CN108503584A - A kind of 1,2,3,4- tetrahydroquinolines sulfamide compound and its application - Google Patents

A kind of 1,2,3,4- tetrahydroquinolines sulfamide compound and its application Download PDF

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CN108503584A
CN108503584A CN201710106749.8A CN201710106749A CN108503584A CN 108503584 A CN108503584 A CN 108503584A CN 201710106749 A CN201710106749 A CN 201710106749A CN 108503584 A CN108503584 A CN 108503584A
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salt
compound
methyl
disease
substituent
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CN108503584B (en
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付伟
孙囡囡
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Fudan University
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D401/02—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
    • 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

Abstract

The invention belongs to pharmaceutical technology fields, it is related to the compound with formula (I) structure feature, wherein R1, R2, X1, X2, Cy1, the definition of m and n is referring to specification, such compound and its pharmaceutically acceptable salt, isomers, pro-drug cocrystallization compound, hydrate, solvate can be used for inhibiting the relevant orphan receptor γ of retinoic acid (ROR γ), and prevent or treat the inflammation that ROR γ are mediated, metabolism, autoimmunity and Other diseases or illness such as psoriasis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, asthma, lupus erythematosus, oneself immunity hepatitis or I types and type-2 diabetes mellitus, with efficient, low toxicity, the good feature of metabolic stability.

Description

A kind of 1,2,3,4- tetrahydroquinolines sulfamide compound and its application
Technical field
The invention belongs to pharmaceutical technology fields, are related to 1,2,3,4- tetrahydroquinoline sulfamide compounds of one kind and its application. More specifically, can be used as inflammatory syndrome, obstacle or disease of the RORgt conditioning agents for preventing, treating or improving RORgt mediations Disease.
Background technology
Prior art discloses retinoic acid receptors related orphan receptors（retinoic acid recetor-related Orphan receptor, ROR）Belong to a member of the transcription factor nuclear receptor superfamily of ligand-dependent.RORgt is the Asias RORs man One of race's Major Members, are distributed mainly on thymus gland, are expressed in the key cells in immune system.Studies have reported that RORgt promotees Into T-helper 17（Th17）Cell differentiation simultaneously generates inflammatory cytokine interleukin-17（IL-17）Key regulator, and Th17 cells and the IL-17 of its secretion play key effect in the occurrence and development of inflammation and autoimmune disease.
2011, the Littman professor seminars of New York University and the Burris professors seminar of Scripps research institutes were same When delivered that RORgt micromolecular inhibitors are related to be studied on Nature magazines：Littman groups sieve from compound library Select cardiotonic digoxin（Digoxin）And find its inhibitory activity with RORgt；Burris groups report first non-steroid Body micromolecular SR1001 can be used as ROR α and RORgt double inhibitors.The same year, professor's Dong class of Anderson Cancer centers Topic group reports the ursolic acid extracted from natural plants the also activity with selective depression RORgt.2014, Japan The Sano seminars of dept. of dermatology of Kochi universities are in Japanology Dermatology meeting（SID）Year-end meeting (Annual Meeting of The Society-for-Investigative-Dermatology) on report a RORgt inhibitor, by take orally to Medicine can mitigate mouse psoriasiform skin injury.It is before treatment psoriasis has very much that the result of study, which successfully illustrates RORgt, The target spot of scape.
At the beginning of 2015, by the monoclonal antibody for treating psoriasis by specific inhibition IL-17 of Novartis Co., Ltd's exploitation Cosentyx（Secukinumab/AIN457）FDA approval listings are obtained, this is first work in treatment psoriasis class pharmaceutical market For the drug of IL-17, illustrate to influence IL-17 signal paths by ROR γ t inhibitor by treat inflammation and autoimmunity The Potential feasibility of disease.Currently, IL-17 in terms of anti-inflammatory it has been recognised that.In addition to psoriasis, IL-17 it is a variety of from It is also played an important role in body immunological diseases, such as rheumatoid arthritis, multiple sclerosis, systemic loupus erythematosus.In addition, Since chronic inflammation is related in the occurrence and development of tumour, people are also exploring effects of the IL-17 in all kinds of tumours.Such as liver cell The cell quantity of expression IL-17A and the survival rate of patient infiltrated in cancer specimens is negatively correlated；Patient with breast cancer Tumor tissues in the Expressions In Lymphocytes IL-17A that infiltrates promote the proliferation etc. of cancer cell, the following IL-17 families control for tumour Treat good target spot is provided it is highly likely that, therefore, RORgt is considered as anti-inflammatory, antitumor and autoimmune disease The novel targets of medicament research and development can be used as the inflammation such as cancer, psoriasis, rheumatoid arthritis, multiple sclerosis and autoimmunity The new way of disease treatment.
Invention content
The purpose of the present invention is the present situations for the prior art, provide a kind of 1,2,3,4- tetrahydroquinoline sulfonamides chemical combination Object.
Another purpose of the present invention is to provide pharmaceutically may be used for described 1,2,3,4- tetrahydroquinoline sulfamide compounds Salt, solvate, precursor compound or the polymorph of receiving.
Another purpose of the present invention is to provide the preparation side of described 1,2,3,4- tetrahydroquinoline sulfamide compounds Method.
Fourth object of the present invention is to provide a kind of pharmaceutical composition.
The 5th purpose of the present invention, provides that described 1,2,3,4- tetrahydroquinoline sulfamide compounds, it pharmaceutically may be used The salt of receiving, the purposes in medicine preparation of solvate, pro-drug or polymorph.
To achieve the above object, the technical solution adopted by the present invention is that：
A kind of 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives, which is characterized in that the derivant structure general formula is：
Wherein：
X1 is C or N；
X2 is halogen, NH or O；
M is optionally from 0,1；
N is optionally from 0,1,2 or 3；
Substituent R 1 is selected from：H, (C1- C3) alkyl, halogen (C1- C3) alkyl, aryl, heteroaryl, heterocycle and naphthenic base；
Substituent R 2 is not present or is located at least one of 2,3,4,5,6 positions, is unsubstituted, mono-substituted, double take It is generation or polysubstituted, the one kind in following groups of substituent R 2, two or more：Hydrogen, halogen, nitro, hydroxyl, carboxylic Base, trifluoromethyl, cyano, substituted or unsubstituted amino, phenyl, substituted or unsubstituted (C1-C6) alkyl, substitution do not take (C1-C6) alkoxy ,-CONH in generation2、-CONHR3、 -CON(R3)2,-COOR3 ,-COR3 ,-NHCOR3 ,-NHCOOR3 bases Group, wherein R3 is optionally from H, (C1-C6) alkyl, trifluoromethyl, phenyl；When R2 is double or three substitution, substituent group can be identical Or it is different；
Cy1 be not present or optionally from：H, Ar1, Hetar1 or (C3-C7) naphthenic base；
Above Ar1 indicates to have the monocyclic aromatic hydrocarbon system of 6-10 carbon atom or bicyclic aromatic hydrocarbon system and ring aromatic hydrocarbon and satisfies And member ring systems, the system is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following：(C1-C6) Alkyl, (C3-C7) naphthenic base, (C1-C6) alkoxy, carbonyl, carboxyl, amino ,-CONH2、-COOR4、-COR4、-NHCOR4、- NHCOOR4、-COH(CF3)2、-SONH2,-SOOR4 ,-SOR4 ,-NHSOR4 ,-NHSOOR4 groups substitution；Wherein R4 optionally from H, (C1-C6) alkyl；
The above Hetar1 indicates saturation 4,5,6,7,8,9 or 10 circle heterocyclic rings with 1,2 or 3 N and/or O and/or S atom, should Heterocycle is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following：(C1-C6) alkyl, (C3- C7) naphthenic base, (C1-C6) alkoxy, carbonyl, carboxyl, amino ,-CONH2、-COOR4、-COR4、-NHCOR4、-NHCOOR4、- COH(CF3)2、-SONH2,-SOOR4 ,-SOR4 ,-NHSOR4 ,-NHSOOR4 groups substitution；Wherein R4 is optionally from H, (C1-C6) alkane Base.
Preferably, the R1 is selected from methyl.
Preferably, the substituent R 2 is located at least one of 2,3,4,5,6 positions, is unsubstituted, monosubstituted , it is disubstituted or polysubstituted, one kind in following groups of the substituent group, two or more：Hydrogen, fluorine, chlorine, trifluoro Methyl, cyano, methyl, phenyl, trifluoromethoxy, tertiary butyl, when R2 is double or three substitution, substituent group can be identical or not Together.
Preferably, the X1 is optionally from C or N.
Preferably, the X2 is optionally from bromine or N.
Preferably, the Cy1 is optional certainly：1- acetylpiperazinyls, 1- (propiono)-piperazinyl, 1- cyclopropane carbonyl piperazines Piperazine base, 1- pivaloyl groups piperazinyl, 1- pivaloyl groups piperazinyl, 1- mesylpiperazinyls, 1- piperazine sulfonamide Base, 1- ethylsulfonyls piperazinyl, morpholinyl, piperazinyl, methyl benzoate base, benzoxy, naphthalene, tetralyl, 3,4- bis- Hydrogen -1 (2H)-naphthalenone base, piperidyl, 4- piperidine methyl formates base, 4- piperidinecarboxylic acids base, 4- acetamido piperidyls.
It is furthermore preferred that the Cy1 is optionally certainly：1- acetylpiperazinyls, 1- mesylpiperazinyls, 1- ethylsulfonyl piperazines Base, morpholinyl, methyl benzoate base, 3,4- dihydros -1 (2H)-naphthalenone base, 4- piperidine methyl formates base, benzoxy, 4- piperidines Formyl, 4- acetamido piperidyls.
Unless otherwise indicated, (C1-C6) alkoxy of the present invention is (C1-C6) straight or branched alkoxyl, refers to Alkoxy containing 1-6 carbon atom, including but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, Isobutoxy, sec-butoxy, tert-butoxy, amoxy, hexyloxy, oxygroup in heptan or octyloxy.
Unless otherwise indicated, (C1-C6) alkyl of the present invention is (C1-C6) linear or branched alkyl group, refer to containing The alkyl of 1-6 carbon atom, including but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, uncle Butyl, amyl, hexyl, heptyl or octyl.
Unless otherwise indicated, (C3-C7) naphthenic base of the present invention refers to the naphthenic base containing 3-7 carbon atom, packet Include but be not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring third and cyclopenta, ring third and cyclohexyl.
Unless otherwise indicated, term halogen is halogen substituent group, including but not limited to fluorine, chlorine, bromine and/or iodine.
Wherein, the term " polysubstituted " in the present invention and " a variety of " refer to three kinds or more, and what is appeared below is also phase Same meaning.
As best one of embodiment, of the present invention 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives are as follows Particular compound：
- 1 (2H)-Methanesulfomide of 6- (4- Acetylpiperazines)-N- Benzyl-N-methyl -1,2,3,4- tetrahydroquinolines
6- (4- Acetylpiperazines)-N- (the fluoro- benzyls of 2-)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (the fluoro- benzyls of 4-)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (the fluoro- benzyls of 3-)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (4- Methyl-benzvls)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (2,4- diiluoro-benzyls)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (the chloro- benzyls of 4-)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (3- romethyl-benzies)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- (4- Acetylpiperazines)-N- (the chloro- benzyls of 3-)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (2- romethyl-benzies)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- (4- Acetylpiperazines)-N- (4- trifluoromethvl-Dvrimidins)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-sulfonamide
6- (4- Acetylpiperazines)-N- (the chloro- benzyls of 2-)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (3- Methyl-benzvls)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (the fluoro- benzyls of the chloro- 6- of 2-)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- (4- Acetylpiperazines)-N- (4- romethyl-benzies)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- (4- Acetylpiperazines)-N- (2- Methyl-benzvls)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- (4- phenyl-benzyls)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- Acetylpiperazines)-N- phenethyl-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-ethyl sulfonamide
6- (4- Acetylpiperazines)-N- phenylpropyl base-N- methyl-1s, the-the third sulfonamide of 2,3,4- tetrahydroquinolines -1 (2H)
6- (4- Acetylpiperazines)-N- (4- trifluoromethoxies-benzyl)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulphur Amide
6- (4- Acetylpiperazines)-N- (4- Cyano-benzyls)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
- 1 (2H)-Methanesulfomide of 6- (4- Nmethanesulphonylpiperazines)-N- Benzyl-N-methyl -1,2,3,4- tetrahydroquinolines
6- (4- Nmethanesulphonylpiperazines)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- (4- ethylsulfonyls piperazine)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- morpholines-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- amino-benzoic acid methyl esters)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-first Sulfonamide
6- (4- amino-benzoic acids)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- (- 1 (2H)-naphthalenone of 4- amino -3,4- dihydros)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines - 1 (2H)-Methanesulfomide
6- (4- piperidine methyl formates)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine
6- (4- piperidinecarboxylic acids)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- piperidine formamides)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
6- (4- amino-benzoic acids)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-methylsulfonyl Amine receives salt
6- (4- piperidinecarboxylic acids)-N- (4- tert-Butyl-benzyIs)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide sodium Salt
The bromo- N- of 6- (4- tert-Butyl-benzyIs) -1,2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide
The bromo- N- of 6- (4- tert-Butyl-benzyIs) -1,2,3,4- tetrahydroquinolines -1 (2H)-methanesulfonamide hydrochloride
The bromo- N- of 6- (4- tert-Butyl-benzyIs) -1,2,3,4- tetrahydroquinolines -1 (2H)-methanesulfonamide maleat.
To realize above-mentioned second purpose, the technical solution adopted by the present invention is that：
Pharmaceutically acceptable salt, solvate, the precursor chemical combination of the 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives Object or polymorph.
Pharmaceutically acceptable salt, solvate, pro-drug or polymorph, which is characterized in that described pharmaceutically The salt of receiving is inorganic salts, organic salt or amino-acid salt；
Wherein inorganic salts are：Sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromate or nitric acid Salt；
Wherein organic salt is：Maleate, acetate, fumarate, tartrate, succinate, lactate, p-methyl benzenesulfonic acid Salt, salicylate, oxalates；
Wherein amino-acid salt is：Arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycinate, Guang Propylhomoserin salt, cysteine salt, tyrosine salt, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, egg Propylhomoserin salt, tryptophan salt, glutamate, aspartate, valine salt, methionine salt, proline salt or hydroxyproline salt.
To realize above-mentioned third purpose, the technical solution adopted by the present invention is that：
Described 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives preparation methods, can synthesize to obtain, including such as by following below scheme Lower step：
Prepare intermediate b
Raw material a and chlorosulphonyl isocyanate and the tert-butyl alcohol are dissolved in dichloromethane, are stirred at room temperature, is condensed up to intermediate b.
Prepare intermediate c
By intermediate b and R1X（X is Cl, Br or I）It is dissolved in n,N-Dimethylformamide, return stirring is to get intermediate c.
Prepare intermediate d
Intermediate c and Cy1 are subjected to coupling reaction or substitution reaction obtains intermediate d.
Prepare intermediate e
Addition trifluoroacetic acid in intermediate d is sloughed to the tertbutyloxycarbonyl of intermediate d.
Prepare compound I
By intermediate d and different halides（Halides f）In being dissolved in n,N-Dimethylformamide, K is added2CO3Stirring, i.e., Obtain chemical compounds I.
Halides f：
Wherein, the preparation method of 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives pharmaceutically acceptable salts can be according to ability Prepared by domain conventional method, the compound of the present invention is usually detached as former state, or in the form of its pharmaceutically acceptable salt, Such as it is reacted and is obtained under normal conditions with inorganic salts, organic salt or amino-acid salt.
To realize above-mentioned 4th purpose, the technical solution adopted by the present invention is that：
A kind of pharmaceutical composition, it includes a）Above-mentioned 1,2,3,4- tetrahydroquinolines sulfonic acid amide derivatives, and/or above-mentioned 1,2,3, Pharmaceutically acceptable salt, solvate, precursor compound or the polymorph and b of 4- tetrahydroquinoline sulfonic acid amide derivatives） Its pharmaceutically acceptable carrier.
Described pharmaceutical composition can be the pharmaceutical preparation of solid form or liquid form, the agent of described pharmaceutical composition Type includes but not limited to tablet, capsule, powder agent, granule, suspension or injection.
To realize above-mentioned 5th purpose, the technical solution adopted by the present invention is that：
Described 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives, pharmaceutically acceptable salt, solvate, precursor medicine The purposes of object, polymorph or pharmaceutical composition in medicine preparation applies in general to inhibit RORgt.Therefore, in some implementations In example, the present invention provides a kind of relevant orphan receptor γ of inhibition retinoic acid (ROR γ), and prevents or treat ROR γ mediations Inflammation, metabolism, autoimmunity and Other diseases or illness, it includes administering provide compound or composition.More precisely It says, compounds and compositions described herein serve as the conditioning agent of ROR γ.
The disease and the patient's condition that can be treated according to the method for the present invention include but is not limited to inflammation, the generation that ROR γ are mediated Thank, autoimmunity and Other diseases or illness, as psoriasis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Asthma, lupus erythematosus, oneself immunity hepatitis or I types and II types glycosuria, diabetic complication, nephrosis, diabetes Property retinopathy, diabetic retinitis, diabetic microangiopathy, ophthalmology disease, uveitis, atherosclerosis, Psoriasis arthropathica, atopic dermatitis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, ephritis, organ are of the same race Allograft rejection, fibroid lung, cystic fibrosis, renal insufficiency, pulmonary tuberculosis, Chronic Obstructive Pulmonary Disease, meat sample It is inflammation, allergic rhinitis, allergic conjunctivitis after tumor disease, invasive staphyloderma, cataract operation, chronic Nettle rash, systemic loupus erythematosus, asthma, allergic asthma, steroid resistant asthma, neutrophilic asthma, periodontal Disease, periodontitis, gingivitis, gum disease, diastolic cardiomyopathies, myocardial infarction, myocarditis, chronic heart failure, blood vessel are narrow Narrow, restenosis, Reperfu- sion obstacle, glomerulonephritis, solid tumor and cancer, chronic lymphocytic leukemia, chronic granulocyte Property leukaemia, Huppert's disease, pernicious myeloma, Hodgkin's disease and carcinoma of urinary bladder, breast cancer, cervix cancer, colon cancer, Lung cancer, prostate cancer or gastric cancer.
Further, the present invention also provides described 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives or its pharmacy to connect Application of salt, solvate, precursor compound or the polymorph received in the drug for preparing treatment inflammation disease.
Further, the present invention also provides described 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives or its pharmacy to connect Application of salt, solvate, precursor compound or the polymorph received in the drug for preparing treatment autoimmune disease.
Further, the present invention also provides described 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives or its pharmacy to connect Application of salt, solvate, precursor compound or the polymorph received in the drug for preparing treatment metabolism related diseases.
Further, the present invention also provides described 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives or its pharmacy to connect Application of salt, solvate, precursor compound or the polymorph received in the drug for preparing treating cancer disease.
Best, the present invention also provides described 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives or its is pharmaceutically acceptable Salt, solvate, precursor compound or polymorph preparing psoriasis, the rheumatoid joint that treatment is mediated by ROR γ Inflammation, multiple sclerosis, ulcerative colitis, asthma, lupus erythematosus, oneself immunity hepatitis or I types and type-2 diabetes mellitus, Crow Engler's disease, breast cancer, lung cancer, colon cancer drug in application.
Specific implementation mode
The present invention is explained further below in conjunction with specific embodiment, but embodiment does not do any type of limit to the present invention It is fixed.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or suggest according to manufacturer Condition.
In chemicals of the present invention, when any variable (such as R1, R2 etc.) occurs more than once in any component, Then its definition occurred every time is independently of other definition occurred every time.Equally, allow the combination of substituent group and variable, as long as this Kind combination makes compound stablize.Indicate that signified key may be connected to any ring original that can replace from the line of substituent group cut-in loop system On son.If loop system is polycyclic, it means that this key is connected only on any carbon atom appropriate of adjacent loops.It is appreciated that Those of ordinary skill in the art may be selected the compounds of this invention substituent group and substitution pattern and provide chemically stable and can The compound being readily synthesized from readily available raw material by art technology and the method for following proposition.If substituent group Itself it is exceeded a group substitution, it should be understood that these groups can be in identical carbon atoms or on different carbon atoms, as long as making knot Structure is stablized.Phrase " being optionally substituted by one or more substituents " is considered and phrase " optionally being replaced by least one substituent group " Quite and preferred embodiment will have 0-3 substituent group in the case.
Terms used herein " alkyl " and " alkylidene " mean include have particular carbon atom number branch and straight chain Saturated fat alkyl.For example, in " C1-C6 alkyl " definition of " C1-C6 " include with linear chain or branched chain arrange have 1,2, 3, the group of 4,5 or 6 carbon atoms.For example, " C1-6 alkyl " specifically includes methyl, ethyl, n-propyl, isopropyl, positive fourth Base, tertiary butyl, isobutyl group, amyl, sec-butyl, tertiary butyl, hexyl.Term " naphthenic base " refers to the list with particular carbon atom number Ring filling aliphatic group.Such as " naphthenic base " includes cyclopropyl, methyl-cyclopropyl, 2,2- dimethyl-cyclobutyls, 2- ethyls-ring Amyl, cyclohexyl etc..
Terms used herein " heteroaryl " represents in ring up to 6 in the monocycle of the stabilization of up to 6 atoms or each ring A atom bicyclic carbocyclic, wherein at least one ring are aromatic rings and the hetero atom selected from O, N and S containing 1-4.This definition Heteroaryl in range includes but not limited to：Imidazole radicals, triazolyl, pyrazolyl, base, the thienyl, oxazolyl, isoxazoles of muttering of barking Base, pyrazinyl, pyridazinyl, pyridyl group, pyrimidine radicals, pyrrole radicals.Definition for following heteroaryl, " heteroaryl " also are understood as wrapping Include the N- oxide derivatives of any heteroaryl containing nitrogen.In heteroaryl substituent be bicyclic and ring is non-containing there are one Armaticity does not contain in heteroatomic example, it should be understood that respectively through aromatic rings or through being connected containing heteroatomic ring.
Term " heterocycle " used herein or " heterocycle " refer to containing 1-4 be selected from O, N and S heteroatomic 5 yuan Or 6 yuan of armaticity or non-aromatic heterocyclic rings, and include bicyclic radicals." heterocycle " therefore include above mentioned heteroaryl, Including its dihydro and tetrahydro analog." heterocycle " further example includes but not limited to：It is imidazole radicals, indazolyl, different Thiazolyl, isoxazolyl, oxadiazolyl, oxazolyls, oxetanyl, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine Base, pyrimidine radicals, pyrrole radicals, quinoxalinyls, tetrazole radical, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, 4- alkyl dioxins, Pyrrolidinyl, glyoxalidine base, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyls, dihydro-oxazole base, dihydro pyrrole Piperazine base, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazole radical, thiodiazoline base, dihydro Thiazolyl, dihydrothiophene, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl and its N- oxygen Compound.The connection of heterocyclic substituent can be realized by carbon atom or by hetero atom.
As will be appreciated by a person skilled in the art, " halogen " used herein means to include chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, naphthenic base, aryl, heteroaryl and heterocyclyl substituent can be considered it is unsubstituted or Substitution.For example, (C1-C4) alkyl can be selected from OH, halogen, alkoxy, dialkyl amido or miscellaneous by one, two or three The substituent group of ring group, such as morpholinyl, piperidyl etc. replaces.
The present invention includes the free form of type I compound, also includes its pharmaceutically acceptable salt and stereoisomer.This The specific exemplary compounds of some in text are the protonated salt of aminated compounds.Term " free form " refers to non-salt shape The aminated compounds of formula.The pharmaceutically acceptable salt being included includes not only the exemplary of specific compound described herein Salt also includes the typical pharmaceutically acceptable salt of all type I compound free forms.Techniques known in the art point can be used Free form from the compound specific salts.For example, can by with alkali dilute aqueous solution appropriate such as NaOH dilute aqueous solutions, Potassium carbonate dilute aqueous solution, weak aqua ammonia and sodium bicarbonate dilute aqueous solution, which handle the salt, makes free form regenerate.Free form is certain Physical property for example in polar solvent respectively more or less distinguish solubility with its by salifie form, but for invention purpose this Respectively free form is suitable with its in terms of other pharmacy for kind hydrochlorate and alkali salt.
It can synthesize the present invention's from the compounds of this invention of alkaline part or acidic moiety is contained by conventional chemical processes Pharmaceutically acceptable salt.In general, by ion-exchange chromatography or passing through free alkali and stoichiometric amount or excessive required salt The reaction in the combination of appropriate solvent or multi-solvents of the inorganic or organic acid of form prepares the salt of alkali compounds.Similar, The salt of acid compound is formed by being reacted with appropriate inorganic or organic base.
Therefore, the pharmaceutically acceptable salt of the compounds of this invention includes by alkaline the compounds of this invention and inorganic or have Machine acid reacts the conventional non-toxic salts for the compounds of this invention to be formed.For example, conventional nontoxic salts include deriving from inorganic acid such as salt The salt of acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc. also includes from organic acid such as acetic acid, propionic acid, succinic acid, second Alkyd, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, Glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2- acetoxyl groups-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, The salt of the preparations such as ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.
If the compounds of this invention is acid, " pharmaceutically acceptable salt " appropriate refers to by pharmaceutically acceptable Nontoxic alkali include salt prepared by inorganic base and organic base.Salt derived from inorganic base includes aluminium salt, ammonium salt, calcium salt, mantoquita, iron Salt, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc..Particularly preferred ammonium salt, calcium salt, magnesium salts, sylvite And sodium salt.Salt derived from pharmaceutically acceptable organic nontoxic alkali, the alkali include the salt of primary amine, secondary amine and tertiary amine, substitution Amine include naturally occurring substitution amine, cyclic amine and deacidite such as arginine, glycine betaine, caffeine, courage Alkali, N, N'- dibenzyl-ethylenediamins, diethylamine, 2- DEAE diethylaminoethanols, 2- dimethylaminoethanols, ethylaminoethanol, second Hydramine, ethylenediamine, N- ethyl morpholines, N- ethyl piperidines, gucosamine, Glucosamine, histidine, hydroxycobalamin, isopropyl Amine, lysine, methyl glucose osamine, morpholine, piperazine, piperidines, croak smack one's lips, polyamines resin, procaine, purine, theobromine, three Ethamine, trimethylamine, tripropyl amine (TPA), tromethamine etc..
Since the acidic moiety such as carboxyl of deprotonation in compound in physiological conditions can be anion, and it is this The charge carried then can be by the internal protonated or alkylated alkaline part such as quaternary nitrogen atom with cation Balance is offset, it is noted that the compounds of this invention is potential inner salt or amphoteric ion.
Composition of the present invention can be liquid, semiliquid or solid form, according to being suitable for administration way used The mode of diameter is prepared.Composition of the present invention can be administered according to following administering mode：In oral, parenteral, peritonaeum, it is quiet The modes such as arteries and veins is interior, transdermal, sublingual, intramuscular, rectum, oral cavity, intranasal, liposome.
Orally administered composition can be solid, gel or liquid.The example of solid pharmaceutical preparation includes but not limited to tablet, capsule Agent, granule and bulk powder.These preparations can selectively contain adhesive, diluent, disintegrant, lubricant, glidant, Sweetener and corrigent etc..The example of adhesive includes but not limited to microcrystalline cellulose, glucose solution, mucialga of arabic gummy, bright Sol solution, sucrose and gelatinized corn starch；The example of lubricant includes but not limited to talcum, starch, magnesium stearate, calcium stearate, tristearin Acid；The example of diluent includes but not limited to lactose, sucrose, starch, mannitol, Dicalcium Phosphate；The example of glidant includes But it is not limited to silica；The example of disintegrant includes but not limited to croscarmellose sodium, primojel, algae Acid, cornstarch, potato starch, methylcellulose, agar and carboxymethyl cellulose.
The present composition is given with parenteral, generally based on injection, including subcutaneous, intramuscular or intravenous injection.Note Any conventionally form can be made by penetrating agent, and such as liquid solution or suspension is suitable for being dissolved or suspended in liquid before injection In solid form or emulsion.The example that can be used for the carrier of the pharmaceutical acceptable of injection of the present invention includes but not limited to Aqueous carrier, non-aqueous carrier, antimicrobial, isotonic agent, buffer, antioxidant, suspension and dispersant, emulsifier, chelating Agent and other pharmaceutically acceptable substances.The example of aqueous carrier includes sodium chloride injection, woods format injection, isotonic Portugal Grape sugar injection, Sterile Water Injection, glucose and Lactated ringer's injection；The example of non-aqueous carrier includes that plant comes Fixing oil, cottonseed oil, corn oil, sesame oil and the peanut oil in source；The example of antimicrobial includes metacresol, benzylalcohol, neoprene Alcohol, benzalkonium chloride etc.；The example of isotonic agent includes sodium chloride and glucose；Buffer includes phosphate and citrate.
The present composition can also be prepared into sterile freeze drying powder injection, and compound is dissolved in buffer solution of sodium phosphate, Wherein containing glucose or other suitable excipient, then under standard conditions well known by persons skilled in the art by solution without Bacterium is filtered, and is followed by freeze-drying, is obtained required preparation.
Except known in the literature or in addition to the standard method of illustration, can be used as shown in following scheme in experimental arrangement Reaction prepare the compounds of this invention.Therefore, following illustrative approach is purpose to illustrate without being limited to listed chemical combination Object or any specific substituent group.The substituent group number shown in scheme not necessarily meets number used in claim, And for clarity, showing monosubstituted base to be connected under the hereinbefore definition of Formulas I allows to have in the compound of multi-substituent.
The present invention will be further described for following embodiment, but the embodiment is not intended to limit the protection model of the present invention It encloses.
- 1 (2H)-methylsulphur of 1 6- of embodiment (4- Acetylpiperazines)-N- Benzyl-N-methyl -1,2,3,4- tetrahydroquinolines Amide（Compound 1）Preparation
Step 1：Prepare tertiary butyl ((the bromo- 3,4- dihydroquinoline -1 (2H) of 6-) sulfonyl) carbamate（Intermediate (b)）
Chlorosulfonic acid isocyanate (0.75g, 5mmol), the tert-butyl alcohol (0.37g, 5mmol) are dissolved in dichloromethane (15ml), and ice bath stirs Mix 0.5hr.Be added again into reaction solution the bromo- 1,2,3,4- tetrahydroquinolines (1.05g, 5mmol) of 6- and triethylamine (1.5g, 15mmol), 6hr is stirred at room temperature.To the end of reaction, add 15ml water, extracted with dichloromethane (10ml × 3), merges organic phase, Anhydrous sodium sulfate is dried, and concentration, column chromatography for separation (PE are evaporated under reduced pressure after filtering: EtOAc = 20:1) white solid, is obtained 1.3g, yield 67%.Obtain intermediate (b)；
Step 2：Prepare N- tert-butyl-n -s methyl-((the bromo- 3,4- dihydroquinoline -1 (2H) of 6-) sulfonyl) carbamate（In Mesosome (c)）
By intermediate (b) (0.76g, 1.84mmol）With potassium carbonate (0.51g, 3.7mmol）It is dissolved in DMF (15ml), iodine first is added dropwise Alkane (0.18mL, 2.8mmol), 110 DEG C of reflux.TLC detection reactions.It lets cool after reaction, adds 35ml water, use ethyl acetate (30ml × 3) extract, and merge organic phase, and anhydrous sodium sulfate drying is evaporated under reduced pressure concentration, column chromatography for separation (PE after filtering: EtOAc = 20:1) faint yellow solid 0.522g, yield 66%, are obtained.Obtain intermediate (c)；
Step 3：Prepare 6- (4- Acetylpiperazines)-N- tertbutyloxycarbonyl-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-first Sulfonamide（Intermediate (d)）
Intermediate (c) (1.82g, 4.8mmol), palladium (52mg, 0.24mmol), 2- dicyclohexyl phosphines -2 ', 6 '-dimethoxies Base biphenyl (240mg, 0.48mmol), cesium carbonate (2.32g, 7.2mmol) are dissolved in dioxane (15ml), add 1- acetyl piperazines Piperazine (0.92g, 7.2mmol), nitrogen protection, 100 DEG C of return stirring 6hr, reaction solution are in brown clear liquid.Wait for that reaction solution is down to room 15ml water is added in temperature, is extracted with ethyl acetate (10ml × 3), merges organic phase, and anhydrous sodium sulfate drying is depressurized after filtering and steamed Evaporate concentration, column chromatography for separation (PE：EtOAc = 1:1) white solid 1.5g, yield 75%, are obtained.Intermediate (d) is obtained,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)；
Step 4：Prepare 6- (4- Acetylpiperazines)-N- methyl-1s, 2,3,4- tetrahydroquinolines -1 (2H)-Methanesulfomide（It is intermediate Body (e)）
Intermediate (d) (1.5g, 3.3mmol) is dissolved in dichloromethane, and trifluoroacetic acid (3mL, 33mmol) is added, is stirred at room temperature 2hr is slowly added into reaction solution in trash ice (40g), and saturated solution of sodium bicarbonate, stirring, until PH=8, use ethyl acetate is added dropwise (30ml×3）Extraction, merges organic phase, and anhydrous sodium sulfate drying is evaporated under reduced pressure concentration, column chromatography for separation (PE after filtering： EtOAc = 1：2) yellow solid 0.7g, yield 60%, are obtained.Intermediate (e) is obtained,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)；
Step 5：Prepare -1 (2H)-Methanesulfomide of 6- (4- Acetylpiperazines)-N- Benzyl-N-methyl -1,2,3,4- tetrahydroquinolines
Intermediate (e) (0.1g, 0.28mmol) and potassium carbonate (0.07g, 0.56mmol) are dissolved in DMF (5ml), benzyl bromine is added dropwise (0.145mg, 0.85mmol) is stirred at room temperature.TLC detection reactions.It lets cool after reaction, adds 15ml water, use ethyl acetate (10ml × 3) extract, and merge organic phase, and anhydrous sodium sulfate drying is evaporated under reduced pressure concentration, column chromatography for separation (PE after filtering: EtOAc = 1：1) white solid 0.070g, yield 56%, are obtained.Obtain compound 1.
Embodiment 2- 22
Embodiment 1 is repeated, difference is：Using different raw materials, to which compound 2-22 be made.It is specific as follows：
By 2- fluorine bromobenzyl, 4- fluorine bromobenzyl, 3- fluorine bromobenzyl, 4- methyl bromobenzyl, 2,4- difluorobenzyl bromides, 4- chlorine bromobenzyl, 3- trifluoromethyls Bromobenzyl, 3- chlorine bromobenzyl, 2- trifluoromethyls bromobenzyl, the chloro- 4- trifluoromethyl pyrimidines of 2-, 2- chlorine bromobenzyl, 3- methyl bromobenzyl, the chloro- 6- of 2- Fluoro benzyl bromide, 4- trifluoromethyls bromobenzyl, 2- methyl bromobenzyl, 4- tertiary butyls bromobenzyl, 4- phenyl bromobenzyl, (2- bromoethyls) benzene, 1- are bromo- 3- phenyl-propanes, 4- trifluoromethoxies bromobenzyl, 4- cyano-benzyl bromides respectively with the intermediate (e) and potassium carbonate system in above-described embodiment It is standby to form, compound 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 is corresponded to respectively.
- 1 (2H)-methylsulphur of 23 6- of embodiment (4- Nmethanesulphonylpiperazines)-N- Benzyl-N-methyl -1,2,3,4- tetrahydroquinolines The preparation of amide
Embodiment 1 is repeated, difference is：Using different raw materials, to which compound 23 be made.It is specific as follows：
By 1- Nmethanesulphonylpiperazines and intermediate (c) in palladium, 2- dicyclohexyl phosphines -2 ', 6 '-dimethoxy-biphenyls, carbonic acid It is coupled under the catalysis of caesium, then takes off Boc, add bromobenzyl, finally obtained compound 23.
Embodiment 24-32
Embodiment 1 is repeated, difference is：Using different raw materials, to which compound 24-32 be made.It is specific as follows：
By 1- Nmethanesulphonylpiperazines, 1- ethylsulfonyls piperazine, morpholine, 4-aminobenzoic acid methyl esters, 6- amino -3,4- dihydros -1 (2H)-naphthalenone, 4- piperidine methyl formates, N- piperidines -4- methyl acetamides and intermediate (c) are in palladium, 2- dicyclohexyls Phosphine -2 ', 6 '-dimethoxy-biphenyls, cesium carbonate catalysis under be coupled, then take off Boc, add 4- tertiary butyl bromobenzyls, point It Zhi get not compound 24,25,26,27,29,30,32.
By compound 27,30 in the methanol/water solution of sodium hydroxide back hydrolysis, respectively be made compound 33,34, add Acid neutralizes, and extraction obtains compound 28,31 respectively.
Embodiment 35-37
Embodiment 1 is repeated, difference is：Without the coupling of step 2 to methylate with step 3, compound 35 is obtained.Use salt Its salt, i.e. compound 36,37 is made in acid, maleic acid respectively.
The chemical constitution for the target product that the present invention has synthesized is shown in Table 1.Nucleus magnetic hydrogen spectrum, mass spectrometer system characterize target product Chemical constitution, shown in tables of data 2.
The chemical constitution of 1. target product of table
Compound R1 R2 m n X1 X2 Cy1
1 -CH3 H 0 1 C 1- Acetylpiperazines
2 -CH3 2-F 0 1 C 1- Acetylpiperazines
3 -CH3 4-F 0 1 C 1- Acetylpiperazines
4 -CH3 3-F 0 1 C 1- Acetylpiperazines
5 -CH3 4-CH3 0 1 C 1- Acetylpiperazines
6 -CH3 2,4-F 0 1 C 1- Acetylpiperazines
7 -CH3 4-Cl 0 1 C 1- Acetylpiperazines
8 -CH3 3-CF3 0 1 C 1- Acetylpiperazines
9 -CH3 3-Cl 0 1 C 1- Acetylpiperazines
10 -CH3 2-CF3 0 1 C 1- Acetylpiperazines
11 H 3-CF3 0 0 N 1- Acetylpiperazines
12 -CH3 2-Cl 0 1 C 1- Acetylpiperazines
13 -CH3 3-CH3 0 1 C 1- Acetylpiperazines
14 -CH3 2-Cl-6-F 0 1 C 1- Acetylpiperazines
15 -CH3 4-CF3 0 1 C 1- Acetylpiperazines
16 -CH3 2-CH3 0 1 C 1- Acetylpiperazines
17 -CH3 4-C(CH3)3 0 1 C 1- Acetylpiperazines
18 -CH3 4-Ph 0 1 C 1- Acetylpiperazines
19 -CH3 H 0 2 C 1- Acetylpiperazines
20 -CH3 H 0 3 C 1- Acetylpiperazines
21 -CH3 4-OCF3 0 1 C 1- Acetylpiperazines
22 -CH3 4-CN 0 1 C 1- Acetylpiperazines
23 -CH3 H 0 1 C 1- Nmethanesulphonylpiperazines
24 -CH3 4-C(CH3)3 0 1 C 1- Nmethanesulphonylpiperazines
25 -CH3 4-C(CH3)3 0 1 C 1- ethylsulfonyl piperazines
26 -CH3 4-C(CH3)3 0 1 C Morpholine
27 -CH3 4-C(CH3)3 1 1 C NH 4 benzoic acid methyl esters
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- dihydros -1 (2H)-naphthalenone
30 -CH3 4-C(CH3)3 0 1 C 4- piperidine methyl formates,
31 -CH3 4-C(CH3)3 0 1 C 4- piperidinecarboxylic acids
32 -CH3 4-C(CH3)3 0 1 C N- piperidines -4- methyl acetamides
33 -CH3 4-C(CH3)3 1 1 C NH 4 benzoic acid
34 -CH3 4-C(CH3)3 0 1 C 4- piperidinecarboxylic acids
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
The nucleus magnetic hydrogen spectrum of 2. target compound of table, mass spectrometric data
Compound 1H NMR(400 MHz,DMSO-d6) MS(m/z)
1 7.32 (ddd, J = 20.4, 13.9, 7.9 Hz, 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 = 6.5 Hz, 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 = 10.0 Hz, 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]+
Embodiment 33:
Pharmacological activity：
Activity test in vitro：The present invention is using double fluorescence resonance energy transfer (fluorescence resonance energy Transfer, FRET) method validation the compounds of this invention inhibition RORgt protein actives ability.
Test compound is dissolved in dimethyl sulfoxide (DMSO) to prepare 10.0mM stock solutions and be diluted to required dense Degree.DMSO ultimate densities in reaction are no more than 1% (v/v).By in the chemical combination presence or absence of required concentration In the case of object by GST label ROR γ ligand binding domains (LBD) be mixed in containing 25mM HEPES, 100mM NaCl, In the buffer of 5mM DTT and 0 .01%BSA, incubated 1 hour at 25 DEG C.By Steroid Receptor Coactivator-1 (SRC-1), (676-700), biotin labeled and MAb Anti GST-Tb and Streptavidin-d2 is added to reaction mixture and shakes again after five minutes, by reactant again at room temperature incubate 1 hour and At 4 DEG C in SpectraMax Paradigm microplate reader read 620,665 signal, according to 620/665 TR-FRET ratios Rate tests the inhibitory activity of compound to calculate.By using the nonlinear regression analysis of GraphPad Prism softwares, according to Compound concentration suppression curve calculates IC50 values.
Prepared compound is tested using said determination program and acquired results are provided in table 3.It measures described Compound has the IC50 less than 5 μM, preferably smaller than 1 μM, more preferably less than 0.1 μM.
IC50 (μM) value is set forth in table 1, wherein " A " refers to the IC50 values less than 0.1 μM, " B " refers to being more than 0.1 μM And it is less than the IC50 values within the scope of 1 μM, " C " refers to being less than the IC50 values within the scope of 5 μM more than 1 μM, and " D " refers to being more than 5 μM IC50 values, " NA " refers to not detecting.
The FRET activity datas of 3. compound of table
Compound IC50 Compound 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 known from Table 3, the compound of the present invention has inhibitory activity to ROR γ t, this is that exploitation is efficient, novel, high specificity ROR γ the t inflammation, tumour and the autoimmune disease that mediate such as cancer, psoriasis, rheumatoid arthritis, multiple hard The drug of the inflammation such as change and autoimmune disease is laid a good foundation, and has good Development volue.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art Member, under the premise of not departing from the present invention, can also make several improvement and supplement, these are improved and supplement also should be regarded as this hair Bright protection domain.

Claims (10)

1. compound of formula I
（I）
Wherein：
X1 is C or N；
X2 is halogen, NH or O；
M is optionally from 0,1；
N is optionally from 0,1,2 or 3；
Substituent R 1 is selected from：H, (C1- C3) alkyl, halogen (C1- C3) alkyl, aryl, heteroaryl, heterocycle and naphthenic base；
Substituent R 2 is not present or is located at least one of 2,3,4,5,6 positions, is unsubstituted, mono-substituted, double take It is generation or polysubstituted, the one kind in following groups of substituent R 2, two or more：Hydrogen, halogen, nitro, hydroxyl, carboxylic Base, trifluoromethyl, cyano, substituted or unsubstituted amino, phenyl, substituted or unsubstituted (C1-C6) alkyl, substitution do not take (C1-C6) alkoxy in generation ,-CONH2、-CONHR3、 -CON(R3)2、 -COOR3、 -COR3、 -NHCOR3、 -NHCOOR3 Group, wherein R3 are optionally from H, (C1-C6) alkyl, trifluoromethyl, phenyl；When R2 is double or three substitution, substituent group it is identical or It is different；
Cy1 be not present or optionally from：H, Ar1, Hetar1 or (C3-C7) naphthenic base
Above Ar1 indicates to have the monocyclic aromatic hydrocarbon system of 6-10 carbon atom or bicyclic aromatic hydrocarbon system and aromatic hydrocarbon to be saturated simultaneously Member ring systems, the system is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following：(C1-C6)- Alkyl, (C1-C6)-alkoxy, (C3-C7)-naphthenic base, carbonyl, carboxyl, amino ,-CONH2、-COOR4、-COR4、- NHCOR4、-NHCOOR4、-COH(CF3)2,-SONH2 ,-SOOR4 ,-SOR4 ,-NHSOR4 ,-NHSOOR4 groups substitution；Wherein R4 is optionally from H, (C1-C6) alkyl；
The above Hetar1 indicates saturation 4,5,6,7,8,9 or 10 circle heterocyclic rings with 1,2 or 3 N and/or O and/or S atom, should Heterocycle is unsubstituted or is replaced by one or more identical or different substituent groups selected from the following：(C1-C6)-alkyl, (C1- C6)-alkoxy, (C3-C7)-naphthenic base, carbonyl, carboxyl, amino ,-CONH2、-COOR4、-COR4、-NHCOR4、- NHCOOR4、-COH(CF3)2,-SONH2 ,-SOOR4 ,-SOR4 ,-NHSOR4 ,-NHSOOR4 groups substitution；Wherein R4 is optionally certainly H, (C1-C6) alkyl.
2. compound according to claim 1, which is characterized in that the substituent R 1 occurs being methyl every time.
3. compound according to claim 1 or claim 2, which is characterized in that the substituent R 2 is located in 2,3,4,5,6 extremely A few position, is unsubstituted, mono-substituted, disubstituted or polysubstituted, the substituent R 2 is in following groups One kind, two or more：Hydrogen, fluorine, chlorine, trifluoromethyl, cyano, methyl, phenyl, trifluoromethoxy, tertiary butyl, when R2 is double Or when three substitutions, substituent group is identical or different.
4. according to the compound of claims 1 to 3, which is characterized in that the X2 is selected from bromine or N.
5. according to any one of claims 1 to 4 compound, which is characterized in that the Cy1 is optionally certainly：1- acetyl group Piperazinyl, 1- (propiono)-piperazinyl, 1- cyclopropane carbonyls piperazinyl, 1- pivaloyl groups piperazinyl, 1- pivaloyls Base piperazinyl, 1- mesylpiperazinyls, 1- piperazines sulfoamido, 1- ethylsulfonyls piperazinyl, morpholinyl, piperazinyl, benzene first Sour carbomethoxy, benzoxy, naphthalene, tetralyl, 3,4- dihydros -1 (2H)-naphthalenone base, piperidyl, 4- piperidine methyl formates Base, 4- piperidinecarboxylic acids base, 4- acetamido piperidyls.
6. claim 1-5 any one of them 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives is pharmaceutically acceptable Salt, solvate, precursor compound or polymorph.
7. the pharmaceutically acceptable salt, solvate, precursor compound according to claims 1-6 or polymorph, It is characterized in that, the pharmaceutically acceptable salt is inorganic salts, organic salt or amino-acid salt；
Wherein inorganic salts are：Sodium salt, hydrochloride, sulfate, phosphate, diphosphate, hydrobromate or nitrate；
Wherein organic salt is：Acetate, maleate, fumarate, tartrate, succinate, lactate, p-methyl benzenesulfonic acid Salt, salicylate or oxalates；
Wherein amino-acid salt is：Arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycinate, Guang Propylhomoserin salt, cysteine salt, tyrosine salt, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, egg Propylhomoserin salt, tryptophan salt, glutamate, aspartate, valine salt, methionine salt, proline salt or hydroxyproline salt.
8. a kind of pharmaceutical composition, which is characterized in that it includes a）Any 1,2,3,4- tetrahydroquinolines sulphurs of claim 1-5 The pharmaceutically acceptable salt of 1,2,3,4- tetrahydroquinoline sulfonic acid amide derivatives described in amide derivatives, claim 6, The one or more and b of solvate, precursor compound and polymorph）Its pharmaceutically acceptable carrier.
9. any 1,2,3, the 4- tetrahydroquinoline sulfonic acid amide derivatives of claim 1-5,1,2 described in claim 6, Pharmaceutically acceptable salt, its solvate, pro-drug or the polymorph of 3,4- tetrahydroquinoline sulfonic acid amide derivatives, or Pharmaceutical composition according to any one of claims 8 is being prepared for treating in inflammation, autoimmune disease, diabetes, cancer at least A kind of purposes in the drug of disease.
10. purposes as described in claim 9, which is characterized in that the disease is：It is diabetes, encephalomyelitis, multiple hard Change disease, rheumatic arthritis, Collagen-induced Arthritis, psoriasis, inflammatory bowel disease, clone's disease, asthma, lung's disease At least one of disease, chronic obstructive pulmonary disease (COPD), asthma, colitis and ulcerative colitis.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109568321A (en) * 2019-01-14 2019-04-05 山东轩竹医药科技有限公司 ROR gamma modulators
CN112830893A (en) * 2019-10-28 2021-05-25 成都倍特药业股份有限公司 ROR gamma inhibitor, preparation method and medical application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012064744A2 (en) * 2010-11-08 2012-05-18 Lycera Corporation Tetrahydroquinoline and related bicyclic compounds for inhibition of rorϒ activity and the treatment of disease
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012064744A2 (en) * 2010-11-08 2012-05-18 Lycera Corporation Tetrahydroquinoline and related bicyclic compounds for inhibition of rorϒ activity and the treatment of disease
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

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109568321A (en) * 2019-01-14 2019-04-05 山东轩竹医药科技有限公司 ROR gamma modulators
CN112830893A (en) * 2019-10-28 2021-05-25 成都倍特药业股份有限公司 ROR gamma inhibitor, preparation method and medical application thereof

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