CN104926733B - Compound as ROR gamma modulators - Google Patents

Compound as ROR gamma modulators Download PDF

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CN104926733B
CN104926733B CN201510117243.8A CN201510117243A CN104926733B CN 104926733 B CN104926733 B CN 104926733B CN 201510117243 A CN201510117243 A CN 201510117243A CN 104926733 B CN104926733 B CN 104926733B
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CN104926733A (en
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薛海
赵涛
马涛
车美英
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Beijing Hanmi Pharmaceutical Co Ltd
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Abstract

The present invention relates to compound, its pharmaceutical composition and its purposes in pharmacy for can be used as retinoic acid related orphan receptor y (ROR γ) regulator.The compound has structural formula I:

Description

Compound as ROR gamma modulators
Technical field
The present invention relates to compound, its pharmaceutical compositions for can be used as retinoic acid related orphan receptor y (ROR γ) regulator Object and its purposes in pharmacy.
Background technique
Nuclear receptor is the transcription factor superfamily of a kind of ligand-dependent, widely distributed in vivo, in metabolism, hair It educates, biological rhythm, inflammation and immunoregulation etc. play a role.The ligand of nuclear receptor include thyroid hormone, steroids swash Element, retinoic acid, fatty acid, sterol etc., in addition there are one kind there is presently no determine ligand nuclear receptor, referred to as orphan's core by Body.Retinoic acid related orphan receptor (retinoid-related orphan receptors, RORs), also known as NF1R is this kind of Nuclear receptor due in gene order with retinoic acid receptors (retinoic acid receptor, RAR) and retinoic acid X receptor (retinoid X receptor, RXR) is similar and gains the name.RORs subfamily mainly includes ROR α, ROR β and ROR γ etc. three Member, it is more to ROR α and ROR γ and its ligand (regulator) research at present.ROR α extensive table in each histoorgan in vivo Reach, it can reside in brain, kidney, liver, testis, ovary, skeletal muscle, thymus gland, skin, lung, in adipose tissue, wherein in brain tissue Middle expression highest, especially cerebellum and thalamus.Recently it studies and also shows that ROR α makes bone promotive factor by stimulation, inhibit scorching Disease reaction is movable come the osteoblast for participating in human body.ROR γ mainly includes two kinds of hypotypes of ROR γ 1 and ROR γ t (ROR γ 2), Middle ROR γ 1 is distributed in skeletal muscle, thymus gland, testis, pancreas, prostate, heart and liver etc.；And ROR γ t is only expressed in and exempts from In epidemic disease cell, it is a kind of distinctive ROR γ hypotype of T cell.Th17 cell is that a kind of energy specificity generation confirmed recently is thin The Th cell subsets of intracellular cytokine IL-17, it participate in inducing autoimmune disease, have very strong rush inflammatory effect, and with it is a variety of from The occurrence and development of body immunological disease are related, such as arthritis, multiple sclerosis and asthma.ROR γ be Th17 cell differentiation and The crucial driven factor of one of regulation, therefore it is increasingly becoming the drug development of an emerging potential autoimmune disease Target spot.ROR inverse agonist (antagonist) adjusts the proliferation and growth of Th17 cell by the function of influence ROR γ, inhibits thin The generation of intracellular cytokine IL-17 is to block the occurrence and development of inflammation.In recent years, more paper studies show, in body It is outer inhibit cell factor IL-17 generate experiment in and mouse autoimmune disease model in (CIA model, EAE model etc.) all Confirm this important physiological function (Nature 2011,472,486-490 of ROR γ；Nature 2011,472,491- 496；ACS Chem.Biol.2012,7,672-677；Bioorg.Med.Chem.Lett.23(2013)532–536； Gastroenterology.2009；136(1):257–267；Journal Exp Med.2008；205(5):1063–1075； Immunol Res.2001；23(2–3):99–109；Cell 126,1121–1133,September 22,2006； WO2012158784；WO2012100732；US8389739B1；WO2013160418；WO2013092939；WO2013169704； WO2013178362；ACS Med.Chem.Lett.,2014,5(1),65–68).
In view of ROR γ important function played in the occurrence and development of various autoimmune disease, synthesize a series of new Compound have very important significance to adjust the function of ROR γ, this can lay the foundation for the treatment of autoimmune disease.
Summary of the invention
On the one hand, the present invention provides a kind of compound or its stereoisomer, tautomer or its can pharmaceutically connect There is structural formula I (to be hereinafter also sometimes referred to as Formulas I chemical combination for the salt received or its solvate or its prodrug, the compound Object):
Wherein:
X is selected from-C (O)-,-CH2C (O)-or-CH2CH2-；
L is selected from-C (O)-,-S (O)-,-S (O)2Or-CH2-；
A is selected from aryl or heteroaryl, and the aryl or heteroaryl are optionally independently taken by one or more groups below Generation: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, alkyl sulfonyl Base, sulfonamido, acylamino-, carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl；
B is divalent ring selected from the following: naphthenic base, heterocycle, aryl or heteroaryl, the naphthenic base, heterocycle or virtue Base or heteroaryl are optionally independently replaced by one or more groups below: halogen, amino, cyano, hydroxyl, carboxyl, nitro, Alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, Alkyl amino sulfonyl, dialkyl amino sulfonyl, carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl, acyl Amino or alkyl acyl；
M is 0,1,2,3 or 4；
N is 0,1 or 2；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；
RbSelected from alkyl, amino, alkyl amino or dialkyl amido；And
R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl acyl oxygroup, alkyl, alkoxy, halogenated Alkyl or halogenated alkoxy.
In one embodiment, the present invention provides a kind of compound or its stereoisomer, tautomer or its Pharmaceutically acceptable salt or its solvate or its prodrug, the compound have formula II (hereinafter sometimes also by Referred to as Formula II compound):
Wherein:
Q is N or-CR4；
X is selected from-C (O)-,-CH2C (O)-or-CH2CH2-；
L is selected from-C (O)-,-S (O)2Or-CH2-；
A is selected from C6-12Aryl or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl are optionally independently following One or more groups replace: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, Dialkyl amido, alkyl sulphonyl, sulfonamido, acylamino-, carbamoyl, alkyl-carbamoyl, dialkyl amido first Acyl group or alkyl acyl；
M is 0,1,2,3 or 4；
N is 0,1 or 2；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；
RbSelected from alkyl, amino, alkyl amino or dialkyl amido；
R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl acyl oxygroup, alkyl, alkoxy, halogenated Alkyl or halogenated alkoxy；
R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, amino Formoxyl, alkyl-carbamoyl or dialkyl carbamoyl；And
R4Selected from hydrogen, halogen or alkyl.
In a specific embodiment, the present invention provides a kind of compound or its stereoisomers, tautomer Or its pharmaceutically acceptable salt or its solvate or its prodrug, the compound have formula II a (hereinafter sometimes Also referred to as Formula II a compound):
Wherein:
Q is N or-CR4；
L is selected from-C (O)-,-S (O)2Or-CH2-；
A is selected from C6-12Aryl or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl are optionally independently following One or more groups replace: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, Dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；
M is 0,1,2,3 or 4；
N is 0,1 or 2；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；
RbSelected from alkyl, amino, alkyl amino or dialkyl amido；
R2When it is present independently selected from halogen, cyano, hydroxyl, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy；
R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, amino Formoxyl, alkyl-carbamoyl or dialkyl carbamoyl；And
R4Selected from hydrogen, halogen or alkyl.
In a specific embodiment, the present invention provides a kind of compound or its stereoisomers, tautomer Or its pharmaceutically acceptable salt or its solvate or its prodrug, the compound have formula II b (hereinafter sometimes Also referred to as Formula II b compound):
Wherein:
Q is N or-CR4；
L is selected from-C (O)-or-S (O)2-；
A is selected from C6-12Aryl or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl ring optionally independently by with Under one or more groups replace: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl ammonia Base, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；
M is 0,1,2,3 or 4；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；
RbSelected from alkyl, amino, alkyl amino or dialkyl amido；
R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl acyl oxygroup, alkyl, alkoxy, halogenated Alkyl or halogenated alkoxy；
R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, amino Formoxyl, alkyl-carbamoyl or dialkyl carbamoyl；And
R4Selected from hydrogen, halogen or alkyl.
In a specific embodiment, the present invention also provides a kind of compound or its stereoisomers, tautomerism There is formula II c (hereinafter to have for body or its pharmaceutically acceptable salt or its solvate or its prodrug, the compound When also referred to as Formula II c compound):
Wherein:
Q is N or-CR4；
L is selected from-C (O)-or-S (O)2-；
A is selected from C6-12Aryl or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl are optionally independently following One or more groups replace: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, Dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；
M is 0,1,2,3 or 4；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；
RbSelected from alkyl, amino, alkyl amino or dialkyl amido；
R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl acyl oxygroup, alkyl, alkoxy, halogenated Alkyl or halogenated alkoxy；
R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, amino Formoxyl, alkyl-carbamoyl or dialkyl carbamoyl；And
R4It is hydrogen, halogen or alkyl.
Another aspect of the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes one or more present invention Formulas I, Formula II, Formula II a, Formula II b, Formula II c compound or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or its prodrug and pharmaceutically acceptable excipient.
Another aspect of the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes one or more present invention Formulas I, Formula II, Formula II a, Formula II b, Formula II c compound or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or its prodrug；One or more anti-inflammatory agents selected from the following: non-steroid anti-inflammatory drug (NSAID), non-spy Anisotropic and COX-2 specificity cyclooxygenase-2 inhibitors, gold compound, corticoid, Tumor Necrosis Factor Receptors antagonist, water Poplar acid esters or salt, immunosuppressor and methotrexate；And pharmaceutically acceptable excipient.
Another aspect of the present invention relates to Formulas I of the invention, Formula II, Formula II a, Formula II b, Formula II c compound or its solids Isomers, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug are being prepared for adjusting ROR γ Purposes in active drug.
Another aspect of the present invention relates to Formulas I of the invention, Formula II, Formula II a, Formula II b, Formula II c compound or its solids Isomers, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug are in preparation for treating or pre- Purposes in the drug for the disease that anti-ROR γ is mediated.
Another aspect of the present invention relates to Formulas I of the invention, Formula II, Formula II a, Formula II b, Formula II c compound or its solids Isomers, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug are adjusted in preparation as ROR γ Purposes in the drug of agent.
Specific embodiment
Unless otherwise defined, the connotation that all scientific and technical terminologies have herein and claim theme fields technology The normally understood connotation of personnel is identical.
It should be understood that above-mentioned summary and being specified as exemplary and being only used for for example, without to present subject matter hereafter It imposes any restrictions.
All documents or literature department quoted in the application point include but is not limited to patent, patent application, article, books, Operation manual and paper are integrally incorporated herein by reference.
The certain chemical groups defined herein indicate carbon atom present in the group previously by symbol is simplified Sum.For example, C1-4Alkyl refers to the alkyl as defined below with 1 to 4 carbon atom in total；C6-12Aryl refers to tool There is the aryl as defined below of 6 to 12 carbon atoms in total.Simplify symbol in the total number of carbon atoms do not include there may be Carbon in the substituent group of the group.
In addition to aforementioned, when being used in the description of the present application and claims, unless otherwise specified, otherwise Following term has meaning as follows.
In this application ,-C (O)-indicates acyl group or carbonyl ,-S (O)2Indicate that sulfonyl ,-S (O)-indicate sulfinyl.
In this application, term " halogen " refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
In this application, a part as group or other groups, term " alkyl " mean only by carbon atom and hydrogen The group of atom composition, linear chain or branched chain without unsaturated bond and by the connection of the rest part of singly-bound and molecule.Alkyl can To have such as 1 to 18, preferably 1 to 8,1 to 6 more preferable, more preferable 1 to 4 carbon atom.The example of alkyl include but It is not limited to methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, n-pentyl, 2- amyl, hexyl, heptyl, 2- first Base hexyl, 3- methylhexyl, octyl, nonyl and decyl etc., preferably methyl, ethyl.
In this application, term " halogenated alkyl " refers to the alkyl replaced by one or more halogen atoms, wherein alkyl As hereinbefore defined.The example of halogenated alkyl includes but is not limited to trifluoromethyl, trichloromethyl, dichloromethyl, bromomethyl, iodine first Base, 1,2- Dichloroethyl etc., preferably trifluoromethyl.
In this application, term " alkoxy " refers to formula-ORaGroup, wherein RaFor alkyl as defined above.Alcoxyl The example of base includes but is not limited to methoxyl group, ethyoxyl, isopropoxy, n-butoxy, isobutoxy, tert-butoxy etc., preferably Methoxyl group.
In this application, term " halogenated alkoxy " refers to the alkoxy replaced by one or more halogen atoms, wherein Alkoxy is as hereinbefore defined.
In this application, refer to formula-NH when term " amino " is used as independent groups2Group.
In this application, term " alkyl amino " refers to formula-NHRaGroup, wherein RaFor alkyl as defined above.Alkane The example of base amino includes but is not limited to methylamino, ethylamino, isopropylamino etc..
In this application, term " dialkyl amido " refers to-NRaRbGroup, wherein RaAnd RbSeparately for as above Defined alkyl.The example of dialkyl amido includes but is not limited to dimethylamino, diethylamino, dipropylamino, first Base ethylamino etc., preferably dimethylamino.
In this application, term " alkyl sulphonyl " refers to-S (O)2RaGroup, wherein RaFor alkane as defined above Base.The example of alkyl sulphonyl includes but is not limited to mesyl, ethylsulfonyl, isopropelsulfonyl etc., preferably mesyl.
In this application, term " alkyl sulfonyl amino " refers to-N (Rb)S(O)2RaGroup, wherein RaSuch as to be determined above The alkyl of justice, RbFor hydrogen or alkyl as defined above.The example of alkyl sulfonyl amino includes but is not limited to mesyl ammonia Base, mesyl (methyl) amino, ethylsulfonyl (methyl) amino, ethylsulfonyl (ethyl) amino etc..
In this application, term " amino-sulfonyl " refers to formula-S (O)2NH2Group.
In this application, term " alkyl amino sulfonyl " refers to-S (O)2NHRaGroup, wherein RaIt is as hereinbefore defined Alkyl.The example of alkyl amino sulfonyl includes but is not limited to methylaminosulfonyl, ethylaminosulfonyl, isopropyl ammonia Base sulfonyl, tert-butylamino sulfonyl etc..
In this application, term " dialkyl amino sulfonyl " refers to-S (O)2NRaRbGroup, wherein RaAnd RbRespectively such as Alkyl defined above.The example of dialkyl amino sulfonyl includes but is not limited to dimethylamino-sulfonyl, diethyl amino Base sulfonyl, (methyl) (ethyl) amino-sulfonyl etc..
In this application, term " carbamoyl " refers to formula-C (O) NH2Group.
In this application, term " alkyl-carbamoyl " refers to formula-C (O) NHRaGroup, wherein RaSuch as to be determined above The alkyl of justice.The example of alkyl-carbamoyl includes but is not limited to methylcarbamoyl, ethylaminocarbonyl etc..
In this application, term " dialkyl carbamoyl " refers to formula-C (O) NRaRbGroup, wherein RaAnd RbRespectively Alkyl as defined above.The example of dialkyl carbamoyl includes but is not limited to formyl-dimethylamino, diethyl Carbamoyl, (methyl) (ethyl) carbamoyl etc., preferably formyl-dimethylamino.
In this application, term " acylamino- " refers to formula-NRaC(O)RbGroup, wherein RaFor hydrogen or as defined above Alkyl, RbFor hydrogen or alkyl as defined above.The example of acylamino- includes but is not limited to Formylamino, acetyl group ammonia Base, acetyl group (methyl) amino etc..
In this application, term " alkyl acyl " refers to-C (O) RaGroup, wherein RaFor hydrogen or alkane as defined above Base.The example of alkyl acyl includes but is not limited to formoxyl, acetyl group, propiono, iso-propionyl, tertiary bytyry etc..
In this application, term " alkyl acyl oxygroup " refers to-OC (O) RaGroup, wherein RaFor hydrogen or as hereinbefore defined Alkyl.The example of alkyl acyl oxygroup includes but is not limited to formoxyl oxygroup, acetyl group oxygroup, propiono oxygroup, isopropyl acyl Base oxygroup, tertiary bytyry oxygroup etc..
In this application, term " alkyloxycarbonyl " refers to-C (O) ORaGroup, wherein RaFor alkane as defined above Base.The example of alkyloxycarbonyl includes but is not limited to methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl group, isopropyl Base Epoxide carbonyl, t-butyloxycarbonyl etc., preferably methyloxycarbonyl, ethyloxycarbonyl.
In this application, term " naphthenic base " means the stable monovalence non-aromatic being only made of carbon atom and hydrogen atom Monocycle or multi-ring alkyl may include condensed ring system or bridged-ring system, have 3 to 15 carbon atoms, preferably have 3 to 10 Carbon atom more preferably has 3 to 8 carbon atoms, and it is saturation or unsaturation and can pass through via any suitable carbon atom The connection of the rest part of singly-bound and molecule.The example of naphthenic base include but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Suberyl, cyclooctyl, 1H- indenyl, indanyl, 1,2,3,4- tetrahydro-naphthalenyl, 5,6,7,8- tetrahydro-naphthalenyl, 8,9- Dihydro -7H- benzo ring heptene -6- base, 6,7,8,9- tetrahydro -5H- benzocyclohepta alkenyl, 5,6,7,8,9,10- hexahydro-benzo ring Octenyl, fluorenyl, two rings [2.2.1] heptyl ,-two ring of 7,7- dimethyl [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl, two rings [3.1.1] heptyl, two rings [3.2.1] octyl, two rings [2.2.2] octenyl, two rings [3.2.1] octene Base, adamantyl, octahydro -4,7- methylene -1H- indenyl and octahydro -2,5- methylene-pentalene base etc..
In this application, a part as group or other groups, term " heterocycle " mean by 2 to 12 carbon originals Stable 3 yuan that son and 1 to 6 hetero atom selected from nitrogen, oxygen and sulphur form are to 18 yuan of non-aromatic cyclic groups.Unless this It is in addition specialized in specification, otherwise heterocycle can be the ring system of monocycle, bicyclic, tricyclic or more, may include Condensed ring system or bridged-ring system.For purposes of the invention, heterocycle preferably includes 1 to 3 selected from nitrogen, oxygen and sulphur Heteroatomic stable 3 yuan, to octonary non-aromatic monocyclic or bicyclic radicals, are more preferably selected from nitrogen, oxygen and sulphur comprising 1 to 3 Heteroatomic stable 5 yuan to octonary non-aromatic monocyclic group, more preferably comprising 1 to 2 selected from the miscellaneous of nitrogen, oxygen and sulphur Stable 5 yuan of atom are to 6 yuan of non-aromatic monocyclic groups.Nitrogen, carbon or sulphur atom in heterocycle are optionally oxidized；Nitrogen Atom is optionally quaternized；And heterocycle can be partially or completely to be saturated.Heterocycle can be via carbon atom or miscellaneous original Son is simultaneously connect by singly-bound with molecule rest part.In the heterocycle comprising condensed ring, one or more rings can be aryl or Heteroaryl, it is non-aromatic annular atom that condition, which is with the tie point of molecule rest part,.The example of heterocycle includes but is not limited to: Pyranose, THP trtrahydropyranyl, thiapyran base, tetrahydrofuran base, morpholinyl, thio-morpholinyl, piperazinyl, piperidyl, oxazines base, two Oxygen cyclopenta, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidine Base, isoxazolidinyl, indolinyl, octahydro indyl, octahydro isoindolyl, pyrrolidinyl, pyrazolidinyl, phthalyl Imino group etc..
In this application, a part as group or other groups, term " aryl " mean (excellent with 6 to 18 It is selected as 6 to 10) system of carbon atom and at least one aromatic rings.For purposes of the invention, aryl can be monocycle, double The ring system of ring, tricyclic or more may include fused rings or bridged-ring system.Aryl passes through list via aromatic ring atom The connection of the rest part of key and molecule.The example of aryl includes but is not limited to phenyl, naphthalene, anthryl, phenanthryl, fluorenyl, 2- benzo Oxazoline ketone, 2H-1,4- benzoxazine -3 (4H) -one -7- base etc., preferably phenyl.
In this application, a part as group or other groups, term " heteroaryl " mean there is 1 to 15 in ring 5 yuan selected from nitrogen, the hetero atom of oxygen and sulphur and at least one aromatic rings of a (preferably 1 to 10) carbon atom and 1 to 4 To 16 ring system groups.Unless in addition specialize in this specification, otherwise heteroaryl can be monocycle, bicyclic, tricyclic or more Polycyclic ring system, may include condensed ring system or bridged-ring system, and condition is that tie point is aromatic ring atom.In heteroaryl Nitrogen, carbon or sulphur atom be optionally oxidized；Nitrogen-atoms is optionally quaternized.For purposes of the invention, heteroaryl Base preferably includes 1 to 3 heteroatomic stable 5 yuan to the 12 yuan aromatic monocyclics or bicyclic radicals for being selected from nitrogen, oxygen and sulphur, Heteroatomic stable 5 yuan to 10 yuan aromatic monocyclics or bicyclic radicals more preferably comprising 1 to 3 selected from nitrogen, oxygen and sulphur, Heteroatomic stable 5 yuan to 6 yuan aromatic monocyclics or bicyclic radicals more preferably comprising 1 to 2 selected from nitrogen, oxygen and sulphur. The example of heteroaryl include but is not limited to thienyl, furyl, pyrrole radicals, [1,3,4] oxadiazoles base, [1,2,4] thiadiazolyl group, [1,3,4] thiadiazolyl group, imidazole radicals, benzimidazolyl, pyrazolyl, benzopyrene oxazolyl, triazolyl, tetrazole radical, pyridyl group, pyrazine Base, triazine radical, pyrimidine radicals, pyridazinyl, indolizine base, indyl, isoindolyl, indazolyl, iso indazolyl, purine radicals, quinolyl, Isoquinolyl, phenodiazine naphthalene, naphthyridines base, quinoxaline base, pteridyl, carbazyl, carboline base, phenanthridinyl, phenanthroline, acridine Base, thiazolyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, isoxazolyl, oxadiazoles base, dislikes three at phenazinyl Oxazolyl, cinnoline base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, phenoxazine base, phenothiazinyl, 4,5,6,7- Tetrahydro benzo [b] thienyl, naphtho- pyridyl group etc., preferably pyrrole radicals, pyrazolyl, imidazole radicals, thienyl, furyl, triazolyl, Tetrazole radical, oxazolyl, isoxazolyl, pyrimidine radicals, pyridazinyl etc., more preferable pyridyl group.
" stereoisomer " refers to be made of same atoms, is bonded by identical key, but with different three-dimensional structures Compound.The present invention will cover various stereoisomers and its mixture.
" tautomer " refers to another atom from an atom transfer of molecule to identical molecule of proton and is formed Isomers.All tautomeric forms of the compound of the present invention also will within the scope of the present invention.
In this application, term " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically may be used The base addition salts of receiving.
" pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects , with inorganic acid or organic acid be formed by salt.The inorganic acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphorus Acid etc.；The organic acid include but is not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, caproic acid, capric acid, undecenoic acid, Glycolic, gluconic acid, lactic acid, oxalic acid, decanedioic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, winestone Acid, citric acid, palmitinic acid, stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzene Formic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, alginic acid, ascorbic acid, salicylic acid, 4-ASA, naphthalenedisulfonic acid etc..
" pharmaceutically acceptable base addition salts " refer to the biological effectiveness for being able to maintain free acid and without other side effects Salt.These salt are prepared and inorganic base or organic base are added to free acid.Salt derived from inorganic base include but It is not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..Preferably inorganic salts are Ammonium salt, sodium salt, sylvite, calcium salt and magnesium salts.Salt derived from organic base includes but is not limited to the salt of following alkali: primary amine, secondary amine and Tertiary amines, substituted amine, including natural substituted amine, cyclic amine and deacidite, for example (,) it is ammonia, different Propylamine, trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA), ethanol amine, diethanol amine, triethanolamine, dimethylethanolamine, 2- diformazan Ethylaminoethanol, 2-diethylaminoethanol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, choline, glycine betaine, second two Amine, gucosamine, methyl glucose osamine, theobromine, tromethamine, purine, piperazine, piperidines, N-ethylpiperidine, polyamino resin Deng.
According to the chemical valence of the number of electrically charged functional group and cation or anion, the compounds of this invention can contain more A cation or anion.
In general, crystallization effect can generate the solvate of the compounds of this invention.In this application, " solvate " refers to Aggregation comprising one or more the compounds of this invention molecules and one or more solvent molecules.They are anti-in a solvent It answers or Precipitation or is crystallized out from solvent.Solvent can be water, and solvate in this case is hydrate.Or Person, solvent are also possible to organic solvent.The solvate of the compounds of this invention also belongs within the scope of the invention.
In this application, term " prodrug " expression can be hydrolyzed under physiological conditions or be converted to via enzyme reaction The compound of bioactive compound of the invention.Therefore, term " prodrug " refers to can pharmaceutically connecing for the compound of the present invention The metabolic precursor thereof received.But when being given individual in need, prodrug can not have activity, but be converted to the present invention in vivo Reactive compound.Prodrug usually conversion rapidly in vivo, and parent compound of the invention is generated, such as by blood Hydrolysis is to realize.Prodrug compound provides the advantages of solubility, histocompatbility or sustained release usually in mammalian organism. Following documents may refer to for the commentary of prodrug: Kevin Beaumont, et al., Current Drug Metabolism, 4(6),461-485,2003；Peter Ettmayer,et al.,Journal of Medicinal Chemistry,47 (10),2393-2404,2004；Stella V.J.,Expert Opinion on Therapeutic Patents,14(3), 277-280,2004；Jarkko Rautio,et al.,Nature Review Drug Discovery,7(3),255-270, 2008。
It is well-known to those skilled in the art to be, the ester of carboxylic compound (such as the compounds of this invention), such as medicine Acceptable ester on, can be used as the prodrug of the compounds of this invention, is decomposed into human body or animal body as parent acid. Pharmaceutically acceptable ester includes but is not limited to Arrcostab, such as methyl esters, ethyl ester or propyl ester etc.；Alkoxy methyl ester, such as methoxy Ylmethyl ester；Alkanoyloxymethyl ester, such as acetoxy-methyl ester；Alkyl-substituted formamido Arrcostab, such as N, N- Dimethylformamide ylmethyl ester and N, N- diethylformamide ylmethyl ester etc. (for example, see patent document US5073641).
In this application, " pharmaceutical composition " refers to that the compounds of this invention is used to live biology with what this field usually received Property compound is delivered to the preparation of the medium of mammal (such as people).The medium includes pharmaceutically acceptable excipient.
In this application, " pharmaceutically acceptable excipient " includes but is not limited to any by relevant government administration section License is acceptable adjuvant, carrier, excipient, glidant, sweetener, diluent, the preservative, dye used for the mankind or domestic animal Material/colorant, corrigent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier Deng.
In this application, " treatment effective dose " refers to when giving the compounds of this invention to mammal (such as people), It is enough to effectively treat the amount of the compounds of this invention of the disease of the mammal (such as people).Constitute " treatment effective dose " The amount of the compounds of this invention depend on particular compound used, specific illness to be treated, the cause of illness, drug target Point, the severity of disease, administration mode and age, weight, the physical condition of mammal to be treated etc., but can be conventional Ground is determined by those skilled in the art according to the knowledge and present disclosure of its own.
Terms used herein " prevention " includes a possibility that making the generation or deterioration of sufferer reduction disease or illness.
The term as used herein " treatment " includes following meanings with other similar synonyms:
(i) prevent disease or illness to occur in mammals, especially when this kind of mammal be susceptible to the disease or Illness, but when being not yet diagnosed as having suffered from the disease or illness；
(ii) inhibit disease or illness, that is, contain its development；
(iii) alleviate disease or illness, that is, the state of the disease or illness is made to subside；Or
(iv) mitigate symptom caused by the disease or illness.
Term " disease " used herein may be used interchangeably from " illness " or may be different.
In this application, term " disease that ROR γ is mediated " refers to wherein ROR γ or the generation by ROR γ itself Or change activity level, or by causing a kind of cell factor such as (but not limited to) the release of IL-17 or IL-23 and act as Any disease or other harmful situations.The disease that ROR γ is mediated can be autoimmune disease and/or inflammatory disease Disease, the example include but is not limited to rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn disease, asthma, systematicness Lupus erythematosus, chronic obstructive pulmonary disease, tissue graft rejection reaction and the rejection of transplant organ, chorionitis, purpura, from Body immune hemolytic and thrombocytopenic symptom, irritable bowel syndrome, osteoarthritis, Kawasaki disease, Hashimoto thyroid gland Inflammation, mucous membrane leischmaniasia, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung are metabolized rejection, children Rheumatoid arthritis, ankylosing spondylitis, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis Inflammation, sjorgen syndrome, optic neuritis, diabetes, neuromyelitis optica, myasthenia gravis, uveitis, guillain-Barre Syndrome, psoriasis arthropathica, Ge Ruifushi disease or sclerotitis.
In this application, " ROR gamma modulators " refer to point for having interaction with target spot ROR γ and influencing ROR γ function Son, this interaction includes but is not limited to: antagonism, excitement, reverse excitement and other similar interactions.
In this application, " optional ", " optionally " or " optionally " indicates that the event then described or situation may occur It may not also occur, and the description includes the case where that the event or situation occur and do not occur simultaneously.For example, " optionally by one The alkyl that a or multiple halogens replace " indicates that alkyl is unsubstituted or is replaced by one or more halogens, and the description is wrapped simultaneously Include substituted alkyl and unsubstituted alkyl.
On the one hand, the present invention provides a kind of compound or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, wherein the compound has structural formula I:
Wherein:
X is selected from-C (O)-,-CH2C (O)-or-CH2CH2-；
L is selected from-C (O)-,-S (O)-,-S (O)2Or-CH2-；
A is selected from aryl or heteroaryl, and the aryl or heteroaryl are optionally independently taken by one or more groups below Generation: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, alkyl sulfonyl Base, sulfonamido, acylamino-, carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl；
B is divalent ring selected from the following: naphthenic base, heterocycle, aryl or heteroaryl, the naphthenic base, heterocycle or virtue Base or heteroaryl are optionally independently replaced by one or more groups below: halogen, amino, cyano, hydroxyl, carboxyl, nitro, Alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, Alkyl amino sulfonyl, dialkyl amino sulfonyl, carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl, acyl Amino or alkyl acyl；
M is 0,1,2,3 or 4；
N is 0,1 or 2；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；
RbSelected from alkyl, amino, alkyl amino or dialkyl amido；And
R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl acyl oxygroup, alkyl, alkoxy, halogenated Alkyl or halogenated alkoxy.
In some embodiments of compound of formula I of the invention, L is selected from-C (O)-.In other embodiments, L Selected from-S (O)-.In other embodiments, L is selected from-S (O)2-.In other preferred embodiment, L is selected from-CH2-。
In some embodiments of compound of formula I of the invention, A is selected from aryl or heteroaryl, preferably C6-12Aryl Or 5-12 unit's heteroaryl, the aryl or heteroaryl are optionally independently replaced by one or more groups below: halogen, ammonia Base, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, alkyl sulphonyl, sulphonyl ammonia Base, acylamino-, carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl.
In some embodiments of compound of formula I of the invention, A is selected from C6-12Aryl or 5-12 unit's heteroaryl, it is described C6-12Aryl or 5-12 unit's heteroaryl are optionally independently replaced by one or more groups below: halogen, amino, cyano, hydroxyl Base, carboxyl, C1-8Alkyl, C1-8Alkoxy, halogenated C1-8Alkyl, C1-8Alkyl amino, two C1-8Alkyl amino, C1-8Alkyl sulfonyl Base, sulfonamido, acylamino-, carbamoyl, C1-8Alkyl-carbamoyl, two C1-8Alkyl-carbamoyl or C1-8Alkyl Acyl group.
In some embodiments of compound of formula I of the invention, A is selected from C6-10Aryl or 5-10 unit's heteroaryl, it is described C6-10Aryl or 5-10 unit's heteroaryl are optionally independently replaced by one or more groups below: halogen, amino, cyano, hydroxyl Base, carboxyl, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl, C1-4Alkyl amino, two C1-4Alkyl amino, carbamoyl, C1-4Alkyl-carbamoyl or two C1-4Alkyl-carbamoyl.
In some embodiments of compound of formula I of the invention, A be selected from phenyl or 5-6 unit's heteroaryl, the phenyl or 5-6 unit's heteroaryl is optionally independently replaced by one or more groups below: halogen, cyano, C1-4Alkyl, C1-4Alkoxy or Halogenated C1-4Alkyl.
In some embodiments of compound of formula I of the invention, A be selected from phenyl, the phenyl optionally independently by with Under one or more groups replace: halogen, C1-4Alkyl or halogenated C1-4Alkyl.
In some embodiments of compound of formula I of the invention, B is divalent ring selected from the following: naphthenic base, heterocycle Base, aryl or heteroaryl, the naphthenic base, heterocycle or aryl or heteroaryl are optionally independently by one or more below Group replaces: halogen, amino, cyano, hydroxyl, carboxyl, nitro, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amino Base, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, amino first Acyl group, alkyl-carbamoyl, dialkyl carbamoyl, acylamino- or alkyl acyl.
In some preferred embodiments of compound of formula I of the invention, B is divalent ring selected from the following: C6-12Aryl Or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl are optionally independently taken by one or more groups below Generation: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, acylamino-, Carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl.
In some embodiments of compound of formula I of the invention, X is-C (O)-.In other embodiments, X be- CH2C(O)-.In other embodiments, X is-CH2CH2-。
In some embodiments of compound of formula I of the invention, m 0,1,2,3 or 4.In some embodiments, m It is 0, R at this time2It is not present.In other embodiments, 1 m.In yet other embodiments, 2 m.
In some embodiments of compound of formula I of the invention, n 0.In other embodiments, 1 n.Again In some embodiments, n 2.
In some embodiments of compound of formula I of the invention, R1Selected from-C (O) Ra, wherein RaSelected from hydroxyl, alcoxyl Base, amino, alkyl amino or dialkyl amido.In other embodiments, R1Selected from-C (O) Ra, wherein RaSelected from hydroxyl, C1-4Alkoxy, amino, C1-4Alkyl amino or two C1-4Alkyl amino.In other embodiments, R1Selected from-C (O) Ra, Middle RaFor hydroxyl, alkoxy or amino.In other embodiment, R1Selected from-C (O) Ra, wherein RaFor hydroxyl.
In some embodiments of compound of formula I of the invention, R1Selected from-S (O)2Rb, wherein RbSelected from alkyl, ammonia Base, alkyl amino or dialkyl amido.In other embodiments, R1Selected from-S (O)2Rb, wherein RbSelected from C1-4Alkyl, ammonia Base, C1-4Alkyl amino or two C1-4Alkyl amino.In other embodiment, R1Selected from-S (O)2Rb, wherein RbFor alkyl, Preferably C1-4Alkyl.
In some embodiments of compound of formula I of the invention, R2When it is present independently selected from halogen, cyano, nitre Base, hydroxyl, alkyl acyl oxygroup, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy.
In some embodiments of compound of formula I of the invention, R2When it is present independently selected from halogen, cyano, nitre Base, hydroxyl, C1-4Alkyl acyl oxygroup, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl or halogenated C1-4Alkoxy.
In some embodiments of compound of formula I of the invention, R2When it is present independently selected from halogen, cyano, C1-4 Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl or halogenated C1-4Alkoxy.
In some embodiments of compound of formula I of the invention, R2When it is present independently selected from halogen, C1-4Alkyl Or halogenated C1-4Alkyl.In some embodiments of compound of formula I of the invention, R2When it is present independently selected from halogen.
In compound of formula I of the invention, above-mentioned A, B, L, X, R1、R2, m and n can carry out group in any suitable way It closes, is such as, but not limited to combined into Formula II compound described below, Formula II a compound, Formula II b compound, Formula II c chemical combination Object, all these combinations are encompassed by the scope of the invention.
In some specific embodiments, the present invention provides a kind of compound or its stereoisomers, tautomer Or its pharmaceutically acceptable salt or its solvate or its prodrug, wherein there is the compound formula II (to have below When referred to as Formula II compound):
Wherein:
Q is selected from N or-CR4；
R3Selected from hydrogen, halogen, amino, cyano, hydroxyl, carboxyl, nitro, alkyl, alkoxy, halogenated alkyl, alkyl amino, Dialkyl amido, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amido sulphonyl Base, carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl, acylamino- or alkyl acyl；And
X、L、A、m、n、R1And R2As above defined in compound of formula I.
In some embodiments of Formula II compound of the invention, in Formula II, Q is selected from N or-CR4；X is selected from-C (O)-、-CH2C (O)-or-CH2CH2-；L is selected from-C (O)-,-S (O)2Or-CH2-；A is selected from C6-12Aryl or 5-12 member heteroaryl Base, the C6-12Aryl or 5-12 unit's heteroaryl are optionally independently replaced by one or more groups below: halogen, amino, Cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, alkyl sulphonyl, sulfonamido, Acylamino-, carbamoyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl；M is 0,1,2,3 or 4；N is 0,1 or 2；R1Selected from-C (O) RaOr-S (O)2Rb；RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；RbChoosing From alkyl, amino, alkyl amino or dialkyl amido；R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl Acyloxy, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy；R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alcoxyl Base, halogenated alkyl, alkyl amino, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl； And R4Selected from hydrogen, halogen or alkyl.
In some embodiments of Formula II compound of the invention, in Formula II, Q is selected from N or-CR4；A is selected from C6-10Virtue Base or 5-10 unit's heteroaryl, the C6-10Aryl or 5-10 unit's heteroaryl are optionally independently taken by one or more groups below Generation: halogen, amino, cyano, hydroxyl, carboxyl, C1-4Alkyl, alkoxy, halogenated alkyl, alkyl amino, dialkyl amido, amino Formoxyl, alkyl-carbamoyl or dialkyl carbamoyl；N is 0,1 or 2；M is 0,1 or 2；R1Selected from-C (O) RaOr-S (O)2Rb；RaSelected from hydroxyl, C1-4Alkoxy, amino, C1-4Alkyl amino or two C1-4Alkyl amino；RbSelected from C1-4Alkyl, ammonia Base, C1-4Alkyl amino or two C1-4Alkyl amino；R2When it is present independently selected from halogen, cyano, hydroxyl, alkyl, alkoxy, Halogenated alkyl or halogenated alkoxy；R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl amino, two Alkyl amino, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；And R4Selected from hydrogen, halogen or alkyl.
In some specific embodiments of Formula II compound, the present invention provides a kind of compound or its alloisomerisms Body, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug, wherein the compound has structure Formula II a (is sometimes referred to as Formula II a compound) below:
Wherein Q, L, A, R1、R2、R3, m and n be as defined in Formula II.
In the certain preferred embodiments of Formula II a compound, in Formula II a, Q is selected from N or-CR4；L is selected from-C (O)-、-S(O)2Or-CH2-；A is selected from C6-12Aryl or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl are optional Independently replaced by one or more groups below: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, alkyl halide Base, alkyl amino, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；M is 0,1,2,3 Or 4；N is 0,1 or 2；R1Selected from-C (O) RaOr-S (O)2Rb；RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amino Base；RbSelected from alkyl, amino, alkyl amino or dialkyl amido；R2When it is present independently selected from halogen, cyano, hydroxyl, alkane Base, alkoxy, halogenated alkyl or halogenated alkoxy；R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, halogenated alkyl, Alkyl amino, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；And R4Selected from hydrogen, halogen Element or alkyl.
In some embodiments of Formula II a compound, Q is selected from N or-CR4；L is selected from-C (O)-,-S (O)2Or-CH2-； A is selected from phenyl or 5-6 unit's heteroaryl, and the phenyl or 5-6 unit's heteroaryl are optionally independently by one or more groups below Replace: halogen, cyano, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl；M is selected from 0,1 or 2；N is selected from 0 or 1；R1Selected from-C (O)RaOr-S (O)2Rb；RaSelected from hydroxyl, C1-4Alkoxy, amino, C1-4Alkyl amino or two C1-4Alkyl amino；RbSelected from C1-4 Alkyl, amino, C1-4Alkyl amino or two C1-4Alkyl amino；R2When it is present independently selected from halogen, cyano, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；R3Selected from hydrogen, halogen, cyano, C1-4Alkyl, C1-4Alkoxy, halogen For C1-4Alkyl, carbamoyl, C1-4Alkyl-carbamoyl or two C1-4Alkyl-carbamoyl；And R4Selected from hydrogen, halogen or C1-4Alkyl.
In some embodiments of Formula II a compound, Q is selected from N or-CR4；L is selected from-C (O)-,-S (O)2Or-CH2-； A is selected from phenyl or 5-6 unit's heteroaryl, and the phenyl or 5-6 unit's heteroaryl are optionally independently by one or more groups below Replace: halogen, cyano, C1-4Alkyl or halogenated C1-4Alkyl；M is 0 or 1；N is 0 or 1；R1Selected from-C (O) RaOr-S (O)2Rb；Ra Selected from hydroxyl, C1-4Alkoxy or amino；RbSelected from alkyl；R2When it is present independently selected from halogen, C1-4Alkyl or halogenated C1-4 Alkyl；R3Selected from hydrogen, halogen, C1-4Alkyl, C1-4Alkoxy or two C1-4Alkyl-carbamoyl；And R4Selected from hydrogen, halogen or C1-4 Alkyl.
In the other embodiment of Formula II a compound, Q is selected from N or-CR4；L is selected from-C (O)-or-CH2-；A is selected from Phenyl, the phenyl are optionally independently replaced by one or more groups below: halogen, C1-4Alkyl or halogenated C1-4Alkyl；m It is 0 or 1；N is 0；R1Selected from carboxyl；R2When it is present independently selected from halogen, C1-4Alkyl or halogenated C1-4Alkyl；R3Selected from hydrogen； And R4Selected from hydrogen, halogen or C1-4Alkyl.
In some specific embodiments of Formula II compound, the present invention provides a kind of compound or its alloisomerisms Body, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug, wherein the compound has structure Formula II b (is sometimes referred to as Formula II b compound) below:
Wherein Q, L, A, R1、R2、R3With m as defined in Formula II.
In some specific embodiments of Formula II b compound, in Formula II b, Q is selected from N or-CR4；L is selected from-C (O)- Or-S (O)2-；A is selected from C6-12Aryl or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl ring optionally independently by One or more group below replaces: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl ammonia Base, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；M is 0,1,2,3 or 4；R1Choosing From-C (O) RaOr-S (O)2Rb；RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；RbSelected from alkyl, ammonia Base, alkyl amino or dialkyl amido；R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl acyl oxygroup, Alkyl, alkoxy, halogenated alkyl or halogenated alkoxy；R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, alkyl halide Base, alkyl amino, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；And R4It is selected from Hydrogen, halogen or alkyl.
In some specific embodiments of Formula II b compound, in Formula II b, Q is selected from N or-CR4；L is selected from-C (O)- Or-S (O)2-；A is selected from phenyl or 5-6 unit's heteroaryl, and the phenyl or 5-6 unit's heteroaryl ring are optionally independently by below one A or multiple groups replace: halogen, C1-4Alkyl, halogenated C1-4Alkyl or cyano；M is 0 or 1；R1Selected from-C (O) RaOr-S (O)2Rb；RaSelected from hydroxyl, C1-4Alkoxy or amino；RbSelected from C1-4Alkyl；R2When it is present independently selected from halogen or C1-4Alkyl； R3Selected from hydrogen, halogen, C1-4Alkyl, C1-4Alkoxy, carbamoyl, C1-4Alkyl-carbamoyl or two C1-4Alkyl amino first Acyl group；And R4Selected from hydrogen, halogen or C1-4Alkyl.
In some specific embodiments of Formula II compound, the present invention provides a kind of compound or its alloisomerisms Body, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug, wherein the compound has structure Formula II c (is sometimes referred to as Formula II c compound) below:
Wherein Q, L, A, R1、R2、R3With m as defined in Formula II.
In some specific embodiments of Formula II c compound, in Formula II c, Q is selected from N or-CR4；L is selected from-C (O)- Or-S (O)2-；A is selected from C6-12Aryl or 5-12 unit's heteroaryl, the C6-12Aryl or 5-12 unit's heteroaryl optionally independently by with Under one or more groups replace: halogen, amino, cyano, hydroxyl, carboxyl, alkyl, alkoxy, halogenated alkyl, alkyl ammonia Base, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；M is 0,1,2,3 or 4；R1Choosing From-C (O) RaOr-S (O)2Rb；RaSelected from hydroxyl, alkoxy, amino, alkyl amino or dialkyl amido；RbSelected from alkyl, ammonia Base, alkyl amino or dialkyl amido；R2When it is present independently selected from halogen, cyano, nitro, hydroxyl, alkyl acyl oxygroup, Alkyl, alkoxy, halogenated alkyl or halogenated alkoxy；R3Selected from hydrogen, halogen, cyano, carboxyl, alkyl, alkoxy, alkyl halide Base, alkyl amino, dialkyl amido, carbamoyl, alkyl-carbamoyl or dialkyl carbamoyl；And R4Be hydrogen, Halogen or alkyl.
In some specific embodiments of Formula II c compound, in Formula II c, Q is selected from N or-CR4；L is selected from-C (O)- Or-S (O)2-；A is selected from phenyl or 5-6 unit's heteroaryl, and the phenyl or 5-6 unit's heteroaryl ring are optionally independently by below one A or multiple groups replace: halogen, C1-4Alkyl, halogenated C1-4Alkyl or cyano；M is 0 or 1；R1Selected from-C (O) RaOr-S (O)2Rb；RaSelected from hydroxyl, C1-4Alkoxy or amino；RbSelected from C1-4Alkyl；R2When it is present independently selected from halogen or C1-4Alkyl； R3Selected from hydrogen, halogen, C1-4Alkyl, C1-4Alkoxy, carbamoyl, C1-4Alkyl-carbamoyl or two C1-4Alkyl amino first Acyl group；And R4Selected from hydrogen, halogen or C1-4Alkyl.
In some embodiments, the compound of the present invention is selected from:
Formulas I, Formula II, Formula II a, Formula II b and Formula II c compound of the invention or its pharmaceutically acceptable salt may contain one A or multiple asymmetric carbon atoms, each asymmetric carbon atom can be R or S configuration, and two kinds of configurations are all within the scope of the present invention. Therefore, compound can be used as enantiomter, diastereoisomer or their mixture and exist.Above compound can be selected Racemic modification, diastereoisomer or enantiomter are selected as raw material or intermediate.Optically active isomers can be used Prepared by chiral synthon or chiral reagent, perhaps split using routine techniques and for example tied by chiral chromatography or segmentation Crystallization.
The routine techniques of preparation/separation individual isomeric includes being synthesized by the chirality of suitable optical voidness precursor, or make Racemic modification (or racemic modification of salt or derivative) is parsed with such as chiral hplc, see, for example, Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols, Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations, Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH Ed.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128.
Another aspect of the present invention relates to pharmaceutical compositions, and it includes one or more Formulas I of the invention, Formula II, formula IIa, Formula II b and Formula II c compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvation Object or its prodrug and pharmaceutically acceptable excipient.
Pharmaceutical composition of the invention can be configured to solid-state, semisolid, liquid or gaseous state preparation, as tablet, capsule, Pulvis, granule, paste, solution, suppository, injection, inhalant, gelling agent, microballoon and aerosol.
Pharmaceutical composition of the invention can be prepared by method well known in pharmaceutical field.Such as, it is intended to drug administration by injection Pharmaceutical composition can be by by the distilled water of the compound of the present invention or its pharmaceutically acceptable salt or prodrug and sterilizing Combination is to prepare, to form solution.Surfactant can be added to promote to be formed homogeneous solution or suspension.Prepare drug The practical methods of composition are that known to the skilled artisan see, for example, The Science and Practice of Pharmacy (Pharmaceutical Sciences and practice), 20th Edition(Philadelphia College of Pharmacy and Science,2000)。
The administration route of pharmaceutical composition of the invention includes but is not limited to oral, part, percutaneous, muscle, vein, suction Enter, parenteral, sublingual, rectum, vagina and intranasal.For example, be suitble to oral administration dosage form include capsule, tablet, granule with And syrup etc..Formulas I of the invention, Formula II, Formula II a, Formula II b or the Formula II c compound for including in these preparations can be solid Powder or particle；Solution or suspension in aqueous or non-aqueous liquid；Water-In-Oil or oil-in-water emulsion etc..Above-mentioned dosage form can It is made with one or more carriers or auxiliary material via general practice of pharmacy of reactive compound.Above-mentioned carrier is needed and is lived Property compound or other auxiliary materials it is compatible.For solid pharmaceutical preparation, common non-toxic carrier includes but is not limited to mannitol, lactose, shallow lake Powder, magnesium stearate, cellulose, glucose, sucrose etc..Carrier for liquid preparation includes but is not limited to water, physiological saline, Portugal Grape sugar aqueous solution, ethylene glycol and polyethylene glycol etc..Reactive compound can form solution or suspension with above-mentioned carrier.Specifically Administration mode and dosage form are depending on the physicochemical property of compound itself and applied the severity of disease etc..Art technology Knowledge that personnel can have according to above-mentioned factor and in conjunction with its own determines specific administration route.It see, for example: Lee Person of outstanding talent, " clinical pharmacology ", People's Health Publisher, 2008.06；Ding Yufeng, by Clinical Dosage Form Factors and the rational use of medicines, medicine is led Report, 26 (5), 2007；Howard C.Ansel, Loyd V.Allen, Jr., Nicholas G.Popovich write, Jiang Zhiqiang master It translates, " pharmaceutical dosage form and drug delivery system ", China Medical Science Press, 2003.05.
The compound of the present invention or pharmaceutical composition of the invention can also combine with one or more anti-inflammatory agents or group It closes and uses.The anti-inflammatory agent includes but is not limited to: NSAID, non-specificity and COX-2 specificity cyclooxygenase-2 inhibitors, aurification Close object, corticoid, Tumor Necrosis Factor Receptors antagonist, salicylate or salt, immunosuppressor and methotrexate.
Another aspect of the present invention relates to Formulas I of the invention, Formula II, Formula II a, Formula II b or Formula II c compound or its solids Isomers, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug are being prepared for adjusting ROR Purposes in the drug of gamma activity.
Another aspect of the present invention relates to Formulas I of the invention, Formula II, Formula II a, Formula II b or Formula II c compound or its solids Isomers, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug preparation for preventing or Treat the purposes in the drug of the disease of ROR γ mediation.
Another aspect of the present invention relates to Formulas I of the invention, Formula II, Formula II a, Formula II b or Formula II c compound or its solids Isomers, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug are being prepared as ROR γ tune Save the purposes in the drug of agent.
The compound of this paper is the regulator of retinoic acid related orphan receptor ROR, the especially regulator of ROR γ.These Regulator can be used for treating the disease of mammal (especially people) mediated by ROR γ.In some embodiments, ROR The disease that γ is mediated can be one or more autoimmunities and/or inflammatory disease, and the disease includes but is not limited to rheumatoid Property arthritis, multiple sclerosis, psoriasis, Crohn disease, asthma, systemic loupus erythematosus, chronic obstructive pulmonary disease, tissue The rejection of graft rejection and transplant organ, chorionitis, purpura, autoimmune haemolytic and thrombocytopenic disease Shape, irritable bowel syndrome, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, mucous membrane leischmaniasia, bronchitis, allergy Property rhinitis, atopic dermatitis, cystic fibrosis, lung be metabolized rejection, children's rheumatoid arthritis, ankylosing spondylitis, pancreas Adenositis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, sjorgen syndrome, optic neuritis, sugar Urinate disease, neuromyelitis optica, myasthenia gravis, uveitis, Guillain-Barre syndrome, psoriasis arthropathica, Ge Ruifushi Disease or sclerotitis.
Pharmaceutical composition of the invention is prepared in a manner of meeting medical practice specification, quantitative and administration.Chemical combination of the present invention " treatment effective dose " of object by particular compound used, specific illness to be treated, the cause of illness, drug target spot, The factors such as the severity of disease, the age of administration mode and mammal to be treated, weight, physical condition determine.It is logical Often, the dosage through parenteral administration can be 1-200mg/kg, and the dosage of oral administration can be 1-1000mg/kg.
The range of effective dose presented herein is not meant to limit the scope of the present disclosure, but represents preferred agent Measure range.But most preferred dosage can be adjusted for specific individual, this is that those skilled in the art understand and can (such as being write refering to Berkow et al., Merck handbook, the 16th edition, Merck company, Rahway, N.J., 1992) determined.
The preparation of the compounds of this invention
Following reaction scheme illustratively illustrates the preparation method of compound of formula I of the invention.
It will be appreciated by those skilled in the art that in the following description, only when the combination of substituent group is available stable When compound, the combination of this kind of substituent group is just allowed.
It should also be appreciated by one skilled in the art that midbody compound functional group may need in method discussed below It to be protected by protecting group appropriate.Such functional group includes hydroxyl, amino, amidino groups, guanidine radicals, sulfydryl and carboxylic group.Properly Hydroxyl protection base include trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, T-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl etc..Suitable amino, amidino groups and guanidine radicals Protecting group include tertbutyloxycarbonyl, benzyloxycarbonyl group etc..Suitable sulfhydryl protected base includes-C (O)-R " (wherein R " be alkyl, Aryl or aralkyl), to methoxy-benzyl, trityl etc..Suitable carboxyl-protecting group includes alkyl, aryl or aralkyl ester Class.
Protecting group can be introduced and be removed according to standard technique well known by persons skilled in the art and as described herein.
The use of protecting group is specified in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organic Synthesis (protecting group in organic synthesis), (1999), 4thEd., in Wiley.Protecting group can be also polymerization Resin.
The compound of the present invention can be prepared according to method shown in following reaction route:
Scheme 1:
Wherein, X is-C (O)-；A,B,R1、R2, L, m and n be as defined in structural formula I.
According to scheme 1, it is with adjacent nitro fluoro aromatic ring or adjacent nitro fluorine that wherein X, which is the synthesis of the compound of formula I of-C (O)-, It is starting material for hetero-aromatic ring B, step 1 carries out substitution reaction for ring B and substituted aniline phase under the conditions of alkaline (such as NaH) Even, nitro is restored (such as zinc powder/ammonium chloride) by step 2, and then step 3 utilizes triphosgene under alkali (such as triethylamine) catalysis Simultaneously ring intermediate is prepared, final step 4 is under the conditions of alkaline (such as NaH) with various substituted or non-substituted carboxylic acid halides, benzyl Base halogen, sulfonic acid halide or sulfenyl halogen react to obtain target compound of formula I.
Scheme 2:
Wherein, X is-CH2C (O)-or-CH2CH2-；Z is-CH2Or-C (O)-；A,B,R1、R2, L, m and n such as structural formula I Defined in.
According to scheme 2, wherein X is-CH2C (O)-or-CH2CH2The synthesis of compound of formula I be equally with adjacent nitro fluorine It is starting material for aromatic ring or adjacent nitro fluoro hetero-aromatic ring B, step 1 carries out substitution reaction under the conditions of alkaline (such as NaH) will Ring B is connected with substituted aniline, obtained anil in step 2 under the conditions of alkaline (such as NaH) with 1,2- dibromo second Alkane is reacted with bromoacetyl chloride, then in step 3 by nitro reduction (such as stannous chloride/hydrochloric acid, reflux) at amino, while one Pot occurs ring closure reaction and obtains simultaneously ring intermediate, and final step 4 is under the conditions of alkaline (preferably NaH) with various substituted or non-substituted Carboxylic acid halides, benzyl halide, sulfonic acid halide or sulfenyl halogen react to obtain target compound.
Above-mentioned general synthetic route only represents the conventional method of most of embodiments, to the chemical combination for having special substituent Object can carry out variation known to those of ordinary skill in the art in certain step reaction.Such as the chemical combination with ester group Object, the step of ester hydrolysis can be added in the reaction.
Embodiment
The following examples illustrate the preparation and biological evaluation of compound within the scope of the present invention.
These following embodiments are provided to enable those skilled in the art to be more clearly understood that and can practice The present invention.They are not construed as limiting the scope of the invention, and be merely illustrative and it is representative.
Starting material used in testing in the present invention or purchase are from reagent suppliers or via method well known in the art It is prepared by known raw material.Unless otherwise indicated, the embodiments herein applies following conditions:
The unit of temperature is degree Celsius (DEG C)；The definition of room temperature is 18-25 DEG C；
Organic solvent is dry using anhydrous magnesium sulfate or anhydrous sodium sulfate；Using Rotary Evaporators in the case where depressurizing Elevated Temperature Conditions Be spin-dried for (such as: 15mmHg, 30 DEG C)；
Use 200-300 mesh silica gel as carrier when column chromatography for separation, TLC indicates thin-layered chromatography；
Under normal conditions, the progress of reaction is monitored by TLC or LC-MS；
The identification of final products is by nuclear magnetic resonance (Bruker AVANCE 300,300MHz) and LC-MS (Bruker Esquine 6000, Agilent 1200series) it completes.
Embodiment 1:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- of 3- (2,6- dichloro-benzoyl base) -7- Base) benzoic acid
Preparing 1 compound of embodiment, specific step is as follows:
(1) preparation of 4- (the fluoro- 6- nitro-phenylamino of 2-) methyl benzoate (1-1):
4-aminobenzoic acid methyl esters (302mg, 2mmol) is dissolved in tetrahydrofuran (THF) (20mL) and dimethyl formyl It in amine (DMF) (4mL), at room temperature, is slowly added to sodium hydride (NaH) (60%, 120mg, 3mmol), stirs 10min, then again The fluoro- 3- nitrobenzene (318mg, 2mmol) of 1,2- bis- is added to stir 5 hours, water (10mL) is added to be quenched, is extracted with ethyl acetate (50mL) It takes, organic phase is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure, by concentrate through silica gel column chromatography (eluant, eluent: n-hexane: acetic acid second Ester=50:1) it isolates and purifies, 4- (the fluoro- 6- nitro-phenylamino of 2-) methyl benzoate 1-1 (300mg) is obtained, is yellow solid. Yield 52%.MS+H+=291.
(2) preparation of 4- (2- amino -6- fluoro-phenyl amino) methyl benzoate (1-2):
4- (the fluoro- 6- nitro-phenylamino of 2-) methyl benzoate (290mg, 1mmol) is dissolved in tetrahydrofuran (20mL) In water (2mL), zinc powder (390mg, 6mmol) and ammonium chloride (321mg, 6mmol) are added at room temperature, stirs 2 hours.Stop anti- It answers, reaction mixture filtering；Aqueous phase separation in filtrate is gone out, organic phase is dried over anhydrous sodium sulfate, and filtering is concentrated under reduced pressure It is colorless oil, obtained product is without further to 4- (2- amino -6- fluoroanilino) methyl benzoate 1-2 (260mg) Purifying can be used to react in next step.MS+H+=261.1.
(3) preparation of 4- (the fluoro- 1,2- dihydro -2- ketone of 4--benzo [d] imidazo-3-yl) methyl benzoate (1-3)
4- (2- amino -6- fluoro-phenyl amino) methyl benzoate (260mg, 1mmol) is dissolved in methylene chloride (DCM) In (20mL), it is added triethylamine (606mg, 6mmol).- 78 DEG C are cooled to, is added triphosgene (297mg, 1mmol), is slowly heated up To room temperature.Water (10mL) is added to be quenched, ethyl acetate extracts (20mL × 3), and organic phase is dried over anhydrous sodium sulfate, and filtering subtracts Pressure concentration, concentrate is isolated and purified through silica gel column chromatography (n-hexane: ethyl acetate=1:1), obtains 4- (fluoro- 1, the 2- bis- of 4- Hydrogen -2- ketone-benzo [d] imidazo-3-yl) methyl benzoate 1-3 (250mg) is pale solid.MS+H+=287.2.
(4) preparation of 4- (the fluoro- 1,2- dihydro -2- ketone of 4--benzo [d] imidazo-3-yl) benzoic acid (1-4)
LiOH (188mg, 7.86mmol) is dissolved in 10mL water, 4- (fluoro- 1, the 2- dihydro -2- ketone-benzo of 4- is added [d] imidazo-3-yl) methyl benzoate (250mg, 0.87mmol) is dissolved in the solution in 20mL methanol.It is stirred at room temperature 3 hours. It removes methanol under reduced pressure, 20mL water is added, water phase washes (20mL × 3) three times with ethyl acetate, hydrochloric acid is added to be acidified to pH=5, is precipitated Solid filters, dry, obtains 4- (fluoro- 1, the 2- dihydro -2- ketone of 4--benzo [d] imidazo-3-yl) benzoic acid 1-4 (230mg), is White solid, yield 97%.MS+H+=273.2.
(5) 4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base of 3- (2,6- dichloro-benzoyl base) -7-) benzene The preparation of formic acid (compound 1)
4- (fluoro- 1, the 2- dihydro -2- ketone of 4--benzo [d] imidazo-3-yl) benzoic acid (27mg, 0.1mmol) is dissolved in In DMF (2mL), sodium hydride (60%, 12mg, 0.3mmol) is added at room temperature, stirs 5min, 2,6- dichloro-benzenes first is then added Acyl chlorides (31mg, 0.15mmol) stirs 10min, is quenched with water (5mL), and hydrochloric acid is added to be acidified to pH=5, ethyl acetate extraction (10mL × 3), after organic phase is dried over anhydrous sodium sulfate, filtering, filtrate concentration, concentrate is through silica gel column chromatography (eluant, eluent: just Hexane: ethyl acetate=1:1) it isolates and purifies to obtain 10mg target compound, it is white solid, yield 22%.Data characterization is such as Under: MS+Na+=467.4；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.29 (d, J=8.1Hz, 1H), 8.20 (d, J= 8.7Hz,2H),7.56(dd,J1=8.7Hz, J2=2.7Hz, 1H), 7.40~7.25 (m, 4H), 7.13-7.06 (m, 2H).
Embodiment 2:4- (3- (2,6- dichloro-benzoyl base) -7- methyl -2- ketone -2,3- dihydro -1H- benzo [d] imidazoles - 1- yl) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists The fluoro- 3- nitrobenzene of 1,2- bis- is replaced by raw material using 1- methyl -2- fluoro- 3- nitrobenzene in step 1.Relevant characterization data are such as Under: MS+H+=441.7；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.36 (d, J=8.1Hz, 1H), 8.22 (d, J=8.4Hz, 2H),7.51(d,J1=8.4Hz, 1H), 7.37~7.19 (m, 4H), 7.06 (d, J=8.1Hz, 1H), 1.87 (s, 3H).
Embodiment 3:4- (3- (4- fluorophenylsulphonyl) -7- methyl -2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base) Benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 2, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 4- fluorophenylsulfonyl chloride in step 5.Relevant characterization data are as follows: MS+H+= 427.5；1H-NMR(CD3OD, 300MHz) δ: ppm 8.22~8.18 (m, 2H), 8.11 (d, J=8.4Hz, 2H), 7.90 (d, J =8.1Hz, 1H), 7.41~7.36 (m, 4H), 7.18~7.13 (m, 1H), 7.01 (m, 1H), 1.78 (s, 3H).
Embodiment 4:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- of 3- (2,4 difluorobenzene formoxyl) -7- Base) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 2,4 difluorobenzene formyl chloride in step 5.Relevant characterization data are as follows: MS+H+=413.9；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.21 (d, J=8.7Hz, 2H), 8.03 (d, J=8.1Hz, 1H), 7.71~7.63 (m, 1H), 7.56 (dd, J1=8.7Hz, J2=2.7Hz, 2H), 7.05~6.21 (m, 1H), 7.09~6.84 (m,3H)。
Embodiment 5:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- of 3- (the chloro- 6- fluoro benzoyl of 2-) -7- Base) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 2- chloro- 6- fluorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+ Na+=451.5；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.20 (d, J=8.1Hz, 1H), 8.14 (d, J=8.7Hz, 2H), 7.51(dd,J1=8.7Hz, J2=2.7Hz, 1H), 7.24~7.17 (m, 4H), 7.05-6.99 (m, 2H).
Embodiment 6:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base of 3- (4- fluoro benzoyl) -7-) benzene Formic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 4- fluorobenzoyl chloride in step 5.Relevant characterization data are as follows:
1H-NMR(DMSO-d6, 300MHz) and δ: ppm 8.08 (d, J=8.7Hz, 2H), 8.03~7.99 (m, 2H), 7.76 (d, J=7.2Hz, 1H), 7.68 (dd, J1=8.7Hz, J2=2.1Hz, 2H), 7.38~7.18 (m, 4H).
Embodiment 7:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles-of 3- (4- trifluoromethylbenzoyl) -7- 1- yl) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 4- trifluoromethyl benzoyl chloride in step 5.Relevant characterization data are as follows: MS +Na+=467.2；1H-NMR(DMSO-d6, 300MHz) and δ: ppm 13.2 (brs, 1H), 8.08~8.05 (m, 4H), 7.90~ 7.86(m,3H),7.67(dd,J1=8.7Hz, J2=2.1Hz, 2H), 7.32~7.19 (m, 2H).
Embodiment 8:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base of 3- benzyl -7-) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using benzyl bromide in step 5.Relevant characterization data are as follows: MS+H+=363.2；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.24 (d, J=8.7Hz, 2H), 7.65 (dd, J1=8.7Hz, J2=2.7Hz, 2H), 7.41~7.30 (m, 5H), 7.07~7.00 (m, 1H), 6.86 (d, J=8.4Hz, 1H), 6.79 (d, J=8.1Hz, 1H), 5.14(s,2H)。
Embodiment 9:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base of 3- (2,6- dichloro benzyl) -7-) benzene Formic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 2,6- benzyl dichloride bromide in step 5.Relevant characterization data are as follows: MS+H+ =433.3；1H-NMR(CDCl3, 300MHz) δ: ppm 8.22 (d, J=6.9Hz, 2H), 7.64~7.59 (m, 2H), 7.38 (d, J=7.5Hz, 2H), 7.27~7.24 (m, 1H), 7.00~6.93 (m, 1H), 6.84~6.78 (m, 1H), 6.67 (d, J= 7.8Hz,1H),5.45(s,2H)。
Embodiment 10:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- of 3- (4- cyanobenzoyl) -7- Base) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 4- cyano-benzoyl chloride in step 5.Relevant characterization data are as follows: MS+Na+ =425.1；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.24 (d, J=8.7Hz, 2H), 7.98 (d, J=8.1Hz, 1H), 7.78 ~7.69 (dd, J1=8.4Hz, J2=24.3Hz, 4H), 7.59 (dd, J1=2.7Hz, J2=8.7Hz, 2H), 7.13 (m, 1H).
Embodiment 11:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- of 3- (2,6- dichloro-benzoyl base) -7- Base) methyl benzoate
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists In omitting lithium hydrate, (i.e. step 4) directly carries out the next step.Relevant characterization data are as follows: MS+Na+=481.7；1H- NMR(CDCl3, 300MHz) and δ: ppm 8.28 (d, J=8.1Hz, 1H), 8.13 (d, J=8.4Hz, 2H), 8.02 (s, 1H), 7.53~7.50 (m, 2H), 7.39~7.23 (m, 3H), 7.11~7.04 (m, 1H), 3.93 (s, 3H).
Embodiment 12:4- (3- (2,6- dichloro-benzoyl base) -5- formyl-dimethylamino -2- ketone -2,3- dihydro -1H- Benzo [d] imidazoles -1- base) ethyl benzoate
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists The fluoro- 3- nitrobenzene of 1,2- bis- is replaced using the fluoro- 3- nitrobenzoic acid of 4- in step 1 and uses 4-aminobenzoic acid ethyl ester generation For 4-aminobenzoic acid methyl esters, and the reaction that carboxyl is converted to formyl-dimethylamino is added between step 1 and step 2 Product 4- (4 '-carbethoxy phenyl amino) -3- nitrobenzoic acid that the first step is reacted is dissolved in suitable DMF by step In, the tetramethylurea hexafluorophosphoric acid ester (HATU) of 1 equivalent and the diisopropylethylamine (DIEA) of 2 equivalents is then added, room temperature is stirred Dimethylamine/tetrahydrofuran solution of 2 equivalents is added after mixing 15 minutes, after being stirred overnight, silica gel column chromatography (eluant, eluent: n-hexane: Ethyl acetate=1:1) it isolates and purifies.Relevant characterization data are as follows: MS+H+=527.8.
Embodiment 13:1- (2,6- dichloro-benzoyl base) the fluoro- 3- of -4- (4- methylsulfonyl phenyl) -1H- benzo [d] miaow Azoles -2 (3H) -one
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 4-aminobenzoic acid methyl esters is replaced by raw material using 4- methylsulfonylaniline in step 1.Relevant characterization data are as follows: MS+H+=479.7；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.30 (d, J=8.1Hz, 1H), 8.04 (d, J=8.7Hz, 2H), 7.66(dd,J1=8.7Hz, J2=2.7Hz, 2H), 7.40~7.27 (m, 4H), 7.39~7.23 (m, 3H), 7.15~7.08 (m,1H),3.06(s,3H)。
Embodiment 14:4- (3- (2,6- dichloro-benzoyl base) -6- methoxyl group -2- ketone -2,3- dihydro -1H- benzo [d] miaow Azoles -1- base) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists The fluoro- 3- nitrobenzene of 1,2- bis- is replaced by raw material using 1- methoxyl group -3- fluoro- 4- nitrobenzene in step 1.Relevant characterization data are such as Under: MS+H+=459.2；1H-NMR(DMSO-d6, 300MHz) and δ: ppm 8.20 (d, J=9Hz, 1H), 8.13 (d, J=8.7Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 7.61~7.52 (m, 3H), 6.94 (dd, J1=8.7Hz, J2=2.4Hz, 1H), 6.70 (d, J=2.4Hz, 1H), 3.80 (s, 3H).
Embodiment 15:4- (1- (2,6- dichloro-benzoyl base) -2- ketone -1H- imidazoles [4,5-b] and pyridine -3 (2H)-yl) Benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists The fluoro- 3- nitrobenzene of 1,2- bis- is replaced by raw material using 2- fluoro- 3- nitropyridine in step 1.Relevant characterization data are as follows: MS+H+=428.1；1H-NMR(DMSO-d6, 300MHz) and δ: ppm 13.090 (brs, 1H), 8.527-8.498 (dd, 1H, J1= 7.8Hz,J2=0.9Hz), 8.281-8.260 (dd, 1H, J1=5.1Hz, J2=1.2Hz), 8.130-7.947 (m, 3H), 7.786-7.757 (d, 2H, J=8.7Hz), 7.651-7.545 (m, 3H), 7.426-7.382 (m, 1H).
Embodiment 16:4- (3- (2,6- dichloro-benzoyl base) -2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base) benzene Formic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists The fluoro- 3- nitrobenzene of 1,2- bis- is replaced by raw material using 1- fluoro- 2- nitrobenzene in step 1.Relevant characterization data are as follows: MS+H+ =401.2；1H-NMR(DMSO-d6, 300MHz) and δ: ppm 13.20 (s, 1H), 8.28-8.31 (m, 1H), 8.12 (d, J= 8.4Hz, 2H), 7.69 (d, J=8.7Hz, 2H), 7.52-7.63 (m, 3H), 7.36-7.39 (m, 2H), 7.19-7.22 (m, 1H)。
Embodiment 17:4- (the chloro- 3- of 7- (2,6- dichloro-benzoyl base) -2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- Base) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists The fluoro- 3- nitrobenzene of 1,2- bis- is replaced by raw material using the chloro- 2- of 1- fluoro- 3- nitrobenzene in step 1.Relevant characterization data are as follows: MS+H+=459.1；1H-NMR(DMSO-d6, 300MHz) and δ: ppm 13.185 (brs, 1H), 8.314-8.289 (d, 1H, J= 7.5Hz), 8.054-8.026 (d, 2H, J=8.4Hz), 7.656-7.539 (m, 5H), 7.421-7.351 (m, 2H)
Embodiment 18:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- of 3- (2,6- dichloro-benzoyl base) -7- Base) -2- fluobenzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 4- amino-benzoic acid methyl ester is replaced by raw material using 4- amino -2- fluorophenyl carbamate in step 1.Relevant characterization data are such as Under: MS+H+=463.2；1H-NMR(CDCl3, 300MHz) and δ: ppm 8.30 (d, J=8.1Hz, 1H), 8.12 (dd, J1= 8.7Hz,J2=7.8Hz, 1H), 7.39~7.29 (m, 6H), 7.12 (ddd, J1=8.7Hz, J2=7.8Hz, J3=0.9Hz, 1H)。
Embodiment 19:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base of 3- phenylacetyl group -7-) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using phenyllacetyl chloride in step 5.Relevant characterization data are as follows: MS+Na+= 413.2；1H-NMR(DMSO-d6, 300MHz) and δ: ppm 7.39~7.29 (m, 2H), 8.01 (d, J=7.5Hz, 1H), 7.70 (dd,J1=8.4Hz, J2=2.1Hz, 2H), 7.38~7.14 (m, 7H), 4.50 (s, 2H).
Embodiment 20:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- base of 3- (4- chloro acetyl) -7-) Benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference exists 2,6- dichlorobenzoyl chloride is replaced by raw material using 4- chlorophenylacetyl chloride in step 5.Relevant characterization data are as follows: MS+Na+= 447.3；1H-NMR(DMSO-d6, 300MHz) and δ: ppm 8.12 (d, J=8.7Hz, 2H), 7.99 (d, J=7.2Hz, 1H), 7.69 (dd,J1=8.7Hz, J2=2.1Hz, 2H), 7.41~7.14 (m, 6H), 4.50 (s, 2H).
Embodiment 21:4- (fluoro- 2- ketone -2,3- dihydro -1H- benzo [d] imidazoles -1- of 3- (2,6- dichloro-benzoyl base) -7- Base) benzamide
It weighs 20mg compound 1 (being obtained from embodiment 1) to be placed in 50mL round-bottomed bottle, 5mL thionyl chloride, agitating and heating is added It is complete molten to be back to compound 1, after 30 minutes, solvent is evaporated off, then residue is dissolved in 10mL methylene chloride, is delayed at room temperature Slow ammonia/dioxane solution the 5mL for instilling 0.5N stirs 10 minutes, 10mL washing, organic phase anhydrous slufuric acid is then added Magnesium dries, filters, and is isolated and purified after concentration with thin layer silica gel (GF-254) plate (n-hexane: ethyl acetate=1:1), obtains 17mg mark Compound is inscribed, is white powder, yield: 87%.Relevant characterization data are as follows: MS+H+=444.0；1H-NMR(CDCl3, 300MHz) δ: ppm 8.29 (d, J=8.1Hz, 1H), 7.90 (d, J=8.4Hz, 2H), 7.53 (dd, J1=8.7Hz, J2= 2.4Hz, 2H), 7.40~7.25 (m, 4H), 7.11~7.07 (m, 1H).
Embodiment 22:4- (fluoro- -1 (the 2H)-yl of 2- ketone -3,4- dihydro-quinoxaline of 4- (2,6- dichloro-benzoyl base) -8-) benzene Formic acid
Preparing 22 compound of embodiment, specific step is as follows:
(1) step 1 is identical as the preparation step 1 of 1 compound of embodiment, obtains intermediate 4- (the fluoro- 6- nitrobenzophenone ammonia of 2- Base) methyl benzoate (1-1)
(2) preparation of 4- (the bromo- N- of 2- (the fluoro- 6- nitrobenzene of 2-) base-acetylamino) ethyl benzoate (22-2)
Intermediate 1-1 (152mg, 0.5mmol) is dissolved in 3mL DMF, at room temperature be added NaH (60%, 60mg, 1.5mmol), it after 0.5h being stirred at room temperature, is added 2- bromoacetyl chlorine (118mg, 0.75mmol), 2h is stirred at room temperature, TLC detects 1- After 1 completely disappears, quenching reaction, reaction solution is poured into 30mL water, ethyl acetate (30mL × 3) extraction.Organic phase after merging It is successively washed through saturated sodium bicarbonate and saturated salt solution, anhydrous sodium sulfate dries, filters, concentration, thin layer silica gel (GF-254) It is 22-2, yield 60.4% that plate, which separates (n-hexane: ethyl acetate=3:1) and obtains 128mg faint yellow solid,.
(3) preparation of 4- (fluoro- -1 (the 2H)-yl of 2- ketone -3,4- dihydro-quinoxaline of 8-) ethyl benzoate (22-3)
Intermediate 22-2 (106mg, 0.25mmol) is dissolved in 5mL ethyl alcohol, room temperature addition stannous chloride (237mg, 1.25mmol), it is heated to reflux 3.5h, after TLC detection 22-2 is completely disappeared, concentration is evaporated reaction solution, residue obtained addition 30mL It in ethyl acetate, stirs and evenly mixs, then successively washs said mixture with saturated sodium bicarbonate, saturated salt solution, have after liquid separation Machine is mutually dried over anhydrous sodium sulfate, filtering, is obtained after filtrate concentration with thin layer chromatography board separation (n-hexane: ethyl acetate=1:1) 46mg faint yellow solid is 22-3, yield 58.6%.
(4) 4- (fluoro- -1 (the 2H)-yl of 2- ketone -3,4- dihydro-quinoxaline of 4- (2,6- dichloro-benzoyl base) -8-) benzoic acid second The preparation of ester (22-4)
Intermediate 22-3 (31.4mg, 0.1mmol) is dissolved in 3mL DMF, room temperature be added NaH (60%, 12mg, 0.3mmol), it after 0.5h being stirred at room temperature, is added acyl chlorides (41.9mg, 0.2mmol), 2h is stirred at room temperature, TLC detection 22-3 disappears completely After mistake, quenching reaction, reaction solution is poured into 10mL water, ethyl acetate (10mL × 3) extraction.Merge organic phase, uses unsaturated carbonate Hydrogen sodium, saturated salt solution successively wash, and the dry organic phase of anhydrous sodium sulfate, filtering is concentrated filtrate, separates through thin layer chromatography board pure Changing (n-hexane: ethyl acetate=5:1) to obtain 35mg faint yellow solid is 22-4, yield 72%.
(5) 4- (fluoro- -1 (the 2H)-yl of 2- ketone -3,4- dihydro-quinoxaline of 4- (2,6- dichloro-benzoyl base) -8-) benzoic acid (22) preparation
Intermediate 22-4 (35mg, 0.072mmol) is dissolved in 5mL THF, 1mL H is added2LiOH is added in O at room temperature H2O (28.8mg, 0.72mmol), reaction solution is stirred overnight at room temperature, and after TLC detection 22-4 is completely disappeared, 3mL H is added2O is added 1mL 1N aqueous hydrochloric acid solution, stirs 5min, and ethyl acetate (5mL × 3) extraction merges organic phase, through saturated common salt water washing, nothing Aqueous sodium persulfate dries, filters, and filtrate is concentrated, and it is faint yellow to obtain 16mg through thin layer chromatography board separation (n-hexane: ethyl acetate=3:1) Solid 22, yield 48.5%.Relevant characterization data are as follows: MS+H+=463.2；1H-NMR(DMSO-d6, 300MHz) and δ: Ppm13.248 (brs, 1H), 8.119-8.091 (d, 2H, J=8.4Hz), 7.806-7.778 (m, 2H), 7.635-7.539 (m, 4H),7.365-7.126(m,2H),5.500(s,2H)。
Embodiment 23:4- (fluoro- -1 (the 2H)-yl of 3,4- dihydro-quinoxaline of 4- (2,6- dichloro-benzoyl base) -8-) benzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 22, and difference exists Replace the substitution reaction of 2- bromoacetyl chlorine progress amino by raw material using glycol dibromide in step 2.Relevant characterization number According to as follows: MS+H+=445.2；1H-NMR(CDCl3, 300MHz) and δ: ppm, 4.10 (t, J=5.7Hz, 2H), 4.30 (t, J= 5.7Hz, 2H), 6.61-6.70 (m, 1H), 6.97 (d, J=8.4Hz, 2H), 7.25-7.35 (m, 5H), 7.97 (d, J= 8.4Hz,2H)。
Bioactivity screening
The bioactivity of adjustable (inhibition) the nuclear receptor ROR γ of the compound of the present invention, this adjusts (inhibition) effect Power can screen system by TR-FRET to evaluate.Nuclear receptor co-factor (the co-activation factor and the co-suppression factor) by with core The transcription of the adjustable target gene of interaction of receptor.If ligand (test-compound) affects nuclear receptor and co-factor Interaction, then this ligand (test-compound) can adjust the transcription of corresponding gene.
This method uses LanthaScreen TR-FRET (the time-resolved fluorescence energy of Life Technologies company Measure resonance transfer) technology measurement compound is (exciting or reversed swash to the regulating power of ROR γ and its co-activation factor interaction It is dynamic).The anti-GST antibody (Life Technologies#PV3550) of terbium (Tb) label is by being incorporated in ROR γ-LBD (Life Technologies#PV5887 indirect label is carried out to ROR γ-LBD on GST label).There is no ROR in the presence of ligand γ can persistently be combined with the fluorescein-labeled co-activation factor, agonist in conjunction with ROR γ after ROR γ and fluorescence can be enhanced The interaction of the co-activation factor of element label；Inverse agonist in conjunction with ROR γ after ROR γ and fluorescein can be inhibited to mark The co-activation factor interaction.Anti-GST antibody-ROR the label that the fluorescein-labeled co-activation factor is marked with terbium is total to Sharp compound is close to each other can to occur energy transfer to certain distance, generate TR-FRET signal.The co-activation that this method uses The factor is not limited to Fluorescein-D22 (Life Technologies#PV4386), Fluorescein-SRC1-2 (Life Technologies#PV4578), Fluorescein-SRC1-4 (Life Technologies#PV4582) etc..
(1) final concentration and reaction condition of this method reaction system are as follows: (table 1)
(2) experimental method
It prepares Complete TR-FRET Coregulator Buffer D (hereinafter referred to as completely buffering liquid D): to TR- DTT (Life Technologies# is added in FRET Coregulator Buffer D (Life Technologies#PV4420) P2325) to the final concentration of 5mM of DTT.
Using liquid D preparation 2X Fluorescein-D22 is completely buffered, (0.3 μM, used when other co-activation peptides referring to table 1) with the mixed solution of the anti-GST antibody (4nM) of 2X Tb label, 10 holes μ L/ are added in 384- orifice plate (Corning3376).
Using DMSO prepare 100X final concentration gradient dilution untested compound, then using completely buffer liquid D will be to be measured To 4X (DMSO content is 4%), 5 holes μ L/ are added in above-mentioned 384- orifice plate diluted chemical compound, are uniformly mixed.Positive control wells In with 5 holes μ L/ be added completely buffer liquid D (no untested compound) containing 4%DMSO.
4X ROR γ-LBD (8nM) is prepared using liquid D is completely buffered, 5 holes μ L/ are added in above-mentioned 384- orifice plate, are mixed Uniformly.5 holes μ L/ are added in negative control hole and completely buffer liquid D (no ROR γ-LBD).384- orifice plate is placed in constant temperature oscillator In, incubation is protected from light 4~5 hours in 23 DEG C.
Fluorescence intensity: 1) excitation wavelength 332/20nm, launch wavelength 490/10nm is measured using Tecan M1000Pro, is increased Benefit value: optimization, flash of light: mode 2 (100Hz), 100 μ s of delay time, 200 μ s of integrating time；2) excitation wavelength 332/20nm, hair The long 520/20nm of ejected wave, yield value: optimization, flash of light: mode 2 (100Hz), 100 μ s of delay time, 200 μ s of integrating time.
(3) data are analyzed
TR-FRET ratio F520/F490-compound concentration logarithmic curve is drawn using program GraphPad Prism, And EC50 value is calculated, this numerical value is smaller to illustrate that compound adjusts (being in the present embodiment inhibition) effect to receptor ROR γ It is stronger.
Section Example compound see the table below the EC50 value that ROR γ is acted on: (table 2)
Foregoing invention is described in detail in mode by way of illustration and example, with the mesh for illustrating and understanding 's.It will be apparent to one skilled in the art that can be changed and improve in the range of appended claims. It will therefore be appreciated that above description is illustrative rather than restrictive.Therefore, the scope of the present invention should not refer to Description above and determine, and should be with reference to the whole of following appended claims and the equivalent by claims issue Range and determine.

Claims (11)

1. a kind of compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein the compound With formula II a:
Wherein:
Q is N or-CR4；
L is selected from-C (O)-,-S (O)2Or-CH2-；
A is selected from phenyl or 5-6 unit's heteroaryl, and the phenyl or 5-6 unit's heteroaryl are optionally independently by one or more below Group replaces: halogen, cyano, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl；
M is 0,1 or 2；
N is 0 or 1；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, C1-4Alkoxy, amino, C1-4Alkyl amino or two C1-4Alkyl amino；
RbSelected from C1-4Alkyl, amino, C1-4Alkyl amino or two C1-4Alkyl amino；
R2When it is present independently selected from halogen, cyano, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl or halogenated C1-4Alcoxyl Base；
R3Selected from hydrogen, halogen, cyano, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkyl, carbamoyl, C1-4Alkyl amino first Acyl group or two C1-4Alkyl-carbamoyl；And
R4Selected from hydrogen, halogen or C1-4Alkyl.
2. compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutically acceptable salt, Wherein, in Formula II a:
Q is N or-CR4；
L is selected from-C (O)-,-S (O)2Or-CH2-；
A is selected from phenyl, and the phenyl is optionally independently replaced by one or more groups below: halogen, cyano, halogenated C1-4 Alkyl；
M is 0 or 1；
N is 0 or 1；
R1Selected from-C (O) RaOr-S (O)2Rb；
RaSelected from hydroxyl, C1-4Alkoxy, amino, C1-4Alkyl amino or two C1-4Alkyl amino；
RbSelected from C1-4Alkyl；
R2When it is present independently selected from halogen, C1-4Alkyl or halogenated C1-4Alkyl；
R3Selected from hydrogen, C1-4Alkoxy, carbamoyl, C1-4Alkyl-carbamoyl or two C1-4Alkyl-carbamoyl；And
R4Selected from hydrogen, halogen or C1-4Alkyl.
3. compound according to claim 1 or 2 or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt, wherein in Formula II a:
Q is selected from N or-CR4；
L is selected from-C (O)-or-CH2-；
A is phenyl, and the phenyl is optionally independently replaced by one or more groups below: halogen, C1-4Alkyl is halogenated C1-4Alkyl；
M is 0 or 1；
N is 0；
R1For-COOH；
R2When it is present independently selected from halogen, C1-4Alkyl or halogenated C1-4Alkyl；
R3Selected from hydrogen；And
R4Selected from hydrogen, halogen or C1-4Alkyl.
4. compound according to claim 1 or 2 or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt, wherein the compound is selected from:
5. a kind of pharmaceutical composition includes compound of any of claims 1-4 or its stereoisomer, mutually variation Structure body or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.
6. pharmaceutical composition according to claim 5 also includes one or more anti-inflammatory agents selected from the following: nonsteroidal Anti-inflammatory agent, gold compound, corticoid and immunosuppressor.
7. pharmaceutical composition according to claim 5 also includes one or more anti-inflammatory agents selected from the following: non-specific With COX-2 specificity cyclooxygenase-2 inhibitors, gold compound, corticoid, Tumor Necrosis Factor Receptors antagonist, salicylic acid Ester or salt and methotrexate.
8. compound according to any one of claim 1 to 4 or its stereoisomer, tautomer or its pharmaceutically Acceptable salt is preparing the purposes in the drug as ROR gamma modulators.
9. compound according to any one of claim 1 to 4 or its stereoisomer, tautomer or its pharmaceutically Purposes of the acceptable salt in the drug for the disease that preparation prevention or treatment ROR γ mediate.
10. purposes according to claim 9, wherein the disease that the ROR γ is mediated is selected from: rheumatoid arthritis, more Hair property sclerosis, psoriasis, Crohn disease, asthma, systemic loupus erythematosus, chronic obstructive pulmonary disease, tissue graft rejection The rejection of reaction and transplant organ, chorionitis, purpura, autoimmune haemolytic and thrombocytopenic symptom, irritability Bowel syndrome, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, mucous membrane leischmaniasia, bronchitis, allergic rhinitis, spy It is answering property dermatitis, cystic fibrosis, lung metabolism rejection, ankylosing spondylitis, pancreatitis, Autoimmune ophthalmopathy, exedens Colitis, sjorgen syndrome, optic neuritis, diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Green- Barre syndrome, Ge Ruifushi disease or sclerotitis.
11. purposes according to claim 9, wherein the disease that the ROR γ is mediated is selected from: children's rheumatoid arthritis, Psoriasis arthropathica or autoimmune diabetes.
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