CN111635373B

CN111635373B - Polycyclic sulfonamide ROR gamma modulators

Info

Publication number: CN111635373B
Application number: CN202010110712.4A
Authority: CN
Inventors: 刘斌
Original assignee: Xuanzhu Pharma Co Ltd
Current assignee: Shandong Xuanzhu Pharma Co Ltd
Priority date: 2019-03-01
Filing date: 2020-02-24
Publication date: 2022-07-12
Anticipated expiration: 2040-02-24
Also published as: CN111635373A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a ROR gamma small molecule regulator, pharmaceutically acceptable salts, esters and isomers thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salts, the esters and the isomers thereof, a method for preparing the compound, the pharmaceutically acceptable salts, the esters and the isomers thereof, and applications of the compound, the pharmaceutically acceptable salts, the esters and the isomers thereof.

Description

Polycyclic sulfonamide ROR gamma modulators

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to polycyclic sulfonamide ROR gamma regulator compounds, pharmaceutically acceptable salts, esters and isomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts, esters and isomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts, esters and stereoisomers thereof, and applications of the compounds, pharmaceutically acceptable salts, esters and isomers thereof.

Background

The tumor immunotherapy is to control and kill tumor cells by activating the immune system of the body and enhancing the anti-tumor immunity of the body, and it directly acts on the immune system of the human body rather than on the tumor. Tumor immunity has attracted attention in recent years and is the focus of the field of tumor therapy. The treatment method shows strong antitumor activity on some existing tumor types such as melanoma, non-small cell lung cancer and the like, and is expected to become a new treatment means in the tumor field after surgery, chemotherapy, radiotherapy and targeted treatment.

Retinoic acid Related Orphan Receptors (RORs) are members of the nuclear receptor family, which are capable of modulating a variety of physiological and life processes. The ROR family contains three types ROR α, ROR β, and ROR γ. Three different receptors can be expressed in different tissues and control different physiological processes, and ROR α is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain. ROR β acts primarily on the central nervous system. ROR γ can be expressed in many tissues, including liver, animal fat, and skeletal muscle. ROR γ mainly includes two types of ROR γ 1 and ROR γ 2(ROR γ t), ROR γ 1 is mainly distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart, liver and the like, and ROR γ t is expressed only in some immune cells. ROR γ T is a characteristic transcription factor of helper T cell 17(T helper 17cells, abbreviated as Th17), plays an important role in the differentiation of Th17, and is a key regulator of Th17 differentiation.

Research reports that Th17 is a newly discovered helper T cell subtype, mainly secretes interleukin 17 (IL-17), and Th17 is found to play an important role in the development of autoimmunity and inflammation. It has been found that Th17 is widely present in tumor tissues and can exert tumor immune function by promoting the activation of cytotoxic T cells. It was found that IL-17A deficient mice are more prone to melanoma and that treatment with IL-17A secreting T cells is effective in preventing the development of tumors if T cell therapy is applied to the mice, and more importantly, Th17 cells show a stronger therapeutic effect than TH1 cells with the aid of IL-17A. In addition, it was found that treatment with Th17 cells was also effective in activating tumor-specific CD8⁺T cells of which CD8⁺T cells are essential cells for anti-tumor. Studies have shown that Th17 cells recruit dendritic cells into tumor tissue and enable CD8 α⁺Dendritic cells are aggregated into tumor groupsAnd (5) weaving. In addition, Th17 cells can activate tumor tissue chemotactic factor CCL 20.

Therefore, the Th17 cell differentiation can be increased by regulating ROR gamma T, so that the activation of cytotoxic T cells is promoted, and the tumor-specific CD8 is promoted⁺The activity of T cells, the regulation of the expression and secretion of IL-17 and the function of tumor immunity.

ROR γ t has also been found to be associated with a variety of other diseases, such as autoimmune diseases, inflammation, metabolic diseases, infectious diseases, and the like.

In conclusion, ROR gamma t can be used as a potential target of tumor immunotherapy, and the search for small-molecule ROR gamma t modulators and the application of the small-molecule ROR gamma t modulators in clinical treatment are of great significance.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a polycyclic sulfonamide compound which has a novel structure and regulating activity on ROR gamma. Furthermore, the compounds can be used for increasing the differentiation of Th17 cells in a subject, thereby enhancing the immunity of the body to tumors. Further, such compounds are useful for treating one or more diseases mediated by ROR γ, particularly cancer. The compounds have good inhibition effect on various cancer cells, and have higher exposure and better in-vivo drug effect in organisms.

The technical scheme of the invention is as follows:

in one aspect, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or an isomer thereof,

wherein,

M₁、X₁、X₄each independently selected from-C (R)₃)(R₄)-、-C(O)-、-O-、-N(R₅) -, -S-, -S (O) -or-S (O)₂-；

X₂、X₃Each independently selected from-C (R)₆) -or-N-;

each L₁、L₂Each independently selected from-C (R)₇)(R₈)-、-O-、-N(R₉) -or-S-;

ring A, ring B are selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with 1 or more Q;

each Q is independently selected from halogen, hydroxyl, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy or amino C_1-6An alkoxy group;

R₂selected from the group consisting of-C (O) R^a、-C(O)OR^a、-OC(O)R^a、-OC(O)OR^a、-OC(O)N(R^a)(R^b)、-C(O)N(R^a)(R^b)、-N(R^a)C(O)R^b、-N(R^a)C(O)OR^b、-N(R^a)C(O)N(R^a)(R^b)、-S(O)R^a、-S(O)OR^a、-OS(O)R^a、-OS(O)OR^a、-OS(O)N(R^a)(R^b)、-S(O)N(R^a)(R^b)、-N(R^a)S(O)R^b、-N(R^a)S(O)OR^b、-N(R^a)S(O)N(R^a)(R^b)、-S(O)₂R^a、-S(O)₂OR^a、-OS(O)₂R^a、-OS(O)₂OR^a、-OS(O)₂N(R^a)(R^b)、-S(O)₂N(R^a)(R^b)、-N(R^a)S(O)₂R^b、-N(R^a)S(O)₂OR^bor-N (R)^a)S(O)₂N(R^a)(R^b)；

Each R₁、R^a、R^bEach independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano and C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, aminoC_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, amino C_1-6Alkoxy, 3-10 membered cycloalkyl or 3-10 membered heterocyclyl;

R₃、R₄、R₅、R₆、R₇、R₈、R₉each independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl and C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, halo C_1-6Alkoxy or C_1-6An alkylcarbonyl group;

m, n, p and q are respectively and independently selected from 0, 1,2,3,4 or 5.

In certain embodiments, the compound, a pharmaceutically acceptable salt thereof, an ester thereof, or an isomer thereof, wherein ring a is selected from 3-8 membered monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclyl, phenyl, or 5-8 membered monocyclic heteroaryl;

ring B is selected from 3-8 membered monocyclic cycloalkyl, 8-10 membered fused ring alkyl, 3-8 membered monocyclic heterocyclyl, 8-10 membered fused heterocyclic group, 6-8 membered monocyclic aryl, 8-10 membered fused ring aryl, 5-8 membered monocyclic heteroaryl or 8-10 membered fused heteroaryl optionally substituted with 1 or more Q;

each Q is independently selected from halogen, hydroxyl, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy or amino C_1-6An alkoxy group.

In certain embodiments, ring a is selected from a 5-6 membered monocyclic cycloalkyl, a 5-6 membered heteromonocyclic group, phenyl, or a 5-6 membered monoheteroaryl.

In certain embodiments, ring B is selected from 3-8 membered monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclyl, 6-8 membered monocyclic aryl, or 5-8 membered monocyclic heteroaryl, optionally substituted with 1 or 2Q;

each Q is independently selected from halogen and hydroxylAmino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy or amino C_1-6An alkoxy group.

In certain embodiments, the compounds of the present invention, pharmaceutically acceptable salts thereof, esters thereof, or isomers thereof, wherein,

ring a is selected from phenyl or 5-6 membered mono heteroaryl.

Preferably, ring a is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

ring B is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl or 5-6 membered monocyclic heteroaryl, optionally substituted with 1 or 2Q;

preferably, ring B is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrothienyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, optionally substituted with 1 or 2Q;

each Q is independently selected from halogen, cyano, C_1-6Alkyl radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl radical, C_1-6Alkoxy or halo C_1-6An alkoxy group.

In certain embodiments, ring B is selected from phenyl or 5-6 membered monoheteroaryl optionally substituted with 1 or 2Q;

each Q is independently selected from fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

M₁selected from-C (O) -, -S (O) -or-S (O)₂-；

X₁Is selected from-C (R)₃)(R₄)-、-C(O)-、-O-、-N(R₅) -or-S-;

X₂、X₃each independently is-CH-or-N-;

X₄is selected from-CH₂-, -O-, -NH-or-S-;

R₃、R₄、R₅each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl or halo C_1-6An alkoxy group.

In certain embodiments, X₁Is selected from-CH₂-, -C (O) -, -O-, -NH-or-S-.

In certain embodiments, X₁Is selected from-CH₂-, -C (O) -, -O-or NH; preferably-CH₂-or-C (O) -.

each R₁Are respectively provided withIndependently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy or amino C_1-6An alkoxy group;

R₂selected from the group consisting of-C (O) R^a、-C(O)OR^a、-OC(O)R^a、-OC(O)OR^a、-OC(O)N(R^a)(R^b)、-C(O)N(R^a)(R^b)、-N(R^a)C(O)R^b、-N(R^a)C(O)OR^b、-S(O)R^aor-S (O)₂R^a；

R^a、R^bEach independently selected from hydrogen and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, 3-6 membered monocyclic cycloalkyl or 3-6 membered monocyclic heterocyclyl.

In certain embodiments, each R is₁Each independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano and C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, or halo C_1-6An alkoxy group.

In certain embodiments, R₂Selected from the group consisting of-C (O) R^a、-C(O)OR^a、-OC(O)R^a、-C(O)N(R^a)(R^b)、-N(R^a)C(O)R^b、-S(O)R^aor-S (O)₂R^a(ii) a preferably-C (O) OR^a、-OC(O)R^a、-C(O)N(R^a)(R^b) or-N (R)^a)C(O)R^b。

R^a、R^bEach independently selected from hydrogen and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, 3-4 membered monocyclic cycloalkyl or 3-4 membered monocyclic heterocyclyl.

In certain embodiments, each L is₁、L₂Each independently selected from-C (R)₇)(R₈) -or-N (R)₉) -; preferably-C (R)₇)(R₈)-；

R₇、R₈、R₉Each independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl and C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, halo C_1-6Alkoxy or C_1-6An alkylcarbonyl group.

In certain embodiments, m, n are each independently selected from 0, 1 or 2;

p and q are respectively and independently selected from 1,2 or 3.

In certain embodiments, m is selected from 0 or 1.

In certain embodiments, n is selected from 0, 1 or 2; preferably n is 1.

In certain embodiments, p is selected from 1,2 or 3; preferably p is 1 or 2.

In certain embodiments, q is selected from 1 or 2; preferably q is 1.

M₁selected from-C (O) -, -S (O) -or-S (O)₂-；

X₁Is selected from-CH₂-, -C (O) -, -O-, -NH-or-S-;

X₂、X₃each is independently selected from-CH-or-N-;

X₄is selected from-CH₂-, -O-, -NH-or-S-;

each L₁、L₂Each independently selected from-C (R)₇)(R₈) -or-N (R)₉)-；

Ring a is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl;

ring B is selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrothienyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, optionally substituted with 1 or 2Q;

Each R₁Independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, or trifluoroisopropoxy;

R₂selected from the group consisting of-C (O) R^a、-C(O)OR^a、-OC(O)R^a、-C(O)N(R^a)(R^b) or-N (R)^a)C(O)R^b；

R^a、R^bEach independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, cyclopropyl, cyclobutyl, oxetanyl, aziridinyl, oxetanyl or azetidinyl;

R₇、R₈、R₉each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethylFluoroethyl, trifluoropropyl, trifluoroisopropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy or trifluoroisopropoxy;

m and n are respectively and independently selected from 0, 1 or 2;

p and q are respectively and independently selected from 1,2 or 3.

In certain embodiments, M₁Selected from-C (O) -, -S (O) -or-S (O)₂-; preferably-S (O)₂-。

In certain embodiments, X₁Is selected from-CH₂-, -C (O) -, -O-, -NH-or-S-; preferably-CH₂-or-C (O) -.

In certain embodiments, X₂、X₃Each is independently selected from-CH-or-N-; preferably X₂、X₃Are all-CH-.

In certain embodiments, X₄Is selected from-CH₂-, -O-, -NH-or-S-; preferably-CH₂-or-O-.

In certain embodiments, each L is₁、L₂Each independently selected from-C (R)₇)(R₈) -or-N (R)₉)-。

R₇、R₈、R₉Each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In certain embodiments, each L is₁、L₂Each independently selected from-C (R)₇)(R₈)-；

R₇、R₈Each independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

preferably, R₇、R₈Each independently selected from hydrogen, fluorine, chlorine, methyl and methoxyTrifluoromethyl or trifluoromethoxy.

In certain embodiments, ring a is selected from phenyl or pyridyl.

In certain embodiments, ring B is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl substituted with 1Q;

preferably, ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl substituted with 1Q;

q is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In certain embodiments, each R is₁Each independently selected from hydrogen, fluoro, chloro, hydroxy, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In certain embodiments, R₂Selected from-C (O) OR^aor-NHC (O) R^b；

R^a、R^bEach independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, oxacyclopropyl, aziridinyl, oxacyclobutyl or azetidinyl.

In certain embodiments, the compounds of the present invention, pharmaceutically acceptable salts thereof, esters thereof, or isomers thereof, have the structure shown in formula (II) below:

wherein X₁、X₃、L₁、L₂、R₁、R₂、M₁Ring A, ring B, p, q are as defined above.

The technical solutions of the present invention can be combined with each other to form a new technical solution, and the formed new technical solution is also included in the scope of the present invention.

In certain embodiments, the compound of formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof is selected from the group consisting of

In another aspect, the present invention also provides a pharmaceutical preparation, which contains the compound of the aforementioned general formula (I) or (II), its pharmaceutically acceptable salt, its ester or its stereoisomer, and one or more pharmaceutically acceptable excipients, and can be in any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are substances which are non-toxic, compatible with the active ingredient and otherwise biologically suitable for use in the organism. The choice of a particular excipient will depend on the mode of administration or disease type and state used to treat a particular patient. Examples of the pharmaceutically acceptable excipient include, but are not limited to, solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, mold release agents, coating agents, flavoring agents, antioxidants, and the like, which are conventional in the pharmaceutical field. If necessary, a flavor, a preservative, a sweetener, and the like may be further added to the pharmaceutical composition.

In certain embodiments, the pharmaceutical formulations described above may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration, among others. For oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, conventional oral solid preparations such as tablets, capsules, pills, granules and the like; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical preparations can also be prepared into injections, including injections, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalation formulation, aerosol, powder spray, or the like.

In another aspect, the present invention also relates to the use of a compound of the aforementioned general formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, for the preparation of a medicament for the treatment and/or prevention of a related disease mediated by ROR γ.

Further, the invention also relates to application of a pharmaceutical preparation containing the compound shown in the general formula (I) or (II), pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof in preparing a medicament for treating and/or preventing related diseases mediated by ROR gamma.

In certain embodiments, the ROR γ -mediated associated disease is selected from one or more of cancer, bacterial infectious disease, fungal infectious disease, parasite-induced associated disease, metabolic disease, chronic obstructive pulmonary disease, asthma, autoimmune disease, inflammatory disease, myocardial infarction, atherosclerosis, sarcoidosis.

It is understood that the occurrence of a disease may be mediated by a variety of pathological responses, and that the same disease may be classified into different disease types, e.g., rheumatoid arthritis is both associated with autoimmune responses and inflammatory. The classification of diseases in the present invention is based only on a certain pathological mechanism in common. The classification of diseases in the present invention should not be construed as limiting the scope of the present invention.

In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of the aforementioned general formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, and one or more second therapeutically active agents which are useful in combination with the ROR γ modulator compounds of the present invention for the treatment and/or prevention of a related disorder mediated thereby.

In certain embodiments, the second therapeutically active agent can be an antineoplastic agent, including but not limited to: mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cytostatic agents, targeting antibodies, HMG-CoA reductase inhibitors, prenyl protein transferase inhibitors, and the like.

In certain embodiments, the second therapeutic activity can be an anti-inflammatory drug, including but not limited to steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs.

In certain embodiments, the second therapeutically active agent can be a drug for treating autoimmune diseases, including but not limited to, disease modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, glucocorticoid drugs, TNF antagonists, cyclophosphamide, mycophenolate, cyclosporine, and the like.

In certain embodiments, the second therapeutically active agent can be a drug that reduces or reduces one or more side effects of the compounds of the invention when used to treat a disease in a subject, or can be a drug that enhances the efficacy of the compounds of the invention.

In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, as described above.

In certain embodiments, the compound of formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, and the second therapeutically active agent may be present in the same formulation, i.e., in a combined formulation, or may be present in separate formulations for simultaneous or sequential administration to a subject.

Further, the invention also relates to the application of a pharmaceutical composition containing the compound shown in the general formula (I) or (II), the pharmaceutically acceptable salt, the ester or the stereoisomer thereof in preparing a medicament for treating and/or preventing related diseases mediated by ROR gamma, wherein the related diseases mediated by ROR gamma are defined as the above.

In another aspect, the present invention also provides a method for treating related diseases mediated by rory, which comprises administering to a patient in need thereof an effective amount of a compound of the aforementioned general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, the aforementioned pharmaceutical preparation or pharmaceutical composition; the rory mediated related diseases are as described hereinbefore.

By "effective amount" is meant a dosage of a drug that prevents, alleviates, retards, inhibits or cures a condition in a subject. The size of the administered dose is determined by the mode of drug administration, the pharmacokinetics of the agent, the severity of the disease, the individual signs (sex, weight, height, age) of the subject, etc.

In the present invention, unless otherwise defined, scientific and technical terms used herein have meanings commonly understood by those skilled in the art, however, in order to better understand the present invention, definitions of some terms are provided below. To the extent that the definitions and explanations of the terms provided herein do not conform to the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided herein shall control.

The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C" according to the invention_1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C_1-4Alkyl group and C_1-3Alkyl group "," C_1-2Alkyl radical“C_2-6Alkyl group "," C_2-5Alkyl group "," C_2-4Alkyl group "," C_2-3Alkyl group "," C_3-6Alkyl group and C_3-5Alkyl group "," C_3-4Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention_1-4Alkyl "means C_1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.

"C" according to the invention_1-6Alkoxy "means" C_1-6alkyl-O- ", said" C_1-6Alkyl "is as defined above. "C" according to the invention_1-4Alkoxy "means" C_1-4alkyl-O- ", said" C_1-4Alkyl "is as defined above.

The "hydroxy group C" of the present invention_1-6Alkyl, amino C_1-6Alkyl, halo C_1-6Alkyl "means C_1-6One or more hydrogens of the alkyl group are each replaced by one or more hydroxyl groups, amino groups or halogens. C_1-6Alkyl is as previously defined

The "hydroxyl group C" of the present invention_1-6Alkoxy, amino C_1-6Alkoxy, halo C_1-6Alkoxy "means" C_1-6One or more hydrogens of "alkoxy" are replaced with one or more hydroxy, amino, or halogen.

"C" according to the invention_1-6Alkylamino radical, di (C)_1-6Alkyl) amino "means each C_1-6alkyl-NH-),

The term "3-to 10-membered cycloalkyl" as used herein is meant to include "3-to 8-membered monocycloalkyl" and "8-to 10-membered fused ring alkyl".

The "3-to 8-membered monocyclic alkyl" as used herein means a saturated or partially saturated monocyclic cyclic alkyl group having 3 to 8 carbon atoms and having no aromaticity, and includes "3-to 8-membered saturated monocyclic alkyl" and "3-to 8-membered partially saturated monocyclic alkyl"; preferred are "3-to 4-membered monocycloalkyl", "3-to 5-membered monocycloalkyl", "3-to 6-membered monocycloalkyl", "3-to 7-membered monocycloalkyl", "4-to 5-membered monocycloalkyl", "4-to 6-membered monocycloalkyl", "4-to 7-membered monocycloalkyl", "5-to 6-membered monocycloalkyl", "5-to 7-membered monocycloalkyl", "6-to 8-membered monocycloalkyl", "7-to 8-membered monocycloalkyl", "3-to 6-membered saturated monocycloalkyl", "5-to 8-membered saturated monocycloalkyl", "5-to 7-membered saturated monocycloalkyl", "5-to 6-membered saturated monocycloalkyl", and the like. Specific examples of said "3-to 8-membered saturated monocycloalkyl" include, but are not limited to: a cyclopropyl group (cyclopropyl), a cyclobutane group (cyclobutyl), a cyclopentyl group (cyclopentyl), a cyclohexyl group (cyclohexyl), a cycloheptyl group (cycloheptyl), a cyclooctyl group (cyclooctyl), etc.; specific examples of the "3-to 8-membered partially saturated monocycloalkyl" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1, 3-diene, cyclohex-1, 4-diene, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl and the like.

The 8-10 membered condensed ring group is a saturated or partially saturated nonaromatic cyclic group which is formed by two or more than two cyclic structures sharing two adjacent carbon atoms and contains 8-10 cyclic atoms, wherein one ring in the condensed ring can be an aromatic ring, but the condensed ring does not have aromaticity on the whole; including "8-9-membered fused ring group", "9-10-membered fused ring group", etc., the fusion mode may be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl and the like. Examples include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentanyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentanyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5, 8 a-hexahydronaphthyl, 10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, and the like.

The "3-to 10-membered heterocyclic group" described in the present invention includes "3-to 8-membered heteromonocyclic group" and "8-to 10-membered fused heterocyclic group".

The "3-to 8-membered heteromonocyclic group" according to the present invention means a saturated or partially saturated and non-aromatic monocyclic cyclic group containing at least one hetero atom (e.g., 1,2,3,4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom and has 3 to 8 ring atoms, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo. The "3-to 8-membered heteromonocyclic group" described in the present invention includes "3-to 8-membered saturated heteromonocyclic group" and "3-to 8-membered partially saturated heteromonocyclic group". Preferably, the "3-8 membered heteromonocyclic group" described herein contains 1-3 heteroatoms; preferably, the "3-to 8-membered heteromonocyclic group" of the present invention contains 1 to 2 hetero atoms selected from nitrogen atom and/or oxygen atom; preferably, the "3-to 8-membered heteromonocyclic group" described herein contains 1 nitrogen atom. The "3-to 8-membered heteromonocyclic group" is preferably "3-to 7-membered heteromonocyclic group", "3-to 6-membered heteromonocyclic group", "4-to 6-membered heteromonocyclic group", "6-to 8-membered heteromonocyclic group", "5-to 7-membered heteromonocyclic group", "5-to 6-membered heteromonocyclic group", "3-to 6-membered saturated heteromonocyclic group", "5-to 6-membered saturated heteromonocyclic group", "3-to 6-membered saturated nitrogen-containing heteromonocyclic group", "5-to 6-membered saturated nitrogen-containing heteromonocyclic group", and the like. For example, containing only 1 or 2 nitrogen atoms, or, alternatively, containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "3-8 membered heteromonocyclic group" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazaziridinyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidinonyl, tetrahydropyridinonyl, dihydropiperidinonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, diazo, and dihydropyrrolyl, Oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl, and the like.

The "8-to 10-membered fused heterocyclic group" as used herein refers to a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms, wherein at least one ring atom of the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, which is formed by two or more cyclic structures sharing two adjacent atoms with each other, and at least one ring atom of the fused ring is a heteroatom, which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) of the cyclic structure may be oxo, and includes, but is not limited to, "8-to 9-membered fused heterocyclic group", "9-to 10-membered fused heterocyclic group" and the like, and may be fused in such a manner that the fused ring is a 5-to 6-membered heterocyclic group, a 5-to 6-membered cycloalkyl group, Benzo 5-6 membered heterocyclyl, benzo 5-6 membered saturated heterocyclyl, 5-6 membered heteroarylo 5-6 membered saturated heterocyclyl; 5-6 membered heteroaryl is as previously defined; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: pyrrolidinyl-cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-morpholinyl, piperidinyl-morpholinyl, benzopyrrolinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolinyl, benzimidazolidinyl, benzoxazolinyl, benzothiazolinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopyridyl, benzomorpholinyl, benzopyrinyl, benzotetrahydropyranyl, pyridocyclopentyl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridoisoxazolidinyl, pyridoisothiazolidinyl, pyridopiperidinyl, pyridomorpholinyl, pyridoisothiazolidinyl, pyridomorpholinyl, and the like, Pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazoimidazolidinyl, pyrimidooxazolidinooxazolidinyl, pyrimidoiizolidinyl, pyrimidoiisoxazolidinyl, pyrimidoiisothiazolidinyl, pyrimidoipiperidinyl, pyrimidoimorpholinyl, pyrimidopiperazinyl, pyrimidoitetrahydropyranyl; tetrahydroimidazo [4,5-c ] pyridyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, octahydro cyclopenta [ c ] pyrrolyl, 4H-1, 3-benzoxazinyl and the like.

The term "benzocyclopentyl", the structure of which refers to

(also referred to as 2, 3-dihydro-1H-indenyl); the term "benzo-pyrrolidine" structurally includes

Etc.; the term "pyridotetrahydrofuranyl" structurally includes

Specific examples of the other "other condensed heterocyclic group as defined above" have a cyclic structure similar thereto.

The "6-to 10-membered aryl" as referred to herein includes "6-to 8-membered monocyclic aryl" and "8-to 10-membered fused-ring aryl".

The "6-to 8-membered monocyclic aryl" as referred to herein means a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.

The "8-to 10-membered fused ring aryl" as referred to herein means an unsaturated aromatic cyclic group having 8 to 10 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms with each other, and is preferably a "9-to 10-membered fused ring aryl", and specific examples thereof are naphthyl and the like.

The "5-to 10-membered heteroaryl" as referred to herein includes "5-to 8-membered monoheteroaryl" and "8-to 10-membered fused heteroaryl".

The "5-to 8-membered monoheteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "5-to 8-membered monoheteroaryl group" includes, for example, "5-to 7-membered monoheteroaryl group", "5-to 6-membered nitrogen-containing monoheteroaryl group", "6-membered nitrogen-containing monoheteroaryl group", and the like, in which the hetero atom contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and the other 1 or 2 hetero atoms (for example, oxygen atom and/or sulfur atom), or contains 2 nitrogen atoms and the other 1 or 2 hetero atoms (for example, oxygen atom and/or sulfur atom). Specific examples of "5-to 8-membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, azepinyl, and the like. The "5-6 membered monoheteroaryl" refers to a specific example containing 5 to 6 ring atoms in a 5-8 membered heteroaryl.

The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic cyclic structure having 8 to 10 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., which can be fused in a benzo-5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.

The expression "carbon atom, nitrogen atom or sulfur atom is oxo" as used herein means that C-O, N-O, S-O or SO is formed₂The structure of (1).

The term "optionally substituted" as used herein means both the case where one or more hydrogen atoms on a substituent may be "substituted" or "unsubstituted" by one or more substituents.

"pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH, -SO) present in a compound₃H, etc.) with a suitable inorganic or organic cation (base),including salts with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts of basic functional groups present in the compounds (e.g., -NH2, etc.) with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).

"isomers" as used herein means when the compounds of the present invention contain one or more asymmetric centers and thus are present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain an olefinic double bond, include cis-isomers and trans-isomers, unless otherwise specified. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. The compounds of the present invention contain a spiro ring structure, and substituents on the ring may be present on both sides of the ring to form the opposite cis (cis) and trans (trans) isomers, depending on the steric structure of the ring. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometrical isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.

The term "ester" as used herein means the presence of an acid group, such as-COOH, -SO, in the structure of the compound₃H、-PO₄H, etc., which can form an ester with an organic alcohol compound; when an-OH is present in the structure of the compound, it may form an ester with an organic acid, an inorganic acid, or an inorganic acid salt. The esters can be hydrolyzed in vivo to free compounds to exert therapeutic effects.

The compounds of the invention may be prepared by enantiospecific synthesis or by resolution from a mixture of enantiomers in such a way as to give the individual enantiomers. Conventional resolution techniques include the formation of salts of the free base of each of the enantiomers of an enantiomeric pair using optically active acids (followed by fractional crystallization and regeneration of the free base), the formation of salts of the acid form of each of the enantiomers of an enantiomeric pair using optically active amines (followed by fractional crystallization and regeneration of the free acid), the formation of esters or amides of each of the enantiomers of an enantiomeric pair using optically pure acids, amines or alcohols (followed by chromatographic separation and removal of the chiral auxiliary), or the resolution of mixtures of the enantiomers of the starting materials or final products using various well-known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. The optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

The "dosage form" of the present invention refers to a form prepared from the drug suitable for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injections and concentrated solutions for injections), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.

In another aspect, the invention also provides a process for the preparation of a compound of the invention:

a process for the preparation of a compound of formula (I):

wherein X ═ Cl, Br, I; corresponding to X₁-X₄、R₁-R₂、M₁、L₁-L₂A, B, m, n, p, q are as defined above.

The intermediate 1 and boron doublet react under the alkaline condition and the action of a palladium catalyst to generate an intermediate 2.

The intermediate 2 and the intermediate 3 react under the conditions of alkaline condition, palladium catalyst action and inert gas protection to generate an intermediate 4; the intermediate 4 is subjected to a series of cyclization reactions and substitution reactions under an acidic condition to obtain a compound (X) with a general formula (I)₁Selected from the group consisting of-C (O) -, -O-, -N (R)₅) -, -S-, -S (O) -or-S (O)₂-, or further subjected to a reductive elimination reaction under acidic conditions to give a compound (X) of the general formula (I)₁is-C (R)₃)(R₄)-)。

In the above preparation method, all reactions can be carried out in a conventional solvent, including but not limited to DMSO, DMF, acetonitrile, methanol, tetrahydrofuran, toluene, DMF, dimethyl ether, dichloromethane, chloroform, 1, 4-dioxane, trifluoroacetic acid, and water, and a single organic solvent or a mixed solvent of two or more solvents can be used in the reaction process. Alternatively, if a certain reactant is a liquid, the reaction may be carried out in the absence of another solvent.

The alkaline condition refers to the condition containing organic base or inorganic base, and the organic base comprises but is not limited to pyridine, triethylamine, N-dimethylaniline, sodium methoxide, potassium ethoxide, potassium tert-butoxide and the like; preferred inorganic bases include, but are not limited to, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, and the like.

The acidic condition refers to a condition containing organic acid or inorganic acid, and the organic acid includes but is not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid and the like; inorganic acids include, but are not limited to, hydrochloric acid, concentrated sulfuric acid, hydrobromic acid, hydrofluoric acid, nitric acid, nitrous acid, boric acid, and the like.

Such palladium catalysts include, but are not limited to: pd (PPh)₃)₄、PdCl₂(PPh₃)₂、PdCl₂(MeCN)₂、Pd(dppf)Cl₂、Ph₂P(CH₂)₂PPh₂(dppe)、Ph₂P(CH₂)₃PPh₂(dppp), palladium chloride, palladium acetate, palladium triphenylphosphine, and the like.

The cyclization reaction is a reaction for generating a ring, such as a reaction for generating lactone and lactam, or a reaction for generating fluorenone oxime by benzoate and phenyl connected with the benzoate under the action of concentrated sulfuric acid

The reaction of (2), and the like.

The substitution reaction refers to a reaction in which any atom or atom group in a compound molecule is replaced by another atom or atom group of the same type in another reactant, and may be, for example, a reaction in which an acid and an alcohol form an ester, a reaction in which an alcohol forms an ether by dehydration, a reaction in which a carboxylic acid forms an anhydride by dehydration, a reaction in which an ester is hydrolyzed to form an acid or an alcohol, a reaction in which an amide is hydrolyzed to form an acid or an organic amine, a reaction in which a hydroxyl group is reacted with a halide, or the like.

The reductive elimination reaction refers to a reaction in which a group in a reactant is eliminated after being reduced. For example, the carbonyl group in the reactant is reduced and then eliminated under acidic conditions to form an alkane or substitute for an alkane.

In the present invention, the compounds and intermediates of the present invention can be isolated and purified using methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to: chromatography on a solid support (e.g. silica gel, alumina or silica derivatized with alkylsilanes), thin-layer chromatography, distillation at various pressures, vacuum sublimation, trituration, for example, by the methods described below: "Vogel's Textbook of Practical Organic Chemistry",5th edition (1989), Furniss et al, pub. Longman Scientific & Technical, Essex CM 202 JE, England.

It is understood that the chemical reaction, if involving reactive groups such as-NH-which need not participate in the reaction₂OH, -COOH and the likeThe reactive groups may be protected prior to further reaction by methods known to those skilled in the art, including but not limited to, formation of the reactive groups into esters, amides, alkylamines, ethers, and the like. Common methods of carboxyl protection include, but are not limited to, ester formation with aliphatic or aromatic alcohols, amide or hydrazide formation with amines or hydrazines. Common amino protecting groups include, but are not limited to: (1) alkoxycarbonyl amino-protecting groups such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyl methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsiloxyethoxycarbonyl (Teoc), and the like; (2) acyl amino groups such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o- (p) nitrobenzenesulfonyl (Ns), pivaloyl and the like; (3) alkyl amino protecting groups, trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn), and the like. Common hydroxyl protecting groups include, but are not limited to, silyl ether protecting groups, benzyl ether protecting groups, alkoxymethyl ethers or alkoxy-substituted methyl ethers, acetyl, benzoyl, pivaloyl and the like. After the reaction, the protecting group can be deprotected by a method known to those skilled in the art, and the deprotection conditions include, but are not limited to, deprotection under acidic conditions, deprotection under basic conditions, hydrogenation deprotection, and the like.

The raw materials and/or intermediates directly used in the preparation method of the present invention can be commercially or self-prepared, and the intermediate can be obtained by a person skilled in the art according to a known conventional chemical reaction preparation method, and the preparation method thereof is also within the protection scope of the present invention.

Advantageous effects of the invention

1. The compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof has excellent ROR gamma regulation activity, has good pharmacokinetic property in organisms, has lasting effect and high exposure and bioavailability, and can treat and/or prevent diseases mediated by ROR gamma.

2. The compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof have better therapeutic effect on ROR gamma mediated cancer.

3. The compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.

Detailed description of the preferred embodiments

The technical solutions of the present invention will be described below in conjunction with the specific embodiments, and the above-mentioned contents of the present invention will be further described in detail, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Abbreviations:

EA: ethyl acetate; DCM: dichloromethane; MeOH: methanol; DMSO, DMSO: dimethyl sulfoxide; DMF: n, N-dimethylformamide; PE: petroleum ether; THF: tetrahydrofuran; TFA: trifluoroacetic acid; TES triethylsilane.

EXAMPLE 1 preparation of (S) -3- (9- (difluoromethoxy) -7-fluoro-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionic acid

Preparation of 2, 4-difluoro-6-iodobenzoic acid

2-amino-4, 6-difluorobenzoic acid (21.5g,124.2mmol) was added to 2N HCl (310.5mL), sodium nitrite (9.4g,136.2mmol) was added in portions at 0 ℃ to react for 30 minutes, and then an aqueous solution (150mL) containing potassium iodide (41.2g,248.2mmol) and cuprous iodide (11.8g,62.0mmol) was added to react at 0 ℃ for 30 minutes, and then reacted at 25 ℃ for 2 hours. The system was filtered under reduced pressure, the filtrate was extracted with EA (300mL) and water (200mL) and the organic phase was concentrated and purified by silica gel column chromatography (DCM: MeOH ═ 20:1) to give the product (25.0g, 70.9% yield).

Preparation of 2, 4-fluoro-2-hydroxy-6-iodobenzoic acid

2, 4-difluoro-6-iodobenzoic acid (12.0g,42.2mmol), NaOH (4.2g,105.0mmol) were added to DMSO (150mL) and reacted at 120 ℃ for 16 hours, the reaction was completed, the system was adjusted to pH 5 with 1N HCl, the separated liquid was extracted with EA (250mL) and aqueous sodium chloride (200mL), the organic phase was concentrated and subjected to silica gel column chromatography (DCM: MeOH ═ 30:1) to obtain crude product (10.0g), followed by purification by C18 reverse phase high pressure preparative purification (water: acetonitrile ═ 4:6) to obtain product (4.2g, yield 35.3%).

Preparation of methyl 3, 4-fluoro-2-hydroxy-6-iodobenzoate

4-fluoro-2-hydroxy-6-iodobenzoic acid (3.6g,12.8mmol) was added to 30mL of DCM followed by oxalyl chloride (3.2g,25.2mmol) and DMF (0.3mL) and reacted at 25 ℃ for 1 hour. Then the system was slowly added to methanol (30mL), and at 25 ℃ for 16 hours, the system was concentrated and subjected to silica gel column chromatography (PE: EA ═ 100:1) to give a crude product (3.2g), and then purified by C18 reverse phase high pressure preparative purification (water: methanol ═ 3:7) to give the product (2.4g, yield 63.3%).

Preparation of (S) -2, 2-dimethyl-3- (oxiran-2-yl) propionitrile

Diisopropylamine (10.1g,100.0mmol) was added to THF (150mL) at 0 deg.C, n-butyllithium (2.5M,40.0mL,100.0mmol) was then slowly added, the reaction was carried out at 0 deg.C for 30 minutes, the system was then slowly added to THF (150mL) containing isobutyronitrile (6.9g,100.0mmol) and (S) -2- (chloromethyl) oxirane (9.25g,100.0mmol) at-45 deg.C, the reaction was carried out at 25 deg.C for 16 hours, the system was slowly added aqueous ammonium chloride (100mL), EA (400mL) and aqueous sodium chloride (200mL), the layers were separated by extraction, the organic phase was dried over anhydrous sodium sulfate, and the product was concentrated (9.3g, 74.3% yield)

Preparation of (S) -5- (chloromethyl) -3, 3-dimethyldihydrofuran-2 (3H) -one

(S) -2, 2-dimethyl-3- (oxiran-2-yl) propionitrile (2.6g,20.8mmol) was added to concentrated hydrochloric acid (5mL) and reacted at 25 ℃ for 10 minutes, followed by addition of acetic acid (10mL) and reaction at 50 ℃ for 2 hours. The temperature was reduced to 25 ℃ and water (50mL) was added to the system, extracted with EA (50mL), dried over anhydrous sodium sulfate, and concentrated to give the product (2.5g, 74.1% yield).

6. Preparation of methyl (S) -2, 2-dimethyl-3- (oxiran-2-yl) propionate

(S) -5- (chloromethyl) -3, 3-dimethyldihydrofuran-2 (3H) -one (2.5g,15.4mmol) was added to methanol (10mL), and then a methanol solution (5M,3.4mL,17.0mmol) containing sodium methoxide was added and reacted at 25 ℃ for 2 hours. The system was filtered with suction, the filtrate was concentrated, EA (100mL) and water (80mL) were added for extraction and liquid separation, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the product (1.7g, 69.8% yield).

7. Preparation of methyl (S) -5- ((N- (5-bromo-2-fluorophenyl) -3- (trifluoromethyl) phenyl) sulfonylamino) -4-hydroxy-2, 2-dimethylpentanoate

Methyl (S) -2, 2-dimethyl-3- (oxiran-2-yl) propionate (1.7g,10.8mmol), N- (5-bromo-2-fluorophenyl) -3- (trifluoromethyl) benzenesulfonamide (3.6g,9.0mmol), tetrabutylammonium bromide (290.2mg,0.9mmol) and K₂CO₃(124.4mg,0.9mmol) was added to a 50mL eggplant-shaped flask and reacted at 90 ℃ for 28 hours. After the reaction is finished, the reaction is cooled and then directly carried out to the next step.

Preparation of (S) -3- (6-bromo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionic acid

The crude methyl (S) -5- ((N- (5-bromo-2-fluorophenyl) -3- (trifluoromethyl) phenyl) sulfonamido) -4-hydroxy-2, 2-dimethylpentanoate was dissolved in THF (10mL), sodium hydroxide (1.44g,36.0mmol) and tetrabutylammonium bromide (290.2mg,0.9mmol) were added, and after addition, reaction was carried out at 70 ℃ for 4 hours. After the reaction was completed, the pH of the system was adjusted to 5 with 1N HCl, and then water (100mL) and EA (100mL) were added to extract and separate the solution, and the organic phase was concentrated and purified by silica gel column chromatography (PE: EA ═ 4:1) to obtain a product (1.2g, yield in two steps 24.9%).

9. Preparation of methyl (S) -3- (6-bromo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate

(S) -3- (6-bromo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropanoic acid (1.2g,2.3mmol) was added to methanol (20mL) followed by thionyl chloride (2mL) at 0 ℃ and reaction at 25 ℃ for 16H. The resulting solution was concentrated and purified by silica gel column chromatography (PE: EA ═ 8:1) to give a product (930mg, yield 75.6%).

10. Preparation of methyl (S) -2, 2-dimethyl-3- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- ((3- (trifluoromethyl) phenyl)) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) propionate

Methyl (S) -3- (6-bromo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate (980mg,1.8mmol), diboron (685.8mg,2.7mmol), potassium acetate (441.9mg,4.5mmol), and palladium tetratriphenylphosphine (208.0mg,0.18mmol) were added to 1, 4-dioxane (25mL), reacted under nitrogen at 103 ℃ for 16H, and the reaction-terminated system was used directly in the next step.

11. Preparation of methyl (S) -4-fluoro-2-hydroxy-6- (2- (3-methoxy-2, 2-dimethyl-3-oxopropyl) -4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) benzoate

Methyl 4-fluoro-2-hydroxy-6-iodobenzoate (532.8mg,1.8mmol), tetratriphenylphosphine palladium (208.0mg,0.18mmol), potassium carbonate (621.9mg,4.5mmol), water (4mL) was added to a crude system containing methyl (S) -2, 2-dimethyl-3- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- ((3- (trifluoromethyl) phenyl)) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) propionate under nitrogen protection at 100 ℃ for 2 hours. Purification by C18 reverse phase high pressure preparative purification (water: methanol ═ 1:9) gave the product (650mg, 57.8% yield over two steps).

Preparation of (S) -3- (7-fluoro-9-hydroxy-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionic acid

Methyl (S) -4-fluoro-2-hydroxy-6- (2- (3-methoxy-2, 2-dimethyl-3-oxopropyl) -4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) benzoate (600mg,0.96mmol) was added to concentrated sulfuric acid (4mL) and reacted at 25 ℃ for 3 hours. EA (80mL) and water (60mL) were added to the reaction mixture for extraction, and the organic phase was concentrated to give the crude product (500mg) which was used directly in the next step.

13. Preparation of methyl (S) -3- (7-fluoro-9-hydroxy-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate

(S) -3- (7-fluoro-9-hydroxy-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionic acid (500mg crude) was added to methanol (15mL), followed by thionyl chloride (0.5mL) at 0 ℃ and reaction at 25 ℃ for 16 hours. The system was concentrated and purified by silica gel column chromatography (PE: EA ═ 3:1) to give the product (200mg, two-step yield 35.1%).

14. Preparation of methyl (S) -3- (9- (difluoromethoxy) -7-fluoro-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate

Methyl (S) -3- (7-fluoro-9-hydroxy-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate (180mg,0.30mmol), potassium carbonate (165.8mg,1.2mmol), sodium difluorochloroacetate (115.7mg,0.76mmol) were added to DMF (15mL), reacted at 100 ℃ for 30 minutes, water (60mL) and EA (80mL) were added to the system to extract and separate, the organic phase was concentrated and purified by silica gel column chromatography (PE: EA ═ 6:1) to give a product (110mg, yield 50.7%).

Preparation of (S) -3- (9- (difluoromethoxy) -7-fluoro-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionic acid

Methyl (S) -3- (9- (difluoromethoxy) -7-fluoro-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate (45.0mg,0.07mmol) was added to THF (5mL), followed by addition of an aqueous solution (0.5mL) containing LiOH monohydrate (14.7mg,0.35mmol), and reaction at 50 ℃ for 16 hours. The system was adjusted to pH 5 with 1N HCl, then water (20mL) and EA (20mL) were added to extract the layers, the organic layer was concentrated and purified over silica gel large plate (DCM: MeOH ═ 40:1) to give the product (38mg, yield 86.6%).

The molecular formula is as follows: c₂₈H₂₁F₆NO₇S moleculeQuantity: 629.1 LC-MS (M/e): 652.1(M + Na)

¹HNMR(400MHz,CDCl₃)δ:8.03(s,1H),7.89(d,J＝7.6Hz,1H),7.76-7.74(m,1H),7.65-7.59(m,2H),7.05-6.71(m,4H),4.24-4.19(m,1H),3.55-3.35(m,2H),2.21-2.11(m,1H),1.65-1.56(m,1H),1.29-1.27(m,6H).

EXAMPLE 2 preparation of (S) -3- (9- (difluoromethoxy) -7-fluoro-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionic acid

Reacting (S) -3- (9- (difluoromethoxy) -7-fluoro-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2, 3-b)][1,4]Oxazin-2-yl) -2, 2-dimethylpropionic acid (20mg, 32. mu. mol) was dissolved in TFA (7mL) and triethylsilane (7.4mg, 64. mu. mol) was added. The system was heated to 75 ℃ and reacted for 2 hours. After the reaction is finished, the system is directly dried by spinning and purified by a C18 column (acetonitrile/H)₂O82: 18) to give the product (7mg, yield 35.8%).

Molecular formula C₂₈H₂₃F₆NO₆S molecular weight 615.1 LC-MS (M/e):637.8(M + Na)⁺)

¹H-NMR(400MHz,CDCl₃)δ:8.13(s,1H),8.00(s,1H)，7.82-7.84(d,J＝8Hz,1H),7.74-7.76(d,J＝8Hz，1H),7.58-7.60(m,1H),7.27(s,1H),6.89(s,1H),6.81(s,1H),6.44-6.78(t,J＝135.2Hz,1H),4.31-4.36(m,1H),3.55-3.71(m,3H),3.26-3.29(m,1H),1.96-2.03(m,1H),1.71-1.72(m,1H),1.26(s,3H),1.18(s,3H)。

EXAMPLE 3 preparation of (S) -3- (7- (difluoromethoxy) -9-fluoro-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropanoic acid

Preparation of 1.2-amino-6-fluoro-4-methoxybenzonitrile

2, 6-difluoro-4-methoxybenzonitrile (12.0g,71.0mmol) was added to a sealed tube containing DMSO (50mL), ammonia gas was bubbled through the system for three minutes, and then reacted at 90 ℃ for 16 hours. The system was cooled to 25 ℃, EA (150mL) and water (100mL) were added for extraction and separation, the organic phase was concentrated and purified by silica gel column chromatography (PE: EA ═ 3:1) to give the product (8.0g, yield 67.8%).

Preparation of 2, 2-amino-6-fluoro-4-methoxybenzoic acid

2-amino-6-fluoro-4-methoxybenzonitrile (6.3g,37.9mmol) was added to an aqueous solution (80mL) containing KOH (21.2g,378.6mmol), and the reaction was completed at 120 ℃ for 16 hours. The system was cooled to 25 deg.C, EA (150mL) and water (100mL) were added for extraction and the aqueous phase was adjusted to pH 5 with 2N HCl, then EA (200mL) and aqueous sodium chloride (200mL) were added for extraction and the organic phase was spin dried to give the product (5.9g, 84.1% yield).

Preparation of 3, 2-fluoro-6-iodo-4-methoxybenzoic acid

2-amino-6-fluoro-4-methoxybenzoic acid (6.5g,35.1mmol) was added to 2N HCl (176.0mL) and sodium nitrite (4.84g,70.1mmol) was added in portions at-10 deg.C, and after 60 minutes of reaction, potassium iodide (11.6g,69.9mmol) was added and then reacted at 25 deg.C for 16 hours. After the reaction was completed, EA (300mL) and water (200mL) were added to the reaction system to extract and separate, and the organic phase was concentrated and purified by silica gel column chromatography (PE: EA ═ 1:1) to obtain the product (3.7g, yield 35.6%).

Preparation of 4, 2-fluoro-4-hydroxy-6-iodobenzoic acid

2-fluoro-6-iodo-4-methoxybenzoic acid (3.5g,11.8mmol) was added to DCM (50mL), boron tribromide (29.6g,118.2mmol) was slowly added at 0 ℃, and then returned to 25 ℃ to react for 8 hours, the system was quenched with methanol (30mL), the solvent was concentrated and purified by silica gel column chromatography (DCM: MeOH ═ 40:1) to give the product (2.8g, 84.2% yield)

5. Preparation of methyl 2-fluoro-4-hydroxy-6-iodobenzoate

2-fluoro-4-hydroxy-6-iodobenzoic acid (2.7g,9.6mmol) was added to DCM (20mL), followed by oxalyl chloride (2.43g,19.1mmol) and DMF (0.2mL) and reacted at 25 ℃ for 0.5 h. Then, the system was slowly added to methanol (20mL), and at 25 ℃ for 1 hour, the solvent was concentrated and purified by silica gel column chromatography (PE: EA ═ 4:1) to obtain the product (2.5g, yield 88.0%).

6. Preparation of methyl (S) -2, 2-dimethyl-3- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- ((3- (trifluoromethyl) phenyl)) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) propionate

Methyl (S) -3- (6-bromo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate (2.7g,5.0mmol), diboron (1.9g,7.5mmol), potassium acetate (1.2g,12.2mmol), palladium tetratriphenylphosphine (583.2mg,0.50mmol) were added to 1, 4-dioxane (60mL) and reacted for 18 hours at 100 ℃ under nitrogen protection, and the reaction was used directly in the next step.

7. Preparation of methyl (S) -2-fluoro-4-hydroxy-6- (2- (3-methoxy-2, 2-dimethyl-3-oxopropyl) -4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) benzoate

Methyl 2-fluoro-4-hydroxy-6-iodobenzoate (1.33g,4.5mmol), tetratriphenylphosphine palladium (519.4mg,0.45mmol), potassium carbonate (1.24g,8.97mmol), water (10mL) were added to a crude system (60mL) containing methyl (S) -2, 2-dimethyl-3- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- ((3- (trifluoromethyl) phenyl)) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-2-yl) propionate and reacted for 2 hours at 100 ℃ under nitrogen protection. After the reaction was completed, EA (100mL) and water (60mL) were added to the reaction system to extract and separate the liquid, and the organic phase was concentrated and purified by C18 column chromatography (water: methanol ═ 2:8) to obtain the product (2.0g, yield 71.1%).

8. Preparation of methyl (S) -3- (9-fluoro-7-hydroxy-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate

Methyl (S) -2-fluoro-4-hydroxy-6- (2- (3-methoxy-2, 2-dimethyl-3-oxopropyl) -4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) benzoate (900mg,1.4mmol) was added to concentrated sulfuric acid (10mL) and reacted at 25 ℃ for 3 hours. After the reaction was completed, EA (80mL) and water (30mL) were added to the reaction system to extract and separate the solution, and the organic phase was purified by silica gel column chromatography (PE: EA ═ 3:1) (350mg, yield 36.9%).

9. Preparation of methyl (S) -3- (7- (difluoromethoxy) -9-fluoro-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate

Methyl (S) -3- (9-fluoro-7-hydroxy-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate (200mg,0.34mmol), potassium carbonate (139.8mg,1.01mmol), sodium difluorochloroacetate (154.3mg,1.01mmol) were added to DMF (20mL), reacted at 100 ℃ for 60 minutes, water (20mL) and EA (40mL) were added to the system to extract the fractions, and the organic phase was concentrated and purified by silica gel column chromatography (PE: EA ═ 5:1) to give a product (180mg, yield 82.3%).

10. Preparation of methyl (S) -3- (7- (difluoromethoxy) -9-fluoro-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate

Methyl (S) -3- (7- (difluoromethoxy) -9-fluoro-10-oxo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate (175mg,0.27mmol) was added to TFA (14mL), followed by triethylsilane (94.9mg,0.82mmol), and reacted at 80 ℃ for 2 hours. The system was concentrated and purified by silica gel column chromatography (PE: EA ═ 10:1) to give the product (130mg, yield 75.9%).

Preparation of (S) -3- (7- (difluoromethoxy) -9-fluoro-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorene [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionic acid

Methyl (S) -3- (7- (difluoromethoxy) -9-fluoro-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 10-tetrahydrofluorenyl [2,3-b ] [1,4] oxazin-2-yl) -2, 2-dimethylpropionate (100mg,0.16mmol) was added to THF (12mL), followed by addition of an aqueous solution (4mL) containing LiOH monohydrate (26.7mg,0.64mmol), and reaction at 50 ℃ for 48 hours. The system was adjusted to pH 5 with 1N HCl, then water (20mL) and EA (30mL) were added to extract the layers, and the organic layer was purified by spin drying over silica gel large plate (DCM: MeOH ═ 50:1) to give the product (35mg, yield 35.6%).

The molecular formula is as follows: c₂₈H₂₃F₆NO₆S molecular weight: 615.5 LC-MS (M/e): 638.2(M + Na)

¹HNMR(400MHz,CDCl₃)δ:8.17(s,1H),8.01(s,1H),7.84(d,J＝8.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.61-7.56(m,1H),7.28-7.25(m,1H),6.94(m,1H),6.81-6.40(m,2H),4.38-4.30(m,1H),3.83-3.65(m,2H),3.54-3.50(m,1H),3.29-3.20(m,1H),1.96-1.86(m,1H),1.71-1.61(m,1H),1.29-1.18(m,6H).

Experimental protocol

An exemplary experimental scheme of some of the compounds of the present invention is provided below to show the advantageous activity and advantageous technical effects of the compounds of the present invention. It should be understood, however, that the following experimental protocols are only illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.

Experimental example 1 in vitro cytological Activity of Compounds of the invention

The test substance inventive Compound 3, self-made, whose chemical name and structure are given in the preparation examples.

The abbreviations used in the following experiments have the following meanings:

HEK 293T: human embryonic kidney cell-derived cell lines;

ROR γ: retinoic acid receptor-related orphan receptor gamma;

gla 4: a yeast transcriptional activator;

pGL4.35: a luciferase reporter gene vector;

PBS: phosphate buffer solution;

DMSO, DMSO: dimethyl sulfoxide;

DMEM: daperbok modified eagle's medium;

FBS: fetal bovine serum;

EC₅₀: half the effective concentration;

emax%: percentage of maximum effect.

The experimental method comprises the following steps: the assay of compounds for modulation of ROR γ activity was performed using the Gal4-ROR γ luciferase reporter assay.

The experimental steps are as follows:

1. cell suspension preparation and inoculation

1.1 the cultured cells were grown to exponential growth phase, the medium was removed and washed with PBS.

1.2 trypsinization to disperse the cells. Washed once with complete growth medium.

1.3 the supernatant was removed and washed twice with PBS. Resuspended to the appropriate concentration with culture medium.

1.4 inoculation of 6X 10 per plate⁶Single cell, 37 ℃, 5% CO₂The culture was carried out in an incubator for 16 hours.

2. Cell transfection

2.1 mix the transfection reagent and transfection medium up-side down and mix well and incubate for 5 minutes at room temperature.

2.2 the Gal4-ROR containing plasmid and pGL4.35 luciferase plasmid were added to the mixture, mixed by inversion and incubated at room temperature for 20 min.

2.3 Add the mixture to the cell-seeded dish at 37 deg.C with 5% CO₂Culturing in an incubator for 5-6 hours.

3. Adding a compound

3.1 Compounds were formulated in 10mM stock solutions in DMSO in 3-fold gradient over 10 concentrations.

3.2 take 25nL compound dilution and add to 384-well plate. Vehicle control wells and baseline control wells were added with 25nL of DMSO.

3.3 cell suspensions were prepared using phenol red free medium containing filtered FBS, and 384 well plates were seeded with 15,000 cells per well.

3.4 Add 0.25 μ M ursolic acid per well in addition to the baseline control well.

3.5 37℃，5％CO₂Culturing in an incubator for 16-20 hours.

4. Reading luminous value

4.1 the cells and detection reagents are brought to room temperature.

4.2 Add 25. mu.L of assay reagent per well and shake for 5 minutes in the dark.

4.3 the microplate reader reads the luminescence value.

5. Data processing

5.1% Activity values were fitted to EC using Graphpad 5.0₅₀The value and Emax%.

Results of the experiment

TABLE 1 in vitro cytological Activity of Compounds of the invention

Conclusion of the experiment

As shown in Table 1, the compound has effective regulation effect on ROR gamma, can effectively promote differentiation of Th17 cells, and has potential clinical value for treating cancers.

Experimental example 2 in vitro protein binding Activity of the Compound of the present invention

ROR γ: retinoic acid receptor-related orphan receptor gamma;

DMSO, DMSO: dimethyl sulfoxide;

LBD: a ligand binding region;

SRC steroid receptor costimulator 1;

anti GST-Eu: a europium-labeled GST antibody;

d2: an energy acceptor of europium;

EC₅₀: half the effective concentration;

emax%: percentage of maximum effect.

The experimental method comprises the following steps:

and (3) carrying out a protein binding experiment by adopting a time-resolved fluorescence energy resonance transfer method, and detecting the activity regulation by the binding of the compound and ROR gamma.

The experimental steps are as follows:

1. preparation of 1 Xbuffer containing 5mM dithiothreitol, 50mM potassium fluoride, 100mM sodium chloride, 0.01% bovine serum albumin and 0.01% Tween-20:

2. dilution of Compounds

2.1 Compounds were made up to 10mM stock solution in DMSO, adjusted to a maximum concentration of 500. mu.M, diluted in DMSO in a 3-fold gradient for a total of 10 concentrations.

2.2 all compounds were diluted 12.5 fold with 1 Xbuffer, vortexed for 5 minutes and 5. mu.L of each was added to 384 well plates.

3. A mixture of ROR γ t-LBD (20nM) and ursolic acid (0.4. mu.M) was prepared with pre-cooled 1 Xbuffer, and 5. mu.L was added to 384-well plates.

4. A mixture of biotin-labeled SRC (100nM), anti GST-Eu (1:200) and streptavidin-D2 (25nM) was prepared in pre-cooled 1 Xbuffer, and 10. mu.L of this mixture was added to a 384-well plate.

5.384 well plates were centrifuged at 1000g for 1 min.

6. Incubate at room temperature in the dark for 4 hours.

7. The microplate reader reads 665nm and 615nm fluorescence values.

8. Data processing

8.1% Activity values were fitted to EC using Graphpad 5.0₅₀The value and Emax%.

Results of the experiment

TABLE 2 in vitro protein binding Activity of Compounds of the invention

Conclusion of the experiment

The compound has good ROR gamma protein binding effect, can effectively regulate the activity of ROR gamma receptors, and can further treat diseases caused by ROR gamma disorder.

Experimental example 3 pharmacokinetic experiment of the Compound of the present invention

For the test, compound 3 of the present invention, the preparation of which is described in the examples of the present specification.

Control compound D, prepared according to the method disclosed in prior art WO2016201225a1, has the structure shown below:

experimental animals: mice, 9/group.

Preparation of test solution

1. Preparation of Compound 3 solution

(1) Iv bolus administration (iv): taking the compound 3(2.58mg), adding 125 mu L of DMSO, carrying out ultrasonic dissolution, continuously adding Kolliphor HS 15(75 mu L), carrying out vortex mixing, finally adding 2.3mL of sterilized water for injection, and carrying out vortex mixing to obtain a colorless transparent solution with the concentration of 1 mg/mL.

(2) Oral administration (po): placing compound 3(4.86mg) in a tissue grinder, adding 4.709mL solvent 2% HPC + 0.1% Tween 80, grinding at 1000rpm, and vortex mixing to obtain a uniform suspension with a final concentration of 1 mg/mL.

2. Preparation of Compound D solution

(1) Iv bolus administration (iv): taking the compound D (2.33mg), adding 1.756mg/mL Na2CO3 in 0.9% sodium chloride solution 2.281mL, vortexing, performing ultrasonic treatment until the solution is clear, performing heat preservation in a water bath at 50 ℃ for 20 minutes, clarifying, vortexing, mixing uniformly, and filtering with a 0.22 mu m filter membrane to obtain the compound D with the concentration of 1 mg/mL.

(2) Oral administration (po): placing compound D (4.71mg) in a tissue grinder, adding 4.611mL (2% HPC + 0.1% Tween 80), ultrasonically suspending the compound to form an anti-sticking wall, and uniformly grinding at 1000rpm to obtain a uniform suspension with a final concentration of 1 mg/mL.

Experimental methods

Administration of drugs

(iv) the test sample is administered by intravenous bolus injection, wherein the administration dose is 5mg/kg, and the administration volume is 5 mL/kg;

oral administration (po) was carried out at a dose of 10mg/kg and a volume of 10 mL/kg.

Blood sampling

Blood was collected from the orbit 0.083, 0.25, 0.5, 1,2,4, 6,8, 24h after administration, about 100. mu.L of whole blood was collected at each time point, plasma was separated by centrifugation at 8000rpm for 6min, and the plasma was frozen at-80 ℃ in a freezer.

Plasma sample analysis

Adopting a protein precipitation method: and (3) taking 20 mu L of plasma to a 96-hole deep-hole plate, and adding 200 mu L of acetonitrile solution containing an internal standard, wherein the internal standard is tolbutamide and the concentration is 50 ng/mL. Vortexing for 10min, centrifuging at 4000 rpm for 20min, collecting 100 μ L supernatant, adding 100 μ L water, and vortexing for 3 min; LC-MS/MS is to be analyzed.

Results of the experiment

TABLE 3 mouse PK evaluation results for compounds of the invention (iv)

Table 4 mouse PK evaluation results (po) for compounds of the invention

Note: data are plotted, concentration RE is greater than or equal to 20%, PK parameters were calculated according to actual dosing dose; accuracy RE ═ (measured-theoretical)/theoretical 100%; t is_1/2Represents the half-life; t is_maxRepresents the time to peak; c_maxRepresents the maximum blood concentration value; AUC_lastArea under curve 0 → t when representing drug; CL represents clearance; MRT represents the mean residence time; vss represents the apparent volume of distribution.

Conclusion of the experiment

The experimental data in tables 3 and 4 show that the compound has higher exposure in organisms by intravenous injection or oral administration, is obviously superior to a reference substance, has appropriate half-life and clearance rate, shows good pharmacokinetic properties and has good clinical application prospect.

Claims

1. A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

wherein,

M₁is-S (O)₂-；

X₁Is selected from-C (R)₃)(R₄)-；

X₃Is selected from-C (R)₆)-；

L₁is-CH₂-；

L₂Is selected from-C (R)₇)(R₈)-；

Ring A is phenyl;

ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with 1 or 2Q;

R₂selected from-C (O) OR^aor-N (R)^a)C(O)R^b；

Each R₁Each independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano and C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy or amino C_1-6An alkoxy group;

R^a、R^beach independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, 3-8 membered monocycloalkyl or 3-8 membered heteromonocyclic group;

R₃、R₄、R₆、R₇、R₈each independently selected from hydrogen, halogen, hydroxyl, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl or halo C_1-6An alkoxy group;

p is selected from 0, 1 or 2; q is 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof,

M₁is-S (O)₂-；

X₁Is selected from-C (R)₃)(R₄)-；

X₃is-CH-;

R₃、R₄each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl or halo C_1-6An alkoxy group.

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof,

R₂selected from-C (O) OR^aor-N (R)^a)C(O)R^b；

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof,

M₁is-S (O)₂-；

X₁is-CH₂-；

X₃is-CH-;

L₁is-CH₂-；

L₂Is selected from-C (R)₇)(R₈)-；

Ring A is phenyl;

ring B is selected from phenyl optionally substituted with 1 or 2Q;

each Q is independently selected from fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy;

each R₁Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, or trifluoroisopropoxy;

R₂selected from-C (O) OR^aor-N (R)^a)C(O)R^b；

R₇、R₈each independently selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, or trifluoroisopropoxy;

p is selected from 1 or 2; q is 1.

5. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

6. a pharmaceutical formulation comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form, comprising one or more pharmaceutically acceptable excipients.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, comprising one or more second therapeutically active agents selected from the group consisting of:

a drug for the treatment of cancer selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal drugs, angiogenesis inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors;

a drug for treating autoimmune diseases selected from the group consisting of disease modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, glucocorticoid drugs, TNF antagonists, cyclophosphamide, mycophenolate mofetil, cyclosporine;

a medicament for the treatment of inflammatory diseases selected from steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs.

8. Use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, the pharmaceutical preparation of claim 6, or the pharmaceutical composition of claim 7 for the preparation of a medicament for the treatment and/or prevention of a related disease mediated by rory, wherein the related disease is selected from one or more of cancer, a bacterial infectious disease, a fungal infectious disease, a parasite-induced related disease, a metabolic disease, an autoimmune disease, and an inflammatory disease.

9. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, a pharmaceutical formulation according to claim 6, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment and/or prevention of a related disease mediated by rory, said related disease being selected from one or more of chronic obstructive pulmonary disease, asthma, myocardial infarction, atherosclerosis, sarcoidosis.

10. A process for the preparation of a compound of formula (I) comprising the steps of:

wherein X ═ Cl, Br, I; said X₁、X₃、R₁-R₂、M₁、L₁-L₂Ring a, ring B, p, q are as defined in any one of claims 1 to 5; m is 0; n is 1; x₂is-CH-; x₄Is O;

the intermediate 1 and the boron doublet react under the alkaline condition and the action of a palladium catalyst to generate an intermediate 2;

the intermediate 2 and the intermediate 3 react under the conditions of alkaline condition, palladium catalyst action and inert gas protection to generate an intermediate 4;

the intermediate 4 is subjected to a series of cyclization reactions, substitution reactions or further reduction elimination reactions under an acidic condition to obtain a compound of a general formula (I);

the reaction processes involved in the above preparation methods can be carried out in conventional solvents.

11. The production method according to claim 10, wherein,

the solvent is selected from one or a mixture of more solvents of DMSO, DMF, acetonitrile, methanol, tetrahydrofuran, toluene, dimethyl ether, dichloromethane, trichloromethane, 1, 4-dioxane, trifluoroacetic acid or water;

the palladium catalyst is selected from Pd (PPh)₃)₄、PdCl₂(PPh₃)₂、PdCl₂(MeCN)₂、Pd(dppf)Cl₂、Ph₂P(CH₂)₂PPh₂(dppe)、Ph₂P(CH₂)₃PPh₂(dppp), palladium chloride, palladium acetate, palladium triphenylphosphine.