl, each R³Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy and-S (═ O)₂-C _1-4An alkyl group.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Selected from phenyl and pyridyl, R³Is C_1-4A haloalkyl group.

In some preferred embodiments of the invention, in the above-described compound of formula I or formula I-A or a pharmaceutically acceptable form thereofRing A²Selected from phenyl, each R³Each independently selected from fluoro, cyano, methyl, trifluoromethyl and methylsulfonyl.

In some more particularly preferred embodiments of the invention, ring A in the above-described compound of formula I or formula I-A, or a pharmaceutically acceptable form thereof²Is phenyl; r³Is trifluoromethyl.

Is composed of

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

ring A¹Is phenyl and 5-6 membered heteroaryl;

each R²Each independently selected from halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_3-6A cycloalkoxy group;

ring A²Selected from phenyl and 5-6 membered heteroaryl;

each R³Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and-S (═ O)₂-C _1-4An alkyl group;

ring A³Selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl;

each R⁵Each independently selected from hydrogen, hydroxy, C_1-3Alkyl, -C_1-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、-C _0-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-S(＝O) ₂-C _1-3Alkyl, -C_1-3alkylene-N (R)^a)(R ^b)、-C _1-3alkylene-C (═ O) -N (R)^a)(R ^b) And 4-6 membered heterocyclyl; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group;

q is 0, 1 or 2;

m is 1 or 2;

n is 1 or 2.

ring A¹Is phenyl;

each R²Each independently selected from fluoro, chloro, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy;

ring A²Selected from phenyl and 5-6 membered heteroaryl;

R ³is trifluoromethyl;

ring A³Selected from pyrazolyl, tetrahydropyridinyl, thiazolyl, piperazinyl, morpholinyl and piperidinyl;

each R⁵Each independently selected from hydrogen, hydroxy, -CH₃、-CH ₂CH ₃、-CH(CH ₃) ₂、-CH ₂COOH、-CH ₂CH ₂OCH ₃、-CH ₂C(＝O)N(CH ₃) ₂、-CH ₂CH ₂N(CH ₃) ₂、

-C(＝O)CH ₂CH ₂COOH、

-COOCH ₃、-COOH、-S(＝O) ₂-CH ₃and-OCH₂CH ₂OCH 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 described above, or a pharmaceutically acceptable form thereof, is a compound of formula I-B1, or a pharmaceutically acceptable form thereof,

wherein, ring A³、R ²、R ⁵M and q are as defined above.

In some embodiments of the invention, each R in the above-described compound of formula I, formula I-A, or formula I-B1, or a pharmaceutically acceptable form thereof²Each independently selected from the group consisting of fluoro, chloro, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.

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

each R²Each independently selected from halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C _3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_3-6A cycloalkoxy group;

q is 0, 1 or 2;

m is 1 or 2.

each R²Each independently selected from halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy and C_1-4A haloalkoxy group;

ring A³Selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

each R⁵Each independently selected from hydrogen, hydroxy, C_1-3Alkyl, -C_1-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、-C _0-3alkylene-C (═ O))-O-R ^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-S(＝O) ₂-C _1-3Alkyl, -C_1-3alkylene-N (R)^a)(R ^b)、-C _1-3alkylene-C (═ O) -N (R)^a)(R ^b) And 4-6 membered heterocyclyl; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group;

q is 0, 1 or 2;

m is 2.

each R⁵Each independently selected from hydrogen, -OH, -CH₃、-CH ₂CH ₃、-CH(CH ₃) ₂、-CH ₂COOH、-CH ₂CH ₂OCH ₃、-CH ₂C(＝O)N(CH ₃) ₂、-CH ₂CH ₂N(CH ₃) ₂、

-C(＝O)CH ₂CH ₂COOH、

-COOCH ₃、-COOH、-S(＝O) ₂-CH ₃and-OCH₂CH ₂OCH 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, or a pharmaceutically acceptable form thereof, described above is a compound of formula I-B, or a pharmaceutically acceptable form thereof,

wherein, ring A³、R ⁵And q is as defined hereinbefore.

In some embodiments of the invention, the ring A in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof³Selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl.

In some embodiments of the invention, the ring A in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof³Selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof³Selected from pyrazolyl, tetrahydropyridinyl, thiazolyl, piperazinyl, morpholinyl and piperidinyl.

In some particularly preferred embodiments of the invention, ring A in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof³Is selected from

In some embodiments of the invention, cEach R in the compound of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof⁵Each independently selected from hydrogen, halogen, cyano, hydroxy, C_1-3Alkyl radical, C_1-3Haloalkyl, C_3-6Cycloalkyl, -C_0-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、C _1-3Haloalkoxy, -C_0-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-C(＝O)-R ⁶、-C _0-3alkylene-S (═ O)₂-R ⁶、-C _0-3alkylene-N (R)^a)(R ^b)、-C _0-3alkylene-C (═ O) -N (R)^a)(R ^b)、-C _0-3alkylene-N (R)^a)-C(＝O)-R ⁶、-C _0-3alkylene-S (═ O)₂-N(R ^a)(R ^b)、-C _0-3alkylene-N (R)^a)-S(＝O) ₂-R ⁶4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group; each R⁶Each independently selected from C_1-3Alkyl and C_3-6A cycloalkyl group.

In some embodiments of the invention, each R in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof⁵Each independently selected from hydrogen, halogen, cyano, hydroxy, C_1-3Alkyl radical, C_1-3Haloalkyl, C_3-6Cycloalkyl, -C_0-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、C _1-3Haloalkoxy, -C_0-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6cycloalkylene-C (═ O) -O-R^a、-C(＝O)-C _1-6Alkyl, -C_0-3alkylene-S (═ O)₂-R ⁶、-C _0-3alkylene-N (R)^a)(R ^b)、-C _0-3alkylene-C (═ O) -N (R)^a)(R ^b)、-C _0-3alkylene-N (R)^a)-C(＝O)-R ⁶、-C _0-3alkylene-S (═ O)₂-N(R ^a)(R ^b)、-C _0-3alkylene-N (R)^a)-S(＝O) ₂-R ⁶4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group; each R⁶Each independently selected from C_1-3Alkyl and C_3-6A cycloalkyl group.

In some preferred embodiments of the invention, each R in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof⁵Each independently selected from hydrogen, hydroxy, C_1-3Alkyl, -C_1-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、-C(＝O)-O-R ^a、-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-S(＝O) ₂-C _1-3Alkyl, -C_1-3alkylene-N (R)^a)(R ^b)、-C _1-3alkylene-C (═ O) -N (R)^a)(R ^b) And 4-6 membered heterocyclic ringA group; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group.

In some particularly preferred embodiments of the invention, each R in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof⁵Each independently selected from hydrogen, hydroxy, methyl, ethyl, isopropyl, -CH₂CH ₂-O-CH ₃、-O-CH ₂CH ₂-O-CH ₃、-C(＝O)-O-H、-C(＝O)-O-CH ₃、-CH ₂-C(＝O)-O-H、-C(＝O)-CH ₂CH ₂-C(＝O)-O-H、

-S(＝O) ₂-CH ₃、-CH ₂CH ₂-N(CH ₃) ₂、-CH ₂-C(＝O)-N(CH ₃) ₂And

in some embodiments of the invention, the ring A in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof³Selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl; each R⁵Each independently selected from hydrogen, halogen, cyano, hydroxy, C_1-3Alkyl radical, C_1-3Haloalkyl, C_3-6Cycloalkyl, -C_0-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、C _1-3Haloalkoxy, -C_0-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-C(＝O)-R ⁶、-C _0-3alkylene-S (═ O)₂-R ⁶、-C _0-3alkylene-N (R)^a)(R ^b)、-C _0-3alkylene-C (═ O) -N (R)^a)(R ^b)、-C _0-3alkylene-N (R)^a)-C(＝O)-R ⁶、-C _0-3alkylene-S (═ O)₂-N(R ^a)(R ^b)、-C _0-3alkylene-N (R)^a)-S(＝O) ₂-R ⁶4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1- ₃An alkyl group; each R⁶Each independently selected from C_1-3Alkyl and C_3-6A cycloalkyl group.

In some preferred embodiments of the invention, ring A in the above-described compound of formula I, formula I-A, formula I-B1, or formula I-B, or a pharmaceutically acceptable form thereof³Selected from pyrazolyl, tetrahydropyridinyl, thiazolyl, piperazinyl, morpholinyl and piperidinyl; each R⁵Each independently selected from hydrogen, hydroxy, C_1-3Alkyl, -C_1-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、-C(＝O)-O-R ^a、-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-S(＝O) ₂-C _1-3Alkyl, -C_1-3alkylene-N (R)^a)(R ^b)、-C _1-3alkylene-C (═ O) -N (R)^a)(R ^b) And 4-6 membered heterocyclyl; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group.

Each R⁵Each independently selected from hydrogen, hydroxy, methyl, ethyl, isopropyl, -CH₂CH ₂-O-CH ₃、-O-CH ₂CH ₂-O-CH ₃、-C(＝O)-O-H、-C(＝O)-O-CH ₃、-CH ₂-C(＝O)-O-H、-C(＝O)-CH ₂CH ₂-C(＝O)-O-H、

in some more particularly preferred embodiments of the invention, in the above-described compound of formula I, formula I-A, formula I-B1 or formula I-B or a pharmaceutically acceptable form thereof

Is selected from

In addition, the present 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:

[ production method ]

The present invention provides a process for the preparation of a compound of formula I as described above, comprising the steps of:

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

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

or comprises the following steps:

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

(3 ') reacting the compound D ' with a 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 preparation method is performed in a suitable solvent, which includes, but is 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 present invention, step (1) of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium, palladium acetate, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium, preferably [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex. In some embodiments of the present invention, step (1) of the above preparation method is performed in an alkaline environment, and suitable agents providing 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, the reaction temperature for step (1) of the above preparation method is suitably 60 to 120 ℃. In some embodiments of the present invention, the reaction time of step (1) of the above preparation method is suitably 2 to 8 hours.

In some embodiments of the present invention, step (2) of the above preparation method is carried out 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 preparation process is carried out in the presence of suitable nitrites including, but not limited to, isoamyl nitrite and tert-butyl nitrite. In some embodiments of the present invention, step (2) of the above preparation process is carried out in the presence of suitable brominating agents including, but not limited to, cuprous bromide, cupric bromide and N-bromosuccinimide, preferably cuprous bromide. In some embodiments of the present invention, the reaction temperature in step (2) of the above preparation method is suitably from-10 to 80 ℃. In some embodiments of the present invention, the reaction time of step (2) of the above preparation method is suitably 2 to 8 hours.

In some embodiments of the present invention, the reduction reaction in step (3) of the above preparation method is performed in a suitable solvent, and the solvent includes, but is 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 preparation method is carried out 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, the reduction reaction in step (3) of the above 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 present invention, the reaction temperature suitable for the reduction reaction in step (3) of the above-mentioned production method is 20 to 100 ℃. In some embodiments of the present invention, the reaction time for the reduction reaction in step (3) of the above-described production method is suitably 2 to 8 hours. In some embodiments of the present invention, the N-alkylation reaction in step (3) of the above preparation process is carried out in the presence of suitable alkylating agents including, but not limited to, alkyl halides, alcohols and alkyl sulfates, preferably alkyl halides. In some embodiments of the present invention, the N-alkylation reaction in step (3) of the above preparation method is carried out in an alkaline environment, and suitable reagents 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 preparation method is carried out 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 preparation method is performed in an alkaline environment, and suitable reagents for providing an alkaline 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 present invention, the reaction temperature in step (4) of the above preparation method is suitably 20 to 80 ℃. In some embodiments of the present invention, the reaction time of step (4) of the above preparation method is suitably 2 to 8 hours.

In some embodiments of the present invention, the step (5) of the above preparation method is performed in a suitable solvent, and the solvent includes, but is 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 present invention, step (5) of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium, palladium acetate, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium, preferably [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex. In some embodiments of the present invention, step (5) of the above preparation method is performed in an alkaline environment, and suitable agents providing 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, the reaction temperature of step (5) of the above preparation method is suitably 60 to 120 ℃. In some embodiments of the present invention, the reaction time of step (5) of the above preparation method is suitably 2 to 8 hours.

In some embodiments of the present invention, step (1') of the above preparation process is carried out 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 preparation method is performed in a basic environment, and suitable reagents 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 present invention, the reaction temperature for step (1') of the above preparation method is suitably 40 to 80 ℃. In some embodiments of the present invention, the reaction time of step (1') of the above preparation method is suitably 2 to 24 hours.

In some embodiments of the present invention, the reduction reaction in step (2') of the above preparation method is carried out 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 preparation method is carried out in the presence of a suitable metal reagent including, but not limited to, raney nickel, palladium 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 present invention, a suitable reaction temperature for the reduction reaction in step (2') of the above-described production method is 40 to 80 ℃. In some embodiments of the present invention, the reaction time for the reduction reaction in step (2') of the above-described production method is suitably 2 to 12 hours. In some embodiments of the present invention, the N-alkylation reaction in step (2') of the above preparation process is carried out in the presence of suitable alkylating agents including, but not limited to, alkyl halides, alcohols and alkyl sulfates, preferably alkyl halides. In some embodiments of the present invention, the N-alkylation reaction in step (2') of the above preparation method is carried out in an alkaline environment, and suitable reagents 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 preparation process is carried out 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 present invention, the reaction temperature in step (3') of the above preparation method is suitably 40 to 80 ℃. In some embodiments of the present invention, the reaction time of step (3') of the above preparation method is suitably 2 to 8 hours.

In some embodiments of the present invention, step (4') of the above preparation method is carried out 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 present invention, step (4 ') of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium, triphenylphosphine palladium, palladium acetate, [1,1 ' -bis (diphenylphosphino) ferrocene ] dichloropalladium, preferably [1,1 ' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex. In some embodiments of the present invention, step (4') of the above preparation method is performed in an alkaline environment, and suitable agents providing 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 present invention, the reaction temperature in step (4') of the above preparation method is suitably 60 to 100 ℃. In some embodiments of the present invention, the reaction time of step (4') of the above preparation method is suitably 2 to 8 hours.

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

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

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

(3) carrying out reduction reaction on the compound D-A to obtain a compound E-A;

(4) reacting the compound E-A with the compound F to obtain a compound G-A;

(5) reacting the compound G-A with a compound H to obtain a compound shown as a formula I-A;

wherein, ring A¹Ring A²Ring A³、R ²、R ³、R ⁵M, 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 a compound F ' -A;

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

wherein, ring A¹Ring A²Ring A³、R ²、R ³、R ⁵M, 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)Thus) F, Cl, Br and I, preferably F and Cl.

In some embodiments of the present invention, step (3) of the above preparation method is performed in a suitable solvent, which includes, but is 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 preparation method is carried out 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 preparation process 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 present invention, the reaction temperature in step (3) of the above preparation method is suitably 20 to 100 ℃. In some embodiments of the present invention, the reaction time of step (3) of the above preparation method is suitably 2 to 8 hours.

In some embodiments of the present invention, step (2') of the above preparation method is carried out 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 preparation method 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 acids including, but not limited to, hydrochloric acid, formic acid and acetic acid, preferably acetic acid. In some embodiments of the present invention, the reaction temperature for step (2') of the above preparation method is suitably 40 to 80 ℃. In some embodiments of the present invention, the reaction time of step (2') of the above preparation method is suitably 2 to 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 a pharmaceutical excipient that is 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 adjusters, solvents, co-solvents, surfactants, and the like.

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

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

[ medical use ]

Both the compounds of formula I, or pharmaceutically acceptable forms thereof, and the pharmaceutical compositions described above, exhibit modulating (especially agonistic) effects on ROR γ, the EC against ROR γ₅₀Values that can be below 110nM, individually even below 10nM, can be used as ROR gamma modulators. Accordingly, the present invention provides the use of a compound of formula I as described above or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above as a ROR γ modulator. In the present invention, the ROR γ modulator is used for the prevention and/or treatment of a disease mediated at least in part by ROR γ.

In addition, the present application provides the use of a compound of formula I as described above or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by rory.

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

[ method of treatment ]

The present invention provides a method for the prevention and/or treatment of a disease mediated at least in part by rory, comprising the steps of: administering to a patient in need thereof 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.

The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient that is capable of inducing 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 invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to a patient or a cell, tissue, organ, biological fluid, etc. site thereof, such that the pharmaceutically active ingredient or pharmaceutical composition contacts the patient or the cell, tissue, organ, biological fluid, etc. site thereof. 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 by a physician or other caregiver that a patient needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors of the physician or other caregiver in their area of expertise.

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

[ combination drug ]

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, and at least one further modulator of homeotropic ROR γ.

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

The present invention provides a method for preventing and/or treating cancer, inflammation or autoimmune disease, comprising the steps of: administering 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 to a patient in need thereof.

The present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof 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 ROR γ agonist.

The present invention provides a method for preventing and/or treating inflammation, comprising the steps of: administering to a patient in need thereof 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 ROR γ antagonist.

The present invention provides a method for preventing and/or treating an autoimmune disease, comprising the steps of: administering to a patient in need thereof 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 ROR γ antagonist.

The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. If the experimental method in the following examples does not specify specific conditions, the conventional conditions or the conditions recommended by the manufacturer (for example, room temperature is 20 to 30 ℃ C.). Reagents used were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Teber Chemical science and technology, Inc., and the like. Unless otherwise indicated, percentages and parts appearing in the following examples are by weight.

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

abbreviations	Means of
TLC	Thin layer chromatography
CC	Column chromatography
PHPLC	Preparative high performance liquid chromatography
LC-MS	Liquid chromatography-mass spectrometry
Pd(dppf)Cl ₂	[1, 1' -bis (diphenylphosphine)Yl) ferrocene]Palladium dichloride
CD ₃OD	Deuterated methanol
CDCl ₃	Deuterated chloroform
DMSO-d ₆	Hexahydro-deuterated dimethyl sulfoxide
TMS	Tetramethylsilane
NMR	Nuclear magnetic resonance
MS	Mass spectrometry
s	Singlet
d	Doublet peak
t	Triplet peak
q	Quartet peak
dd	Double doublet
m	Multiple peaks
br	Broad peak
J	Coupling constant
Hz	Hertz's scale
h	Hour(s)
min	Minute (min)

When the chemical names and structural formulae of the compounds in the following examples are inconsistent, the structural formulae should be taken as a standard unless the context dictates that the chemical name is correct. The structural formulae of the compounds described in the following examples are given by¹H-NMR or MS.¹The H-NMR analyzer is Bruker 400MHz NMR spectrometer, and the solvent is CD₃OD、CDCl ₃Or DMSO-d₆The internal standard substance is TMS, and all delta values are expressed in ppm. The MS measurement instrument is an Agilent 6120B mass spectrometer, and the ion source is ESI.

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

The separation and purification of the reaction product are carried out by CC or PHPLC. The CC uses 200-300 mesh silica gel as a carrier. The system of the eluent comprises: the volume ratio of the solvent is adjusted according to different polarities of the compounds in a dichloromethane and methanol system and a petroleum ether and ethyl acetate system, and a small amount of triethylamine can also be added for adjustment. PHPLC uses two conditions: 1) the instrument model is as follows: agilent 1260, column: waters Xbridge Prep C₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate; elution gradient: 0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B; 2) the instrument model is as follows: agilent 1260, column: waters SunAire Prep C₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; mobile phase A: 100% acetonitrile; mobile phase B: 100% water (containing 0.05% formic acid); elution gradient: 0 min: 10% A, 90% B; 16.0 min: 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 is as follows: preparation of 3 '- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl-4-amine.

4-bromo-2-nitroaniline (2.00g, 9.22mmol) and 2- (3- (difluoromethoxy) -5-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (3.72g, 12.90mmol) were dissolved in a mixed solvent of 1, 4-dioxane (20mL) and water (5mL), and potassium carbonate (2.54g, 18.43mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (376mg, 0.46mmol) were added, and after nitrogen substitution, heated to 80 ℃ for 2 h. The reaction solution was poured into water (150mL), 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 (2.42g, yield: 88.1%).

MS(ESI):m/z 297.1[M-H] ^-。

The second step is that: preparation of 4-bromo-3 '- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl.

3 '- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl-4-amine (2.50g, 8.38mmol) and cuprous bromide (1.20g, 8.38mmol) were added to acetonitrile (20mL), stirred at 0 ℃ for 0.5h, slowly added dropwise with tert-butyl nitrite (2.59g, 25.15mmol) and reacted at 25 ℃ for 3 h. The reaction solution was poured into water (100mL), 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 (2.8g, yield: 92.2%).

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

4-bromo-3 '- (difluoromethoxy) -5' -fluoro-3-nitrobiphenyl (2.40g, 6.63mmol), iron powder (3.70g, 66.3mmol) and ammonium chloride (3.55g, 66.3mmol) were added to a mixed solvent of ethanol (20mL) and water (10mL), and the mixture was heated to 80 ℃ for reaction for 2 h. The reaction solution was poured into water (150mL), 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 (2.0g, yield: 90.9%).

MS(ESI):m/z 332.0[M+H] ⁺。

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

4-bromo-3 '- (difluoromethoxy) -5' -fluorobiphenyl-3-amine (2.0g, 6.02mmol) was completely dissolved in dichloromethane (50mL), and pyridine (2.38g, 30.11mmol) and 3- (trifluoromethyl) benzenesulfonyl chloride (2.95g, 12.04mmol) were added successively at room temperature, and the mixture was allowed to react for 2h at room temperature. After concentration under reduced pressure, the residue was poured into water (150mL), 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 (2.4g, yield: 73.8%).

MS(ESI):m/z 538.0[M-H] ^-。

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

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

Piperazine-1-carboxylic acid tert-butyl ester (0.5g, 2.69mmol) and triethylamine (0.82g, 8.06mmol) were dissolved in dichloromethane (5mL), and succinic acid monomethyl chloride (0.61g, 4.04mmol) was added dropwise under ice bath and reacted at room temperature for 2 h. The reaction solution was poured into water (30mL), 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 (0.6g, yield: 74.1%).

MS(ESI):m/z 301.0[M+H] ⁺。

The second step is that: preparation of methyl 4-oxo-4- (piperazin-1-yl) butanoate.

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

MS(ESI):m/z 201.1[M+H] ⁺。

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

Using a synthesis method similar to intermediate preparation example 2, the starting material in the first step was replaced from succinic acid monomethyl ester acid chloride with 1- (chloroformyl) cyclopropanecarboxylic acid methyl ester to give the title compound (0.25g, 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 is as follows: preparation of ethyl 2- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetate.

1H-pyrazole-3-boronic acid pinacol ester (1.5g, 7.73mmol) was completely dissolved in acetonitrile (5mL), and potassium carbonate (3.20g, 23.19mmol) and ethyl bromoacetate (1.55g, 9.28mmol) were added successively with stirring at room temperature, and the reaction was maintained at room temperature for 2H. The reaction solution was poured into water (100mL), 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 (2.0g, yield: 92.4%).

MS(ESI):m/z 281.1[M+H] ⁺。

The second step is that: 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 (200mg, 0.37mmol) and ethyl 2- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetate (207.4mg, 0.74mmol) were dissolved in a mixed solvent of 1, 4-dioxane (8mL) and water (2mL), potassium carbonate (102.2mg, 0.74mmol) and [1,1 ' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (14mg, 0.018mmol) were added, and after nitrogen substitution, heated to 80 ℃ for 2H. The reaction solution was poured into water (100mL), 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 chromatography (condition 1) to give the title compound of this step (82mg, yield: 36.1%).

MS(ESI):m/z 614.1[M+H] ⁺。

The third step: 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 (70mg, 0.11mmol) was dissolved in a mixed solvent of ethanol (5mL) and water (1mL), and sodium hydroxide (10mg, 0.23mmol) was added to continue the reaction with stirring at 60 ℃ for 1H. The reaction solution was poured into water (50mL), pH was adjusted to 2 with 2N dilute hydrochloric acid, ethyl acetate was extracted three times, 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 chromatography (condition 2) to give the title compound (10mg, yield: 15.0%).

MS(ESI):m/z 586.1[M+H] ⁺。

¹H-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 from ethyl bromoacetate to 2-bromoethyl methyl ether to give the title compound (30mg, yield: 21.5%).

MS(ESI):m/z 586.1[M+H] ⁺。

¹H-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 from ethyl bromoacetate with 2-bromo-N, N-dimethylacetamide to give the title compound (15mg, yield: 21.2%).

MS(ESI):m/z 613.1[M+H] ⁺。

¹H-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 (100mg, 0.18mmol) and 1-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (87.4mg, 0.37mmol) were dissolved in a mixed solvent of 1, 4-dioxane (4mL) and water (1mL), potassium carbonate (51mg, 0.37mmol) and [1,1 ' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (7mg, 0.009mmol) were added, and after nitrogen substitution, heated to 80 ℃ for 2H. The reaction solution was poured into water (20mL), 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 (20mg, yield: 18.6%).

MS(ESI):m/z 570.1[M+H] ⁺。

¹H-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 is as follows: preparation of N, N-dimethyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethylamine.

4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5g, 7.73mmol) was completely dissolved in acetonitrile (5mL), and potassium carbonate (3.20g, 23.19mmol) and 2-chloro-N, N-dimethylethylamine (998mg, 9.28mmol) were added successively under stirring at room temperature, followed by reaction at 80 ℃ for 6H. The reaction solution was poured into water (100mL), 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 (1.8g, yield: 88.2%).

MS(ESI):m/z 266.0[M+H] ⁺。

The second step is that: 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 (200mg, 0.37mmol) and N, N-dimethyl-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethylamine (196.1mg, 0.74mmol) were dissolved in a mixed solvent of 1, 4-dioxane (8mL) and water (2mL), potassium carbonate (102.2mg, 0.74mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (14mg, 0.018mmol) were added, and after nitrogen substitution, the mixture was heated to 80 ℃ for reaction for 2 hours. The reaction solution was poured into water (50mL), 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 chromatography (condition 1) to give the title compound (8mg, yield: 5.9%).

MS(ESI):m/z 599.2[M+H] ⁺。

¹H-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, the starting material 2-chloro-N, N-dimethylethylamine was replaced with 2-bromoethyl methyl ether to give the title compound (30mg, yield: 21.5%).

MS(ESI):m/z 586.1[M+H] ⁺。

¹H-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 synthesis method similar to example 5, the starting material 2-chloro-N, N-dimethylethylamine was replaced with (S) -3-bromotetrahydrofuran to give the title compound (12mg, yield: 39.1%).

MS(ESI):m/z 598.1[M+H] ⁺。

¹H-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, the starting material 2-chloro-N, N-dimethylethylamine was replaced with (R) -3-bromotetrahydrofuran to give the title compound (42mg, yield: 41.2%).

MS(ESI):m/z 598.1[M+H] ⁺。

¹H-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 synthesis method similar to example 4, the starting material 1-isopropyl-4- (4,4,5, 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 (30mg, yield: 25.6%).

MS(ESI):m/z 556.1[M+H] ⁺。

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

MS(ESI):m/z 599.0[M-H] ^-。

¹H-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 (210mg, 0.37mmol), tributyl (thiazol-4-yl) stannane (210mg, 0.56mmol), and lithium chloride (71mg, 1.66mmol) were added to 1, 4-dioxane (6mL) solvent and dissolved with stirring at room temperature. Tetrakis (triphenylphosphine) palladium (46mg, 0.04mmol) was added, and the mixture was stirred at 100 ℃ for 4 hours after nitrogen substitution. 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 (125mg, yield: 63.7%).

MS(ESI):m/z 545.1[M+H] ⁺。

¹H-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- (cyclopropylformyl) piperazin-1-yl) -3 '- (difluoromethoxy) -5' -fluorobiphenyl-3-yl) -3- (trifluoromethyl) benzenesulfonamide (compound 12).

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

4-bromo-1-fluoro-2-nitrobenzene (0.50g, 2.27mmol), 1-cyclopropylformylpiperazine (0.49g, 3.18mmol) and cesium carbonate (1.56g, 4.55mmol) were dissolved in N, N-dimethylformamide (5mL) and the reaction was stirred at 60 ℃ for 12 hours, then the reaction mixture was poured into water (60mL), 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 (0.65g, yield: 81.2%).

MS(ESI):m/z 354.1[M+H] ⁺。

The second step is that: preparation of (4- (2-amino-4-bromophenyl) piperazin-1-yl) (cyclopropyl) methanone.

(4- (4-bromo-2-nitrophenyl) piperazin-1-yl) (cyclopropyl) methanone (0.65g, 1.84mmol) was dissolved in ethanol (8mL) and water (2mL), iron powder (0.31g, 5.52mmol) and ammonium chloride (0.31g, 5.52mmol) were added, and after stirring for 2h at 80 ℃, filtration, concentration, dilution with ethyl acetate, washing with water, liquid separation, drying, filtration, concentration, and purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (V/V) ═ 3/1) gave the title compound of this step (0.29mg, yield: 48.8%).

MS(ESI):m/z 324.0[M+H] ⁺。

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

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

MS(ESI):m/z 532.1[M+H] ⁺。

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

Dissolving N- (5-bromo-2- (4-cyclopropylformyl) piperazin-1-yl) phenyl) -3- (trifluoromethyl) benzenesulfonamide (180mg, 0.32mmol), 2- (3- (difluoromethoxy) -5-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (108mg, 0.35mmol) and potassium carbonate (93.8mg, 0.64mmol) in 1, 4-dioxane (4mL) and water (1mL), adding [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (13.8mg, 0.16mmol), reacting at 80 ℃ for 2h under nitrogen protection, filtering to remove insoluble matter in the reaction solution, concentrating, adding ethyl acetate and saturated brine, extracting, drying the organic phase over anhydrous sodium sulfate, filtration, spin-drying of the solvent and purification of the residue by preparative high performance liquid chromatography (condition 1) gave the title compound of this step (17mg, yield: 8.2%).

MS(ESI):m/z 614.1[M+H] ⁺。

¹H-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 is as follows: preparation of methyl 4- (4- (3 '-difluoromethoxy) -5' -fluoro-3- (3- (trifluoromethyl) benzenesulfonylamino) biphenyl-4-yl) piperazin-1-yl) -4-oxobutanoate.

Using a synthesis method similar to example 12, substituting 1-cyclopropylformylpiperazine with methyl 4-oxo-4- (piperazin-1-yl) butyrate, the title compound of this step was obtained (350mg, yield: 60.9%).

MS(ESI):m/z 659.7[M+H] ⁺。

The second step is that: 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) piperazin-1-yl) -4-oxobutanoate (350mg, 0.50mmol) was dissolved in a mixed solvent of methanol (5mL) and water (1mL), and sodium hydroxide (61.7mg, 1.50mmol) was added to stir the reaction at room temperature for 2 h. The reaction solution was poured into water (30mL), the pH was adjusted to 4 with 2N hydrochloric acid, ethyl acetate was extracted three times, 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 chromatography (condition 2) to give the title compound (138mg, yield: 40.3%).

MS(ESI):m/z 645.8[M+H] ⁺。

¹H-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-formyl) cyclopropanecarboxylic acid (compound 14).

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

MS(ESI):m/z 658.0[M+H] ⁺。

¹H-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 1-cyclopropylformylpiperazine with morpholine, the title compound (17mg, yield: 9.1%) was obtained.

MS(ESI):m/z 545.0[M-H] ^-。

¹H-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 synthesis method similar to example 12, 1-cyclopropylformylpiperazine was replaced with piperidine-4-carboxylic acid methyl ester to give the title compound (219mg, yield: 77.2%).

MS(ESI):m/z 601.0[M-H] ^-。

¹H-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-yl) piperidine-4-carboxylate (162.1mg, 0.26mmol) was dissolved in a mixed solvent of methanol (5mL) and water (1mL), and sodium hydroxide (43.1mg, 1.04mmol) was added thereto, followed by stirring at 60 ℃ for 1 h. The reaction solution was poured into water (10mL), the pH was adjusted to 4 with 2N hydrochloric acid, ethyl acetate was extracted three times, 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 chromatography (condition 2) to give the title compound (79mg, yield: 49.9%).

MS(ESI):m/z 587.0[M-H] ^-。

¹H-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 is as follows: preparation of methyl 2- (1- (4-bromo-2-nitrophenyl) piperidin-4-yl) acetate.

After 4-bromo-1-fluoro-2-nitrobenzene (0.50g, 2.27mmol), methyl 2- (4-piperidinyl) acetate (0.43g, 2.73mmol) and cesium carbonate (1.11g, 3.41mmol) were dissolved in N, N-dimethylformamide (5mL) and stirred at 60 ℃ for 12 hours, the reaction mixture was poured into water (60mL), 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 obtain the title compound of this step (0.60g, yield: 75.0%).

MS(ESI):m/z 357.0[M+H] ⁺。

The second step is that: preparation of methyl 2- (1- (2-amino-4-bromophenyl) piperidin-4-yl) acetate.

Methyl 2- (1- (4-bromo-2-nitrophenyl) piperidin-4-yl) acetate (0.60g, 1.68mmol) was dissolved in ethanol (8mL) and water (2mL), and iron powder (0.47g, 8.40mmol) and ammonium chloride (0.45g, 8.40mmol) were added, and after stirring for 2h at 80 ℃, filtration, concentration, dilution with ethyl acetate, washing with water, liquid separation, drying, filtration, concentration, and purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (V/V) ═ 2/1) were obtained to obtain the title compound of this step (0.38g, yield: 69.1%).

MS(ESI):m/z 327.1[M+H] ⁺。

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

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

MS(ESI):m/z 535.0[M+H] ⁺。

The 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) benzenesulfonamido) phenyl) piperidin-4-yl) acetate (600mg, 1.12mmol), 2- (3- (difluoromethoxy) -5-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (387mg, 1.34mmol) and potassium carbonate (310mg, 2.24mmol) were dissolved in 1, 4-dioxane (10mL) and water (2mL), a [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (91mg, 0.11mmol) was added, nitrogen protected, reacted at 80 ℃ for 2 hours, the reaction solution was filtered to remove insoluble matter, concentrated, ethyl acetate and saturated brine were added, extracted, the organic phase was dried over anhydrous sodium sulfate, filtration, spin-drying of the solvent and purification of the residue by preparative high performance liquid chromatography (condition 1) gave the title compound of this step (200mg, yield: 28.9%).

MS(ESI):m/z 617.2[M+H] ⁺。

The 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 (200mg, 0.32mmol) was dissolved in a mixed solvent of methanol (5mL) and water (1mL), and sodium hydroxide (51.2mg, 1.28mmol) was added thereto, followed by stirring at room temperature for 2 h. The reaction solution was concentrated, and then water (15mL) was added to the concentrate to adjust pH 2 with 4N hydrochloric acid, followed by filtration and drying of the cake to obtain the title compound (150mg, yield: 76.9%).

MS(ESI):m/z 603.1[M+H] ⁺。

¹H-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-cyclopropylformylpiperazine to give the title compound (26mg, yield: 23.7%).

MS(ESI):m/z 575.2[M+H] ⁺。

¹H-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-cyclopropylformylpiperazine to give the title compound (20mg, yield: 22.8%).

MS(ESI):m/z 623.1[M+H] ⁺。

¹H-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-cyclopropylformylpiperazine to give the title compound (48mg, yield: 10.1%).

MS(ESI):m/z 619.2[M+H] ⁺。

¹H-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) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan and 3-chloro-5-methoxyphenylboronic acid to give the title compound (68mg, yield: 91.4%).

MS(ESI):m/z 583.3[M+H] ⁺。

¹H-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, the starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan and 3-fluoro-5-methoxyphenylboronic acid to give the title compound (92mg, yield: 74.5%).

MS(ESI):m/z 567.2[M+H] ⁺。

¹H-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) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan and 3-methoxy-5-methylphenylboronic acid to give the title compound (25mg, yield: 32.5%).

MS(ESI):m/z 563.2[M+H] ⁺。

¹H-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, the starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan and 3-chloro-5- (difluoromethoxy) phenylboronic acid to give the title compound (60mg, yield: 53.8%).

MS(ESI):m/z 619.1[M+H] ⁺。

¹H-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, the starting material in the fourth step was replaced with 2- (3- (difluoromethoxy) -5-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan and 3-chloro-5-ethoxyphenylboronic acid to give the title compound (25mg, yield: 45.8%).

MS(ESI):m/z 597.0[M+H] ⁺。

¹H-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) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan and 3-chloro-5-trifluoromethoxyphenylboronic acid to give the title compound (67mg, yield: 48.6%).

MS(ESI):m/z 637.1[M+H] ⁺。

¹H-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 ROR γ -LBD.

1. Experimental materials and instruments:

ROR γ -LBD (diabrotica spp.);

biotin-SRC 1(Perkin Elmer);

LANCE Eu-anti-6 × His antibody (Perkin Elmer);

Allophycocyanin-Streptavidin(Perkin Elmer)；

microplate reader (B MG Labtech).

2. The experimental method comprises the following steps:

solution preparation: reaction buffer (25mM HEPES, pH 7.0, 100mM NaCl, 0.01% Tween 20, 0.2% BSA, 5mM DTT) was prepared. A solution A1 containing 1nM of LANCE Eu-anti-6 XHis antibody, a solution A2 containing 1nM of LANCE Eu-anti-6 XHis antibody and 15nM ROR γ -LBD, and a solution B containing 200nM biotin-SRC 1 and 15nM allophycycanin-Streptavidin were prepared in reaction buffer, all on ice, and were used.

Test compounds were diluted in DMSO at 5 μ M starting concentration, diluted 4-fold, and 10 concentration points were taken. Adding 0.25 mu L of diluted compound to be tested, 15 mu L of solution A2 and 10 mu L of solution B into a compound to be tested hole in a 384-hole plate; negative control wells were added 0.25. mu.L DMSO, 15. mu.L solution A1, and 10. mu.L solution B; solvent control wells were added 0.25. mu.L DMSO, 15. mu.L solution A2, and 10. mu.L solution B. Sealing with tape, shaking for 2min, and mixing the reaction solution. The 384-well plate is placed at 4 ℃ overnight, then the 384-well plate is taken out to room temperature for balancing and centrifugation, and then the plate is read by a microplate reader (detection wavelength is 665nm/615 nm).

3. Data processing:

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

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

EC was calculated by GraphPad Prism software₅₀The value is obtained.

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 stage; when the maximum activation rate is more than 0, the test compound has an excitation effect on ROR gamma.

4. As a result:

the results of the agonist activity of the test compounds of the present invention against ROR γ are shown in table 1.

TABLE 1 agonistic activity of the compounds of the present invention on ROR γ

Compound numbering	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 can be seen that the compounds of the invention have significant agonistic effects on ROR γ with, for example, an EC of less than 110nM, preferably less than 20nM, more preferably less than 10nM₅₀The maximum activation rate is above 50%.

Experimental example 2: ROR γ -luciferase reporter gene assay.

1. Experimental materials and instruments:

plasmid pcDNA3.1(GAL4DBD/ROR gamma LBD), pGL4.35(luc2P/9XGAL4UAS/Hygro) (Nanjing Kebai biological construction);

Lipofectamine 3000(Invitrogen)；

Bright-Glo ^TM(Promega)；

ursolic acid (Cayman Chemical);

enzyme-linked immunosorbent assay (BMG Labtech);

293T cells (purchased from ATCC);

test compounds (10 mM stock in DMSO).

2. The experimental method comprises the following steps:

293T cells were cultured in a DMEM high-glucose medium (containing 10% FBS) in a T25 cell culture flask and grown to a confluence of about 80%, according to the instructions of Lipofectamine 3000Liposomes encapsulating the plasmid were prepared. The liposomes were mixed with a certain volume of DMEM high-sugar medium (containing 10% FBS), the original medium in T25 flask was removed, and 293T cells were transfected with the above mixture of liposomes and DMEM high-sugar medium. 24h after transfection, cells were digested and counted. Diluting the cells with DMEM high-glucose medium (containing 10% FBS, 2 μ M ursolic acid) to a certain concentration, and uniformly spreading onto 96-well culture plate with each well containing about 10 cells⁵And (4) respectively. The stock solution of the compound to be tested and a solvent control (DMSO) were diluted in a DMEM high-glucose medium (containing 10% FBS and 2. mu.M ursolic acid), and 100. mu.M was used as an initial concentration, and the stock solution was diluted 3 times to obtain 10 concentration points. The diluted test compound and solvent control were 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 mix the compound to be tested with the culture medium thoroughly, and mixing at 37 deg.C with 5% CO₂The incubator is continued for 24 h. The 96 well cell culture plates were removed and allowed to equilibrate to room temperature for 10min, and Bright-Glo was added as per the instructions^TMAnd mixing the mixture completely. And (3) rapidly transferring the mixed solution to a detection plate, and detecting the luminous intensity by using an enzyme-labeling instrument.

3. Data processing:

the activation rate is the mean luminescence of the experimental wells/solvent control wells x 100%.

The mean luminescence of the solvent control wells was defined as 100%, data analysis and plotting were performed using Graphpad Prism 5 software, and EC was calculated as log of activation rate versus compound concentration via a four parameter fit curve₅₀A value; the maximum activation rate is the activation rate of the corresponding concentration point when the fitting curve is in the upper plateau stage; when the maximum activation rate is more than 100%, the test compound has an agonistic effect on ROR gamma.

4. As a result:

the results of the agonist activity of the compounds of the present invention on ROR γ in cells are shown in table 2.

TABLE 2 agonistic activity of the compounds of the present invention on ROR γ

Compound numbering	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 invention have a significant agonistic effect on ROR γ in cells with, for example, an EC of less than 2000nM₅₀And a maximum activation rate greater than 300%.

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

Claims

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

wherein the content of the first and second substances,

ring A¹Selected from phenyl and 5-6 membered heteroaryl;

ring A²Selected from phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl;

ring A³Selected from phenyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 4-10 membered heterocyclyl;

Z ¹、Z ²and Z³Each independently selected from CR⁴And N;

R ¹selected from hydrogen and C_1-6An alkyl group;

each R²Each independently selected from halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy and C_3-6A cycloalkoxy group;

each R³Each independently selected from halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy and-S (═ O)₂-R ⁶；

Each R⁴Each independently selected from hydrogen, halogenCyano, C_1-6Alkyl and C_1-6An alkoxy group;

each R⁵Each independently selected from hydrogen, halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, -C_0-6alkylene-O-R^a、-O-C _1-6alkylene-O-R^a、C _1-6Haloalkoxy, -C_0-6alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-6alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-C(＝O)-C _1-6Alkyl, -C_0-6alkylene-S (═ O)₂-R ⁶、-C _0-6alkylene-N (R)^a)(R ^b)、-C _0-6alkylene-C (═ O) -N (R)^a)(R ^b)、-C _0-6alkylene-N (R)^a)-C(＝O)-R ⁶、-C _0-6alkylene-S (═ O)₂-N(R ^a)(R ^b)、-C _0-6alkylene-N (R)^a)-S(＝O) ₂-R ⁶4-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl; wherein: each R^aEach independently selected from hydrogen and C_1-6An alkyl group; each R^bEach independently selected from hydrogen and C_1-6An alkyl group; or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;

each R⁶Each independently selected from C_1-6Alkyl and C_3-6A cycloalkyl group;

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

wherein, ring A¹Ring A²Ring A³、R ²、R ³、R ⁵M, n and q are as defined in claim 1.
A compound or pharmaceutically acceptable form thereof according to claim 2, wherein,

ring A¹Selected from phenyl and pyridyl; each R²Each independently selected from halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_3-6A cycloalkoxy group.
A compound or pharmaceutically acceptable form thereof according to claim 2 or 3, wherein,

ring A²Selected from phenyl and 5-6 membered heteroaryl; each R³Each independently selected from halogen, cyano, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3- ₆Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and-S (═ O)₂-C _1-4An alkyl group.
A compound according to claim 2, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-B1, or a pharmaceutically acceptable form thereof,

wherein, ring A³、R ²、R ⁵M and q are as defined in claim 2.
A compound according to claim 5 or a pharmaceutically acceptable form thereof,

wherein each R is²Each independently selected from halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy and C_3-6A cycloalkoxy group;

ring A³Selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl;

each R⁵Each independently selected from hydrogen, hydroxy, C_1-3Alkyl, -C_1-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、-C _0-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-S(＝O) ₂-C _1-3Alkyl, -C_1-3alkylene-N (R)^a)(R ^b)、-C _1-3alkylene-C (═ O) -N (R)^a)(R ^b) And 4-6 membered heterocyclyl; wherein: each one of which isR is^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group;

q is 0, 1 or 2;

m is 1 or 2.
A compound according to claim 6 or a pharmaceutically acceptable form thereof,

wherein the content of the first and second substances,

each R²Each independently selected from halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy and C_1-4A haloalkoxy group;

ring A³Selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

each R⁵Each independently selected from hydrogen, hydroxy, C_1-3Alkyl, -C_1-3alkylene-O-R^a、-O-C _1-3alkylene-O-R^a、-C _0-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _1-3alkylene-C (═ O) -O-R^a、-C(＝O)-C _3-6Cycloalkyl, -C (═ O) -C_3-6cycloalkylene-C (═ O) -O-R^a、-S(＝O) ₂-C _1-3Alkyl, -C_1-3alkylene-N (R)^a)(R ^b)、-C _1-3alkylene-C (═ O) -N (R)^a)(R ^b) And 4-6 membered heterocyclyl; wherein: each R^aEach independently selected from hydrogen and C_1-3An alkyl group; each R^bEach independently selected from hydrogen and C_1-3An alkyl group;

q is 0, 1 or 2;

m is 2.
A compound according to claim 7, or a pharmaceutically acceptable form thereof,

wherein the content of the first and second substances,

each R²Each independently selected from fluoro, chloro, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy;

ring A³Selected from pyrazolyl, tetrahydropyridinyl, thiazolyl, piperazinyl, morpholinyl and piperidinyl;

each R⁵Each independently selected from hydrogen, -OH, -CH₃、-CH ₂CH ₃、-CH(CH ₃) ₂、-CH ₂COOH、-CH ₂CH ₂OCH ₃、-CH ₂C(＝O)N(CH ₃) ₂、-CH ₂CH ₂N(CH ₃) ₂、
-C(＝O)CH ₂CH ₂COOH、
-COOCH ₃、-COOH、-S(＝O) ₂-CH ₃and-OCH₂CH ₂OCH ₃；

q is 0, 1 or 2;

m is 2.
A compound according to any one of claims 5 to 8, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula I-B, or a pharmaceutically acceptable form thereof,

wherein, ring A³、R ⁵And q is as defined in any one of claims 5 to 8.
A compound or pharmaceutically acceptable form thereof according to claim 1, wherein the compound is selected from:

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.
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;

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

(3) carrying out reduction reaction and optional N-alkylation reaction on the compound D to obtain a compound E;

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

(5) reacting the compound G with a compound H to obtain a compound of a formula I;

wherein, ring A¹Ring A²Ring A³、Z ¹、Z ²、Z ³、R ¹、R ²、R ³、R ⁵M, n and q are as defined in claim 1; x represents a leaving group selected from a halogen atom, a mesyloxy group and a trifluromesyloxy group;

or comprises the following steps:

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

(2 ') subjecting the compound C ' to a reduction reaction and an optional N-alkylation reaction to obtain a compound D ';

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

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

wherein, ring A¹Ring A²Ring A³、Z ¹、Z ²、Z ³、R ¹、R ²、R ³、R ⁵M, n and q are as defined in claim 1; x represents a leaving group selected from a halogen atom, a mesyloxy group and a trifluromesyloxy group; hal represents a halogen atom selected from F, Cl, Br and I.
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.
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 further modulator of homeotropic rory.
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, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by rory.
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, for use in the prevention and/or treatment of a disease mediated at least in part by rory.
A method for preventing and/or treating cancer, inflammation or autoimmune disease comprising the steps of: administering a therapeutically effective amount 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, to a patient in need thereof.