CN104926733A - Compound used as RORgamma conditioning agent - Google Patents
Compound used as RORgamma conditioning agent Download PDFInfo
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- CN104926733A CN104926733A CN201510117243.8A CN201510117243A CN104926733A CN 104926733 A CN104926733 A CN 104926733A CN 201510117243 A CN201510117243 A CN 201510117243A CN 104926733 A CN104926733 A CN 104926733A
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- alkyl
- alkylamino
- amino
- carbamoyl
- alkoxyl group
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- 0 CC(CCC(C)[N+])CC(C)(C)* Chemical compound CC(CCC(C)[N+])CC(C)(C)* 0.000 description 3
- SCZFDRLMGCHGQL-UHFFFAOYSA-N CC[IH]NC(C)O Chemical compound CC[IH]NC(C)O SCZFDRLMGCHGQL-UHFFFAOYSA-N 0.000 description 1
- WNLCADFRHIZYAB-OZRTXJSJSA-N OC(C[C@H]([C@H](CC1)Cl)C1Cl)Cl Chemical compound OC(C[C@H]([C@H](CC1)Cl)C1Cl)Cl WNLCADFRHIZYAB-OZRTXJSJSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N c1ccccc1 Chemical compound c1ccccc1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a compound which can be used as a sulfoacid-related orphan receptor gamma (RORgamma) conditioning agent, a drug composition of the compound, and the uses of the compound in drug preparation. The compound has a formula I as shown in the description.
Description
Technical field
The present invention relates to the compound, its pharmaceutical composition and its purposes in pharmacy that can be used as vitamin A acid related orphan receptor y (ROR γ) conditioning agent.
Background technology
Nuclear receptor is the transcription factor superfamily of a class ligand-dependent, and it is widely distributed in vivo, plays a role in metabolism, growth, biorhythm, inflammation and immunoregulation etc.The part of nuclear receptor comprises Triiodothyronine, steroid hormone, vitamin A acid, lipid acid, sterol etc., also has a class also not determine the nuclear receptor of part at present in addition, is called orphan nuclear receptor.Vitamin A acid related orphan acceptor (retinoid-related orphan receptors, RORs), be also called NF1R, this nuclear receptor due in gene order with retinoic acid receptor (RAR) (retinoic acid receptor, RAR) and vitamin A acid X acceptor (retinoid X receptor, RXR) similar and gain the name.RORs subfamily mainly comprises three members such as ROR α, ROR β and ROR γ, studies more at present to ROR α and ROR γ and part (conditioning agent) thereof.ROR α is wide expression in each histoorgan in vivo, and it may reside in brain, kidney, liver, testis, ovary, skeletal muscle, thymus gland, skin, lung, fatty tissue, and wherein in cerebral tissue, expression level is the highest, particularly cerebellum and thalamus.Recently study and also show ROR α and make bone promotive factor by stimulation, the sclerocyte that inflammation-inhibiting reaction participates in human body is movable.ROR γ mainly comprises ROR γ 1 and ROR γ t (ROR γ 2) two kinds of hypotypes, and wherein ROR γ 1 is distributed in the places such as skeletal muscle, thymus gland, testis, pancreas, prostate gland, heart and liver; And ROR γ t is only expressed in immunocyte, it is the distinctive a kind of ROR γ hypotype of T cell.Th17 cell is the Th cell subsets that a kind of energy specificity recently confirmed produces cytokine IL-17, it is sick that it participates in inducing autoimmune, there is very strong short inflammatory effect, and with the generation of various autoimmune disease with develop relevant, as sacroiliitis, multiple sclerosis and asthma etc.ROR γ is a crucial driving factors of Th17 cytodifferentiation and regulation and control, therefore becomes the drug development target spot of an emerging potential autoimmune disorder gradually.ROR inverse agonist (antagonist), by affect the function of ROR γ, regulates propagation and the growth of Th17 cell, the generation of T suppression cell factor IL-17 thus the generation of blocking-up inflammation and development.In recent years, there are many sections of paper studies displays, in vitro T suppression cell factor IL-17 produce experiment in and in mouse autoimmune disease model (CIA model, EAE model etc.) all confirm this important physiological function (Nature 2011 of ROR γ, 472,486-490; 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 in the generation of various autoimmune disease and development the vital role that rises, synthesize a series of new compound and have very important significance to regulate the function of ROR γ, this treatment that can be autoimmune disease lays the foundation.
Summary of the invention
On the one hand, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, described compound has structural formula I (being also sometimes referred to as formula I hereinafter):
Wherein:
X be selected from-C (O)-,-CH
2c (O)-or-CH
2cH
2-;
L be selected from-C (O)-,-S (O)-,-S (O)
2-or-CH
2-;
A is selected from aryl or heteroaryl, and described aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, sulfonamido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl;
B is selected from following divalence ring: cycloalkyl, heterocyclic radical, aryl or heteroaryl, and described cycloalkyl, heterocyclic radical or aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, nitro, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, formamyl, alkyl-carbamoyl, dialkyl carbamoyl, amido or alkyl acyl;
M is 0,1,2,3 or 4;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido; And
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present.
In one embodiment, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, described compound has formula II (being also sometimes referred to as formula II compound hereinafter):
Wherein:
Q is N or-CR
4;
X be selected from-C (O)-,-CH
2c (O)-or-CH
2cH
2-;
L be selected from-C (O)-,-S (O)
2-or-CH
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, sulfonamido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl;
M is 0,1,2,3 or 4;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4be selected from hydrogen, halogen or alkyl.
In a specific embodiment, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, described compound has formula II a (being also sometimes referred to as formula IIa compound hereinafter):
Wherein:
Q is N or-CR
4;
L be selected from-C (O)-,-S (O)
2-or-CH
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl;
M is 0,1,2,3 or 4;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, hydroxyl, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4be selected from hydrogen, halogen or alkyl.
In a specific embodiment, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, described compound has formula II b (being also sometimes referred to as formula IIb compound hereinafter):
Wherein:
Q is N or-CR
4;
L is selected from-C (O)-or-S (O)
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl ring are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl;
M is 0,1,2,3 or 4;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4be selected from hydrogen, halogen or alkyl.
In a specific embodiment, present invention also offers a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, described compound has formula II c (being also sometimes referred to as formula IIc compound hereinafter):
Wherein:
Q is N or-CR
4;
L is selected from-C (O)-or-S (O)
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl;
M is 0,1,2,3 or 4;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4hydrogen, halogen or alkyl.
Another aspect of the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises one or more formula I of the present invention, formula II, formula IIa, formula IIb, formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, and pharmaceutically acceptable vehicle.
Another aspect of the present invention relates to a kind of pharmaceutical composition, and described pharmaceutical composition comprises one or more formula I of the present invention, formula II, formula IIa, formula IIb, formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug; One or more are selected from following antiphlogiston: non-steroidal anti-inflammatory drugs (NSAID), non-specific and COX-2 specificity cyclooxygenase-2 inhibitors, gold compound, corticosteroids, Tumor Necrosis Factor Receptors antagonist, salicylate or salt, immunosuppressor and MTX; And pharmaceutically acceptable vehicle.
Another aspect of the present invention relates to formula I of the present invention, formula II, formula IIa, formula IIb, formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug purposes in the medicine for the preparation of adjustment ROR gamma activity.
Another aspect of the present invention relates to formula I of the present invention, formula II, formula IIa, formula IIb, formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug purposes in the medicine of the disease for the preparation for the treatment of or prevention ROR γ mediation.
Another aspect of the present invention relates to formula I of the present invention, formula II, formula IIa, formula IIb, formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug in preparation as the purposes in the medicine of ROR gamma modulators.
Embodiment
Unless otherwise defined, otherwise herein the connotation that has of all scientific and technical terminologies is identical with the connotation that claim theme one of ordinary skill in the art understand usually.
Should be understood that above-mentioned summary and being specified as hereafter exemplary and only for illustrating, and present subject matter not to be imposed any restrictions.
The all documents quoted in the application or literature department divide and include but not limited to patent, patent application, article, books, operational manual and paper, and entirety is incorporated to herein all by reference.
Some chemical group defined in this article previously by contracted notation to represent the total number of carbon atoms existed in this group.Such as, C
1-4alkyl refer to have 1 to 4 carbon atom altogether as hereafter the alkyl that defines; C
6-12aryl refer to have 6 to 12 carbon atoms altogether as hereafter the aryl that defines.The total number of carbon atoms in contracted notation does not comprise the carbon in the substituting group that may be present in described group.
Except aforementioned, time in for the specification sheets of the application and claims, unless otherwise specified, otherwise following term has implication as follows.
In this application ,-C (O)-expression acyl group or carbonyl ,-S (O)
2-represent alkylsulfonyl ,-S (O)-expression sulfinyl.
In this application, term " halogen " refers to fluorine, chlorine, bromine or iodine, preferred fluorine or chlorine.
In this application, as group or a part for other group, term " alkyl " means only to be made up of with hydrogen atom carbon atom, the group of straight or branched that is connected with the rest part of molecule containing unsaturated link(age) and by singly-bound.Alkyl can have such as 1 to 18, preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4 carbon atom.The example of alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2-amyl group, hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl group, nonyl and decyl etc., preferable methyl, ethyl.
In this application, term " haloalkyl " refers to the alkyl replaced by one or more halogen atom, and wherein alkyl as hereinbefore defined.The example of haloalkyl includes but not limited to trifluoromethyl, trichloromethyl, dichloromethyl, brooethyl, iodomethyl, 1,2-Dichloroethyl etc., preferred trifluoromethyl.
In this application, term " alkoxyl group " refers to formula-OR
agroup, wherein R
afor alkyl as hereinbefore defined.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy etc., preferred methoxyl group.
In this application, term " halogenated alkoxy " refers to the alkoxyl group replaced by one or more halogen atom, and wherein alkoxyl group as hereinbefore defined.
In this application, term " amino " is as referring to formula-NH during independent groups
2group.
In this application, term " alkylamino " refers to formula-NHR
agroup, wherein R
afor alkyl as hereinbefore defined.The example of alkylamino includes but not limited to methylamino, ethylamino, isopropylamino etc.
In this application, term " dialkyl amido " refers to-NR
ar
bgroup, wherein R
aand R
bit is separately alkyl as hereinbefore defined.The example of dialkyl amido includes but not limited to dimethylamino, diethylamino, dipropylamino, methylethylamine etc., preferred dimethylamino.
In this application, term " alkyl sulphonyl " refers to-S (O)
2r
agroup, wherein R
afor alkyl as hereinbefore defined.The example of alkyl sulphonyl includes but not limited to methylsulfonyl, ethylsulfonyl, isopropelsulfonyl etc., preferred methylsulfonyl.
In this application, term " alkyl sulfonyl is amino " refers to-N (R
b) S (O)
2r
agroup, wherein R
afor alkyl as hereinbefore defined, R
bfor hydrogen or alkyl as hereinbefore defined.The example of alkyl sulfonyl amino includes but not limited to that methane sulfonylamino, methylsulfonyl (methyl) are amino, ethylsulfonyl (methyl) is amino, ethylsulfonyl (ethyl) is amino.
In this application, term " amino-sulfonyl " refers to formula-S (O)
2nH
2group.
In this application, term " alkyl amino sulfonyl " refers to-S (O)
2nHR
agroup, wherein R
afor alkyl as hereinbefore defined.The example of alkyl amino sulfonyl includes but not limited to methylaminosulfonyl, ethylaminosulfonyl, iso-propylaminosulfonyl, tert-butylamino alkylsulfonyl etc.
In this application, term " dialkyl amino sulfonyl " refers to-S (O)
2nR
ar
bgroup, wherein R
aand R
bbe respectively alkyl as hereinbefore defined.The example of dialkyl amino sulfonyl includes but not limited to dimethylamino-sulfonyl, diethylamino alkylsulfonyl, (methyl) (ethyl) amino-sulfonyl etc.
In this application, term " formamyl " refers to formula-C (O) NH
2group.
In this application, term " alkyl-carbamoyl " refers to formula-C (O) NHR
agroup, wherein R
afor alkyl as hereinbefore defined.The example of alkyl-carbamoyl includes but not limited to methylcarbamoyl, ethylaminocarbonyl etc.
In this application, term " dialkyl carbamoyl " refers to formula-C (O) NR
ar
bgroup, wherein R
aand R
bbe respectively alkyl as hereinbefore defined.The example of dialkyl carbamoyl includes but not limited to formyl-dimethylamino, diethylamino formyl radical, (methyl) (ethyl) formamyl etc., preferred formyl-dimethylamino.
In this application, term " amido " refers to formula-NR
ac (O) R
bgroup, wherein R
afor hydrogen or alkyl as hereinbefore defined, R
bfor hydrogen or alkyl as hereinbefore defined.The example of amido includes but not limited to Formylamino, acetylamino, ethanoyl (methyl) amino etc.
In this application, term " alkyl acyl " refers to-C (O) R
agroup, wherein R
afor hydrogen or alkyl as hereinbefore defined.The example of alkyl acyl includes but not limited to formyl radical, ethanoyl, propionyl, iso-propionyl, tertiary butyryl radicals etc.
In this application, term " alkyl acyl oxygen base " refers to-OC (O) R
agroup, wherein R
afor hydrogen or alkyl as hereinbefore defined.The example of alkyl acyl oxygen base includes but not limited to formyl radical oxygen base, ethanoyl oxygen base, propionyl oxygen base, iso-propionyl oxygen base, tertiary butyryl radicals oxygen base etc.
In this application, term " alkyloxycarbonyl " refers to-C (O) OR
agroup, wherein R
afor alkyl as hereinbefore defined.The example of alkyloxycarbonyl includes but not limited to methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl group, isopropyloxycarbonyl group, t-butyloxycarbonyl etc., preferable methyl oxygen base carbonyl, ethyloxycarbonyl.
In this application, term " cycloalkyl " means the stable monovalence non-aromatic monocyclic that is only made up of carbon atom and hydrogen atom or multi-ring alkyl, it can comprise fused ring system or bridged-ring system, there are 3 to 15 carbon atoms, preferably there are 3 to 10 carbon atoms, more preferably there are 3 to 8 carbon atoms, and it is saturated or unsaturated and can be connected with the rest part of molecule by singly-bound via any suitable carbon atom.The example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1H-indenyl, 2, 3-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-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5, 6, 7, 8, 9, 10-six hydrogen-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptyl, 7, 7-dimethyl-two ring [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl group, two rings [3.1.1] heptyl, two rings [3.2.1] octyl group, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene radical-1H-indenyl and octahydro-2, 5-methylene radical-pentalene base etc.
In this application, as group or a part for other group, 3 yuan to the 18 yuan stable non-aromatic cyclic groups that the heteroatoms that term " heterocyclic radical " means to be selected from nitrogen, oxygen and sulphur by 2 to 12 carbon atoms and 1 to 6 forms.Unless specialized in addition in this specification sheets, otherwise heterocyclic radical can be the member ring systems of monocycle, dicyclo, three rings or more ring, and it can comprise fused ring system or bridged-ring system.With regard to object of the present invention, heterocyclic radical preferably comprises 3 yuan to 8 yuan heteroatomic stable non-aromatic monocyclic or the bicyclic radicals that 1 to 3 is selected from nitrogen, oxygen and sulphur, be more preferably and comprise 5 yuan to the 8 yuan heteroatomic stable non-aromatic monocyclic groups that 1 to 3 is selected from nitrogen, oxygen and sulphur, be more preferably and comprise 5 yuan to the 6 yuan heteroatomic stable non-aromatic monocyclic groups that 1 to 2 is selected from nitrogen, oxygen and sulphur.Nitrogen in heterocyclic radical, carbon or sulphur atom are optionally oxidized; Nitrogen-atoms is optionally quaternized; And heterocyclic radical can be partially or completely saturated.Heterocyclic radical can be connected with molecule rest part by singly-bound via carbon atom or heteroatoms.In the heterocyclic radical comprising condensed ring, one or more ring can be aryl or heteroaryl, and condition is non-aromatic annular atoms with the tie point of molecule rest part.The example of heterocyclic radical includes but not limited to: pyranyl, THP trtrahydropyranyl, thiapyran base, tetrahydrofuran base, morpholinyl, thio-morpholinyl, piperazinyl, piperidyl, oxazinyl, dioxy cyclopentyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidyl, quinolizinyl, thiazolidyl, isothiazole alkyl, isoxazole alkyl, indolinyl, octahydro indyl, octahydro pseudoindoyl, pyrrolidyl, pyrazolidyl, phthaloyl imino etc.
In this application, as group or a part for other group, term " aryl " means the system with 6 to 18 (being preferably 6 to 10) carbon atoms and at least one aromatic nucleus.With regard to object of the present invention, aryl can be the member ring systems of monocycle, dicyclo, three rings or more ring, and it can comprise fused rings or bridged-ring system.Aryl is connected with the rest part of molecule by singly-bound via aromatic ring atom.The example of aryl includes but not limited to phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-one-7-base etc., preferred phenyl.
In this application, as group or a part for other group, term " heteroaryl " means to have in ring the heteroatoms that 1 to 15 (being preferably 1 to 10) carbon atom and 1 to 4 are selected from nitrogen, oxygen and sulphur, and 5 of at least one aromatic nucleus yuan to 16 ring system groups.Unless specialized in addition in this specification sheets, otherwise heteroaryl can be the member ring systems of monocycle, dicyclo, three rings or more ring, and it can comprise fused ring system or bridged-ring system, and condition is tie point is aromatic ring atom.Nitrogen in heteroaryl, carbon or sulphur atom are optionally oxidized; Nitrogen-atoms is optionally quaternized.With regard to object of the present invention, heteroaryl preferably comprises 5 yuan to 12 yuan heteroatomic stable aromatic monocyclic or the bicyclic radicals that 1 to 3 is selected from nitrogen, oxygen and sulphur, be more preferably and comprise 5 yuan to 10 yuan heteroatomic stable aromatic monocyclic or the bicyclic radicals that 1 to 3 is selected from nitrogen, oxygen and sulphur, be more preferably and comprise 5 yuan to 6 yuan heteroatomic stable aromatic monocyclic or the bicyclic radicals that 1 to 2 is selected from nitrogen, oxygen and sulphur.The example of heteroaryl includes but not limited to thienyl, furyl, pyrryl, [1,3,4] oxadiazolyls, [1,2,4] thiadiazolyl group, [1,3,4] thiadiazolyl group, imidazolyl, benzimidazolyl-, pyrazolyl, benzopyrazoles base, triazolyl, tetrazyl, pyridyl, pyrazinyl, triazinyl, pyrimidyl, pyridazinyl, indolizine base, indyl, pseudoindoyl, indazolyl, iso indazolyl, purine radicals, quinolyl, isoquinolyl, phenodiazine naphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazyl, carbolinyl, phenanthridinyl, phenanthroline base, acridyl, phenazinyl, thiazolyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazole base, cinnolines base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydro benzo [b] thienyl, naphtho-pyridyl etc., preferred pyrryl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrimidyl, pyridazinyl etc., more preferably pyridyl.
" steric isomer " refers to and is made up of same atoms, by identical key bonding, but has the compound of different three-dimensional structure.The present invention will contain various steric isomer and composition thereof.
" tautomer " refers to that proton is from an atom transfer of molecule to another atom of same molecular and the isomer formed.All tautomeric forms of compound of the present invention also will within the scope of the present invention.
In this application, term " pharmacy acceptable salt " comprises pharmaceutically acceptable acid salt and pharmaceutically acceptable base addition salt.
" pharmaceutically acceptable acid salt " refer to the biological effectiveness that can retain free alkali and without other side effect, the salt that formed with mineral acid or organic acid.Described mineral acid includes but not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., described organic acid includes but not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, sad, caproic acid, capric acid, undecylenic acid, oxyacetic acid, glyconic acid, lactic acid, oxalic acid, sebacic acid, hexanodioic acid, pentanedioic acid, propanedioic acid, toxilic acid, succsinic acid, fumaric acid, tartrate, citric acid, palmitinic acid, stearic acid, oleic acid, styracin, lauric acid, oxysuccinic acid, L-glutamic acid, Pyrrolidonecarboxylic acid, aspartic acid, phenylformic acid, methylsulfonic acid, tosic acid, Lalgine, ascorbic acid, Whitfield's ointment, 4-ASA, naphthalene disulfonic acid etc.
" pharmaceutically acceptable base addition salt " refers to the biological effectiveness that can keep free acid and without the salt of other side effect.These salt are by being added into free acid by mineral alkali or organic bases and preparing.Salt derived from mineral alkali includes but not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc.Preferred inorganic salt are ammonium salt, sodium salt, sylvite, calcium salt and magnesium salts.Salt derived from organic bases includes but not limited to the salt of following alkali: primary amine, secondary amine and tertiary amines, the amine be substituted, comprise and natural be substituted amine, cyclic amine and deacidite, such as ammonia, Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, thanomin, diethanolamine, trolamine, dimethylethanolamine, DMAE, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, choline, trimethyl-glycine, quadrol, glucosamine, methyl glucose osamine, Theobromine, tromethane, purine, piperazine, piperidines, N-ethylpiperidine, versamid 900 etc.
According to the number of electrically charged functional group and the valency of positively charged ion or negatively charged ion, the compounds of this invention can contain multiple positively charged ion or negatively charged ion.
Usually, crystallization effect can produce the solvate of the compounds of this invention.In this application, " solvate " refers to the aggregate comprising one or more the compounds of this invention molecule and one or more solvent molecule.They or in a solvent reaction or from solvent Precipitation or crystallize out.Solvent can be water, and the solvate in this situation is hydrate.Or solvent also can be organic solvent.The solvate of the compounds of this invention also belongs within the scope of the invention.
In this application, term " prodrug " represents the compound that can be hydrolyzed or be converted to via enzyme reaction bioactive compounds of the present invention under physiological conditions.Therefore, term " prodrug " refers to the pharmaceutically acceptable metabolic precursor thereof of compound of the present invention.But when being given individuality in need, prodrug can not have activity, but is converted to active compound of the present invention in vivo.Prodrug transforms rapidly usually in vivo, and produces parent compound of the present invention, such as, realize by being hydrolyzed in blood.Prodrug compound provides the advantage of solubleness, histocompatibility or slowly-releasing usually in mammalian organism.Commentary for prodrug can see with Publication about Document: Kevin Beaumont, et al., Current Drug Metabolism, 4 (6), 461-485,2003; Peter Ettmayer, et al., Journal ofMedicinal Chemistry, 47 (10), 2393-2404,2004; Stella V.J., Expert Opinion onTherapeutic Patents, 14 (3), 277-280,2004; Jarkko Rautio, et al., Nature Review DrugDiscovery, 7 (3), 255-270,2008.
Well-known to those skilled in the art, the ester of carboxylic compound (such as the compounds of this invention), such as pharmaceutically acceptable ester, can as the prodrug of the compounds of this invention, and it is decomposed into as parent acid in human body or animal body.The acceptable ester of pharmacy includes but not limited to alkyl ester, such as methyl esters, ethyl ester or propyl ester etc.; Alkoxy methyl ester, such as methoxymethyl ester; Alkanoyloxymethyl ester, such as acetoxy-methyl ester; The formamido-alkyl ester that alkyl replaces, such as DMF ylmethyl ester and N, N-diethylformamide ylmethyl ester etc. (for example, see patent documentation US5073641).
In this application, " pharmaceutical composition " refers to the preparation of the medium for bioactive compounds being delivered to Mammals (such as people) that the compounds of this invention and this area accept usually.This medium comprises pharmaceutically acceptable vehicle.
In this application, " pharmaceutically acceptable vehicle " include but not limited to any by the government administration section license of being correlated with for accepting for the adjuvant of the mankind or domestic animal, carrier, vehicle, glidant, sweetener, thinner, sanitas, dyestuff/tinting material, correctives, tensio-active agent, wetting agent, dispersion agent, suspending agent, stablizer, isotonic agent, solvent or emulsifying agent etc.
In this application, " treatment effective dose " refers to when the compounds of this invention being given Mammals (such as people), is enough to the amount of the compounds of this invention of the disease of effectively treating this Mammals (such as people).The amount of the compounds of this invention forming " treatment effective dose " depends on the severity of the target spot of the cause of particular compound used, the concrete illness that treat, illness, medicine, disease, administering mode and mammiferous age, body weight, physical appearance etc. to be treated, but can be determined according to the knowledge of himself and content disclosed in the present application by those skilled in the art routinely.
Term used herein " prevention " comprises makes sufferer reduce disease or the generation of illness or the possibility of deterioration.
Term used herein " treatment " and other similar synonym comprise following implication:
I () preventing disease or illness occur in Mammals, particularly when this kind of Mammals easily suffers from this disease or illness, but be not yet diagnosed as when having suffered from this disease or illness;
(ii) suppress disease or illness, namely contain that it develops;
(iii) alleviate disease or illness, that is, make the state of this disease or illness disappear; Or
(iv) symptom that this disease or illness cause is alleviated.
Term used herein " disease " and " illness " can be exchanged and to be used or may be different.
In this application, term " ROR γ mediate disease " refers to wherein ROR γ or by the generation of ROR γ itself or change activity level, or any disease worked by causing the release of a kind of cytokine such as (but being not limited to) IL-17 or IL-23 or other situations about being harmful to.The disease that ROR γ mediates can be autoimmune disease and/or inflammatory diseases, the example includes but not limited to rheumatoid arthritis, multiple sclerosis, psoriatic, Crohn's disease, asthma, systemic lupus erythematous, chronic obstructive pulmonary disease, the rejection of tissue graft rejection reaction and transplant organ, scleroderma, purpura, autoimmune haemolytic and thrombocytopenic symptom, irritable bowel syndrome, osteoarthritis, mucocutaneous lymphnode syndrome, struma lymphomatosa, mucous membrane leischmaniasia, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolism rejection, children's rheumatoid arthritis, ankylosing spondylitis, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, sjorgen syndrome, optic neuritis, diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barre syndrome, psoriasis arthropathica, Ge Ruifushi disease or scleritis.
In this application, " ROR gamma modulators " refers to have with target spot ROR γ the molecule interacting and affect ROR γ function, and this interaction includes but not limited to: antagonism, excitement, oppositely exciting and other similar interaction.
In this application, " optionally ", " optional " or " optionally " represent that the event that describes subsequently or situation may occur also may not occur, and this description comprises the situation that this event or situation occur and do not occur simultaneously.Such as, " optionally by the alkyl of one or more halogen substiuted " represents that alkyl is not substituted or by one or more halogen substiuted, and this description comprises the alkyl and unsubstituted alkyl that are substituted simultaneously.
On the one hand, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or prodrug, wherein said compound has structural formula I:
Wherein:
X be selected from-C (O)-,-CH
2c (O)-or-CH
2cH
2-;
L be selected from-C (O)-,-S (O)-,-S (O)
2-or-CH
2-;
A is selected from aryl or heteroaryl, and described aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, sulfonamido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl;
B is selected from following divalence ring: cycloalkyl, heterocyclic radical, aryl or heteroaryl, and described cycloalkyl, heterocyclic radical or aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, nitro, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, formamyl, alkyl-carbamoyl, dialkyl carbamoyl, amido or alkyl acyl;
M is 0,1,2,3 or 4;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido; And
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present.
In some embodiments of formula I of the present invention, L be selected from-C (O)-.In other embodiments, L be selected from-S (O)-.In other embodiments, L is selected from-S (O)
2-.In other preferred implementation, L is selected from-CH
2-.
In some embodiments of formula I of the present invention, A is selected from aryl or heteroaryl, is preferably C
6-12aryl or 5-12 unit heteroaryl, described aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, sulfonamido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl.
In some embodiments of formula I of the present invention, A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, C
1-8alkyl, C
1-8alkoxyl group, halo C
1-8alkyl, C
1-8alkylamino, two C
1-8alkylamino, C
1-8alkyl sulphonyl, sulfonamido, amido, formamyl, C
1-8alkyl-carbamoyl, two C
1-8alkyl-carbamoyl or C
1-8alkyl acyl.
In some embodiments of formula I of the present invention, A is selected from C
6-10aryl or 5-10 unit heteroaryl, described C
6-10aryl or 5-10 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl, C
1-4alkylamino, two C
1-4alkylamino, formamyl, C
1-4alkyl-carbamoyl or two C
1-4alkyl-carbamoyl.
In some embodiments of formula I of the present invention, A is selected from phenyl or 5-6 unit heteroaryl, and described phenyl or 5-6 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, cyano group, C
1-4alkyl, C
1-4alkoxyl group or halo C
1-4alkyl.
In some embodiments of formula I of the present invention, A is selected from phenyl, and described phenyl is optionally replaced by following one or more groups independently: halogen, C
1-4alkyl or halo C
1-4alkyl.
In some embodiments of formula I of the present invention, B is selected from following divalence ring: cycloalkyl, heterocyclic radical, aryl or heteroaryl, described cycloalkyl, heterocyclic radical, or aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, nitro, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, alkyl sulfonyl is amino, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, formamyl, alkyl-carbamoyl, dialkyl carbamoyl, amido or alkyl acyl.
In some preferred implementations of formula I of the present invention, B is selected from following divalence ring: C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl.
In some embodiments of formula I of the present invention, X be-C (O)-.In other embodiments, X is-CH
2c (O)-.In other embodiments, X is-CH
2cH
2-.
In some embodiments of formula I of the present invention, m is 0,1,2,3 or 4.In some embodiments, m is 0, now R
2do not exist.In other embodiments, m is 1.In other embodiment, m is 2.
In some embodiments of formula I of the present invention, n is 0.In other embodiments, n is 1.In other embodiment, n is 2.
In some embodiments of formula I of the present invention, R
1be selected from-C (O) R
a, wherein R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido.In other embodiments, R
1be selected from-C (O) R
a, wherein R
abe selected from hydroxyl, C
1-4alkoxyl group, amino, C
1-4alkylamino or two C
1-4alkylamino.In other embodiments, R
1be selected from-C (O) R
a, wherein R
afor hydroxyl, alkoxyl group or amino.In other embodiment, R
1be selected from-C (O) R
a, wherein R
afor hydroxyl.
In some embodiments of formula I of the present invention, R
1be selected from-S (O)
2r
b, wherein R
bbe selected from alkyl, amino, alkylamino or dialkyl amido.In other embodiments, R
1be selected from-S (O)
2r
b, wherein R
bbe selected from C
1-4alkyl, amino, C
1-4alkylamino or two C
1-4alkylamino.In other embodiment, R
1be selected from-S (O)
2r
b, wherein R
bfor alkyl, be preferably C
1-4alkyl.
In some embodiments of formula I of the present invention, R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present.
In some embodiments of formula I of the present invention, R
2independent selected from halo, cyano group, nitro, hydroxyl, C when it is present
1-4alkyl acyl oxygen base, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl or halo C
1-4alkoxyl group.
In some embodiments of formula I of the present invention, R
2independent selected from halo, cyano group, C when it is present
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl or halo C
1-4alkoxyl group.
In some embodiments of formula I of the present invention, R
2independent selected from halo, C when it is present
1-4alkyl or halo C
1-4alkyl.In some embodiments of formula I of the present invention, R
2independent selected from halo when it is present.
In formula I of the present invention, above-mentioned A, B, L, X, R
1, R
2, m and n can combine in any suitable way, such as but not limited to the formula II compound be combined into hereinafter described, formula IIa compound, formula IIb compound, formula IIc compound, all these combinations are all contained within the scope of the present invention.
In some specific embodiments, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein said compound has formula II (hereafter sometimes referred to as formula II compound):
Wherein:
Q is selected from N or-CR
4;
R
3be selected from hydrogen, halogen, amino, cyano group, hydroxyl, carboxyl, nitro, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, formamyl, alkyl-carbamoyl, dialkyl carbamoyl, amido or alkyl acyl; And
X, L, A, m, n, R
1and R
2all as above defined in formula I.
In some embodiments of formula II compound of the present invention, in formula II, Q is selected from N or-CR
4; X be selected from-C (O)-,-CH
2c (O)-or-CH
2cH
2-; L be selected from-C (O)-,-S (O)
2-or-CH
2-; A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, sulfonamido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl; M is 0,1,2,3 or 4; N is 0,1 or 2; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido; R
bbe selected from alkyl, amino, alkylamino or dialkyl amido; R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present; R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And R
4be selected from hydrogen, halogen or alkyl.
In some embodiments of formula II compound of the present invention, in formula II, Q is selected from N or-CR
4; A is selected from C
6-10aryl or 5-10 unit heteroaryl, described C
6-10aryl or 5-10 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, C
1-4alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; N is 0,1 or 2; M is 0,1 or 2; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, C
1-4alkoxyl group, amino, C
1-4alkylamino or two C
1-4alkylamino; R
bbe selected from C
1-4alkyl, amino, C
1-4alkylamino or two C
1-4alkylamino; R
2independent selected from halo, cyano group, hydroxyl, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present; R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And R
4be selected from hydrogen, halogen or alkyl.
In some specific embodiments of formula II compound, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein said compound has formula II a (hereafter sometimes referred to as formula IIa compound):
Wherein Q, L, A, R
1, R
2, R
3, m and n all defined such as formula in II.
In the certain preferred embodiments of formula IIa compound, in formula IIa, Q is selected from N or-CR
4; L be selected from-C (O)-,-S (O)
2-or-CH
2-; A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; M is 0,1,2,3 or 4; N is 0,1 or 2; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido; R
bbe selected from alkyl, amino, alkylamino or dialkyl amido; R
2independent selected from halo, cyano group, hydroxyl, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present; R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And R
4be selected from hydrogen, halogen or alkyl.
In some embodiments of formula IIa compound, Q is selected from N or-CR
4; L be selected from-C (O)-,-S (O)
2-or-CH
2-; A is selected from phenyl or 5-6 unit heteroaryl, and described phenyl or 5-6 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, cyano group, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl; M is selected from 0,1 or 2; N is selected from 0 or 1; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, C
1-4alkoxyl group, amino, C
1-4alkylamino or two C
1-4alkylamino; R
bbe selected from C
1-4alkyl, amino, C
1-4alkylamino or two C
1-4alkylamino; R
2independent selected from halo, cyano group, C when it is present
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl or halo C
1-4alkoxyl group; R
3be selected from hydrogen, halogen, cyano group, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl, formamyl, C
1-4alkyl-carbamoyl or two C
1-4alkyl-carbamoyl; And R
4be selected from hydrogen, halogen or C
1-4alkyl.
In some embodiments of formula IIa compound, Q is selected from N or-CR
4; L be selected from-C (O)-,-S (O)
2-or-CH
2-; A is selected from phenyl or 5-6 unit heteroaryl, and described phenyl or 5-6 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, cyano group, C
1-4alkyl or halo C
1-4alkyl; M is 0 or 1; N is 0 or 1; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, C
1-4alkoxyl group or amino; R
bbe selected from alkyl; R
2independent selected from halo, C when it is present
1-4alkyl or halo C
1-4alkyl; R
3be selected from hydrogen, halogen, C
1-4alkyl, C
1-4alkoxyl group or two C
1-4alkyl-carbamoyl; And R
4be selected from hydrogen, halogen or C
1-4alkyl.
In the other embodiment of formula IIa compound, Q is selected from N or-CR
4; L is selected from-C (O)-or-CH
2-; A is selected from phenyl, and described phenyl is optionally replaced by following one or more groups independently: halogen, C
1-4alkyl or halo C
1-4alkyl; M is 0 or 1; N is 0; R
1be selected from carboxyl; R
2independent selected from halo, C when it is present
1-4alkyl or halo C
1-4alkyl; R
3be selected from hydrogen; And R
4be selected from hydrogen, halogen or C
1-4alkyl.
In some specific embodiments of formula II compound, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein said compound has formula II b (hereafter sometimes referred to as formula IIb compound):
Wherein Q, L, A, R
1, R
2, R
3all defined such as formula in II with m.
In some specific embodiments of formula IIb compound, in formula IIb, Q is selected from N or-CR
4; L is selected from-C (O)-or-S (O)
2-; A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl ring are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; M is 0,1,2,3 or 4; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido; R
bbe selected from alkyl, amino, alkylamino or dialkyl amido; R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present; R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And R
4be selected from hydrogen, halogen or alkyl.
In some specific embodiments of formula IIb compound, in formula IIb, Q is selected from N or-CR
4; L is selected from-C (O)-or-S (O)
2-; A is selected from phenyl or 5-6 unit heteroaryl, and described phenyl or 5-6 unit heteroaryl ring are optionally replaced by following one or more groups independently: halogen, C
1-4alkyl, halo C
1-4alkyl or cyano group; M is 0 or 1; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, C
1-4alkoxyl group or amino; R
bbe selected from C
1-4alkyl; R
2independent selected from halo or C when it is present
1-4alkyl; R
3be selected from hydrogen, halogen, C
1-4alkyl, C
1-4alkoxyl group, formamyl, C
1-4alkyl-carbamoyl or two C
1-4alkyl-carbamoyl; And R
4be selected from hydrogen, halogen or C
1-4alkyl.
In some specific embodiments of formula II compound, the invention provides a kind of compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein said compound has formula II c (hereafter sometimes referred to as formula IIc compound):
Wherein Q, L, A, R
1, R
2, R
3all defined such as formula in II with m.
In some specific embodiments of formula IIc compound, in formula IIc, Q is selected from N or-CR
4; L is selected from-C (O)-or-S (O)
2-; A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; M is 0,1,2,3 or 4; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido; R
bbe selected from alkyl, amino, alkylamino or dialkyl amido; R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present; R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And R
4hydrogen, halogen or alkyl.
In some specific embodiments of formula IIc compound, in formula IIc, Q is selected from N or-CR
4; L is selected from-C (O)-or-S (O)
2-; A is selected from phenyl or 5-6 unit heteroaryl, and described phenyl or 5-6 unit heteroaryl ring are optionally replaced by following one or more groups independently: halogen, C
1-4alkyl, halo C
1-4alkyl or cyano group; M is 0 or 1; R
1be selected from-C (O) R
aor-S (O)
2r
b; R
abe selected from hydroxyl, C
1-4alkoxyl group or amino; R
bbe selected from C
1-4alkyl; R
2independent selected from halo or C when it is present
1-4alkyl; R
3be selected from hydrogen, halogen, C
1-4alkyl, C
1-4alkoxyl group, formamyl, C
1-4alkyl-carbamoyl or two C
1-4alkyl-carbamoyl; And R
4be selected from hydrogen, halogen or C
1-4alkyl.
In some embodiments, compound of the present invention is selected from:
Formula I of the present invention, formula II, formula IIa, formula IIb and formula IIc compound or its pharmacy acceptable salt may contain one or more chiral carbon atom, and each unsymmetrical carbon can be R or S configuration, and two kinds of configurations are all within the scope of the invention.Therefore, compound can exist as enantiomer, diastereomer or their mixture.Above-claimed cpd can select racemic modification, diastereomer or enantiomer as raw material or intermediate.Optically active isomer can use chiral synthon or chiral reagent to prepare, or uses routine techniques to split, such as, by chiral chromatography or fractional crystallization.
The routine techniques of preparation/separation individual isomeric comprises by the chiral synthesize of suitable optical purity precursor, or use such as chiral hplc to resolve racemic modification (or racemic modification of salt or derivative), such as can see Gerald G ü bitz 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 OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH Ed., Longman Scientific and TechnicalLtd., Essex, 1991,809-816; Heller, Acc.Chem.Res.1990,23,128.
Another aspect of the present invention relates to pharmaceutical composition, it comprises one or more formula I of the present invention, formula II, formula IIa, formula IIb and formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, and pharmaceutically acceptable vehicle.
Pharmaceutical composition of the present invention can be configured to solid-state, semi-solid state, liquid state or gaseous state preparation, as tablet, capsule, pulvis, granule, paste, solution, suppository, injection, inhalation, gelifying agent, microballoon and aerosol.
Pharmaceutical composition of the present invention can by method preparation known in pharmacy field.Such as, the pharmaceutical composition being intended to drug administration by injection by being combined to prepare by the distilled water of compound of the present invention or its pharmacy acceptable salt or prodrug and sterilizing, thus can form solution.Tensio-active agent can be added to promote to form homogeneous solution or suspension.The practical methods of pharmaceutical compositions is that those skilled in the art are known, such as can see The Science andPractice of Pharmacy (Pharmaceutical Sciences with put into practice), 20
thedition (Philadelphia College of Pharmacyand Science, 2000).
The route of administration of pharmaceutical composition of the present invention include but not limited to oral, locally, in skin, muscle, vein, suction, parenteral, sublingual, rectum, vagina and nose.Such as, the formulation being applicable to oral administration comprises capsule, tablet, granule and syrup etc.The formula I of the present invention, the formula II that comprise in these preparations, formula IIa, formula IIb or formula IIc compound can be pressed powder or particle; Solution in water-based or non-aqueous liquid or suspension; Water-in-oil or oil-in-water emulsion etc.Above-mentioned formulation can be made up via general practice of pharmacy of active compound and one or more carriers or auxiliary material.Above-mentioned carrier needs and active compound or other auxiliary materials compatibility.For solid preparation, conventional non-toxic carrier includes but not limited to N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, Mierocrystalline cellulose, glucose, sucrose etc.Carrier for liquid preparation includes but not limited to water, physiological saline, D/W, ethylene glycol and polyoxyethylene glycol etc.Active compound can form solution or suspension with above-mentioned carrier.Concrete administering mode and formulation depend on compound itself physico-chemical property and apply the severity etc. of disease.Those skilled in the art can determine concrete route of administration according to above-mentioned factor in conjunction with the knowledge that himself has.Such as can be see: Li Jun, " clinical pharmacology ", People's Health Publisher, 2008.06; Ding Yufeng, by Clinical Dosage Form Factors and rational use of drug, medical Leader, 26 (5), 2007; Howard C.Ansel, Loyd V.Allen, Jr., Nicholas G.Popovich work, Jiang Zhiqiang master translates, " pharmaceutical dosage form and drug delivery system ", China Medical Science Press, 2003.05.
Compound of the present invention or pharmaceutical composition of the present invention can also be combined with one or more antiphlogistons or combinationally use.Described antiphlogiston includes but not limited to: NSAID, non-specific and COX-2 specificity cyclooxygenase-2 inhibitors, gold compound, corticosteroids, Tumor Necrosis Factor Receptors antagonist, salicylate or salt, immunosuppressor and MTX.
Another aspect of the present invention relates to formula I of the present invention, formula II, formula IIa, formula IIb or formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug for the preparation of the purposes regulated in the medicine of ROR gamma activity.
Another aspect of the present invention relates to formula I of the present invention, formula II, formula IIa, formula IIb or formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug purposes in the medicine of the disease for the preparation of prevention or treatment ROR γ mediation.
Another aspect of the present invention relates to formula I of the present invention, formula II, formula IIa, formula IIb or formula IIc compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug in preparation as the purposes in the medicine of ROR gamma modulators.
Compound is herein the conditioning agent, the particularly conditioning agent of ROR γ of vitamin A acid related orphan acceptor ROR.These conditioning agents may be used for the disease mediated by ROR γ for the treatment of Mammals (especially people).In some embodiments, the disease that ROR γ mediates can be one or more autoimmunities and/or inflammatory diseases, and described disease includes but not limited to rheumatoid arthritis, multiple sclerosis, psoriatic, Crohn's disease, asthma, systemic lupus erythematous, chronic obstructive pulmonary disease, the rejection of tissue graft rejection reaction and transplant organ, scleroderma, purpura, autoimmune haemolytic and thrombocytopenic symptom, irritable bowel syndrome, osteoarthritis, mucocutaneous lymphnode syndrome, struma lymphomatosa, mucous membrane leischmaniasia, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolism rejection, children's rheumatoid arthritis, ankylosing spondylitis, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, sjorgen syndrome, optic neuritis, diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barre syndrome, psoriasis arthropathica, Ge Ruifushi disease or scleritis.
Pharmaceutical composition of the present invention is prepared in the mode meeting medical practice specification, quantitative and administration." the treatment effective dose " of the compounds of this invention is determined by the severity of the target spot of the cause of particular compound used, the concrete illness that treat, illness, medicine, disease, administering mode and the factor such as mammiferous age, body weight, physical appearance to be treated.Usually, the dosage through parenteral administration can be 1-200mg/kg, and the dosage of oral administration can be 1-1000mg/kg.
The scope of effective dose provided herein is not intended to limit the scope of the invention, but represents preferred dosage range.But most preferred dosage can adjust for concrete individuality, and this is that those skilled in the art understand and decidable (such as consulting the people such as Berkow to write, Merck handbook, the 16th edition, Merck company, Rahway, N.J., 1992).
the preparation of the compounds of this invention
Following reaction scheme exemplarily illustrates the preparation method of formula I of the present invention.
It will be appreciated by those skilled in the art that in the following description, only have when substituent combination can obtain stable compound, this kind of substituent combination is only permission.
Those skilled in the art it is also understood that in method hereinafter described, and midbody compound functional group may need to be protected by suitable protecting group.Such functional group comprises hydroxyl, amino, amidino groups, guanidine radicals, sulfydryl and carboxylic group.Suitable hydroxyl protecting group comprises trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl etc.The protecting group of suitable amino, amidino groups and guanidine radicals comprises tertbutyloxycarbonyl, carbobenzoxy-(Cbz) etc.Suitable sulfhydryl protected base comprises-C (O)-R " (wherein R " is alkyl, aryl or aralkyl), to methoxy-benzyl, trityl etc.Suitable carboxyl-protecting group comprises alkyl, aryl or aralkyl ester class.
Protecting group can be introduced according to standard technique well known by persons skilled in the art and as described herein and remove.
The use of protecting group is specified in Greene, T.W. and P.G.M.Wuts, Protective Groups in OrganicSynthesis (protecting group in organic synthesis), (1999), 4
thed., in Wiley.Protecting group also can be fluoropolymer resin.
Compound of the present invention can be prepared according to the method shown in following reaction scheme:
Scheme 1:
Wherein, X be-C (O)-; A, B, R
1, R
2, L, m and n as in structural formula I define.
According to scheme 1, wherein X be-C (O)-the synthesis of formula I be for starting raw material with adjacent nitro fluoro aromatic ring or adjacent nitro fluoro hetero-aromatic ring B, step 1 is carried out substitution reaction and is connected with the aniline of replacement by ring B under alkalescence (such as NaH) condition, step 2 is by nitroreduction (such as zinc powder/ammonium chloride), then step 3 utilizes triphosgene to prepare and ring intermediate under alkali (such as triethylamine) catalysis, final step 4 alkalescence (such as NaH) condition under with various substituted or non-substituted carboxylic acid halides, benzyl halide, sulfonic acid halide or sulfinyl halogen are obtained by reacting target formula I.
Scheme 2:
Wherein, X is-CH
2c (O)-or-CH
2cH
2-; Z is-CH
2-or-C (O)-; A, B, R
1, R
2, L, m and n as in structural formula I define.
According to scheme 2, wherein X is-CH
2c (O)-or-CH
2cH
2-the synthesis of formula I be for starting raw material equally with adjacent nitro fluoro aromatic ring or adjacent nitro fluoro hetero-aromatic ring B, step 1 is carried out substitution reaction and is connected with the aniline of replacement by ring B under alkalescence (such as NaH) condition, the anils obtained in step 2 alkalescence (such as NaH) condition under with 1, 2-ethylene dibromide or react with bromoacetyl chloride, then in step 3 by nitroreduction (such as tin protochloride/hydrochloric acid, backflow) become amino, one pot of generation ring closure reaction obtains and ring intermediate simultaneously, final step 4 alkalescence (preferred NaH) condition under with various substituted or non-substituted carboxylic acid halides, benzyl halide, sulfonic acid halide or sulfinyl halogen are obtained by reacting target compound.
Above-mentioned general synthetic route only represents the general method of most of embodiment, to the compound with special substituent, can carry out the variation known to those of ordinary skill in the art in certain step reaction.Such as the compound with ester group, esterolytic step can be added in the reaction.
Embodiment
The following examples illustrate preparation and the evaluated biological activity of compound within the scope of the present invention.
There is provided these embodiments below to enable those skilled in the art to more clearly understand and can the present invention be put into practice.They should not be considered to limit the scope of the invention, and be only illustrative with representational.
Test used starting raw material in the present invention or buy and prepared by known raw material from reagent suppliers or via method well known in the art.Except as otherwise noted, the embodiment of this paper applies following condition:
The unit of temperature is degree Celsius (DEG C); The definition of room temperature is 18-25 DEG C;
Organic solvent uses anhydrous magnesium sulfate or anhydrous sodium sulfate drying; Rotary Evaporators is used to be spin-dried for (such as: 15mmHg, 30 DEG C) under decompression Elevated Temperature Conditions;
Use 200-300 order silica gel as carrier during column chromatography for separation, TLC represents tlc;
Under normal circumstances, the progress of reaction is by TLC or LC-MS monitoring;
The qualification of the finished product is completed by nucleus magnetic resonance (Bruker AVANCE 300,300MHz) and LC-MS (Brukeresquine 6000, Agilent 1200series).
Embodiment 1:4-(3-(2,6-dichloro-benzoyl base)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The concrete steps of preparation embodiment 1 compound are as follows:
(1) preparation of 4-(the fluoro-6-nitro-phenylamino of 2-) methyl benzoate (1-1):
By PABA methyl esters (302mg, 2mmol) be dissolved in tetrahydrofuran (THF) (THF) (20mL) and dimethyl formamide (DMF) (4mL), under room temperature, slowly add sodium hydride (NaH) (60%, 120mg, 3mmol), stir 10min, and then add 1, the fluoro-3-oil of mirbane of 2-bis-(318mg, 2mmol) stir 5 hours, add water (10mL) cancellation, extract by ethyl acetate (50mL), organic phase is through anhydrous sodium sulfate drying, concentrating under reduced pressure, by enriched material through silica gel column chromatography (eluent: normal hexane: ethyl acetate=50:1) separation and purification, obtain 4-(the fluoro-6-nitro-phenylamino of 2-) methyl benzoate 1-1 (300mg), for yellow solid.Yield 52%.MS+H
+＝291。
(2) preparation of 4-(the fluoro-phenyl amino of 2-amino-6-) methyl benzoate (1-2):
By 4-(the fluoro-6-nitro-phenylamino of 2-) methyl benzoate (290mg, 1mmol) be dissolved in tetrahydrofuran (THF) (20mL) and water (2mL), zinc powder (390mg is added under room temperature, 6mmol) with ammonium chloride (321mg, 6mmol), stir 2 hours.Stopped reaction, reaction mixture filters; Aqueous phase separation in filtrate is gone out, organic phase is through anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure obtains 4-(2-amino-6-fluoroanilino) methyl benzoate 1-2 (260mg), for colorless oil, namely the product obtained can be used for next step reaction without the need to being further purified.MS+H
+＝261.1。
(3) preparation of 4-(fluoro-1,2-dihydro-2-ketone-benzo [d] imidazo-3-yl of 4-) methyl benzoate (1-3)
4-(the fluoro-phenyl amino of 2-amino-6-) methyl benzoate (260mg, 1mmol) is dissolved in methylene dichloride (DCM) (20mL), adds triethylamine (606mg, 6mmol).Be cooled to-78 DEG C, add triphosgene (297mg, 1mmol), be slowly warmed up to room temperature.Add water (10mL) cancellation, extraction into ethyl acetate (20mL × 3), organic phase is through anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, by enriched material through silica gel column chromatography (normal hexane: ethyl acetate=1:1) separation and purification, obtains 4-(4-fluoro-1,2-dihydro-2-ketone-benzo [d] imidazo-3-yl) methyl benzoate 1-3 (250mg) is pale solid.MS+H
+＝287.2。
(4) preparation of 4-(fluoro-1,2-dihydro-2-ketone-benzo [d] imidazo-3-yl of 4-) phenylformic acid (1-4)
LiOH (188mg, 7.86mmol) be dissolved in 10mL water, add 4-(fluoro-1,2-dihydro-2-ketone-benzo [d] imidazo-3-yl of 4-) methyl benzoate (250mg, 0.87mmol) and be dissolved in solution in 20mL methyl alcohol.Stirring at room temperature 3 hours.Remove methyl alcohol under reduced pressure, add 20mL water, aqueous phase ethyl acetate is washed three times (20mL × 3), adds hydrochloric acid and is acidified to pH=5, separates out solid, filter, drying, obtains 4-(fluoro-1,2-dihydro-2-ketone-benzo [d] imidazo-3-yl of 4-) phenylformic acid 1-4 (230mg), for white solid, yield 97%.MS+H
+＝273.2。
(5) preparation of 4-(3-(2,6-dichloro-benzoyl base)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid (compound 1)
By 4-(4-fluoro-1, 2-dihydro-2-ketone-benzo [d] imidazo-3-yl) phenylformic acid (27mg, 0.1mmol) be dissolved in DMF (2mL), sodium hydride (60% is added under room temperature, 12mg, 0.3mmol), stir 5min, then 2 are added, 6-dichlorobenzoyl chloride (31mg, 0.15mmol), stir 10min, with water (5mL) cancellation, add hydrochloric acid and be acidified to pH=5, extraction into ethyl acetate (10mL × 3), organic phase is after anhydrous sodium sulfate drying, filter, filtrate concentrates, enriched material obtains 10mg target compound through silica gel column chromatography (eluent: normal hexane: ethyl acetate=1:1) separation and purification, for white solid, yield 22%.Data characterization is as follows: MS+Na
+=467.4;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.29 (d, J=8.1Hz, 1H), 8.20 (d, J=8.7Hz, 2H), 7.56 (dd, J
1=8.7Hz, J
2=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-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 1-methyl-2-fluoro-3-oil of mirbane for the fluoro-3-oil of mirbane of raw material replacement 1,2-bis-in step 1.Relevant characterization data are as follows: MS+H
+=441.7;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.36 (d, J=8.1Hz, 1H), 8.22 (d, J=8.4Hz, 2H), 7.51 (d, J
1=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) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 2, and difference is to use 4-fluorophenylsulfonyl chloride for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+H
+=427.5;
1h-NMR (CD
3oD, 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-(3-(2,4 difluorobenzene formyl radical)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 2,4 difluorobenzene formyl chloride for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+H
+=413.9;
1h-NMR (CDCl
3, 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, J
1=8.7Hz, J
2=2.7Hz, 2H), 7.05 ~ 6.21 (m, 1H), 7.09 ~ 6.84 (m, 3H).
Embodiment 5:4-(3-(2-chloro-6-fluoro benzoyl)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use the chloro-6-fluorobenzoyl chloride of 2-for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+Na
+=451.5;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.20 (d, J=8.1Hz, 1H), 8.14 (d, J=8.7Hz, 2H), 7.51 (dd, J
1=8.7Hz, J
2=2.7Hz, 1H), 7.24 ~ 7.17 (m, 4H), 7.05-6.99 (m, 2H).
Embodiment 6:4-(3-(4-fluoro benzoyl)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 4-fluorobenzoyl chloride for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows:
1H-NMR(DMSO-d
6，300MHz)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,J
1＝8.7Hz,J
2＝2.1Hz,2H),7.38～7.18(m,4H)。
Embodiment 7:4-(3-(4-TRIFLUOROMETHYLBENZOYL)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 4-trifluoromethyl benzoyl chloride for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+Na
+=467.2;
1h-NMR (DMSO-d
6, 300MHz) and δ: ppm 13.2 (brs, 1H), 8.08 ~ 8.05 (m, 4H), 7.90 ~ 7.86 (m, 3H), 7.67 (dd, J
1=8.7Hz, J
2=2.1Hz, 2H), 7.32 ~ 7.19 (m, 2H).
Embodiment 8:4-(3-benzyl-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use bromotoluene for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+H
+=363.2;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.24 (d, J=8.7Hz, 2H), 7.65 (dd, J
1=8.7Hz, J
2=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-(3-(2,6-dichloro benzyl)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 2,6-dichloro benzyl bromine to be that raw material replaces 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+H
+=433.3;
1h-NMR (CDCl
3, 300MHz) and 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-(3-(4-cyanobenzoyl)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 4-cyano-benzoyl chloride for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+Na
+=425.1;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.24 (d, J=8.7Hz, 2H), 7.98 (d, J=8.1Hz, 1H), 7.78 ~ 7.69 (dd, J
1=8.4Hz, J
2=24.3Hz, 4H), 7.59 (dd, J
1=2.7Hz, J
2=8.7Hz, 2H), 7.13 (m, 1H).
Embodiment 11:4-(3-(2,6-dichloro-benzoyl base)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) methyl benzoate
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is that 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 (CDCl
3, 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, difference is to use the fluoro-3-nitrobenzoic acid of 4-to replace 1 in step 1, the fluoro-3-oil of mirbane of 2-bis-and use PABA ethyl ester replace PABA methyl esters, and between step 1 and step 2, add reactions steps carboxyl being converted to formyl-dimethylamino, product 4-(4 '-carbethoxy phenyl is amino)-3-nitrobenzoic acid by the first step reaction is dissolved in appropriate DMF, then the tetramethyl-urea phosphofluoric acid ester (HATU) of 1 equivalent and the diisopropylethylamine (DIEA) of 2 equivalents is added, stirring at room temperature adds the dimethylamine/tetrahydrofuran solution of 2 equivalents after 15 minutes, after stirring is spent the night, silica gel column chromatography (eluent: normal hexane: ethyl acetate=1:1) separation and purification.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] imidazoles-2 (3H)-one
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 4-methylsulfonylaniline for raw material replacement PABA methyl esters in step 1.Relevant characterization data are as follows: MS+H
+=479.7;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.30 (d, J=8.1Hz, 1H), 8.04 (d, J=8.7Hz, 2H), 7.66 (dd, J
1=8.7Hz, J
2=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] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 1-methoxyl group-3-fluoro-4-oil of mirbane for the fluoro-3-oil of mirbane of raw material replacement 1,2-bis-in step 1.Relevant characterization data are as follows: MS+H
+=459.2;
1h-NMR (DMSO-d
6, 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, J
1=8.7Hz, J
2=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] pyridine-3 (2H)-Ji) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 2-fluoro-3-nitropyridine for the fluoro-3-oil of mirbane of raw material replacement 1,2-bis-in step 1.Relevant characterization data are as follows: MS+H
+=428.1;
1h-NMR (DMSO-d
6, 300MHz) and δ: ppm 13.090 (brs, 1H), 8.527-8.498 (dd, 1H, J
1=7.8Hz, J
2=0.9Hz), 8.281-8.260 (dd, 1H, J
1=5.1Hz, J
2=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) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 1-fluoro-2-oil of mirbane for the fluoro-3-oil of mirbane of raw material replacement 1,2-bis-in step 1.Relevant characterization data are as follows: MS+H
+=401.2;
1h-NMR (DMSO-d
6, 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) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use the chloro-2-of 1-fluoro-3-oil of mirbane for the fluoro-3-oil of mirbane of raw material replacement 1,2-bis-in step 1.Relevant characterization data are as follows: MS+H
+=459.1;
1h-NMR (DMSO-d
6, 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-(3-(2,6-dichloro-benzoyl base)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base)-2-fluorobenzoic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 4-amino-2-fluorophenyl carbamate for raw material replacement 4-amino-benzoic acid methyl ester in step 1.Relevant characterization data are as follows: MS+H
+=463.2;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.30 (d, J=8.1Hz, 1H), 8.12 (dd, J
1=8.7Hz, J
2=7.8Hz, 1H), 7.39 ~ 7.29 (m, 6H), 7.12 (ddd, J
1=8.7Hz, J
2=7.8Hz, J
3=0.9Hz, 1H).
Embodiment 19:4-(3-phenylacetyl-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use phenyllacetyl chloride for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+Na
+=413.2;
1h-NMR (DMSO-d
6, 300MHz) and δ: ppm 7.39 ~ 7.29 (m, 2H), 8.01 (d, J=7.5Hz, 1H), 7.70 (dd, J
1=8.4Hz, J
2=2.1Hz, 2H), 7.38 ~ 7.14 (m, 7H), 4.50 (s, 2H).
Embodiment 20:4-(3-(4-chloro acetyl)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 1, and difference is to use 4-chlorophenylacetyl chloride for raw material replacement 2,6-dichlorobenzoyl chloride in step 5.Relevant characterization data are as follows: MS+Na
+=447.3;
1h-NMR (DMSO-d
6, 300MHz) and δ: ppm 8.12 (d, J=8.7Hz, 2H), 7.99 (d, J=7.2Hz, 1H), 7.69 (dd, J
1=8.7Hz, J
2=2.1Hz, 2H), 7.41 ~ 7.14 (m, 6H), 4.50 (s, 2H).
Embodiment 21:4-(3-(2,6-dichloro-benzoyl base)-7-fluoro-2-ketone-2,3-dihydro-1H-benzo [d] imidazoles-1-base) benzamide
Take 20mg compound 1 (available from embodiment 1) and be placed in 50mL round-bottomed bottle, add 5mL thionyl chloride, it is entirely molten that stirring heating is back to compound 1, after 30 minutes, steaming desolventizes, then residue is dissolved in 10mL methylene dichloride, ammonia/dioxane solution the 5mL of 0.5N is slowly instilled under room temperature, stir 10 minutes, then 10mL washing is added, organic phase anhydrous magnesium sulfate drying, filter, with thin layer silica gel (GF-254) plate (normal hexane: ethyl acetate=1:1) separation and purification after concentrated, obtain 17mg title compound, for white powder, yield: 87%.Relevant characterization data are as follows: MS+H
+=444.0;
1h-NMR (CDCl
3, 300MHz) and δ: ppm 8.29 (d, J=8.1Hz, 1H), 7.90 (d, J=8.4Hz, 2H), 7.53 (dd, J
1=8.7Hz, J
2=2.4Hz, 2H), 7.40 ~ 7.25 (m, 4H), 7.11 ~ 7.07 (m, 1H).
Embodiment 22:4-(4-(2,6-dichloro-benzoyl base)-8-fluoro-2-ketone-3,4-dihydro-quinoxaline-1 (2H)-Ji) phenylformic acid
The concrete steps of preparation embodiment 22 compound are as follows:
(1) step 1 is identical with the step 1 of preparation embodiment 1 compound, obtains intermediate 4-(the fluoro-6-nitro-phenylamino of 2-) methyl benzoate (1-1)
(2) preparation of 4-(the bromo-N-of 2-(the fluoro-6-oil of mirbane of 2-) base-kharophen) ethyl benzoate (22-2)
Intermediate 1-1 (152mg, 0.5mmol) is dissolved in 3mL DMF, under room temperature, adds NaH (60%, 60mg, 1.5mmol), after stirring at room temperature 0.5h, add 2-bromoacetyl chlorine (118mg, 0.75mmol), after stirring at room temperature 2h, TLC detect 1-1 completely dissolve, cancellation is reacted, reaction solution is poured in 30mL water, and ethyl acetate (30mL × 3) extracts.Organic phase after merging is washed successively through saturated sodium bicarbonate and saturated aqueous common salt, anhydrous sodium sulfate drying, filters, concentrated, it is 22-2 that thin layer silica gel (GF-254) plate separation (normal hexane: ethyl acetate=3:1) obtains 128mg faint yellow solid, yield 60.4%.
(3) preparation of 4-(8-fluoro-2-ketone-3,4-dihydro-quinoxaline-1 (2H)-Ji) ethyl benzoate (22-3)
Intermediate 22-2 (106mg, 0.25mmol) be dissolved in 5mL ethanol, room temperature adds tin protochloride (237mg, 1.25mmol), reflux 3.5h, after TLC detects 22-2 completely dissolve, concentrated evaporate to dryness reaction solution, residue obtainedly add in 30mL ethyl acetate, stirring and evenly mixing, then saturated sodium bicarbonate is used, saturated aqueous common salt washs said mixture successively, after separatory, organic phase is through anhydrous sodium sulfate drying, filter, obtaining 46mg faint yellow solid by thin layer chromatography board separation (normal hexane: ethyl acetate=1:1) after filtrate is concentrated is 22-3, yield 58.6%.
(4) preparation of 4-(4-(2,6-dichloro-benzoyl base)-8-fluoro-2-ketone-3,4-dihydro-quinoxaline-1 (2H)-Ji) ethyl benzoate (22-4)
Intermediate 22-3 (31.4mg, 0.1mmol) is dissolved in 3mL DMF, and room temperature adds NaH (60%, 12mg, 0.3mmol), after stirring at room temperature 0.5h, add acyl chlorides (41.9mg, 0.2mmol), after stirring at room temperature 2h, TLC detect 22-3 completely dissolve, cancellation is reacted, reaction solution is poured in 10mL water, and ethyl acetate (10mL × 3) extracts.Merge organic phase, wash successively with saturated sodium bicarbonate, saturated aqueous common salt, anhydrous sodium sulfate drying organic phase, filter, concentrated filtrate, obtaining 35mg faint yellow solid through thin layer chromatography board separation and purification (normal hexane: ethyl acetate=5:1) is 22-4, yield 72%.
(5) preparation of 4-(4-(2,6-dichloro-benzoyl base)-8-fluoro-2-ketone-3,4-dihydro-quinoxaline-1 (2H)-Ji) phenylformic acid (22)
Intermediate 22-4 (35mg, 0.072mmol) is dissolved in 5mL THF, adds 1mL H
2o, adds LiOHH under room temperature
2o (28.8mg, 0.72mmol), reaction solution stirred overnight at room temperature, TLC adds 3mL H after detecting 22-4 completely dissolve
2o, add 1mL 1N aqueous hydrochloric acid, stir 5min, ethyl acetate (5mL × 3) extracts, and merges organic phase, through saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated filtrate, be separated (normal hexane: ethyl acetate=3:1) through thin layer chromatography board and obtain 16mg faint yellow solid 22, yield 48.5%.Relevant characterization data are as follows: MS+H
+=463.2;
1h-NMR (DMSO-d
6, 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-3,4-dihydro-quinoxaline-1 (the 2H)-Ji of 4-(2,6-dichloro-benzoyl base)-8-) phenylformic acid
The present embodiment compound can be prepared according to the step method similar with previous embodiment 22, and difference is to use in step 2 glycol dibromide to replace 2-bromoacetyl chlorine to carry out amino substitution reaction for raw material.Relevant characterization data are as follows: MS+H
+=445.2;
1h-NMR (CDCl
3, 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 screens
Compound of the present invention can regulate the biological activity of (suppression) nuclear receptor ROR γ, and this power regulating (suppression) to act on is evaluated by TR-FRET system of screening.Nuclear receptor cofactor (the co-activation Summing Factor co-suppression factor) is by regulating transcribing of goal gene with the interaction of nuclear receptor.If part (test-compound) have impact on the interaction of nuclear receptor and cofactor, so this part (test-compound) just can regulate transcribing of corresponding gene.
Present method adopts LanthaScreen TR-FRET (time resolved fluorescence resonance energy transfer) the technical measurement compound of Life Technologies company to the regulating power (excited or oppositely excited) of ROR γ and its co-activation factor interaction.The anti-GST antibody (Life Technologies#PV3550) that terbium (Tb) marks is by the GST label that is combined in ROR γ-LBD (Life Technologies#PV5887) carries out non-immediate mark to ROR γ-LBD.When not having a part, ROR γ can continue combine with the fluorescein-labeled co-activation factor, can strengthen the interaction of ROR γ and the fluorescein-labeled co-activation factor after agonist is combined with ROR γ; The interaction of ROR γ and the fluorescein-labeled co-activation factor can be suppressed after inverse agonist is combined with ROR γ.What the anti-GST antibody-ROR that the fluorescein-labeled co-activation factor and terbium mark marked swash altogether, and mixture is close to each other energy trasfer can occur to certain distance, generation TR-FRET signal.The co-activation factor that present method uses is not limited to Fluorescein-D22 (LifeTechnologies#PV4386), Fluorescein-SRC1-2 (Life Technologies#PV4578), Fluorescein-SRC1-4 (Life Technologies#PV4582) etc.
(1) final concentration of present method reaction system and reaction conditions are as following table: (table 1)
(2) experimental technique
Preparation Complete TR-FRET Coregulator Buffer D (hereinafter referred to as complete damping fluid D): adding DTT (LifeTechnologies#P2325) to DTT final concentration to TR-FRET Coregulator Buffer D (Life Technologies#PV4420) is 5mM.
Use full buffer liquid D and prepare 2X Fluorescein-D22 (0.3 μM, with reference to table 1 when using other co-activation peptide) and the mixing solutions of anti-GST antibody (4nM) of 2X Tb mark, 10 μ L/ holes join in 384-orifice plate (Corning3376).
Use DMSO to prepare the testing compound of 100X final concentration gradient dilution, then use full buffer liquid D and testing compound is diluted to 4X (DMSO content is 4%), 5 μ L/ holes join in above-mentioned 384-orifice plate, mix.The complete damping fluid D (without testing compound) containing 4%DMSO is added with 5 μ L/ holes in Positive control wells.
Use full buffer liquid D and prepare 4X ROR γ-LBD (8nM), 5 μ L/ holes join in above-mentioned 384-orifice plate, mix.The 5 complete damping fluid D in μ L/ hole (without ROR γ-LBD) are added in negative control hole.384-orifice plate is placed in constant temperature oscillator, hatches 4 ~ 5 hours in 23 DEG C of lucifuges.
Use Tecan M1000Pro to measure fluorescence intensity: 1) excitation wavelength 332/20nm, emission wavelength 490/10nm, yield value: to optimize, flash of light: pattern 2 (100Hz), time of lag 100 μ s, integrating time 200 μ s; 2) excitation wavelength 332/20nm, emission wavelength 520/20nm, yield value: optimize, flash of light: pattern 2 (100Hz), time of lag 100 μ s, integrating time 200 μ s.
(3) data analysis
Service routine GraphPad Prism draws the logarithmic curve of TR-FRET ratio F520/F490 – compound concentration, and calculate EC50 value, this numerical value less explanation compound to acceptor ROR γ regulate (in the present embodiment for suppress) to act on stronger.
The EC50 value of section Example compound to ROR γ effect sees the following form: (table 2)
The mode of explanation and embodiment describes foregoing invention in detail by way of example, for the object set forth and understand.It will be apparent to one skilled in the art that and can carry out changes and improvements in the scope of accompanying claim.Therefore, should be appreciated that above-mentioned explanation is illustrative instead of restrictive.Therefore, scope of the present invention should not determined with reference to above-mentioned specification sheets, and with reference to following accompanying claim and should be determined by the four corner of the Equivalent of claims issue.
Claims (14)
1. compound or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, described compound has structural formula I:
Wherein:
X be selected from-C (O)-,-CH
2c (O)-or-CH
2cH
2-;
L be selected from-C (O)-,-S (O)-,-S (O)
2-or-CH
2-;
A is selected from aryl or heteroaryl, and described aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, sulfonamido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl;
B is selected from following divalence ring: cycloalkyl, heterocyclic radical, aryl or heteroaryl, and described cycloalkyl, heterocyclic radical or aryl or heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, nitro, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, alkyl sulfonyl amino, amino-sulfonyl, alkyl amino sulfonyl, dialkyl amino sulfonyl, formamyl, alkyl-carbamoyl, dialkyl carbamoyl, amido or alkyl acyl;
M is 0,1,2,3 or 4;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido; And
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present.
2. compound according to claim 1 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein said compound has formula II:
Wherein:
Q is selected from N or-CR
4;
X be selected from-C (O)-,-CH
2c (O)-or-CH
2cH
2-;
L be selected from-C (O)-,-S (O)
2-or-CH
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, alkyl sulphonyl, sulfonamido, amido, formamyl, alkyl-carbamoyl, dialkyl carbamoyl or alkyl acyl;
M is 0,1,2,3 or 4;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4be selected from hydrogen, halogen or alkyl.
3. compound according to claim 2 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein, in formula II:
Q is N or-CR
4;
X be selected from-C (O)-,-CH
2c (O)-or-CH
2cH
2-;
L be selected from-C (O)-,-S (O)
2-or-CH
2-;
A is selected from C
6-10aryl or 5-10 unit heteroaryl, described C
6-10aryl or 5-10 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl, C
1-4alkylamino, two C
1-4alkylamino, formamyl, C
1-4alkyl-carbamoyl or two C
1-4alkyl-carbamoyl;
M is 0 or 1;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, C
1-4alkoxyl group, amino, C
1-4alkylamino or two C
1-4alkylamino;
R
bbe selected from C
1-4alkyl, amino, C
1-4alkylamino or two C
1-4alkylamino;
R
2independent selected from halo, cyano group, hydroxyl, C when it is present
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl or halo C
1-4alkoxyl group;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl, C
1-4alkylamino, two C
1-4alkylamino, formamyl, C
1-4alkyl-carbamoyl or two C
1-4alkyl-carbamoyl; And
R
4be selected from hydrogen, halogen or C
1-4alkyl.
4. compound according to claim 1 and 2 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein said compound has formula II a:
Wherein:
Q is selected from N or-CR
4;
L be selected from-C (O)-,-S (O)
2-or-CH
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl;
M is 0,1,2,3 or 4;
N is 0,1 or 2;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, hydroxyl, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4be selected from hydrogen, halogen or alkyl.
5. compound according to claim 4 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein, in formula IIa:
Q is N or-CR
4;
L be selected from-C (O)-,-S (O)
2-or-CH
2-;
A is selected from phenyl or 5-6 unit heteroaryl, and described phenyl or 5-6 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, cyano group, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl;
M is 0,1 or 2;
N is 0 or 1;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, C
1-4alkoxyl group, amino, C
1-4alkylamino or two C
1-4alkylamino;
R
bbe selected from C
1-4alkyl, amino, C
1-4alkylamino or two C
1-4alkylamino;
R
2independent selected from halo, cyano group, C when it is present
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl or halo C
1-4alkoxyl group;
R
3be selected from hydrogen, halogen, cyano group, C
1-4alkyl, C
1-4alkoxyl group, halo C
1-4alkyl, formamyl, C
1-4alkyl-carbamoyl or two C
1-4alkyl-carbamoyl; And
R
4be selected from hydrogen, halogen or C
1-4alkyl.
6. compound according to claim 4 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein, in formula IIa:
Q is selected from N or-CR
4;
L is selected from-C (O)-or-CH
2-;
A is phenyl, and described phenyl is optionally replaced by following one or more groups independently: halogen, C
1-4alkyl or halo C
1-4alkyl;
M is 0 or 1;
N is 0;
R
1for-COOH;
R
2independent selected from halo, C when it is present
1-4alkyl or halo C
1-4alkyl;
R
3be selected from hydrogen; And
R
4be selected from hydrogen, halogen or C
1-4alkyl.
7. compound according to claim 1 and 2 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein, described compound has formula II b:
Wherein:
Q is N or-CR
4;
L is selected from-C (O)-or-S (O)
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl ring are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl;
M is 0,1,2,3 or 4;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4be selected from hydrogen, halogen or alkyl.
8. compound according to claim 1 and 2 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein, described compound has formula II c:
Wherein:
Q is N or-CR
4;
L is selected from-C (O)-or-S (O)
2-;
A is selected from C
6-12aryl or 5-12 unit heteroaryl, described C
6-12aryl or 5-12 unit heteroaryl are optionally replaced by following one or more groups independently: halogen, amino, cyano group, hydroxyl, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl;
M is 0,1,2,3 or 4;
R
1be selected from-C (O) R
aor-S (O)
2r
b;
R
abe selected from hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido;
R
bbe selected from alkyl, amino, alkylamino or dialkyl amido;
R
2independent selected from halo, cyano group, nitro, hydroxyl, alkyl acyl oxygen base, alkyl, alkoxyl group, haloalkyl or halogenated alkoxy when it is present;
R
3be selected from hydrogen, halogen, cyano group, carboxyl, alkyl, alkoxyl group, haloalkyl, alkylamino, dialkyl amido, formamyl, alkyl-carbamoyl or dialkyl carbamoyl; And
R
4hydrogen, halogen or alkyl.
9. compound according to claim 1 and 2 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, wherein said compound is selected from:
10. a pharmaceutical composition, comprises compound according to any one of claim 1-9 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug, and pharmaceutically acceptable vehicle.
11. pharmaceutical compositions according to claim 10, also comprise one or more and are selected from following antiphlogiston: non-steroidal anti-inflammatory drugs, non-specific and COX-2 specificity cyclooxygenase-2 inhibitors, gold compound, corticosteroids, Tumor Necrosis Factor Receptors antagonist, salicylate or salt, immunosuppressor and MTX.
12. compounds according to any one of claim 1 to 9 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug in preparation as the purposes in the medicine of ROR gamma modulators.
13. compounds according to any one of claim 1 to 9 or its steric isomer, tautomer or its pharmacy acceptable salt or its solvate or its prodrug purposes in the medicine of the disease of preparation prevention or treatment ROR γ mediation.
14. purposes according to claim 13, the disease that wherein said ROR γ mediates is selected from: rheumatoid arthritis, multiple sclerosis, psoriatic, Crohn's disease, asthma, systemic lupus erythematous, chronic obstructive pulmonary disease, the rejection of tissue graft rejection reaction and transplant organ, scleroderma, purpura, autoimmune haemolytic and thrombocytopenic symptom, irritable bowel syndrome, osteoarthritis, mucocutaneous lymphnode syndrome, struma lymphomatosa, mucous membrane leischmaniasia, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolism rejection, children's rheumatoid arthritis, ankylosing spondylitis, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, sjorgen syndrome, optic neuritis, diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barre syndrome, psoriasis arthropathica, Ge Ruifushi disease or scleritis.
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| CN2014100976485 | 2014-03-18 | ||
| CN201410097648 | 2014-03-18 | ||
| CN201510117243.8A CN104926733B (en) | 2014-03-18 | 2015-03-17 | Compound as ROR gamma modulators |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111418A (en) * | 2017-06-23 | 2019-01-01 | 南京柯菲平盛辉制药有限公司 | A kind of 2,3- dihydro -1H- indenes -4- sulfonamide ROR gamma modulators and application thereof |
| CN109415358A (en) * | 2016-04-27 | 2019-03-01 | 詹森药业有限公司 | 6- aminopyridine -3- base thiazole as ROR γ t regulator |
| US11345666B2 (en) | 2018-06-18 | 2022-05-31 | Janssen Pharmaceutica Nv | Phenyl and pyridinyl substituted imidazoles as modulators of RORγT |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112017014770A2 (en) * | 2015-01-08 | 2018-01-16 | Advinus Therapeutics Ltd | bicyclic compounds, compositions and medical applications thereof |
| TW202220968A (en) * | 2016-01-29 | 2022-06-01 | 美商維它藥物有限責任公司 | Modulators of ror-gamma |
| CN112689637B (en) * | 2018-09-13 | 2023-11-10 | 橘生药品工业株式会社 | Imidazopyridone compounds |
| CN112574191B (en) * | 2019-09-29 | 2024-01-23 | 南京圣和药业股份有限公司 | Isoxazole heterocyclic compound and application thereof |
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| CA2933618A1 (en) * | 2013-10-10 | 2015-04-16 | Glenmark Pharmaceuticals S.A. | Substituted dihydro-benzimidazole compounds as ror gamma modulators |
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- 2015-03-17 CN CN201510117243.8A patent/CN104926733B/en active Active
- 2015-03-17 WO PCT/CN2015/074412 patent/WO2015139619A1/en active Application Filing
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| EP1958947A1 (en) * | 2007-02-15 | 2008-08-20 | Ranbaxy Laboratories Limited | Inhibitors of phosphodiesterase type 4 |
| WO2012027965A1 (en) * | 2010-09-01 | 2012-03-08 | Glaxo Group Limited | Novel compounds |
| WO2012100734A1 (en) * | 2011-01-24 | 2012-08-02 | Glaxo Group Limited | Compounds useful as retinoid-related orphan receptor gamma modulators |
| WO2012131501A1 (en) * | 2011-03-28 | 2012-10-04 | Glenmark Pharmaceuticals S.A. | Substituted benzimidazole compounds as cot kinase inhibitors |
| WO2013171729A2 (en) * | 2013-01-08 | 2013-11-21 | Glenmark Pharmaceuticals S.A. | Aryl and heteroaryl amide compounds as rorgamat modulator |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109415358A (en) * | 2016-04-27 | 2019-03-01 | 詹森药业有限公司 | 6- aminopyridine -3- base thiazole as ROR γ t regulator |
| CN109415358B (en) * | 2016-04-27 | 2022-04-05 | 詹森药业有限公司 | 6-aminopyridin-3-ylthiazoles as ROR gamma t modulators |
| CN109111418A (en) * | 2017-06-23 | 2019-01-01 | 南京柯菲平盛辉制药有限公司 | A kind of 2,3- dihydro -1H- indenes -4- sulfonamide ROR gamma modulators and application thereof |
| CN109111418B (en) * | 2017-06-23 | 2022-10-11 | 江苏柯菲平医药股份有限公司 | 2,3-dihydro-1H-indene-4-sulfonamide ROR gamma regulator and application thereof |
| US11345666B2 (en) | 2018-06-18 | 2022-05-31 | Janssen Pharmaceutica Nv | Phenyl and pyridinyl substituted imidazoles as modulators of RORγT |
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| Publication number | Publication date |
|---|---|
| WO2015139619A1 (en) | 2015-09-24 |
| CN104926733B (en) | 2019-05-10 |
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