CN108503584B - 1,2,3, 4-tetrahydroquinoline sulfonamide compound and application thereof - Google Patents
1,2,3, 4-tetrahydroquinoline sulfonamide compound and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The invention belongs to the technical field of medicines, and relates to a compound with structural characteristics of a formula (I), wherein R1, R2, X1, X2, Cy1, m and n are defined in the specification, the compound and pharmaceutically acceptable salts, isomers, prodrug cocrystal complexes, hydrates and solvates thereof can be used for inhibiting retinoic acid-related orphan receptor gamma (ROR gamma), and preventing or treating ROR gamma-mediated inflammation, metabolism, autoimmunity and other diseases or symptoms such as psoriasis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, asthma, lupus erythematosus, autoimmune hepatitis or type I and type II diabetes, and have the characteristics of high efficiency, low toxicity and good metabolic stability.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a 1,2,3, 4-tetrahydroquinoline sulfonamide compound and application thereof. More particularly, as RORgt modulators for the prevention, treatment or amelioration of RORgt mediated inflammatory syndromes, disorders or diseases.
Background
The prior art discloses that retinoic acid receptor-Related Orphan Receptors (RORs) belong to a member of the ligand-dependent nuclear receptor superfamily of transcription factors. RORgt is one of the major members of the RORs subfamily, is distributed mainly in the thymus, and is expressed in key cells in the immune system. It has been reported that RORgt promotes T-helper 17 (Th 17) cell differentiation and produces a key regulator of the inflammatory cytokine interleukin 17 (IL-17), whereas Th17 cells and IL-17 secreted therefrom play a key role in the development and progression of inflammatory and autoimmune diseases.
In 2011, both the subject group of the Littman professor at New York university and the subject group of the Burris professor at Scripps research institute published studies on RORgt small molecule inhibitors in Nature journal: the Littman group screened the cardiotonic Digoxin (Digoxin) from the library and found it to have RORgt inhibitory activity; the Burris group reported that the first non-steroidal small molecule SR1001 could be used as a dual ROR alpha and RORgt inhibitor. In the same year, the group of professor Dong in Anderson cancer center reported that ursolic acid extracted from natural plants also has selective RORgt-inhibiting activity. In 2014, the Sano project group of Dermatology, university of Kochi, Japan, reported a RORgt inhibitor on the Annual Meeting of the Society of research Dermatology (SID), which could alleviate psoriasis-like skin lesions in mice by oral administration. The results of this study successfully demonstrated that RORgt is a very promising target for the treatment of psoriasis.
The monoclonal antibody Cosentyx (Secukinumab/AIN 457) developed by nova corporation for the treatment of psoriasis by specifically blocking IL-17 was FDA approved for marketing in the 2015, the first drug in the psoriasis-treating drug market to act on IL-17, illustrating the potential for the treatment of inflammation and autoimmune diseases by the effect of ROR γ t inhibitors on the IL-17 signaling pathway. IL-17 is currently recognized as an anti-inflammatory. In addition to psoriasis, IL-17 also plays an important role in a variety of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus. In addition, since chronic inflammation is involved in the development of tumors, the role of IL-17 in various tumors is also being explored. For example, the number of IL-17A expressing cells infiltrating tumor tissue in a patient with hepatocellular carcinoma is inversely related to the survival rate of the patient; the infiltration lymphocytes in the tumor tissues of breast cancer patients express IL-17A to promote the proliferation of cancer cells and the like, and the IL-17 family provides good targets for tumor treatment in the future, so the RORgt is considered as a new target for the research and development of anti-inflammatory, anti-tumor and autoimmune disease medicaments, and can be used as a new way for treating cancers, psoriasis, rheumatoid arthritis, multiple sclerosis and other inflammatory and autoimmune diseases.
Disclosure of Invention
The invention aims to provide a 1,2,3, 4-tetrahydroquinoline sulfonamide compound aiming at the current situation of the prior art.
It is still another object of the present invention to provide pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs of the 1,2,3, 4-tetrahydroquinoline sulfonamide compounds.
Another object of the present invention is to provide a method for preparing the 1,2,3, 4-tetrahydroquinoline sulfonamide compound.
A fourth object of the present invention is to provide a pharmaceutical composition.
The fifth object of the present invention provides the use of the 1,2,3, 4-tetrahydroquinoline sulfonamide compound, the pharmaceutically acceptable salt, the solvate, the prodrug or the polymorph thereof in the preparation of a medicament.
In order to achieve the purpose, the invention adopts the technical scheme that:
the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative is characterized in that the structural general formula of the derivative is as follows:
wherein:
x1 is C or N;
x2 is halogen, NH or O;
m is optionally selected from 0, 1;
n is optionally selected from 0, 1,2 or 3;
the substituent R1 is selected from: H. (C1-C3) alkyl, halo (C1-C3) alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl;
the substituent R2 is absent or located in at least one of the 2,3,4, 5, 6 positions and is unsubstituted, mono-, di-or poly-substituted, and the substituent R2 is selected from one, two or more of the following groups: hydrogen, halogen, nitro, hydroxy, carboxy, trifluoromethyl, cyano, substituted or unsubstituted amino, phenyl, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) alkoxy, -CONH2、-CONHR3、 -CON(R3)2-COOR3, -COR3, -NHCOR3, -NHCOOR3 groups, wherein R3 is selected from H, (C1-C6) alkyl, trifluoromethyl, phenyl; when R2 is di-or tri-substituted, the substituents may be the same or different;
cy1 is absent or optionally selected from: H. ar1, Hetar1, or (C3-C7) cycloalkyl;
ar1 above represents a monocyclic aromatic hydrocarbon system or a bicyclic aromatic hydrocarbon system and a cyclic aromatic hydrocarbon saturated ring system having 6 to 10 carbon atoms, which system is unsubstituted or substituted by one or more identical or different substituents selected from: (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy, carbonyl, carboxyl, amino, -CONH2、-COOR4、-COR4、-NHCOR4、-NHCOOR4、-COH(CF3)2、-SONH2-SOOR4, -SOR4, -NHSOR4, -NHSOOR4 groups; wherein R4 is optionally selected from H, (C1-C6) alkyl;
the above Hetar1 represents a saturated 4, 5, 6, 7, 8, 9 or 10 membered heterocyclic ring having 1,2 or 3N and/or O and/or S atoms, which heterocyclic ring is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of: (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy, carbonyl, carboxyl, amino, -CONH2、-COOR4、-COR4、-NHCOR4、-NHCOOR4、-COH(CF3)2、-SONH2-SOOR4, -SOR4, -NHSOR4, -NHSOOR4 groups; wherein R4 is optionally selected from H, (C1-C6) alkyl.
Preferably, R1 is selected from methyl.
Preferably, the substituent R2 is located in at least one of the 2,3,4, 5, 6 positions and is unsubstituted, mono-, di-or poly-substituted, and the substituent is selected from one, two or more of the following groups: hydrogen, fluoro, chloro, trifluoromethyl, cyano, methyl, phenyl, trifluoromethoxy, tert-butyl, when R2 is di-or tri-substituted, the substituents may be the same or different.
Preferably, said X1 is optionally selected from C or N.
Preferably, the X2 is selected from bromine or N.
Preferably, said Cy1 is optionally selected from: 1-acetylpiperazinyl, 1- (propionyl) -piperazinyl, 1-cyclopropylformylpiperazinyl, 1-trimethylacetylpiperazinyl, 1-methanesulfonylpiperazinyl, 1-piperazinesulfonamido, 1-ethanesulfonylpiperazinyl, morpholinyl, piperazinyl, carbomethoxy benzoate, benzoyloxy, naphthyl, tetrahydronaphthyl, 3, 4-dihydro-1 (2H) -naphthalenonyl, piperidinyl, 4-piperidinecarboxylate, 4-piperidinecarboxyloxy, 4-acetamidopiperidinylpiperidinyl.
More preferably, the Cy1 is optionally selected from: 1-acetylpiperazinyl, 1-methanesulfonylpiperazinyl, 1-ethanesulfonylpiperazinyl, morpholinyl, carbomethoxy benzoate, 3, 4-dihydro-1 (2H) -naphthalenonyl, carbomethoxy 4-piperidinecarboxylate, benzoic acid, carbomethoxy 4-piperidinecarboxylate, and piperidinopiperidyl 4-acetamidopiperidine.
Unless otherwise indicated, (C1-C6) alkoxy in the present invention is (C1-C6) straight or branched chain alkoxy, and means alkoxy having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy.
Unless otherwise indicated, (C1-C6) alkyl as used herein is (C1-C6) straight or branched chain alkyl, and refers to alkyl groups containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl.
As used herein, (C3-C7) cycloalkyl refers to cycloalkyl groups containing 3-7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, unless otherwise specified.
Unless otherwise specified, the term halogen is a halogen substituent, including but not limited to fluorine, chlorine, bromine, and/or iodine.
In the present invention, the terms "multi-substituted" and "plural" mean three or more, and the same meanings are shown below.
In a preferred embodiment, the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative of the present invention is a specific compound selected from the group consisting of:
6- (4-acetylpiperazine) -N-benzyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (2-fluoro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-fluoro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (3-fluoro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-methyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (2, 4-difluoro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-chloro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (3-trifluoromethyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (3-chloro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (2-trifluoromethyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-trifluoromethyl-pyrimidine) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -sulphonamide
6- (4-acetylpiperazine) -N- (2-chloro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (3-methyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (2-chloro-6-fluoro-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-trifluoromethyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (2-methyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-phenyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N-phenethyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -ethanesulfonamide
6- (4-acetylpiperazine) -N-phenylpropyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -propanesulfonamide
6- (4-acetylpiperazine) -N- (4-trifluoromethoxy-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-acetylpiperazine) -N- (4-cyano-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-Methanesulfonylpiperazine) -N-benzyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-Methanesulfonylpiperazine) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-Ethanesulfonylpiperazine) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6-morpholine-N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-amino-benzoic acid methyl ester) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-amino-benzoic acid) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-amino-3, 4-dihydro-1 (2H) -naphthalenone) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-Piperidinecarboxylic acid methyl ester) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-Piperidinecarboxylic acid) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-Piperidinecarboxamide) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6- (4-amino-benzoic acid) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide sodium salt
6- (4-Piperidinecarboxylic acid) -N- (4-tert-butyl-benzyl) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide sodium salt
6-bromo-N- (4-tert-butyl-benzyl) -1,2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
6-bromo-N- (4-tert-butyl-benzyl) -1,2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide hydrochloride
6-bromo-N- (4-tert-butyl-benzyl) -1,2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide maleate.
In order to achieve the second object, the invention adopts the technical scheme that:
the pharmaceutically acceptable salt, solvate, precursor compound or polymorph of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative.
A pharmaceutically acceptable salt, solvate, prodrug or polymorph, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt is: sodium salts, hydrochlorides, trifluoroacetates, sulfates, phosphates, diphosphates, hydrobromides or nitrates;
wherein the organic salt is: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, oxalate;
wherein the amino acid salt is: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine salt, cystine salt, cysteine salt, caseinate, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, methionine salt, tryptophan salt, glutamate, aspartate salt, valine salt, methionine salt, proline salt, or hydroxyproline salt.
In order to achieve the third object, the invention adopts the technical scheme that:
preparation of intermediate b
Dissolving the raw material a, chlorosulfonyl isocyanate and tertiary butanol in dichloromethane, stirring at room temperature, and condensing to obtain an intermediate b.
Preparation of intermediate c
Intermediate b and R1Dissolving X (X is Cl, Br or I) in N, N-dimethylformamide, and refluxing and stirring to obtain an intermediate c.
Preparation of intermediate d
And carrying out coupling reaction or substitution reaction on the intermediate c and Cy1 to obtain an intermediate d.
Preparation of intermediate e
And (3) adding trifluoroacetic acid into the intermediate d to remove the tert-butyloxycarbonyl group of the intermediate d.
Preparation of Compound I
Dissolving intermediate d and different halides (halide f) in N, N-dimethylformamide, and adding K2CO3Stirring to obtain the compound I.
A halide f:
among them, the preparation method of the pharmaceutically acceptable salts of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivatives can be prepared according to the conventional method in the field, and the compounds of the present invention are usually isolated as they are, or obtained by reacting with inorganic salts, organic salts or amino acid salts under the conventional conditions in the form of pharmaceutically acceptable salts thereof.
In order to achieve the fourth object, the invention adopts the technical scheme that:
a pharmaceutical composition comprising a) the above 1,2,3, 4-tetrahydroquinoline sulfonamide derivative, and/or a pharmaceutically acceptable salt, solvate, precursor compound or polymorph of the above 1,2,3, 4-tetrahydroquinoline sulfonamide derivative, and b) a pharmaceutically acceptable carrier thereof.
The pharmaceutical composition may be a solid form or a liquid form of pharmaceutical formulation, and the dosage form of the pharmaceutical composition includes, but is not limited to, tablets, capsules, powders, granules, suspensions or injections.
In order to achieve the fifth object, the invention adopts the technical scheme that:
the application of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative, the pharmaceutically acceptable salt, the solvate, the prodrug, the polymorph or the pharmaceutical composition thereof in preparing the medicament is generally applicable to inhibiting RORgt. Accordingly, in some embodiments, the present invention provides a method of inhibiting retinoic acid-related orphan receptor gamma (ROR γ), and preventing or treating ROR γ -mediated inflammation, metabolism, autoimmunity, and other diseases or disorders comprising administering a provided compound or composition. More specifically, the compounds and compositions described herein act as modulators of ROR γ.
Diseases and conditions that may be treated according to the methods of the present invention include, but are not limited to, ROR γ -mediated inflammation, metabolism, autoimmunity, and other diseases or disorders such as psoriasis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, asthma, lupus erythematosus, autoimmune hepatitis or type I and type II diabetes, diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, ophthalmic diseases, uveitis, atherosclerosis, psoriatic arthritis, atopic dermatitis, crohn's disease, ulcerative colitis, ankylosing spondylitis, nephritis, organ allograft rejection, fibrotic lung, cystic fibrosis, renal insufficiency, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphylococcal skin suppuration, inflammation following cataract surgery, inflammatory diseases, inflammatory bowel disease, allergic rhinitis, allergic conjunctivitis, chronic urticaria, systemic lupus erythematosus, asthma, allergic asthma, steroid resistant asthma, neutrophilic asthma, periodontal disease, periodontitis, gingivitis, gum disease, diastolic myocardial disease, myocardial infarction, myocarditis, chronic heart failure, vascular stenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, malignant myeloma, hodgkin's disease, and bladder, breast, cervical, colon, lung, prostate, or stomach cancer.
Furthermore, the invention also provides application of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating inflammatory diseases.
Furthermore, the invention also provides application of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating autoimmune diseases.
Furthermore, the invention also provides application of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing medicines for treating metabolic related diseases.
Furthermore, the invention also provides application of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating cancer diseases.
Most preferably, the invention also provides the application of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating ROR gamma-mediated psoriasis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, asthma, lupus erythematosus, autoimmune hepatitis or type I and type II diabetes, Crohn's disease, breast cancer, lung cancer and colon cancer.
Detailed Description
The present invention is further explained below with reference to specific examples, which are not intended to limit the present invention in any way. Experimental procedures in the following examples, in which specific conditions are not specified, are generally carried out under conventional conditions or conditions recommended by the manufacturer.
In the chemistry described herein, when any variable (e.g., R1, R2, etc.) occurs more than one time in any constituent, its definition in each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable. The phrase "optionally substituted with one or more substituents" is considered equivalent to the phrase "optionally substituted with at least one substituent" and preferred embodiments in this case will have from 0 to 3 substituents.
The terms "alkyl" and "alkylene" as used herein are intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1,2,3,4, 5, or 6 carbon atoms in a straight or branched chain arrangement. For example, "C1-6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, sec-butyl, t-butyl, hexyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
The term "heteroaryl" as used herein represents a stable monocyclic or bicyclic carbon ring of up to 6 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to: imidazolyl, triazolyl, pyrazolyl, barklynyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl. For the following definition of heteroaryl, "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. In the case where the heteroaryl substituent is bicyclic and contains one ring that is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
The term "heterocycle" or "heterocyclyl" as used herein refers to a 5-or 6-membered aromatic or nonaromatic heterocycle containing 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. "Heterocyclyl" thus includes the above-mentioned heteroaryl groups, as well as the dihydro and tetrahydro analogues thereof. Further examples of "heterocyclyl" include, but are not limited to: imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l, 4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl and tetrahydrothienyl, and N-oxides thereof. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.
As understood by those skilled in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituents may be considered unsubstituted or substituted. For example, (C1-C4) alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, e.g., morpholinyl, piperidinyl, and the like.
The invention includes the free forms of the compounds of formula i, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat in certain physical properties, such as solubility in polar solvents, from their respective salt forms, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
The compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner appropriate to the route of administration used. The compositions of the present invention may be administered as follows: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, and the like.
Oral compositions may be solid, gel or liquid. Examples of solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solutions, acacia mucilage, gelatin solutions, sucrose and starch pastes; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose.
The compositions of the present invention are administered parenterally, typically by injection, including subcutaneous, intramuscular, or intravenous injection. Injectables can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions. Examples of pharmaceutically acceptable carriers that may be used in the injections of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents, and other pharmaceutically acceptable materials. Examples of aqueous carriers include sodium chloride injection, ringer's injection, isotonic glucose injection, sterile water injection, dextrose and lactated ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, and the like; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.
The compositions of the present invention may also be prepared as sterile lyophilized powders for injection, by dissolving the compound in a buffered solution of sodium phosphate containing dextrose or other suitable excipient, followed by sterile filtration of the solution under standard conditions known to those skilled in the art, followed by lyophilization to provide the desired formulation.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing for multiple substituents under the definition of formula I above.
The invention is further described in the following examples, which are not intended to limit the scope of the invention.
EXAMPLE 16 preparation of N-benzyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide (Compound 1)
Step 1: preparation of tert-butyl ((6-bromo-3, 4-dihydroquinoline-1 (2H)) sulfonyl) carbamate (intermediate (b))
Chlorosulfonic acid isocyanate (0.75g, 5mmol) and tert-butanol (0.37g, 5mmol) were dissolved in dichloromethane (15ml) and stirred in ice bath for 0.5 hr. 6-bromo-1, 2,3, 4-tetrahydroquinoline (1.05g, 5mmol) and triethylamine (1.5g, 15mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 15ml of water was added, extraction was performed with dichloromethane (10ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (PE: EtOAc = 20: 1) to obtain 1.3g of a white solid with a yield of 67%. To obtain intermediate (b);
step 2: preparation of N-tert-butyl-N-methyl- ((6-bromo-3, 4-dihydroquinoline-1 (2H)) sulfonyl) carbamate (intermediate (c))
Intermediate (b) (0.76g, 1.84 mmol) and potassium carbonate (0.51g, 3.7 mmol) were dissolved in DMF (15mL) and iodomethane (0.18mL, 2.8mmol) was added dropwise and refluxed at 110 ℃. The reaction was checked by TLC. After the reaction, the reaction mixture was cooled, 35ml of water was added, extraction was performed with ethyl acetate (30 ml. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (PE: EtOAc = 20: 1) to obtain 0.522g of a pale yellow solid in 66% yield. To obtain intermediate (c);
and step 3: preparation of 6- (4-acetylpiperazine) -N-tert-butoxycarbonyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide (intermediate (d))
Intermediate (c) (1.82g, 4.8mmol), palladium acetate (52mg,0.24mmol), 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl (240mg, 0.48mmol), cesium carbonate (2.32g, 7.2mmol) were dissolved in dioxane (15ml), 1-acetylpiperazine (0.92g, 7.2mmol) was added thereto under nitrogen protection, and the reaction solution was refluxed and stirred at 100 ℃ for 6 hours to give a brown clear solution. After the reaction solution was cooled to room temperature, 15ml of water was added, extraction was performed with ethyl acetate (10ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to column chromatography (PE: EtOAc = 1: 1) to obtain 1.5g of a white solid with a yield of 75%. To obtain an intermediate (d),1H NMR (400 MHz, dmso): δ 7.20 (d, J = 9.0 Hz, 1H), 6.81 (dd, J = 9.0, 2.7 Hz, 1H), 6.76 (s, 1H), 3.76 – 3.64 (m, 2H), 3.55 (s, 4H), 3.16 (s, 3H), 3.14 – 2.96 (m, 4H), 2.71 (t, J = 6.5 Hz, 2H), 2.03 (s, 5H), 1.94 – 1.79 (m, 2H), 1.26 (s, 9H)；
and 4, step 4: preparation of 6- (4-acetylpiperazine) -N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide (intermediate (e))
Intermediate (d) (1.5g, 3.3mmol) was dissolved in dichloromethane, trifluoroacetic acid (3mL, 33mmol) was added, stirring was carried out at room temperature for 2hr, the reaction solution was slowly added to crushed ice (40g), a saturated solution of sodium hydrogencarbonate was added dropwise, stirring was carried out until PH =8, extraction was carried out with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated by distillation under reduced pressure, and column chromatography was carried out (PE: EtOAc = 1: 2) to obtain 0.7g of a yellow solid with a yield of 60%. To obtain an intermediate (e),1H NMR (400 MHz, CDCl3 ) δ 7.44 (d, J = 9.0 Hz, 1H), 6.86 – 6.52 (m, 2H), 4.37 (s, 1H), 3.68 (dd, J = 16.8, 11.1 Hz, 4H), 3.57 (s, 2H), 3.14 – 2.94 (m, 4H), 2.76 (t, J = 6.7 Hz, 2H), 2.59 (d, J = 5.4 Hz, 3H), 2.08 (s, 3H), 1.98 (p, J = 6.7 Hz, 3H)；
and 5: preparation of 6- (4-acetylpiperazine) -N-benzyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide
Intermediate (e) (0.1g, 0.28mmol) and potassium carbonate (0.07g, 0.56mmol) were dissolved in DMF (5ml) and benzyl bromide (0.145mg, 0.85mmol) was added dropwise with stirring at room temperature. The reaction was checked by TLC. After the reaction was completed, the reaction mixture was cooled, 15ml of water was added, extraction was performed with ethyl acetate (10 ml. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (PE: EtOAc = 1: 1) to obtain 0.070g of a white solid in 56% yield. Compound 1 is obtained.
Examples 2 to 22
Example 1 was repeated, with the difference that: different starting materials were used to prepare compounds 2-22. The method comprises the following specific steps:
2-Fluorobromobenzyl, 4-Fluorobromobenzyl, 3-Fluorobromobenzyl, 4-Methylbenzyl, 2, 4-difluorobromobenzyl, 4-chlorobromobenzyl, 3-trifluoromethylbromobenzyl, 3-chlorobromobenzyl, 2-trifluoromethylbromobenzyl, 2-chloro-4-trifluoromethylpyrimidine, 2-chlorobromobenzyl, 3-Methylbenzyl, 2-chloro-6-fluorobenzyl bromide, 4-trifluoromethylbromobenzyl, 2-Methylbenzyl, 4-tert-butylbenzyl, 4-phenylbenzyl, (2-bromoethyl) benzene, 1-bromo-3-phenylpropane, 4-trifluoromethoxy bromobenzyl, 4-cyanobromobenzyl, respectively, with the intermediates (e) and potassium carbonate in the above examples, respectively corresponding to the compounds 2,4, 2-cyanobenzyl, respectively, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22.
Example 236 preparation of N-benzyl-N-methyl-1, 2,3, 4-tetrahydroquinoline-1 (2H) -methanesulfonamide- (4-methanesulfonylpiperazine)
Example 1 was repeated, with the difference that: using different starting materials, compound 23 was prepared. The method comprises the following specific steps:
coupling 1-methylsulfonylpiperazine and the intermediate (c) under the catalysis of palladium acetate, 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl and cesium carbonate, then removing Boc, and adding benzyl bromide to finally prepare the compound 23.
Examples 24 to 32
Example 1 was repeated, with the difference that: various starting materials were used to prepare compounds 24-32. The method comprises the following specific steps:
coupling 1-methylsulfonylpiperazine, 1-ethylsulfonylpiperazine, morpholine, 4-methyl aminobenzoate, 6-amino-3, 4-dihydro-1 (2H) -naphthalenone, 4-methyl piperidinecarboxylate, N-piperidine-4-methyl-acetamide and an intermediate (c) under the catalysis of palladium acetate, 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl and cesium carbonate, then removing Boc, and adding 4-tert-butylbenzyl bromide to prepare compounds 24, 25, 26, 27, 29, 30 and 32 respectively.
Refluxing and hydrolyzing the compounds 27 and 30 in a methanol/water solution of sodium hydroxide to respectively prepare compounds 33 and 34, adding acid for neutralization, and extracting to respectively obtain compounds 28 and 31.
Examples 35 to 37
Example 1 was repeated, with the difference that: methylation in step 2 and coupling in step 3 were not performed to give compound 35. Hydrochloric acid and maleic acid are used for preparing salts thereof, namely the compounds 36 and 37 respectively.
The chemical structure of the synthesized target product is shown in table 1. The nuclear magnetic hydrogen spectrum and mass spectrum system characterize the chemical structure of the target product, and the data is shown in table 2.
TABLE 1 chemical Structure of the target product
| Compound (I) | R1 | R2 | m | n | X1 | X2 | Cy1 |
| 1 | -CH3 | H | 0 | 1 | C | 1-acetylpiperazine | |
| 2 | -CH3 | 2-F | 0 | 1 | C | 1-acetylpiperazine | |
| 3 | -CH3 | 4-F | 0 | 1 | C | 1-acetylpiperazine | |
| 4 | -CH3 | 3-F | 0 | 1 | C | 1-acetylRadical piperazine | |
| 5 | -CH3 | 4-CH3 | 0 | 1 | C | 1-acetylpiperazine | |
| 6 | -CH3 | 2,4-F | 0 | 1 | C | 1-acetylpiperazine | |
| 7 | -CH3 | 4-Cl | 0 | 1 | C | 1-acetylpiperazine | |
| 8 | -CH3 | 3-CF3 | 0 | 1 | C | 1-acetylpiperazine | |
| 9 | -CH3 | 3-Cl | 0 | 1 | C | 1-acetylpiperazine | |
| 10 | -CH3 | 2-CF3 | 0 | 1 | C | 1-acetylpiperazine | |
| 11 | H | 3-CF3 | 0 | 0 | N | 1-acetylpiperazine | |
| 12 | -CH3 | 2-Cl | 0 | 1 | C | 1-acetylpiperazine | |
| 13 | -CH3 | 3-CH3 | 0 | 1 | C | 1-acetylpiperazine | |
| 14 | -CH3 | 2-Cl-6-F | 0 | 1 | C | 1-acetylpiperazine | |
| 15 | -CH3 | 4-CF3 | 0 | 1 | C | 1-acetylpiperazine | |
| 16 | -CH3 | 2-CH3 | 0 | 1 | C | 1-acetylpiperazine | |
| 17 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | 1-acetylpiperazine | |
| 18 | -CH3 | 4-Ph | 0 | 1 | C | 1-acetylpiperazine | |
| 19 | -CH3 | H | 0 | 2 | C | 1-acetylpiperazine | |
| 20 | -CH3 | H | 0 | 3 | C | 1-acetylpiperazine | |
| 21 | -CH3 | 4-OCF3 | 0 | 1 | C | 1-acetylpiperazine | |
| 22 | -CH3 | 4-CN | 0 | 1 | C | 1-acetylpiperazine | |
| 23 | -CH3 | H | 0 | 1 | C | 1-methanesulfonylpiperazine | |
| 24 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | 1-methanesulfonylpiperazine | |
| 25 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | 1-ethanesulfonyl piperazine | |
| 26 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | Morpholine | |
| 27 | -CH3 | 4-C(CH3)3 | 1 | 1 | C | NH | 4-Benzylcarbate |
| 28 | -CH3 | 4-C(CH3)3 | 1 | 1 | C | NH | 4-benzoic acid |
| 29 | -CH3 | 4-C(CH3)3 | 1 | 1 | C | NH | 3, 4-dihydro-1 (2H) -naphthalenones |
| 30 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | 4-piperidinecarboxylic acid methyl ester, | |
| 31 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | 4-Piperidinecarboxylic acid | |
| 32 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | N-piperidine-4-methyl-acetamide | |
| 33 | -CH3 | 4-C(CH3)3 | 1 | 1 | C | NH | 4-benzoic acid |
| 34 | -CH3 | 4-C(CH3)3 | 0 | 1 | C | 4-Piperidinecarboxylic acid | |
| 35 | H | 4-C(CH3)3 | 1 | 1 | C | Br | |
| 36 | H | 4-C(CH3)3 | 1 | 1 | C | Br | |
| 37 | H | 4-C(CH3)3 | 1 | 1 | C | Br |
TABLE 2 nuclear magnetic hydrogen spectrum and mass spectrum data of the target compound
| Compound (I) | 1H NMR(400 MHz,DMSO-d6) | MS(m/z) |
| 1 | 7.32 (ddd, J = 20.4, 13.9, 7.9Hz, 6H), 6.81 (d, J = 8.9 Hz, 1H), 6.74 (s, 1H), 4.29 (s, 2H), 3.65 – 3.59(m, 6H), 3.55 (s, 4H), 3.13 – 3.01 (m, 4H), 2.76 (t, J = 6.6 Hz, 3H), 2.60(s, 4H), 2.04 (s, 6H), 1.99 – 1.89 (m, 2H). | 443.0[M+H]+ |
| 2 | 7.45 – 7.28 (m, 3H), 7.22 (dd,J = 13.0, 6.7 Hz, 2H), 6.79 (d, J = 9.1 Hz, 1H), 6.73 (s, 1H), 4.38 (s, 2H),3.58 (t, J = 9.3 Hz, 6H), 3.10 (d, J = 4.3 Hz, 2H), 3.06 – 2.96 (m, 2H), 2.76(t, J = 6.7 Hz, 2H), 2.66 (s, 3H), 2.04 (s, 3H), 1.94 (dd, J = 12.0, 6.1 Hz,2H) | 461.0[M+H]+ |
| 3 | 7.36 – 7.25 (m, 3H), 7.17 (t, J= 8.7 Hz, 2H), 6.79 (d, J = 9.1 Hz, 1H), 6.75 – 6.68 (m, 1H), 4.27 (s, 2H), 3.58 (dd, J = 14.8, 8.5 Hz, 7H), 3.09 (s, 2H), 3.03 (s, 2H), 2.75 (t, J = 6.5Hz, 3H), 2.59 (s, 3H), 2.03 (s, 3H), 1.97 – 1.78 (m, 2H) | 461.0[M+H]+ |
| 4 | 7.37 (dd, J = 14.7, 7.2 Hz,1H), 7.31 (d, J = 9.0 Hz, 1H), 7.11 (t, J = 6.7 Hz, 2H), 7.02 (d, J = 10.0Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 4.30 (s, 2H), 3.58 (d, J =5.0 Hz, 2H), 3.53 (s, 4H), 3.08 (s, 2H), 3.01 (s, 2H), 2.73 (t, J = 5.8 Hz,2H), 2.61 (s, 3H), 2.01 (s, 3H), 1.97 – 1.79 (m, 2H) | 461.0[M+H]+ |
| 5 | 7.31 (d, J = 9.0 Hz, 1H), 7.13(s, 4H), 6.78 (d, J = 9.1 Hz, 1H), 6.71 (s, 1H), 4.21 (s, 2H), 3.64 – 3.45(m, 6H), 3.11 – 3.04 (m, 2H), 3.04 – 2.96 (m, 2H), 2.74 (t, J = 6.6 Hz, 2H),2.55 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.95 – 1.80 (m, 2H) | 457.0[M+H]+ |
| 6 | 7.38 (dd, J = 15.7, 8.2 Hz,1H), 7.25 (dd, J = 17.9, 9.4 Hz, 2H), 7.08 (t, J = 8.3 Hz, 1H), 6.75 (d, J =9.1 Hz, 1H), 6.70 (s, 1H), 4.32 (s, 2H), 3.54 (s, 7H), 3.07 (s, 2H), 3.01 (s, 2H), 2.73 (t, J = 6.5 Hz, 2H), 2.62 (s, 3H), 2.01 (s, 3H), 1.94 – 1.74 (m, 2H) | 479.0[M+H]+ |
| 7 | 7.38 (d, J = 8.2 Hz, 2H), 7.28(t, J = 8.1 Hz, 3H), 6.77 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 4.26 (s, 2H),3.59 – 3.51 (m, 6H), 3.07 (s, 2H), 3.01 (s, 2H), 2.73 (t, J = 6.6 Hz, 2H),2.58 (s, 3H), 2.01 (s, 3H), 1.96 – 1.79 (m, 2H) | 477.0[M+H]+ |
| 8 | 7.67 (d, J = 5.1 Hz, 1H), 7.62 (s,1H), 7.59 (d, J = 6.0 Hz, 2H), 7.33 (d, J = 9.0 Hz,1H), 6.79 (d, J = 9.1 Hz,1H), 6.74 (s, 1H), 4.41 (s, 2H), 3.68 – 3.60 (m, 2H), 3.56 (d, J = 4.0 Hz,4H), 3.14 – 3.07 (m, 2H), 3.07 – 2.97 (m, 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.64 (s, 3H), 2.04 (s, 3H), 1.99 – 1.87 (m, 2H) | 511.0[M+H]+ |
| 9 | 7.43 – 7.17 (m, 5H), 6.78 (dd,J = 9.1, 2.5 Hz, 2H), 6.72 (s, 0H), 4.28 (s, 1H), 3.64 – 3.56 (m, 6H), 3.53 (d, J = 4.7 Hz, 2H), 3.14 – 3.04 (m, 4H), 3.04 – 2.97 (m, 1H), 2.73 (t, J = 6.7 Hz, 1H), 2.60 (s, 2H), 2.01 (s, 1H), 1.92 (dd, J = 12.0, 6.1 Hz, 2H) | 477.0[M+H]+ |
| 10 | 7.78 – 7.61 (m, 2H), 7.58 –7.44 (m, 2H), 7.30 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 1H), 6.72 (s, 1H), 4.47 (s, 2H), 3.63 – 3.57 (m, 2H), 3.53 (s, 4H), 3.08 (s, 2H), 3.02 (s, 2H),2.73 (t, J = 6.5 Hz, 6H), 2.68 (s, 3H), 2.48 (s, 2H), 2.01 (s, 6H), 1.97 – 1.88 (m, 2H) | 510.9[M+H]+ |
| 11 | 9.00 (d, J = 4.9 Hz, 1H), 7.64(d, J = 5.0 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.79 (dd, J = 9.0, 2.5 Hz, 1H),6.70 (d, J = 2.0 Hz, 1H), 3.98 – 3.87 (m, 2H), 3.57 (s, 13H), 3.53 (s, 4H), 3.13 – 3.03 (m, 4H), 3.02 – 2.91 (m, 2H), 2.62 (t, J = 6.3 Hz, 2H), 2.02 (s,5H), 1.96 – 1.82 (m, 2H) | 499.0[M+H]+ |
| 12 | 7.49 – 7.41 (m, 1H), 7.41 – 7.26 (m, 4H), 6.78 (dd, J = 9.1, 2.4 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 4.40 (s,2H), 3.64 – 3.56 (m, 7H), 3.53 (d, J = 4.8 Hz, 4H), 3.12 – 3.05 (m, 4H), 3.03– 2.95 (m, 2H), 2.73 (t, J = 6.7 Hz, 5H), 2.66 (s, 3H), 2.01 (s, 3H), 1.98 – 1.78 (m, 2H) | 477.0[M+H]+ |
| 13 | 7.32 (d, J = 9.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.14 – 6.95 (m, 2H), 6.78 (d, J = 9.2 Hz, 1H), 6.72 (s, 1H), 4.21 (s, 2H), 3.69 – 3.56 (m, 2H), 3.53 (s, 4H), 3.08 (s, 2H), 3.01 (s, 2H), 2.73 (t, J = 6.5 Hz, 2H), 2.57 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H), 1.96 – 1.79 (m, 2H) | 457.0[M+H]+ |
| 14 | 7.43 (dd, J = 14.3, 8.1 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.33 – 7.20 (m, 2H), 6.81 – 6.71 (m, 1H), 6.69 (s, 1H), 4.43 (s, 2H), 3.60 – 3.51 (m, 7H), 3.07 (d, J = 4.7 Hz, 2H), 3.03–2.92 (m, 2H), 2.73 (t, J = 6.6 Hz, 2H), 2.53 (s, 3H), 2.01 (s, 3H), 1.96 – 1.81 (m, 2H) | 494.9[M+H]+ |
| 15 | 7.70 (s, 2H), 7.48 (d, J = 6.3 Hz, 2H), 7.30 (d, J = 9.0 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.71 (s, 1H), 4.39 (s, 2H), 3.59 (s, 4H), 3.53 (s, 6H), 3.08 (s, 4H), 3.02 (s, 2H), 2.74 (s, 2H), 2.63 (s, 3H), 2.01 (s, 3H), 1.92 (s, 2H) | 511.0[M+H]+ |
| 16 | 7.32 (d, J = 8.9 Hz, 1H), 7.18 (d, J = 10.3 Hz, 4H), 6.78 (d, J = 8.9 Hz, 1H), 6.71 (s, 0H), 4.28 (s, 1H), 3.59 (s, 9H), 3.53 (s, 1H), 3.08 (s, 1H), 3.01 (s, 1H), 2.74 (t, J = 6.5 Hz, 1H), 2.56 (s, 1H), 2.23 (s, 1H), 2.01 (s, 3H), 1.92 (s, 2H) | 457.0[M+H]+ |
| 17 | 7.31 (t, J = 9.2 Hz, 3H), 7.15 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 9.0 Hz, 1H), 6.70 (s, 1H), 4.21 (s, 2H), 3.63 – 3.42 (m, 6H), 3.06 (s, 4H), 3.00 (s, 2H), 2.72 (t, J = 6.6 Hz, 2H), 2.56 (s, 3H), 2.00 (s, 6H), 1.94 – 1.81 (m, 2H), 1.22 (s, 9H) | 499.3[M+H]+ |
| 18 | 7.72 – 7.58 (m, 4H), 7.46 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.7 Hz, 4H), 6.81 (d, J = 8.9 Hz, 1H), 6.74 (s, 1H), 4.35 (s, 2H), 3.70 – 3.59 (m, 6H), 3.56 (d, J = 4.0 Hz, 4H), 3.07 (d, J = 25.2 Hz, 4H), 2.77 (t, J = 6.5 Hz, 2H), 2.65 (s, 3H), 2.04 (s, 3H), 1.99 – 1.77 (m, 2H) | 519.3[M+H]+ |
| 19 | 7.33 – 7.19 (m, 6H), 6.76 (d, J = 9.7 Hz, 1H), 6.73 (s, 1H), 3.57 (s, 6H), 3.50 (d, J = 5.3 Hz, 2H), 3.10 (s, 2H), 3.03 (s, 2H), 2.80 (d, J = 8.0 Hz, 2H), 2.77 (s, 3H), 2.74 (d, J = 6.6 Hz, 2H), 2.05 (s, 3H), 1.89 (d, J = 4.9 Hz, 2H) | 457.3[M+H]+ |
| 20 | 7.85 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 4.43 (s, 2H), 3.66 – 3.54 (m, 7H), 3.12 (s, 4H), 3.06 (s, 2H), 2.78 (t, J = 6.5 Hz, 2H), 2.67 (s, 3H), 2.06 (s, 3H), 2.00 – 1.87 (m, 2H). | 471.3[M+H]+ |
| 21 | 7.36 (dt, J = 12.6, 8.9 Hz, 5H), 6.80 (d, J = 9.1 Hz, 1H), 6.74 (s, 1H), 4.34 (s, 2H), 3.66 – 3.46 (m, 6H), 3.10 (s, 2H), 3.04 (s, 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.63 (s, 3H), 2.04 (s, 3H), 1.94 (dd, J = 12.0, 6.2 Hz, 2H) | 527.2[M+H]+ |
| 22 | 7.85 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 4.43 (s, 2H), 3.66 – 3.54 (m, 7H), 3.12 (s, 4H), 3.06 (s, 2H), 2.78 (t, J = 6.5 Hz, 2H), 2.67 (s, 3H), 2.06 (s, 3H), 2.00 – 1.87 (m, 2H). | 468.3[M+H]+ |
| 23 | 7.38 – 7.18 (m, 6H), 6.79 (d, J = 9.1 Hz, 1H), 6.72 (s, 1H), 4.26 (s, 2H), 3.63 – 3.51 (m, 2H), 3.18 (d, J = 9.0 Hz, 8H), 2.89 (s, 3H), 2.73 (t, J = 6.6 Hz, 2H), 2.57 (s, 3H), 1.91 (dd, J = 11.9, 6.1 Hz, 2H). | 479.0[M+H]+ |
| 24 | 7.32 (t, J = 9.2 Hz, 3H), 7.16 (d, J = 8.2 Hz, 2H), 6.79 (dd, J = 9.1, 2.6 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 4.22 (s, 2H), 3.62 – 3.51 (m, 2H), 3.18 (dd, J = 13.6, 5.2 Hz, 8H), 2.89 (s, 3H), 2.73 (t, J = 6.6 Hz, 2H), 2.56 (s,2H), 2.00 – 1.84 (m, 2H), 1.23 (s, 9H). | 535.0[M+H]+ |
| 25 | 7.26 (t, J = 9.2 Hz, 3H), 7.10 (d, J = 8.2 Hz, 2H), 6.73 (dd, J = 9.1, 2.6 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 4.16 (s, 2H), 3.58 – 3.44 (m, 2H), 3.13 (d, J = 5.1 Hz, 5H), 3.10 (d, J =5.4 Hz, 4H), 2.83 (s, 3H), 2.67 (t, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1.85 (dd, J = 11.9, 6.1 Hz, 2H), 1.17 (s, 9H) | 549.0[M+H]+ |
| 26 | 7.31 (dd, J = 11.7, 8.7 Hz, 3H), 7.15 (d, J = 8.1 Hz, 2H), 6.75 (dd, J = 9.0, 2.4 Hz, 1H), 6.67 (s, 1H), 4.20 (s, 2H), 3.74 – 3.62 (m, 4H), 3.62 – 3.50 (m, 2H), 3.06 – 2.95 (m, 4H), 2.72 (t, J = 6.6 Hz, 2H), 2.55 (s, 3H), 2.08 – 1.71 (m, 2H), 1.22 (s, 9H) | 458.0[M+H]+ |
| 27 | 8.72 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.7 Hz,1H), 7.38 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.09 – 6.94 (m, 4H), 4.29 (s, 2H), 3.79 (s, 3H), 3.67 (s,2H), 2.80(t, J = 6.2 Hz, 2H), 2.64 (s, 3H), 1.97 (s, 2H), 1.27 (s, 9H). | 522.0[M+H]+ |
| 28 | 8.63 (s, 0H), 7.78 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.12 – 6.92 (m, 2H), 4.28 (s, 1H), 3.65 (s, 1H), 3.18 (s, 0H), 2.79 (t, J= 6.0 Hz, 2H), 2.63 (s, 1H), 1.96 (s, 2H), 1.26 (s, 9H) | 508.0[M+H]+ |
| 29 | 8.72 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.08 – 6.94 (m, 2H), 6.88 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 4.28 (s,2H), 3.72 – 3.60 (m, 2H), 2.81 (d, J = 6.5 Hz, 4H), 2.63 (s, 3H), 2.47 (s, 2H), 1.96 (d, J = 5.1 Hz, 4H), 1.26 (s, 9H). | 532.3[M+H]+ |
| 30 | 7.36 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 9.1 Hz, 1H), 6.71 (s, 1H), 4.24 (s, 2H), 3.62 (s, 3H), 3.61 – 3.52 (m, 4H), 2.82 – 2.64 (m, 4H), 2.59 (s, 3H), 2.48 (d, J = 14.6 Hz, 1H), 1.99 – 1.82 (m, 4H), 1.67 (t, J = 10.6 Hz, 2H), 1.26 (s, 9H). | 514.0[M+H]+ |
| 31 | 12.27 (s, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.32 (s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.81 (s, 2H), 4.24 (s, 2H), 3.59 (dd, J = 16.2, 10.4 Hz, 4H), 2.75 (t, J = 6.5 Hz, 4H), 2.61 (d, J = 16.0 Hz, 3H), 2.39 (s, 1H), 2.00 – 1.81 (m, 4H), 1.68 (s, 2H), 1.26 (s, 9H). | 500.0[M+H]+ |
| 32 | 7.91 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 6.86 (dd, J = 9.1, 2.5 Hz, 1H), 6.80 (s, 1H), 4.33 (s, 2H), 3.76 (d, J = 7.2 Hz, 1H), 3.68 (dd, J = 11.1, 4.8 Hz, 4H), 2.83 (d, J = 7.1 Hz, 4H), 2.68 (s, 3H), 2.06 – 1.98 (m, 2H), 1.88 (s, 5H), 1.54 (dd, J = 20.4, 11.3 Hz, 3H), 1.36 (s, 9H), 1.32 (s, 3H). | 513.1[M+H]+ |
| 33 | 8.63 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.12 – 6.92 (m, 2H), 4.28 (s, 1H), 3.65 (s, 1H), 3.18 (s, 0H), 2.79 (t, J= 6.0 Hz, 2H), 2.63 (s, 1H), 1.96 (s, 2H), 1.26 (s, 9H) | 508.0[M+H]+ |
| 34 | 7.36 (d, J = 8.2 Hz, 2H), 7.32 (s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.81 (s, 2H), 4.24 (s, 2H), 3.59 (dd, J = 16.2, 10.4 Hz, 4H), 2.75 (t, J = 6.5 Hz, 4H), 2.61 (d, J = 16.0 Hz, 3H), 2.39 (s, 1H), 2.00 – 1.81 (m, 4H), 1.68 (s, 2H), 1.26 (s, 9H). | 500.0[M+H]+ |
| 35 | 7.46 – 7.24 (m, 5H), 7.19 (d, J = 8.1 Hz, 2H), 4.28 (s,2H), 3.71 – 3.61 (m, 2H), 2.79 (t, J = 6.5 Hz, 2H), 1.96 – 1.75 (m, 2H), 1.27 (s, 9H). | 437.2[M+H]+ |
| 36 | 7.48 – 7.24 (m, 5H), 7.18 (d, J = 8.1 Hz, 2H), 4.30 (s,2H), 3.73 – 3.61 (m, 2H), 2.79 (t, J = 6.5 Hz, 2H), 1.99 – 1.76 (m, 2H), 1.29 (s, 9H). | 437.2[M+H]+ |
| 37 | 7.46 – 7.24 (m, 5H), 7.19 (d, J = 8.1 Hz, 2H), 4.28 (s,2H), 3.71 – 3.61 (m, 2H), 2.79 (t, J = 6.5 Hz, 2H), 1.96 – 1.75 (m, 2H), 1.27 (s, 9H). | 437.1[M+H]+ |
Example 33:
pharmacological activity:
in vitro activity assay: the compound of the invention is verified to be capable of inhibiting the activity of RORgt protein by a double Fluorescence Resonance Energy Transfer (FRET) method.
Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10.0mM stock solution and diluted to the desired concentration. The final concentration of DMSO in the reaction did not exceed 1% (v/v). By mixing GST-labeled ROR gamma Ligand Binding Domain (LBD) in buffer containing 25mM HEPES, 100mM NaCl, 5mM DTT and 0.01% BSA in the presence or absence of the desired concentration of the compound, incubation at 25 ℃ for 1 hour. After addition of Steroid Receptor activator-1 (SRC-1), (676-700), biotin labeled and MAb Anti GST-Tb and Streptavidin-d2 to the reaction mixture and shaking for an additional 5 minutes, the reactions were incubated for an additional 1 hour at room temperature and the signals of 620, 665 read on a SpectraMax Paradigm microplate reader at 4 ℃ and the inhibitory activity of the test compounds was calculated from the TR-FRET ratio of 620/665. IC50 values were calculated from compound concentration inhibition curves by non-linear regression analysis using GraphPad Prism software.
The compounds prepared were tested using the assay procedure described above and the results obtained are provided in table 3. The compound is measured to have an IC50 of less than 5. mu.M, preferably less than 1. mu.M, more preferably less than 0.1. mu.M.
The IC50 (μ M) values are set forth in Table 1, where "A" refers to IC50 values less than 0.1 μ M, "B" refers to IC50 values in the range greater than 0.1 μ M and less than 1 μ M, "C" refers to IC50 values in the range greater than 1 μ M and less than 5 μ M, "D" refers to IC50 values greater than 5 μ M, and "NA" refers to no detection.
TABLE 3 FRET Activity data for Compounds
| Compound (I) | IC50 | Compound (I) | IC50 |
| 1 | B | 20 | D |
| 2 | D | 21 | C |
| 3 | C | 22 | D |
| 4 | B | 23 | D |
| 5 | C | 24 | B |
| 6 | B | 25 | B |
| 7 | C | 26 | B |
| 8 | D | 27 | B |
| 9 | B | 28 | C |
| 10 | D | 29 | A |
| 11 | C | 30 | NA |
| 12 | B | 31 | NA |
| 13 | B | 32 | NA |
| 14 | B | 33 | NA |
| 15 | C | 34 | NA |
| 16 | B | 35 | NA |
| 17 | B | 36 | NA |
| 18 | C | 37 | NA |
| 19 | B |
As can be seen from Table 3, the compound of the invention has inhibitory activity on ROR gamma t, which lays a foundation for developing high-efficiency, novel and strong-specificity medicaments for ROR gamma t mediated inflammation, tumor and autoimmune diseases such as cancer, psoriasis, rheumatoid arthritis, multiple sclerosis and the like, and the autoimmune diseases, and has good development value.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the present invention, and these modifications and additions should also be considered as the protection scope of the present invention.
Claims (8)
1. A compound of formula I
Wherein:
x1 is C or N;
n is optionally selected from 0, 1,2 or 3;
the substituent R1 is selected from H, (C1-C3) alkyl, halo (C1-C3) alkyl;
the substituent R2 is absent or located in at least one of the 2,3,4, 5, 6 positions and is unsubstituted, mono-, di-or poly-substituted, and the substituent R2 is selected from one, two or more of the following groups: hydrogen, halogen, trifluoromethyl, cyano, phenyl, unsubstituted (C1-C6) alkyl, unsubstituted (C1-C6) alkoxy, trifluoromethoxy; when R2 is di-or tri-substituted, the substituents are the same or different;
Cy1-(X2)mis optionally selected from:
2. the compound of claim 1, wherein each occurrence of said substituent R1 is methyl.
3. A compound according to claim 1 or 2, wherein the substituent R2 is in at least one of positions 2,3,4, 5, 6 and is unsubstituted, mono-substituted, di-substituted or poly-substituted, and the substituent R2 is selected from one, two or more of the following groups: hydrogen, fluoro, chloro, trifluoromethyl, cyano, methyl, phenyl, trifluoromethoxy, tert-butyl, and when R2 is di-or tri-substituted, the substituents are the same or different.
4. A pharmaceutically acceptable salt of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative of any of claims 1-3.
5. The pharmaceutically acceptable salt according to claim 4, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt is: a hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, or nitrate salt;
wherein the organic salt is: acetate, maleate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate or oxalate;
wherein the amino acid salt is: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine salt, cystine salt, cysteine salt, caseinate, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, methionine salt, tryptophan salt, glutamate, aspartate salt, valine salt, methionine salt, proline salt, or hydroxyproline salt.
6. A pharmaceutical composition comprising a) one or more of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivatives of any of claims 1 to 3, the pharmaceutically acceptable salts of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivatives of claim 4, and b) a pharmaceutically acceptable carrier therefor.
7. Use of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative of any of claims 1-3 or the pharmaceutically acceptable salt of the 1,2,3, 4-tetrahydroquinoline sulfonamide derivative of claim 5 for the manufacture of a medicament for the treatment of at least one of inflammation, autoimmune disease, diabetes, cancer.
8. The use according to claim 7, wherein the disease is: at least one of diabetes, encephalomyelitis, multiple sclerosis, rheumatoid arthritis, collagen-induced arthritis, psoriasis, inflammatory bowel disease, crohn's disease, asthma, pulmonary disease, Chronic Obstructive Pulmonary Disease (COPD), asthma, colitis, and ulcerative colitis.
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| CN104284657A (en) * | 2012-05-08 | 2015-01-14 | 默沙东公司 | Bicyclic sulfone compounds for inhibition of RORgamma activity and the treatment of disease |
| CN106458991A (en) * | 2014-05-23 | 2017-02-22 | 豪夫迈·罗氏有限公司 | Benzene sulfonamide derivatives and their use as RORC modulators |
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| CN104284657A (en) * | 2012-05-08 | 2015-01-14 | 默沙东公司 | Bicyclic sulfone compounds for inhibition of RORgamma activity and the treatment of disease |
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