CN110382500A - Carbamide compounds for IDO and TDO double inhibitor - Google Patents

Carbamide compounds for IDO and TDO double inhibitor Download PDF

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CN110382500A
CN110382500A CN201880015782.2A CN201880015782A CN110382500A CN 110382500 A CN110382500 A CN 110382500A CN 201880015782 A CN201880015782 A CN 201880015782A CN 110382500 A CN110382500 A CN 110382500A
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alkyl
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atom
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CN110382500B (en
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王大可
张英利
王树龙
闵汪洋
陈坤成
刘志华
刘希杰
胡远东
赵娜
彭勇
罗鸿
田心
张喜全
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Shouyao Holdings Beijing Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Shouyao Holdings Beijing Co Ltd
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Abstract

The purposes in immunosuppressant disease that carbamide compounds or its pharmaceutically acceptable salt and its preparation preparation method, pharmaceutical composition and treatment IDO and TDO as shown in formula (I) with IDO and TDO dual restraining activities mediate.

Description

Carbamide compounds for IDO and TDO double inhibitor Technical field
The invention belongs to pharmaceutical technology field, be related to the carbamide compounds of IDO and TDO double inhibitor, preparation method, the pharmaceutical composition containing the compound and its diseases and disorder for being mediated in the activity of regulation IDO and TDO and treatment by them purposes.
Background technique
Indoleamine 2,3- dioxygenase (IDO) and tryptophan 2,3- oxygenase (TDO) is two kinds of important enzymes for decomposing tryptophan, it is expressed in kinds of tumor cells and surrounding microenvironment cell, pass through the tryptophan in degradation local organization, generate tryptophan depletion environment and increase local metabolic product kynurenin concentration and influence the immune function of T cell, induce host immune defenses, inhibit T cell immune and antineoplastic immune, induction Maternal-placental immune toler ance and graft immune tolerance in play important metabolic immunoregulation effect.
IDO expression or active exception, which increase, has been found closely related with the pathogenesis of the diseases such as depression, Alzheimer disease, cataract, cancer, and therefore, IDO inhibitor is likely to become a kind of effective ways for treating these diseases.Although many decades have been carried out in the domestic and international research in relation to IDO inhibitor, still listed at present without IDO inhibitor as drug.Current existing IDO inhibitor is broadly divided into following classification: 1) competitive inhibitor, such as tryptophan derivative 1-MT；2) noncompetitive inhibitor, such as phenylimidazole；3) uncompetitive inhibitor agent, such as alkaloid exiguamine A；4) pass through the inhibitor of other mechanism of action.The generally existing inhibition inefficiency of this few class inhibitor, can not be through cell membrane and the problems such as generate indole ring structures metabolin.The 1990s, the derivative 1- methyl tryptophan (1-methyl-tryptophan obtained and the substrate tryptophan to IDO is template progress structure of modification, it 1-MT) is IDO inhibitor general in current inside and outside experiment, inhibition constant (Ki) is 34 μM.So far, the NLG919 compound of U.S. New link Genetics company and the INCB024360 compound of U.S. Incyte company have come into clinical test.
Nearest research causes the survival of tumour cell and the raising of transfer ability and immune system to be suppressed the responsibility of tumour cell, it was also found that TDO is expressed in kinds of tumor cells.The effect that TDO generates tumour cell and immunosupress becomes a new anti-tumor drug target.Therefore, Novel IDO/TDO inhibitor is screened, and studies its activity in vivo, pharmacokinetics, therapeutic effect and adverse reaction etc. and is still one and be worth the field explored.
Summary of the invention
The present invention provides compounds of formula I or its pharmaceutically acceptable salt,
Wherein,
Ring A is not present or ring A is phenyl ring or the 5-6 member hetero-aromatic ring containing 1,2 or 3 selected from N, O or S atom；
Ring B is 5-membered aromatic ring, wherein 1,2,3 or 4 in W, V, X, Y and Z is selected from N or NH, other to be selected from C or CH, specifically,
I) it is CH that Y and V, which is N, Z and W, and X is C；
Ii) Y, Z, V and W are N, and X is C；
Iii it is CH that) X and V, which is N, Z and W, and Y is C；
Iv) Y, Z and V are N, and W is CH, and X is C；
V) X, Z and V are N, and W is CH, and Y is C；
Vi) X is N, and Z, V and W are CH, and Y is C；
Vii) Y is N, and Z, V and W are CH, and X is C；
Viii it be CH, X and Y is C that) Z, which is NH, V and W,；
Ix it be CH, X and Y is C that) V, which is NH, Z and W,；
X) it be CH, X and Y is C that W, which is NH, V and Z,；
Xi) V and W is N or NH, and Z is that CH, X and Y are C；
Xii) V and Z is N or NH, and W is that CH, X and Y are C；
Xiii) Z and W is N or NH, and V is that CH, X and Y are C；
Xiv it is CH that) Y and W, which is N, V and Z, and X is C；
Xv it is CH that) X and W, which is N, V and Z, and Y is C；
Xvi) X and Z is N or NH, and V and W are CH, and Y is C；
Xvii it is CH that) Y and Z, which is N, V and W, and X is C；
Xviii) Y, V and W are N, and Z is CH, and X is C；
Xix) Z, V and W are N or NH, and X and Y are C；
Xx) X, W and V are N, and Z is CH, and Y is C；
Xxi) Y, Z and W are N, and V is CH, and X is C；Or
Xxii) X, Z, V and W are N, and Y is C；
P is C (R 6) or N；
Q is O or S；
D is selected from NH, O, S or CH 2；
E is selected from NH, O or CH 2；
L is selected from singly-bound, S, SO, SO 2, CO, C (O) O, S (O) O or S (O) 2O；
Each R 1Independently selected from halogen, amino, hydroxyl, cyano, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
R 2Selected from C 3-12Naphthenic base, C 3-12Heterocyclylalkyl, 6-12 member aryl or the 5-12 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；
R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2-、-OR 4、-SR 4、-N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-C(O)R 4、-S(O)R 4、-S(O)OR 4、-S(O)N(R 4) 2、-S(O) 2R 4、-S(O) 2OR 4、-S(O) 2N(R 4) 2、-OC(O)R 4、-OC(O)OR 4、-OC(O)N(R 4) 2、-N(R 4)C(O)R 4、-N(R 4)C(O)OR 4、-N(R 4)C(O)N(R 4) 2、-N(R 4)S(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2Optionally it is independently selected by one or more from R 5Group replace；
Each R 4Independently selected from H, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom；
R 5Selected from halogen, amino, cyano, hydroxyl ,-COOH, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
R 6Selected from H, halogen, amino, cyano, hydroxyl ,-COOH or halogenated C 1-3Alkyl；
M is 0,1 or 2.
It should be noted that general formula I is in the absence of ring A
In one embodiment of formula Compound I, ring A is not present or ring A is phenyl ring, furan nucleus, thiphene ring, pyrrole ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, thiazole ring, isothiazole ring, oxazole ring, isozole ring, tetrazole ring or triazine ring.
In one embodiment of formula Compound I, ring A is not present or ring A is phenyl ring or pyridine ring.
In one embodiment of formula Compound I, ring A is not present or ring A is
In one embodiment of formula Compound I, each R 1Independently selected from halogen, halogenated C 1-3Alkyl or C 1-6Alkyl.
In one embodiment of formula Compound I, each R 1Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl.
In one embodiment of formula Compound I, each R 1Independently selected from fluorine, chlorine or trifluoromethyl.
In one embodiment of formula Compound I, m is 0 or 1.
In one embodiment of formula Compound I, ring B is aromatic rings, wherein it is CH that i) Y and V, which is N, Z and W, and X is C；Ii) Y, Z, V and W are N, and X is C；Iii it is CH that) X and V, which is N, Z and W, and Y is C；Iv) Y, Z and V are N, and W is CH, and X is C；V) X, Z and V are N, and W is CH, and Y is C.
In one embodiment of formula Compound I, structural unit It is selected from
In one embodiment of formula Compound I, structural unit It is selected from
In one embodiment of formula Compound I, D is selected from NH, O or CH 2；E is selected from NH, O or CH 2。
In one embodiment of formula Compound I ,-D-C (Q)-E- is selected from-NHC (O) NH- ,-NHC (S) NH- ,-OC (O) NH- ,-NHC (O) CH 2Or-CH 2C(O)NH-。
In one embodiment of formula Compound I, L is selected from singly-bound or SO 2。
In one embodiment of formula Compound I, R 2Selected from C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula Compound I, R 2A hydrogen atom is lost selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, any position Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, are optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula Compound I, R 2A hydrogen atom is lost selected from cyclohexyl, any position Phenyl, pyridyl group or pyrimidine radicals, are optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula Compound I, R 2It is selected from It is optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula Compound I, R 2It is selected from
In one embodiment of formula Compound I, R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Heterocyclylalkyl CH 2-、-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Heterocyclylalkyl contains 1,2 or 3 5-6 unit's heteroaryl or C selected from N, O or S atom 3-6Heterocyclylalkyl CH 2Optionally it is independently selected by one or more from R 5Group replace.
In one embodiment of formula Compound I, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position loses a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Wherein methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position lose a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Optionally it is independently selected by one or more from R 5Group replace.
In one embodiment of formula Compound I, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, any position lose a hydrogen atom Tetrazole radical or Wherein methyl, any position lose a hydrogen atom Tetrazole radical or Optionally it is independently selected by one or more from R 5Group replace.
In one embodiment of formula Compound I, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OCF 3、-SCH 3、-S(O) 2CH 3、-S(O) 2NH 2、-C(O)OCH 3、-COOH、-C(O)NHCH 3、-C(O)NH 2、-NHS(O) 2NH 2、-P(O)(CH 3) 2、-P(O)(OCH 2CH 3) 2、-C(OH)(CF 3) 2、
In one embodiment of formula Compound I, each R4 is independently selected from H, halogenated C 1-3Alkyl or C 1-6Alkyl.
In one embodiment of formula Compound I, each R 4Independently selected from H, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl.
In one embodiment of formula Compound I, each R 4Independently selected from H, trifluoromethyl, methyl or ethyl.
In one embodiment of formula Compound I, R 5Selected from hydroxyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl.
In one embodiment of formula Compound I, R 5Selected from hydroxyl or trifluoromethyl.
In one embodiment of formula Compound I, R 6Selected from H or halogen.
In one embodiment of formula Compound I, R 6Selected from H or chlorine.
On the other hand, the present invention provides compounds of formula II or its pharmaceutically acceptable salt,
Wherein,
Ring A is phenyl ring or the 5-6 member hetero-aromatic ring containing 1,2 or 3 selected from N, O or S atom；
Ring B is aromatic rings, wherein 1,2,3 or 4 in W, V, X, Y and Z is selected from N or NH, other to be selected from C or CH, specifically,
I) it is CH that Y and V, which is N, Z and W, and X is C；
Ii) Y, Z, V and W are N, and X is C；
Iii it is CH that) X and V, which is N, Z and W, and Y is C；
Iv) Y, Z and V are N, and W is CH, and X is C；
V) X, Z and V are N, and W is CH, and Y is C；
Vi) X is N, and Z, V and W are CH, and Y is C；
Vii) Y is N, and Z, V and W are CH, and X is C；
Viii it be CH, X and Y is C that) Z, which is NH, V and W,；
Ix it be CH, X and Y is C that) V, which is NH, Z and W,；
X) it be CH, X and Y is C that W, which is NH, V and Z,；
Xi) V and W is N or NH, and Z is that CH, X and Y are C；
Xii) V and Z is N or NH, and W is that CH, X and Y are C；
Xiii) Z and W is N or NH, and V is that CH, X and Y are C；
Xiv it is CH that) Y and W, which is N, V and Z, and X is C；
Xv it is CH that) X and W, which is N, V and Z, and Y is C；
Xvi) X and Z is N or NH, and V and W are CH, and Y is C；
Xvii it is CH that) Y and Z, which is N, V and W, and X is C；
Xviii) Y, V and W are N, and Z is CH, and X is C；
Xix) Z, V and W are N or NH, and X and Y are C；
Xx) X, W and V are N, and Z is CH, and Y is C；
Xxi) Y, Z and W are N, and V is CH, and X is C；Or
Xxii) X, Z, V and W are N, and Y is C；
P is C (R 6) or N；
Q is O or S；
L is selected from singly-bound, S, SO, SO 2, CO, C (O) O, S (O) O or S (O) 2O；
Each R 1Independently selected from halogen, amino, hydroxyl, cyano, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
R 2Selected from C 3-12Naphthenic base, C 3-12Heterocyclylalkyl, 6-12 member aryl or the 5-12 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；
R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2-、-OR 4、-SR 4、-N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-C(O)R 4、-S(O)R 4、-S(O)OR 4、-S(O)N(R 4) 2、-S(O) 2R 4、-S(O) 2OR 4、-S(O) 2N(R 4) 2、-OC(O)R 4、-OC(O)OR 4、-OC(O)N(R 4) 2、-N(R 4)C(O)R 4、-N(R 4)C(O)OR 4、-N(R 4)C(O)N(R 4) 2、-N(R 4)S(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2Optionally it is independently selected by one or more from R 5Group replace；
Each R 4Independently selected from H, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom；
R 5Selected from halogen, amino, cyano, hydroxyl ,-COOH, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
R 6Selected from H, halogen, amino, cyano, hydroxyl ,-COOH or halogenated C 1-3Alkyl；
M is 0,1 or 2.
In one embodiment of Formula II compound of the present invention, ring A is phenyl ring, furan nucleus, thiphene ring, pyrrole ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, thiazole ring, isothiazole ring, oxazole ring, isozole ring, tetrazole ring or triazine ring.
In one embodiment of Formula II compound of the present invention, ring A is phenyl ring or pyridine ring.
In one embodiment of Formula II compound of the present invention, ring A is not present or ring A is
In one embodiment of Formula II compound of the present invention, each R 1Independently selected from halogen, halogenated C 1-3Alkyl or C 1-6Alkyl.
In one embodiment of Formula II compound of the present invention, each R 1Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl.
In one embodiment of Formula II compound of the present invention, each R 1Independently selected from fluorine, chlorine or trifluoromethyl.
In one embodiment of Formula II compound of the present invention, m is 0 or 1.
In one embodiment of Formula II compound of the present invention, ring B is aromatic rings, wherein it is CH that i) Y and V, which is N, Z and W, and X is C；Ii) Y, Z, V and W are N, and X is C；Iii it is CH that) X and V, which is N, Z and W, and Y is C；Iv) Y, Z and V are N, and W is CH, and X is C；V) X, Z and V are N, and W is CH, and Y is C.
In one embodiment of Formula II compound of the present invention, structural unit It is selected from
In one embodiment of Formula II compound of the present invention, structural unit It is selected from
In one embodiment of Formula II compound of the present invention, L is selected from singly-bound or SO 2。
In one embodiment of Formula II compound of the present invention, R 2Selected from C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace.
In one embodiment of Formula II compound of the present invention, R 2Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, any position loses a hydrogen atom Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, are optionally independently selected by one or more from R 3Group replace.
In one embodiment of Formula II compound of the present invention, R 2A hydrogen atom is lost selected from cyclohexyl, any position Phenyl, pyridyl group or pyrimidine radicals, are optionally independently selected by one or more from R 3Group replace.
In one embodiment of Formula II compound of the present invention, R 2It is selected from It is optionally independently selected by one or more from R 3Group replace.
In one embodiment of Formula II compound of the present invention, R 2It is selected from
In one embodiment of Formula II compound of the present invention, R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Heterocyclylalkyl CH 2-、-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Heterocyclylalkyl contains 1,2 or 3 5-6 unit's heteroaryl or C selected from N, O or S atom 3-6Heterocyclylalkyl CH 2Optionally it is independently selected by one or more from R 5Group replace.
In one embodiment of Formula II compound of the present invention, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position loses a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Wherein methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position lose a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Optionally it is independently selected by one or more from R 5Group replace.
In one embodiment of Formula II compound of the present invention, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, any position lose a hydrogen atom Tetrazole radical or Wherein methyl, any position lose a hydrogen atom Tetrazole radical or Optionally it is independently selected by one or more from R 5Group replace.
In one embodiment of Formula II compound of the present invention, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OCF 3、-SCH 3、-S(O) 2CH 3、-S(O) 2NH 2、-C(O)OCH 3、-COOH、-C(O)NHCH 3、-C(O)NH 2、-NHS(O) 2NH 2、-P(O)(CH 3) 2、 -P(O)(OCH 2CH 3) 2、-C(OH)(CF 3) 2、
In one embodiment of Formula II compound of the present invention, each R 4Independently selected from H, halogenated C 1-3Alkyl or C 1-6Alkyl.
In one embodiment of Formula II compound of the present invention, each R 4Independently selected from H, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl.
In one embodiment of Formula II compound of the present invention, each R 4Independently selected from H, trifluoromethyl, methyl or ethyl.
In one embodiment of Formula II compound of the present invention, R 5Selected from hydroxyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl.
In one embodiment of Formula II compound of the present invention, R 5Selected from hydroxyl or trifluoromethyl.
In one embodiment of Formula II compound of the present invention, R 6Selected from H or halogen.
In one embodiment of Formula II compound of the present invention, R 6Selected from H or chlorine.
On the other hand, the present invention provides -1 compound represented of Formula II or its pharmaceutically acceptable salt,
Wherein, group or atom definition are as described in Compounds of formula II.
On the other hand, the present invention provides -2 compound represented of Formula II or its pharmaceutically acceptable salt,
Wherein, group or atom definition are as described in Compounds of formula II.
On the other hand, the present invention provides -3 compound represented of Formula II or its pharmaceutically acceptable salt,
Wherein, group or atom definition are as described in Compounds of formula II.
On the other hand, the present invention provides -4 compound represented of Formula II or its pharmaceutically acceptable salt,
Wherein, group or atom definition are as described in Compounds of formula II.
On the other hand, the present invention provides -5 compound represented of Formula II or its pharmaceutically acceptable salt,
Wherein, group or atom definition are as described in Compounds of formula II.
On the other hand, the present invention provides compounds of formula III or its pharmaceutically acceptable salt,
Wherein,
Ring B is aromatic rings, wherein 1,2,3 or 4 in W, V, X, Y and Z is selected from N or NH, other to be selected from C or CH, specifically,
I) it is CH that Y and V, which is N, Z and W, and X is C；
Ii) Y, Z, V and W are N, and X is C；
Iii it is CH that) X and V, which is N, Z and W, and Y is C；
Iv) Y, Z and V are N, and W is CH, and X is C；
V) X, Z and V are N, and W is CH, and Y is C；
Vi) X is N, and Z, V and W are CH, and Y is C；
Vii) Y is N, and Z, V and W are CH, and X is C；
Viii it be CH, X and Y is C that) Z, which is NH, V and W,；
Ix it be CH, X and Y is C that) V, which is NH, Z and W,；
X) it be CH, X and Y is C that W, which is NH, V and Z,；
Xi) V and W is N or NH, and Z is that CH, X and Y are C；
Xii) V and Z is N or NH, and W is that CH, X and Y are C；
Xiii) Z and W is N or NH, and V is that CH, X and Y are C；
Xiv it is CH that) Y and W, which is N, V and Z, and X is C；
Xv it is CH that) X and W, which is N, V and Z, and Y is C；
Xvi) X and Z is N or NH, and V and W are CH, and Y is C；
Xvii it is CH that) Y and Z, which is N, V and W, and X is C；
Xviii) Y, V and W are N, and Z is CH, and X is C；
Xix) Z, V and W are N or NH, and X and Y are C；
Xx) X, W and V are N, and Z is CH, and Y is C；
Xxi) Y, Z and W are N, and V is CH, and X is C；Or
Xxii) X, Z, V and W are N, and Y is C；
Q is O or S；
D is selected from NH, O, S or CH 2；
E is selected from NH, O or CH 2；
L is selected from singly-bound, S, SO, SO 2, CO, C (O) O, S (O) O or S (O) 2O；
Each R 1Independently selected from halogen, amino, hydroxyl, cyano, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
R 2Selected from C 3-12Naphthenic base, C 3-12Heterocyclylalkyl, 6-12 member aryl or the 5-12 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；
R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2-、-OR 4、-SR 4、-N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-C(O)R 4、-S(O)R 4、-S(O)OR 4、-S(O)N(R 4) 2、-S(O) 2R 4、-S(O) 2OR 4、-S(O) 2N(R 4) 2、-OC(O)R 4、-OC(O)OR 4、-OC(O)N(R 4) 2、-N(R 4)C(O)R 4、-N(R 4)C(O)OR 4、-N(R 4)C(O)N(R 4) 2、-N(R 4)S(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2Optionally it is independently selected by one or more from R 5Group replace；
Each R 4Independently selected from H, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom；
R 5Selected from halogen, amino, cyano, hydroxyl ,-COOH, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
M is 0,1 or 2.
In one embodiment of formula III compound of the present invention, each R 1Independently selected from halogen, halogenated C 1-3Alkyl or C 1-6Alkyl.
In one embodiment of formula III compound of the present invention, each R 1Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl.
In one embodiment of formula III compound of the present invention, each R 1Independently selected from chlorine or trifluoromethyl.
In one embodiment of formula III compound of the present invention, m is 0 or 1.
In one embodiment of formula III compound of the present invention, ring B is aromatic rings, wherein it is CH that i) Y and V, which is N, Z and W, and X is C；Ii it is CH that) X and V, which is N, Z and W, and Y is C.
In one embodiment of formula III compound of the present invention, structural unit It is selected from
In one embodiment of formula III compound of the present invention, structural unit It is selected from
In one embodiment of formula III compound of the present invention, D is selected from NH, O or CH 2；E is selected from NH, O or CH 2。
In one embodiment of formula III compound of the present invention ,-D-C (Q)-E- is selected from-NHC (O) NH- ,-NHC (S) NH- ,-OC (O) NH- ,-NHC (O) CH 2Or-CH 2C(O)NH-。
In one embodiment of formula III compound of the present invention, L is selected from singly-bound.
In one embodiment of formula III compound of the present invention, R 25-6 unit's heteroaryl selected from phenyl or containing 1,2 or 3 selected from N, O or S atom, is optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula III compound of the present invention, R 2Selected from phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, it is optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula III compound of the present invention, R 2Selected from phenyl, pyridyl group or pyrimidine radicals, it is optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula III compound of the present invention, R 2It is selected from It is optionally independently selected by one or more from R 3Group replace.
In one embodiment of formula III compound of the present invention, R 2It is selected from
In one embodiment of formula III compound of the present invention, R 3Selected from halogen or halogenated C 1-3Alkyl.
In one embodiment of formula III compound of the present invention, R 3Selected from fluorine, chlorine, bromine or trifluoromethyl.
On the other hand, the present invention provides -1 compound represented of formula III or its pharmaceutically acceptable salt,
Wherein, group or atom definition are as described in compound of formula III.
On the other hand, the present invention provides -2 compound represented of formula III or its pharmaceutically acceptable salt,
Wherein, group or atom definition are as described in compound of formula III.
The preferably following compound of the present invention or its pharmaceutically acceptable salt,
On the other hand, the present invention relates to pharmaceutical compositions, and it includes compound of Formula I of the invention, Compounds of formula II and compound of formula III or its pharmaceutically acceptable salts.In some embodiments, pharmaceutical composition of the invention further includes one or more pharmaceutically acceptable carriers or excipient.Pharmaceutical composition of the invention can further contain one or more additional therapeutic agents.
On the other hand, the present invention relates to treatment mammals by indoleamine 2,3- dioxygenase (IDO) and tryptophan 2, the method for the immunosuppressant disease that 3- oxygenase (TDO) mediates, including to need the treatment mammal, preferred mankind's compound of Formula I, Compounds of formula II and compound of formula III or its pharmaceutically acceptable salt or its pharmaceutical composition for giving therapeutically effective amount.
On the other hand, the present invention relates to compound of Formula I, Compounds of formula II and compound of formula III or its pharmaceutically acceptable salts or its pharmaceutical composition in preparation prevention or to treat by indoleamine 2,3- dioxygenase (IDO) and tryptophan 2,3- oxygenase (TDO) mediate immunosuppressant disease drug in purposes.Another aspect, the present invention relates to compound of Formula I, Compounds of formula II and compound of formula III or its pharmaceutically acceptable salts or its pharmaceutical composition for preventing or treating by indoleamine 2,3- dioxygenase (IDO) and tryptophan 2, the purposes for the immunosuppressant disease that 3- oxygenase (TDO) mediates.
In some embodiments of the present invention, the immunosuppressant disease is related to communicable disease or cancer.As preferred embodiment, the immunosuppressant disease may be selected from but not limited to pneumonia, malignant tumour, morbilli, hepatitis, nephrosis or arthritis.
In some embodiments of the present invention, the communicable disease is selected from following virus infection: influenza, Hepatitis C Virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), poliovirus, herpes zoster virus, human immunodeficiency virus (HIV), epstein-Barr virus (EBV) or Coxsackie virus.The cancer is selected from colon cancer, cancer of pancreas, breast cancer, prostate cancer, lung cancer, the cancer of the brain, oophoroma, cervix cancer, carcinoma of testis, kidney, head or neck cancer, lymthoma, leukaemia or melanoma.
Definition and explanation
In the following description, including certain concrete details are to be fully understood by each disclosed embodiment offer.However, those skilled in the relevant art are not, it will be recognized that use one or more of these concrete details, and embodiment can be achieved in the case where using other methods, component, material etc..
Except being required in addition that in non-present invention, in the whole instruction and thereafter in claims, word " including (comprise) " and its English variant for example should be interpreted that meaning open, including formula " including (comprises) " and " including (comprising) ", i.e., " including but not limited to ".
" embodiment " or " embodiment " or " in another embodiment " mentioned in entire this specification or mean " in certain embodiments " include at least one embodiment and relevant specific reference elements, structures, or characteristics described in the embodiment.Therefore, the phrase " in one embodiment " or " in embodiments " or " in another embodiment " or " in certain embodiments " that different location occurs throughout the specification need not all refer to same embodiment.In addition, key element, structure or feature can combine in one or more embodiments in any suitable manner.
It should be appreciated that the article " one " (correspond to English " a ", " an " and " the ") for the singular used in description of the invention and appended claims includes the object of plural number, unless it is other in text it is manifestly intended that.Thus, for example the reaction including " catalyst " mentioned includes a kind of catalyst or two or more catalyst.It is also understood that term "or" is usually with it includes the meaning of "and/or" and uses, unless in text in addition it is manifestly intended that.
Unless otherwise indicated, following term used herein and phrase are intended to following meanings.One specific term or phrase it is no especially define in the case where should not be considered as uncertain or unclear, and should go to understand according to common meaning.When herein presented trade name, it is intended that refer to its corresponding commodity or its active constituent.
Term " optional " " optionally " refers to that the event then described or situation may occur or may not occur, which includes that the event or situation occurs and the event or situation does not occur.For example, ethyl " optional ", which is optionally substituted by halogen, refers to that ethyl can be unsubstituted (CH 2CH 3), mono-substituted (such as CH 2CH 2F), polysubstituted (such as CHFCH 2F、CH 2CHF 2Deng) or substituted (CF completely 2CF 3).It is understood that for any group comprising one or more substituent groups, will not introduce any can not spatially exist and/or the substitution that cannot be synthesized or substitute mode those skilled in the art.
C used herein m-nReferring to has m-n carbon atom in the part.For example, " C 3-10Naphthenic base " refers to that the naphthenic base has 3-10 carbon atom."C 0-6Alkylidene " refers to that the alkylidene has 0-6 carbon atom, and when alkylidene has 0 carbon atom, which is key.It is readily appreciated that, when containing hetero atom, m-n represents the summation of carbon atom and hetero atom quantity.
Digital scope herein refers to each integer in given range.Such as " C 1-10" refer to that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, as long as the compound after the valence state of specific atoms is normal and substitution is stable.When substituent group is ketone group (i.e.=O) (also referred to as oxo base), it is meant that two hydrogen atoms are substituted, and ketone substitution does not occur on aromatic radical.
When any variable (such as R) occurs more than once in the composition of compound or structure, definition at each occurrence is all independent.Thus, for example, the group can be optionally at most replaced two R, and R in each case has independent option if a group is replaced 0-2 R.In addition, the combination of substituent group and/or its variant is only just allowed in the case where such group of credit union generates stable compound.
When the quantity of a linking group is 0, such as-(CRR) 0, indicate that the linking group is singly-bound.
When one of variable is selected from singly-bound, indicate that two groups of its connection are connected directly, for example when L represents singly-bound in A-L-Z indicates that the structure is actually A-Z.
When a substituent group be vacancy when, indicate that the substituent group is not present, for example, in A-X X be vacancy when indicate that the structure is actually A.When the key of a substituent group can be cross connected to two atomic time on a ring, this substituent group can be mutually bonded with the arbitrary atom on this ring.When do not indicate it in cited substituent group by which atom and be connected in general formula of the chemical structure include but be not specifically mentioned compound when, this substituent group can be mutually bonded by its any atom.The combination of substituent group and/or its variant is only just allowed in the case where such group of credit union generates stable compound.For example, structural unit Indicate its can any one position on cyclohexyl or cyclohexadiene replace.
Term " pharmaceutically acceptable ", it is for those compounds, material, composition and/or dosage form, they are suitable for contacting use with the tissue of human and animal within the scope of reliable medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complication, match with reasonable interests/Hazard ratio.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, pharmaceutically acceptable salt as general formula I, general formula II and compounds of formula III, for example, it can be mentioned that metal salt, ammonium salt, the salt formed with organic base, the salt formed with inorganic acid, the salt formed with organic acid, the salt formed with alkalinity or acidic amino acid etc..The non-limiting example of metal salt includes but is not limited to salt of alkali metal, such as sodium salt, sylvite etc.；Salt of alkaline-earth metal, such as calcium salt, magnesium salts, barium salt etc.；Aluminium salt etc..
Pharmaceutically acceptable salt of the invention can be synthesized by the parent compound containing acid group or base by conventional chemical processes.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, reacting via free acid or the compound of alkali form with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that the non-aqueous medias such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.
General formula I, general formula II and compounds of formula III of the invention can exist with nonsolvated forms or solvation form, including hydrate form.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.The compound of general formula I of the invention can exist with polymorph or amorphous form.
General formula I, general formula II and compounds of formula III of the invention can have asymmetric carbon atom (optical centre) or double bond.Racemic modification, diastereoisomer, geometric isomer and single isomers are included within the scope of the present invention.
The diagrammatic representation of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure in the present invention comes from Maehr, J.Chem.Ed.1985,62:114-120.Unless otherwise indicated, the absolute configuration of a Stereocenter is indicated with wedge key and dotted line key.When general formula I of the present invention, general formula II and compounds of formula III contain alkene double bond or other geometry asymmetric centers, unless otherwise prescribed, they include E and Z geometric isomer.Similarly, all tautomeric forms are included within the scope of the present invention.
General formula I, general formula II and compounds of formula III of the invention may exist specific geometry or stereoisomer form.It is contemplated by the invention that all this kind of compounds, including cis and trans isomer, (-)-and (+)-enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers, and its racemic mixture and other mixtures, such as enantiomter or the mixture of diastereomer enrichment, all these mixtures are within the scope of the present invention.Other asymmetric carbon atom may be present in the substituent groups such as alkyl.All these isomers and their mixture are also included within the scope of the present invention.
Optically active (R)-and (S)-isomers and D and L isomers can be prepared by chirality synthesis or chiral reagent or other routine techniques., can be by asymmetric syntheses or prepared by the derivatization with chiral auxiliary if expect a kind of enantiomer of a certain compound of the present invention, wherein gained non-enantiomer mixture is separated, and auxiliary group splits to provide pure required enantiomter.Or, when containing basic functionality (such as amino) or acidic functionality (such as carboxyl) in molecule, the salt of diastereoisomer is formed with optically active acid appropriate or alkali, then diastereoisomer fractionation is carried out by Steppecd crystallization well known by persons skilled in the art or chromatography, then recycling obtains pure enantiomer.In addition, the separation of enantiomter and diastereoisomer is usually to be completed by using chromatography, the chromatography uses chiral stationary phase, and (such as generating carbaminate by amine) is optionally combined with chemical derivatization.
General formula I, general formula II and compounds of formula III of the invention can include the atom isotope of unnatural proportions on one or more atoms for constituting the compound.For example, radioisotope labeled compound can be used, such as tritium ( 3H), iodine-125 ( 125I) or C-14 ( 14C).General formula I, general formula II and the transformation of all isotopics of compounds of formula III of the invention, no matter radioactivity whether, be included within the scope of the present invention.
Term " pharmaceutically acceptable carrier " is that refer to deliver effective quantity active material of the present invention, any preparation for not interfering the bioactivity of active material and having no toxic side effect to host or patient or the representative carrier of mounting medium include water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal enhancer etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other information about carrier, Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott can be referred to, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.
Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.
For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to enough dosages of drug that is nontoxic but can achieving the desired results or medicament.For the peroral dosage form in the present invention, in composition it is a kind of " effective quantity " of active material refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.A effective amount of determination varies with each individual, age and ordinary circumstance depending on receptor, also depends on specific active material, and suitable effective quantity can be determined by those skilled in the art according to routine test in case.
Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, it can effectively treat target disorder, disease or illness.
Word " including (comprise) " or " including (comprise) " and its English variant such as comprises or comprising are interpreted as open, nonexcludability meaning, i.e., " including but not limited to ".
Term " pharmaceutical composition " refers to the mixture of one or more the compound of the present invention or its salt and pharmaceutically acceptable auxiliary material composition.The purpose of pharmaceutical composition is to be conducive to give the compound of the present invention to organism.
Unless otherwise prescribed, term " halogenated " or " halogen " indicate fluorine, chlorine, bromine or iodine atom in itself or as a part of of another substituent group.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl；For example, term " halogenated C 1-3Alkyl " is intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyl and 3- bromopropyl etc..The example of halogenated alkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls.
Term " hydroxyl " refers to-OH.
Term " cyano " refers to-CN.
Term " nitro " refers to-NO 2。
Term " amino " refers to-NH 2,-NH (alkyl) and-N (alkyl) 2, the specific example of amino includes but is not limited to-NH 2、-NHCH 3、-NHCH(CH 3) 2、-N(CH 3) 2、-NHC 2H 5、-N(CH 3)C 2H 5Deng.
Term " alkyl " refers to saturated fat hydrocarbyl group, such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl of the linear chain or branched chain being made of carbon atom and hydrogen atom etc..The specific alkyl includes its all isomer form, such as propyl includes-CH 2CH 2CH 3、-CH(CH 3) 2, such as butyl includes-CH 2CH 2CH 2CH 3、-CH(CH 3)(CH 2CH 3)、-C(CH 3) 3、-CH 2CH(CH 3) 2.Term " C 1-8Alkyl " refers to the alkyl with 1-8 carbon atom.Term " C 1-6Alkyl " refers to the alkyl with 1-6 carbon atom.Term " C 1-4Alkyl " refers to the alkyl with 1-4 carbon atom.Term " C 1-3Alkyl " refers to the alkyl with 1-3 carbon atom." alkyl ", " C 1-8Alkyl ", " C 1-6Alkyl ", " C 1-4Alkyl " or " C 1-3Alkyl " can be non-substituted or be replaced by one or more substituent groups selected from hydroxyl, halogen or amino.
Term " naphthenic base " refers to the aliphatic hydrocarbon group for the single ring filling being only made of carbon atom and hydrogen atom, such as C 3-20Naphthenic base, preferably C 3-6Naphthenic base, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..It includes but is not limited to alkyl, alkyl oxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl and hydroxyl etc. that the naphthenic base, which can be non-substituted or substituted, described substituent group,.
Unless otherwise prescribed, " miscellaneous " the expression hetero atom of term or hetero atom group (containing heteroatomic atomic group), including the atom other than carbon (C) and hydrogen (H) and contain these heteroatomic atomic groups, for example including oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al), boron (B) ,-O- ,-S- ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O) ,-S (=O) 2And optionally substituted-C (=O) N (H)-,-N (H)-,-C (=NH)-,-S (=O) 2N (H)-or-S (=O) N (H)-.
Unless otherwise prescribed, " ring " indicates substituted or unsubstituted naphthenic base, Heterocyclylalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring includes monocycle, connection ring, loop coil and ring or bridged ring.The number of ring atom is generally defined as first number of ring, for example, " 5-7 member ring " refers to around 5-7 atom of arrangement.Unless otherwise prescribed, which optionally includes 1-3 hetero atom.Therefore, " 5-7 member ring " includes such as phenyl, pyridine and piperidyl；On the other hand, term " 5-7 membered heterocycloalkyl ring " includes pyridyl group and piperidyl, but does not include phenyl.Term " ring " further includes the ring system containing at least one ring, each of these " ring " independently conforms to above-mentioned definition.
Term " Heterocyclylalkyl " refers to fully saturated and can be with cyclic group existing for monocycle, bicyclic or loop coil.Unless otherwise directed, which is usually 3 to 7 member rings containing 1 to 3 hetero atom (preferably 1 or 2 hetero atom) independently selected from sulphur, oxygen and/or nitrogen.The example of 3 membered heterocycloalkyls includes but is not limited to Oxyranyle, thiirane base, azirane base, the non-limiting example of 4 membered heterocycloalkyls includes but is not limited to azete piperidinyl, dislike fourth ring group, thiophene fourth ring group, the example of 5 membered heterocycloalkyls includes but is not limited to tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazole alkyl, thiazolidinyl, imidazolidinyl, tetrahydro-pyrazole base, pyrrolinyl, dihydrofuryl, dihydrothiophene, the example of 6 membered heterocycloalkyls includes but is not limited to piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, morpholinyl, piperazinyl, 1, 4- thiophene oxane base, 1, 4- dioxane, thio-morpholinyl, 1, 2- dithianyl, 1, 4- dithianyl, dihydropyridine base, tetrahydro pyridyl, dihydro pyranyl, THP trtrahydropyranyl, two Hydrogen thiapyran base, the example of 7 membered heterocycloalkyls include but is not limited to nitrogen heterocyclic heptyl, oxepane alkyl, thia cycloheptyl alkyl.Preferably with the monocyclic heterocycloalkyl of 5 or 6 annular atoms.
Term " aryl " refers to the full carbon monocycle of the pi-electron system with conjugation or the aromatic group of fused polycycle.For example, aryl can have 6-20 carbon atom, 6-14 carbon atom or 6-12 carbon atom.The non-limiting example of aryl includes but is not limited to phenyl, naphthalene, anthryl and 1,2,3,4-tetralin etc..
Term " heteroaryl " refers to monocycle or fused polycycle system, wherein being selected from the annular atom of N, O, S containing at least one, remaining annular atom is C, and has at least one aromatic rings.Preferred heteroaryl has single 4 to 8 member ring, especially 5 to 8 member rings, or multiple fused rings comprising 6 to 14, especially 6 to 10 annular atoms.The non-limiting example of heteroaryl includes but is not limited to pyrrole radicals, furyl, thienyl, imidazole radicals, oxazolyl, pyrazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, quinolyl, isoquinolyl, tetrazole radical, triazolyl, triazine radical, benzofuranyl, benzothienyl, indyl, isoindolyl etc..
Pharmaceutical composition of the invention can by by the compound of the present invention with suitable pharmaceutically acceptable auxiliary material combination and prepare, such as solid-state, semisolid, liquid or gaseous state preparation, such as tablet, pill, capsule, pulvis, granule, paste, emulsion, suspending agent, suppository, injection, inhalant, gelling agent, microballoon and aerosol can be configured to.
It gives the compounds of this invention or its pharmaceutically acceptable salt or the classical pathway of its pharmaceutical composition including but not limited to takes orally, rectum, part, sucking, parenteral, sublingual, intravaginal, intranasal, intraocular, peritonaeum is interior, intramuscular, subcutaneous, intravenous administration.
Pharmaceutical composition of the invention can be manufactured using method well-known in the art, such as conventional mixing method, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying.
In some embodiments, pharmaceutical composition is oral form.For oral administration, the pharmaceutical composition can be prepared by mixing reactive compound with pharmaceutically acceptable auxiliary material well known in the art.These auxiliary materials can make the compound of the present invention be formulated into tablet, pill, pastille, sugar-coat agent, capsule, liquid, gelling agent, slurry agent, suspending agent etc., for the oral administration to patient.
Solid oral composition can be prepared by conventional mixing, filling or tabletting method.For example, can be obtained by following methods: the reactive compound being mixed with solid adjuvant material, other suitable auxiliary materials are added if necessary, the mixture is then processed into particle, have obtained the core of tablet or sugar-coat agent for resulting mixture of optionally milling.Suitable auxiliary material includes but is not limited to: adhesive, diluent, disintegrating agent, lubricant, glidant, sweetener or corrigent etc..
Pharmaceutical composition could be applicable to parenteral administration, such as sterile solution agent, suspension or the freeze-drying prods of suitable unit dosage forms.
In all method of administration of general formula I as described herein, general formula II and compound of formula III, the dosage of daily administration is 0.01 to 200mg/kg weight, preferably 0.01 to 20mg/kg weight, more preferable 0.01 arrives 10mg/kg weight, in the form of independent or separate doses.
The compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, combination including the specific embodiment, itself and other chemical synthesis process that are set forth below is formed by embodiment and art technology equivalent replacement mode known to personnel, and preferred embodiment includes but is not limited to the embodiment of the present invention.
The chemical reaction of the specific embodiment of the invention is completed in a suitable solvent, and the solvent must be suitable for chemical change of the invention and its required reagent and material.In order to obtain the compound of the present invention, it is sometimes desirable to which those skilled in the art modify or select to synthesis step or reaction process on the basis of existing embodiment.
An important consideration factor in the planning of this field synthetic route is for the suitable protecting group of reactive functional groups (such as the amino in the present invention) selection; such as; it can refer to Greene's Protective Groups in Organic Synthesis (4th Ed) .Hoboken; New Jersey:John Wiley&Sons; Inc., all bibliography that the present invention quotes are incorporated herein on the whole.
Synthetic route general formula A:
Wherein, group and atom definition are as described in compound of Formula I.
General formula compound 1 reacts to obtain general formula compound 2 in methylene chloride with triphosgene；General formula compound 2 in pyridine with R 2-L-NH 2Reaction obtains general formula compound 3.
Synthetic route Formula B:
Wherein, group and atom definition are as described in compound of Formula I.
General formula compound 1 reacts to obtain general formula compound 4 in methylene chloride with thiophosgene；General formula compound 4 in pyridine with R 2-L-NH 2Reaction obtains general formula compound 5.
Specific embodiment
Following specific embodiment, the purpose is to so that those skilled in the art is more clearly understood that and implement the application.They should not be considered as the limitation to the application range, and the only exemplary illustration and Typical Representative of the application.Those skilled in the art should understand that: there are also the other route of synthesis for forming the application compound, and provided below are non-limiting embodiments.
Unless otherwise indicated, temperature is Celsius temperature.Reagent is purchased from Chinese medicines group chemical reagent Beijing Co., Ltd, the commercial suppliers such as AlfaAesar (Alfa Aesar) or Beijing lark prestige Science and Technology Ltd., and these reagents and can be used directly without being further purified, unless otherwise indicated.Unless otherwise indicated, following reaction in anhydrous solvent, the direct draught of nitrogen or argon gas or carried out using drying tube；Diaphragm of rubber is housed on reaction flask, substrate and reagent is added will pass through syringe；Glassware drying and/or heat drying.
Unless otherwise indicated, column chromatography purifying uses the 200-300 mesh silica gel of Haiyang Chemical Plant, Qingdao；Prepare the thin-layer chromatography silica gel prefabricated board (HSGF254) that TLC separation uses Yantai Chemical Industry Research Inst. to produce；The measurement of MS Thermo LCQ Fleet type (ESI) liquid chromatograph-mass spectrometer.
Unless otherwise indicated, nuclear magnetic data ( 1H-NMR it) is run using Varian equipment in 400MHz.The solvent that nuclear magnetic data uses has CDCl 3、CD 3OD、D 2O、DMSO-d 6Deng on the basis of tetramethylsilane (0.00ppm) or (CDCl on the basis of residual solvent 3: 7.26ppm；CD 3OD:3.31ppm；D 2O:4.79ppm；DMSO-d 6: 2.50ppm).When indicating peak shape diversity, following shorthand indicates different peak shapes: s (unimodal), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublets), dt (double triplets).If giving coupling constant, with Hertz (Hz) for unit.
Unless otherwise indicated, eq. represents molar equivalent；NBS represents N- bromo-succinimide；M-CPBA represents m-chloro-benzoic acid peroxide；NCS represents N-chlorosuccinimide；DPPA represents diphenyl phosphate azide；Boc- represents tertbutyloxycarbonyl；20-30 DEG C of Room temperature stands.
Synthesize general formula A
Step 1: the synthesis of general formula compound 2
At 0 DEG C, triphosgene (0.6eq.) is added into the dichloromethane solution of general formula compound 1 (1.0eq.), reaction solution is warmed to room temperature stirring 2 hours.After reaction, it is concentrated under reduced pressure and removes solvent, residual solids general formula compound 2 is directly used in step 2.
Step 2: the synthesis of general formula compound 3
General formula compound 2 is added to R in batches 2-L-NH 2In the pyridine solution of (0.5eq.), it is stirred at room temperature 12 hours.After reaction, reaction solution is poured into water, is extracted with ethyl acetate, extract liquor saturated common salt water washing, anhydrous sodium sulfate dries, filters, and filtrate concentration, residue obtains general formula compound 3 with silica gel chromatograph column purification.
Synthesize Formula B:
Step 1: the synthesis of general formula compound 4
At 0 DEG C, thiophosgene (1.2eq.) is added into the dichloromethane solution of general formula compound 1 (1.0eq.), is raised to and is stirred at room temperature 2 hours.It is concentrated under reduced pressure and removes solvent, residue obtains general formula compound 4 with silica gel chromatograph column purification.
Step 2: the synthesis of general formula compound 5
General formula compound 4 is added to R in batches 2-L-NH 2In the pyridine solution of (1.0eq.), it is stirred at room temperature 12 hours.Reaction solution is poured into water, and is extracted with ethyl acetate, and extract liquor saturated common salt water washing, anhydrous sodium sulfate dries, filters, and filtrate concentration, residue obtains general formula compound 5 with silica gel chromatography.
Intermediate 1: the synthesis of imidazo [5,1-a] isoquinolin -5- amine
The synthesis of the chloro- 1- methylisoquinolinium of step 1:3-
Under nitrogen protection; to 1; tetrahydrofuran solution (the 139mL of trimethyl aluminium is slowly added dropwise in tetrahydrofuran (500mL) solution of 3- dichloro isoquinolin (49.6g); 2M); then tetra-triphenylphosphine palladium (2.9g) is added, heats the mixture to 85 DEG C and is stirred overnight.Room temperature will be cooled to reaction night to fall back in (200mL), be extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue obtains the chloro- 1- methylisoquinolinium (43.0g) of 3- with silica gel chromatograph column purification (petroleum ether: ethyl acetate=20:1).
The synthesis of step 2:1- bromomethyl -3- chlorine isoquinolin
N- bromo-succinimide (44.0g) and benzoyl peroxide (6.0g) are sequentially added into carbon tetrachloride (300mL) solution of the chloro- 1- methylisoquinolinium (43.0g) of 3-, 80 DEG C is heated the mixture to and is stirred overnight.It is cooled to room temperature, is filtered, filtrate decompression concentration, residue obtains 1- bromomethyl -3- chlorine isoquinolin (50.5g) with silica gel chromatograph column purification (petroleum ether: ethyl acetate=20:1).
The synthesis of step 3:1- azido-methyl -3- chlorine isoquinolin
To 1- bromomethyl -3- chlorine isoquinolin (50.0g) acetone (500mL) and water (50mL) solution in be added Sodium Azide (18.2g), be heated to 50 DEG C stir 2 hours.It is cooled to room temperature, (100mL) is poured into water, is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, obtains 1- azido-methyl -3- chlorine isoquinolin (35.6g) after filtrate decompression concentration.
The synthesis of step 4:1- amino methyl -3- chlorine isoquinolin
To 1- azido-methyl -3- chlorine isoquinolin (35.6g) tetrahydrofuran (300mL) and water (30mL) solution in be added triphenylphosphine (49.8g), mixture is stirred overnight at room temperature.Reaction mixture is poured into water (100mL), is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression is concentrated, residue obtains 1- amino methyl -3- chlorine isoquinolin (27.7g) with silica gel chromatograph column purification (petroleum ether: ethyl acetate=4:1).
The synthesis of step 5:N- ((3- chlorine isoquinolyl-1) methyl) formamide
The mixed liquor of 1- amino methyl -3- chlorine isoquinolin (27.7g) and Ethyl formate (300mL) is heated to 65 DEG C to stir 8 hours.It is cooled to room temperature, is concentrated under reduced pressure to give N- ((3- chlorine isoquinolyl-1) methyl) formamide (30.0g).
The synthesis of step 6:5- chlorine imidazo [5,1-a] isoquinolin
Phosphorus oxychloride (30.7g) is added into methylene chloride (500mL) solution of N- ((3- chlorine isoquinolyl-1) methyl) formamide (30.0g), then triethylamine (82.0g) slowly is added dropwise, mixture is stirred at room temperature 2 hours.Reaction mixture is slowly poured into trash ice, with saturated sodium bicarbonate aqueous solution tune pH to 8, filtering, filtrate liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue obtains 5- chlorine imidazo [5,1-a] isoquinolin (25.0g) with silica gel chromatograph column purification (petroleum ether: ethyl acetate=2:1).
The synthesis of step 7:N- (imidazo [5,1-a] isoquinolin -5- base) -1,1- benzophenone contracting imines
Under nitrogen protection; to 5- chlorine imidazo [5; 1-a] isoquinolin (23.0g) toluene (300mL) solution in be added benzophenone imine (21.7g), tris(dibenzylideneacetone) dipalladium (4.6g), 1; 1'- dinaphthalene -2; the bis- diphenyl phosphines of 2'- (6.2g) and cesium carbonate (71.7g) heat the mixture to 110 DEG C and stir 12 hours.It is cooled to room temperature, is filtered, filtrate decompression concentration, residue obtains N- (imidazo [5,1-a] isoquinolin -5- base) -1,1- benzophenone contracting imines (25.6g) with silica gel chromatograph column purification (methylene chloride: methanol=20:1).
Step 8: the synthesis of imidazo [5,1-a] isoquinolin -5- amine
N- (imidazo [5,1-a] isoquinolin -5- base) -1,1- benzophenone contracting imines (15.0g) is dissolved in tetrahydrofuran (200mL), hydrochloric acid (30mL, 2N) is added into acquired solution, is stirred at room temperature 2 hours.Reaction mixture is poured into water (100mL), pH to 8 is adjusted with saturated sodium bicarbonate aqueous solution, is extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated to get imidazo [5,1-a] isoquinolin -5- amine (6.3g) for filtrate decompression. 1H-NMR (400M, DMSO-d 6): δ 9.38 (s, 1H), 8.55 (s, 1H), 8.20 (d, J=8.0Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 7.49 (t, J=7.2Hz, 1H), 7.37 (t, J=7.2Hz, 1H), 6.70 (brs, 2H), 6.29 (s, 1H).
Intermediate 2: the synthesis of tetrazole simultaneously [5,1-a] isoquinolin -5- amine
The synthesis of step 1:5- chlorine tetrazole simultaneously [5,1-a] isoquinolin
To 1, the N of 3- dichloro isoquinolin (1.5g), azidotrimethylsilane (1.8g) and three hydrations tetrabutyl ammonium fluoride (2.4mg) are sequentially added in dinethylformamide (50mL) solution, are heated to 80 DEG C and are stirred 12 hours.It is cooled to room temperature, reaction solution is poured into water (200mL), is extracted with ethyl acetate.Organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue obtains 5- chlorine tetrazole simultaneously [5,1-a] isoquinolin (0.8g) with silica gel chromatograph column purification (petroleum ether: ethyl acetate=40:1).
The synthesis of step 2:N- (tetrazole simultaneously [5,1-a] isoquinolin -5- base) -1,1- benzophenone contracting imines
With reference to the step 7 in the synthesis of intermediate 1.
Step 3: the synthesis of tetrazole simultaneously [5,1-a] isoquinolin -5- amine
With reference to the step 8 in the synthesis of intermediate 1.LC-MS[M+1] +=186.
The synthesis of intermediate 3:8- flumizole simultaneously [5,1-a] isoquinolin -5- amine
The synthesis of the fluoro- 2- oximido -2,3- dihydro -1H- 1-Indanone of step 1:5-
By 5- fluoro- 2,3- dihydro -1H- 1-Indanone (8.0g) is dissolved in ether (150mL), it is cooled to 0 DEG C, dry hydrogen chloride 3 hours are led into the solution, isoamyl nitrite (12.5g) is then slowly added dropwise, stirring 3 hours is warmed to room temperature after being added dropwise, there is solid, filtering, filter cake is washed with ether, filtration cakes torrefaction is obtained into fluoro- 2- oximido -2, the 3- dihydro -1H- 1-Indanone (7.0g) of 5-.
The synthesis of the chloro- 6- fluorine isoquinolin of step 2:1,3- bis-
At 0 DEG C, by the fluoro- 2- oximido -2 of 5-, 3- dihydro -1H- 1-Indanone (7.0g) is dissolved in phosphorus oxychloride (120mL), then phosphorus oxychloride (1.5g) is added thereto in batches, it finishes and leads to dry hydrogen chloride gas into solution, stop ventilation after 3 hours, reaction solution is heated to 60 DEG C and is stirred 16 hours.It is cooled to room temperature, is concentrated under reduced pressure and removes phosphorus oxychloride, obtained solid is washed with water, vacuum drying obtains the chloro- 6- fluorine isoquinolin (6.0g) of 1,3- bis-.
Step 3,4,5,6,7,8,9 respectively with reference to intermediate 1 synthesis in step 1,2,3,4,5,6,7
The synthesis of step 10:8- flumizole simultaneously [5,1-a] isoquinolin -5- amine
With reference to the step 8 in the synthesis of intermediate 1. 1H-NMR(400MHz,DMSO-d 6): δ 8.586 (s, 1H), 8.036 (s, 1H), 7.945-7.924 (m, 1H), 7.257-7.204 (m, 2H), 6.746 (s, 2H), 6.093 (s, 1H).
The synthesis of intermediate 4:7- flumizole simultaneously [5,1-a] isoquinolin -5- amine
The synthesis of the fluoro- 2- oximido -2,3- dihydro -1H- 1-Indanone of step 1:4-
With reference to the step 1 in the synthesis of intermediate 3, fluoro- 2, the 3- dihydro -1H- 1-Indanone of 5- is replaced with fluoro- 2, the 3- dihydro -1H- 1-Indanone of 4-.
Step 2,3,4,5,6,7,8,9 respectively with reference to intermediate 3 synthesis in step 2,3,4,5,6,7,8,9
The synthesis of step 10:7- flumizole simultaneously [5,1-a] isoquinolin -5- amine
With reference to the step 10 in the synthesis of intermediate 3. 1H-NMR(400MHz,DMSO-d 6): δ 8.464 (s, 1H), 8.086-8.049 (m, 1H), 7.883 (s, 1H), 7.276-7.243 (m, 1H), 7.036-7.030 (m, 1H), 6.608 (s, 2H), 5.939 (s, 1H).
The synthesis of intermediate 5:7- flumizole simultaneously [5,1-a] isoquinolin -5- amine
The synthesis of the chloro- 1- methyl-5-nitro isoquinolin of step 1:3-
At 0 DEG C, the chloro- 1- methylisoquinolinium (8.3g) of 3- is slowly added into the concentrated sulfuric acid (100mL), then potassium nitrate (5.7g) is added portionwise, mixture is stirred 1 hour at 0 DEG C, reaction solution is poured into trash ice, adjusts pH to 9, filtering with ammonium hydroxide, filter cake is washed with water, and the chloro- 1- methyl-5-nitro isoquinolin (6.2g) of 3- is obtained after filter cake is dried in vacuo. 1H-NMR(400MHz,DMSO-d 6): δ 8.713-8.692 (m, 1H), 8.662-8.640 (m, 1H), 8.222 (s, 1H), 7.885-7.845 (m, 1H), 2.968 (s, 3H).
The synthesis of the chloro- 1- methyl -5- aminoisoquinoline of step 2:3-
The chloro- 1- methyl-5-nitro isoquinolin (6.0g) of 3- is dissolved in first alcohol and water (1:1, in the mixed solvent 200mL), it is added ammonium chloride (14.4g), it is heated to 60 DEG C, after solution becomes clarification, it is added reduced iron powder (15.1g), it is stirred 30 minutes at 60 DEG C, it is cooled to room temperature, filtering, filtrate decompression concentration removes methanol, (150mL × 2) are extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains the chloro- 1- methyl -5- aminoisoquinoline (3.9g) of 3- with silica gel chromatography (petroleum ether: ethyl acetate=20:1).
The synthesis of the chloro- 1- methylisoquinolinium of step 3:3,5- bis-
The chloro- 1- methyl -5- aminoisoquinoline (3.9g) of 3- is dissolved in concentrated hydrochloric acid (50mL), it is cooled to 0 DEG C, water (10mL) solution of sodium nitrite (1.5 g) is slowly added dropwise, rate of addition makes reacting liquid temperature keep below 5 DEG C, after twenty minutes, concentrated hydrochloric acid (10mL) solution of stannous chloride (2.4g) is added, is stirred 1 hour at 0 DEG C.Reaction solution is poured into water, (150mL × 2) are extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains the chloro- 1- methylisoquinolinium (4.2g) of 3,5- bis- with silica gel chromatography (petroleum ether: ethyl acetate=20:1).
Step 4,5,6,7,8,9 respectively with reference to intermediate 1 synthesis in step 2,3,4,5,6,7.
The synthesis of step 10:7- flumizole simultaneously [5,1-a] isoquinolin -5- amine
With reference to the step 8 in the synthesis of intermediate 1. 1H-NMR(400MHz,DMSO-d 6): δ 8.543 (s, 1H), 8.053-8.033 (m, 1H), 8.006 (s, 1H), 7.460-7.440 (m, 1H), 7.208-7.169 (m, 1H), 6.819 (s, 2H), 6.231 (s, 1H).
Intermediate 6:[1,2,3] triazole simultaneously [5,1-a] isoquinolin -5- amine synthesis
The synthesis of step 1:2- ((trimethyl silicon substrate) acetenyl) benzaldehyde
Under nitrogen protection; trimethylsilyl acetylene (19.6g), cuprous iodide (0.95g), triethylamine (20.2g) and bi triphenyl phosphorus palladium chloride (3.5g) are sequentially added into tetrahydrofuran (500mL) solution of 2- bromobenzaldehyde (18.5g), reaction solution is heated to 50 DEG C and is stirred overnight.It is cooled to room temperature, it is poured into water, (300mL × 2) are extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains 2- ((trimethyl silicon substrate) acetenyl) benzaldehyde (19.0g) with silica gel chromatography (petroleum ether: ethyl acetate=20:1).
Step 2: the synthesis of trimethyl ((2 (2- nitroethenyl group) phenyl) acetenyl) silane
By 2- ((trimethyl silicon substrate) acetenyl) benzaldehyde (19.0g), ammonium acetate (7.2g) is added in nitromethane (50mL), reaction solution continues stirring 1 hour after being heated to 110 DEG C, it is cooled to room temperature, it is concentrated under reduced pressure, solid residue is dissolved with ethyl acetate (500mL), organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains trimethyl ((2 (2- nitroethenyl group) phenyl) acetenyl) silane (15.3g) with silica gel chromatography (petroleum ether: ethyl acetate=20:1). 1H-NMR(400MHz,CDCl 3): δ 8.460-8.426 (d, 1H), 7.835-7.801 (d, 1H), 7.580-7.535 (m, 2H), 7.441-7.361 (m, 2H), 0.295 (s, 9H).
Step 3:[1,2,3] triazole simultaneously [5,1-a] isoquinolin synthesis
Trimethyl ((2 (2- nitroethenyl group) phenyl) acetenyl) silane (15.3g) and sodium azide (6.0g) are dissolved in dimethyl sulfoxide (150mL), reaction solution is heated to 110 DEG C and stirs 40 minutes.It is cooled to room temperature, it is poured into water, it is extracted with ethyl acetate (300mL × 2), organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains [1,2 with silica gel chromatography (methylene chloride: methanol=20:1), 3] triazole simultaneously [5,1-a] isoquinolin (6.8g).
The synthesis of bromo- [1,2,3] triazole of step 4:5- simultaneously [5,1-a] isoquinolin
Under nitrogen protection, by [1,2,3] triazole, simultaneously [5,1-a] isoquinolin (2.0g) is dissolved in dry toluene (100mL), is cooled to -40 DEG C, is added dropwise n-BuLi hexane solution (2.4M, 13.9mmol).It is added dropwise, reaction solution stirs 2 hours at -40 DEG C, it is added 1,2- dibromo tetrachloroethanes (4.6g), remove cooling, continue during stirring falls back for 2 hours, it is extracted with ethyl acetate (100mL × 2), organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains 5- bromo- [1,2 with silica gel chromatography (methylene chloride: methanol=20:1), 3] triazole simultaneously [5,1-a] isoquinolin (0.54g).
Step 5 and step 6:[1,2,3] triazole simultaneously [5,1-a] isoquinolin -5- amine synthesis
Respectively with reference to the step 7 and step 8 in the synthesis of intermediate 1, [1,2,3] triazole simultaneously [5,1-a] isoquinolin -5- amine is finally obtained. 1H-NMR(400MHz,CDCl 3): δ 8.459 (s, 1H), 8.070-8.050 (d, 1H), 7.603-7.583 (d, 1H), 7.542-7.501 (m, 1H), 7.424-7.383 (m, 1H), 6.354 (s, 1H), 5.262 (s, 2H).
Intermediate 7:[1,2,4] triazole simultaneously [4,3-a] quinolin-4-amines synthesis
The synthesis of step 1:3- bromoquinoline -1- nitrogen oxides
Into methylene chloride (300mL) solution of 3- bromoquinoline (10.0g), m-chloro-benzoic acid peroxide (17.3g) is added portionwise, is then stirred at room temperature 12 hours.Reaction solution pours into saturated sodium bicarbonate aqueous solution, organic phase separation, with saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains 3- bromoquinoline -1- nitrogen oxides (9.4g) with silica gel chromatography (methylene chloride: methanol=50:1).
The synthesis of the bromo- 2- chloroquinoline of step 2:3-
3- bromoquinoline -1- nitrogen oxides (4.0g) and Tritox (5.2g) are dissolved in toluene (200mL), triphenylphosphine (9.4g) then is added, mixed liquor is heated to 115 DEG C and is stirred 4 hours.It is cooled to room temperature, reaction solution is concentrated, residue obtains the bromo- 2- chloroquinoline (0.84g) of 3- with silica gel chromatograph column purification (methylene chloride: methanol=50:1).
The synthesis of the bromo- 2- hydrazinoquinoline of step 3:3-
The bromo- 2- chloroquinoline (0.5g) of 3- is added in hydrazine hydrate (25mL), reaction solution is heated to 140 DEG C and is stirred 1 hour.It is cooled to room temperature, it is poured into water, (100mL × 2) are extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, and residue obtains the bromo- 2- hydrazinoquinoline (0.4g) of 3- with silica gel chromatography (methylene chloride: methanol=20:1).
The synthesis of bromo- [1,2,4] triazole of step 4:4- simultaneously [4,3-a] quinoline
The bromo- 2- hydrazinoquinoline (0.4g) of 3- is added in formic acid (25mL), then it is stirred overnight at room temperature, reaction solution is poured into water, (100mL × 2) are extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated, residue obtains 4- bromo- [1 with silica gel chromatography (methylene chloride: methanol=20:1), 2,4] triazole simultaneously [4,3-a] quinoline (0.32g).
Step 5 and step 6:[1,2,4] triazole simultaneously [4,3-a] quinolin-4-amines synthesis
Respectively with reference to the step 7 and step 8 in the synthesis of intermediate 1, [1,2,4] triazole simultaneously [4,3-a] quinolin-4-amines are finally obtained. 1H-NMR(400MHz,DMSO-d 6): δ 9.916 (s, 1H), 8.244-8.224 (d, 1H), 7.659-7.637 (d, 1H), 7.424-7.365 (m, 2H), 6.573 (s, 1H), 6.085 (s, 2H).
Intermediate 8: the synthesis of imidazo [1,5-a] pyridin-5-amine
Steps 1 and 2,3,4,5,6 respectively with reference to intermediate 1 synthesis in step 2,3,4,5,6,7
Step 7: the synthesis of imidazo [1,5-a] pyridin-5-amine
Referring to the step 8 in the synthesis of intermediate 1, imidazo [1,5-a] pyridin-5-amine is obtained. 1H-NMR(400MHz,DMSO-d 6): δ 8.29 (s, 1H), 7.22 (s, 1H), 6.85 (d, J=8.8Hz, 1H), 6.71 (dd, J=8.8Hz, J=6.8Hz, 1H), 6.44 (brs, 2H), 5.71 (dd, J=6.8Hz, J=1.2Hz, 1H).
Intermediate 9: the synthesis of imidazo [1,5-c] quinazoline -5- amine
The synthesis of step 1:4- methylquinazolin -2- amine
Guanidine carbonate (2.7g) is added into n,N-dimethylacetamide (10mL) solution of 2- fluoro acetophenone (1.4g), mixed liquor is heated to 130 DEG C and is stirred 4 hours.Reaction solution is added in cold water (20mL) after being cooled to room temperature, filtering, and filter cake petroleum ether obtains 4- methylquinazolin -2- amine (1.1g) after dry.
Step 2: the synthesis of imidazo [1,5-c] quinazoline -5- amine
To 4- methylquinoline -2- amine (1.1g), glycine (1.0g), tert-butyl hydroperoxide (3.60g under nitrogen protection; 70% aqueous solution), dimethyl sulfoxide (10mL) is added in the mixture of tetrabutylammonium iodide (0.5g) and acetic acid (1.3g), reaction solution is heated to 95 DEG C and is stirred 10 hours.It is cooled to room temperature, water (30ml) and ethyl acetate (30ml) is added, it is washed after organic phase separation with saturated brine, sodium sulphate is dry, filtering, filtrate decompression concentration, residue obtain imidazo [1,5-c] quinazoline -5- amine (0.26g) through silica gel column chromatography separation (methylene chloride: methanol=20:1). 1H-NMR(400MHz,DMSO-d 6): δ 8.58 (s, 1H), 7.96 (d, J=8.0Hz, 1H), 7.83 (s, 1H), 7.58 (s, 2H), 7.37 (d, J=3.6Hz, 2H), 7.19-7.23 (m, 1H).
Intermediate 10: the synthesis of imidazo [5,1-f] [1,6] naphthyridines -5- amine
The synthesis of step 1:2- (2- ethyoxyl -2- oxoethyl) niacin
Ethyl acetoacetate (26.0g) is slowly added dropwise into the mixture of potassium tert-butoxide (33.7g) and isopropanol (500ml) under nitrogen protection, is stirred 2 hours after being added dropwise.Salicylaldoxime (5.5g, 0.03mol) and 2- chlorine apellagrin (15.8g) are added into reaction solution, is heated to 80 DEG C and stirs 4 hours.It is cooled to room temperature, is quenched with water (500mL), pH is then adjusted to 4 with 2N dilute hydrochloric acid.It is added ethyl acetate (500mL), stirring is filtered after twenty minutes, filtrate liquid separation, organic phase is concentrated under reduced pressure, toluene (300mL) is added to residue, stirs 1 hour, 2- (2- ethyoxyl -2- oxoethyl) niacin (15.5g) is obtained after filtering.
The synthesis of -5,7 (6H, 8H)-diketone of step 2:1,6- naphthyridines
At 0 DEG C, triethylamine (7.5g) and ethyl chloroformate (9.6g) are added into tetrahydrofuran (200mL) solution of 2- (2- ethyoxyl -2- oxoethyl) niacin (15.5g), reaction solution is warmed to room temperature stirring 1 hour.It is slowly added into ammonium hydroxide (5mL), continues stirring 1 hour.It is added water (100mL), pH is adjusted to 7 with dilute hydrochloric acid.1,6- naphthyridines -5,7 (6H, 8H)-diketone (6.5g) is obtained after filtering.
The synthesis of the chloro- 1,6- naphthyridines of step 3:5,7- bis-
1,6- naphthyridines -5,7 (6H, 8H)-diketone (6.5g) is dissolved in phosphorus oxychloride (150mL), is cooled to 0 DEG C, is added n,N-diisopropylethylamine (10.4g), 100 DEG C is then heated to and stirs 16 hours.It is cooled to room temperature, phosphorus oxychloride is removed under reduced pressure, is added cold water (100mL), filtering obtains chloro- 1, the 6- naphthyridines (4.0g) of 5,7- bis- after solid vacuum drying.
Step 4,5,6,7,8,9,10 respectively with reference to intermediate 1 synthesis in step 1,2,3,4,5,6,7.
Step 11: the synthesis of imidazo [5,1-f] [1,6] naphthyridines -5- amine
With reference to the step 8 in the synthesis of intermediate 1.LC-MS[M+1] +=185.
The synthesis of intermediate 11:6- chlorine imidazo [5,1-a] isoquinolin -5- amine
The synthesis of the chloro- 1- methylisoquinolinium -3- amine of step 1:4-
N-chlorosuccinimide (2.7g) is slowly added into methylene chloride (50ml) solution of 1- methylisoquinolinium -3- amine (3.2g), it is stirred at room temperature after finishing 1 hour, cold water (50ml) quenching reaction is added, liquid separation, organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated under reduced pressure, and residue obtains the chloro- 1- methylisoquinolinium -3- amine (3.5g) of 4- with silica gel chromatograph column purification (methylene chloride: methanol=20:1).
The synthesis of step 2:2- (the chloro- 1- methylisoquinolinium -3- base of 4-) iso-indoles -1,3- diketone
The chloro- 1- methylisoquinolinium -3- amine (3.5g) of 4- and phthalic anhydride (4.0g) are sequentially added in acetic acid (50ml) at room temperature, which is heated to 120 DEG C and is stirred 10 hours, is then concentrated under reduced pressure.100ml saturated sodium bicarbonate aqueous solution is added to residue and stirs 1 hour, 2- (the chloro- 1- methylisoquinolinium -3- base of 4-) iso-indoles -1,3- diketone (4.8g) is obtained after filtering.
The synthesis of step 3:2- (1- (bromomethyl) -4- chloroquinoline -3- base) iso-indoles -1,3- diketone
To 2- (the chloro- 1- methylisoquinolinium -3- base of 4-) iso-indoles -1 under nitrogen protection; benzoyl peroxide (0.36g) and carbon tetrachloride (200ml) are added in the mixture of 3- diketone (4.8g) and N- bromo-succinimide (3.2g), is heated to 80 DEG C and is stirred overnight.Be cooled to room temperature, filter, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=50:1) obtain 2- (1- (bromomethyl) -4- chloroquinoline -3- base) iso-indoles -1,3- diketone (3.6g).
The synthesis of step 4:2- (1- (azido methyl) -4- chlorine isoquinolin -3- base) iso-indoles -1,3- diketone
By 2- (1- (bromomethyl) -4- chloroquinoline -3- base) iso-indoles -1,3- diketone (3.6g) and sodium azide (0.88g) are dissolved in acetone and water (10:1, in the mixed solvent 100mL) is heated to 65 DEG C and stirs 3 hours.Cooling is fallen back in (200ml), (100mL × 2) are extracted with ethyl acetate, merge organic phase, and with saturated common salt water washing, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=20:1) obtain 2 to-(1- (azido methyl) -4- chlorine isoquinolin -3- base) iso-indoles -1,3- diketone (2.2g).
The synthesis of step 5:2- (1- (amino methyl) -4- chlorine isoquinolin -3- base) iso-indoles -1,3- diketone
By 2- (1- (azido methyl) -4- chlorine isoquinolin -3- base) iso-indoles -1,3- diketone (2.2g) and triphenylphosphine (2.3g) are dissolved in tetrahydrofuran and water (10:1, in the mixed solvent 50mL), is stirred overnight at room temperature.Reaction mixture pours into water (100mL), (100mL × 2) are extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=20:1) obtain 2- (1- (amino methyl) -4- chlorine isoquinolin -3- base) iso-indoles -1,3- diketone (1.3g).
The synthesis of step 6:2- (6- chlorine imidazo [5,1-a] isoquinolin -5- base) iso-indoles -1,3- diketone
2- (1- (amino methyl) -4- chlorine isoquinolin -3- base) iso-indoles -1,3- diketone (1.3g) is mixed with Ethyl formate (100mL), heated overnight at reflux.It is concentrated under reduced pressure, obtains gray solid, dissolved with tetrahydrofuran (50mL), be slowly added to phosphorus oxychloride (1.2g) and triethylamine (2.3g) at 0 DEG C, be then stirred at room temperature 2 hours.It is concentrated under reduced pressure, ethyl acetate (100ml) dissolution is added to residue, acquired solution saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=20:1) obtain 2- (6- chlorine imidazo [5,1-a] isoquinolin -5- base) iso-indoles -1,3- diketone (0.26g).
The synthesis of chloro- H- imidazo [5,1-a] isoquinolin -5- amine of step 7:6-
2- (6- chlorine imidazo [5,1-a] isoquinolin -5- base) iso-indoles -1,3- diketone (0.26g) is added in 50ml dehydrated alcohol, 5 drop, 85% hydrazine hydrate is added with stirring.Then reaction solution 50 DEG C are heated to stir 10 minutes.It is concentrated under reduced pressure and removes organic solvent, 50ml cold water is added, (50mL × 2) are extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=20:1) obtain chloro- H- imidazo [5, the 1-a] isoquinolin -5- amine (90.5mg) of 6-.LC-MS[M+1] +=218.
The synthesis of intermediate 12:H- imidazo [1,5-a] quinolin-4-amines
The synthesis of step 1:2- methylquinoline -3- Ethyl formate
To reduced iron powder (21.9g) is added portionwise in acetic acid (150mL) solution of 2- nitrobenzaldehyde (11.8g) and ethyl acetoacetate (12.2g), reaction solution is then heated to 50 DEG C and is stirred 2 hours.Reaction solution is cooling, filtering, filtrate is poured into water (200mL), pH to 8 is adjusted with saturated sodium bicarbonate aqueous solution, (250mL × 2) are extracted with ethyl acetate, organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=100:1) obtain 2- methylquinoline -3- Ethyl formate (13.6g).
The synthesis of step 2:2- methylquinoline -3- formic acid
2- methylquinoline -3- Ethyl formate (13.6g) is added to the in the mixed solvent of tetrahydrofuran (50mL), methanol (50mL) and water (50mL), one hydronium(ion) lithia (5.3g) of solid is added into the mixture, it is stirred at room temperature 4 hours, pH to 5 is adjusted with dilute hydrochloric acid (2M), it is concentrated under reduced pressure and removes organic solvent, obtained solid filtering, washing obtain 2- methylquinoline -3- formic acid (8.1g) after dry.
Step 3:(2- methylquinoline -3- base) t-butyl carbamate synthesis
The dry tert-butyl alcohol (10mL), triethylamine (21.6g) and diphenyl phosphate azide (13.1g) are added the 1 of 2- methylquinoline -3- formic acid (8.1g) under nitrogen protection; in 4- dioxane (100mL) solution, reaction solution is heated to 100 DEG C and is stirred 5 hours.Be cooled to room temperature, filter, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=50:1) obtain (2- methylquinoline -3- base) t-butyl carbamate (3.5g).
Step 4: the synthesis of imidazo [1,5-a] quinolyl-4 t-butyl carbamate
To (2- methylquinoline -3- base) t-butyl carbamate (1.8g), glycine (1.0g), tert-butyl hydroperoxide (3.60g under nitrogen protection; 70% aqueous solution), dimethyl sulfoxide (10mL) is added in the mixture of tetrabutylammonium iodide (0.5g) and acetic acid (1.3g), be heated to 95 DEG C and stir 10 hours.It is cooled to room temperature, water (30ml) and ethyl acetate (30ml) is added, it is washed after organic phase separation with saturated brine, sodium sulphate is dry, filtering, filtrate decompression concentration, residue obtain imidazo [1,5-a] quinolyl-4 t-butyl carbamate (0.66g) through silica gel column chromatography separation (methylene chloride: methanol=20:1).
Step 5: the synthesis of imidazo [1,5-a] quinolin-4-amines
By imidazo [1,5-a] quinolyl-4 t-butyl carbamate (0.66g) is added to ethanol solution hydrochloride (20mL, in 4N), then it is stirred at room temperature 4 hours, adjusts pH to 7 with saturated sodium bicarbonate, (100mL × 2) are extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, filtering obtains imidazo [1,5-a] quinolin-4-amines (0.35g) after filtrate decompression concentration. 1H-NMR(400MHz,DMSO-d 6): δ 9.01 (s, 1H), 8.16 (d, J=8.0Hz, 1H), 7.61 (s, 1H), 7.45 (m, 1H), 7.23 (m, 2H), 6.09 (s, 1H), 5.87 (s, 2H).
The synthesis of intermediate 13:7- chlorine imidazo [1,5-a] -5- amine
The synthesis of the chloro- 6- of step 1:4- (ethoxy carbonyl)-pyridine carboxylic acid
At room temperature to 4- chloropyridine -2, water (800mL) solution of sodium hydroxide (7.76g) is slowly added dropwise in ethyl alcohol (330mL) solution of 6- dicarboxylate (50.0g), it is added dropwise within 8 hours, is then stirred overnight at room temperature.It is concentrated under reduced pressure, dissolves the residue in water, adjust pH to 3 with concentrated hydrochloric acid, (300mL × 2) are extracted with ethyl acetate, organic phase is dried, filtered with anhydrous sodium sulfate, and the chloro- 6- of 4- (ethoxy carbonyl)-pyridine carboxylic acid (21.3g) is obtained after reduced pressure.
The synthesis of step 2:6- (tertbutyloxycarbonylamino) -4- chloropyridine Ethyl formate
Under nitrogen protection; the dry tert-butyl alcohol (10mL), triethylamine (21.6g) and diphenyl phosphate azide (13.1g) are added to the chloro- 6- of 4- (ethoxy carbonyl)-pyridine carboxylic acid (9.94g) 1; in 4- dioxane (100mL) solution, reaction solution is heated to 100 DEG C and is stirred 5 hours.Be cooled to room temperature, filter, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=50:1) obtain 6- (tertbutyloxycarbonylamino) -4- chloropyridine Ethyl formate (6.1g).
Step 3:(4- chloro- 6- (methylol) pyridine -2- base) t-butyl carbamate synthesis
Sodium borohydride (4.4g) is added portionwise into ethyl alcohol (150mL) solution of 6- (tertbutyloxycarbonylamino) -4- chloropyridine Ethyl formate (11.5g), reaction mixture is stirred overnight at room temperature.10mL water quenching reaction is slowly added dropwise to reaction mixture, it is concentrated under reduced pressure and removes ethyl alcohol, then saturated sodium bicarbonate aqueous solution is added and adjusts pH to 8, (250mL × 2) are extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=50:1) obtain (4- chloro- 6- (methylol) pyridine -2- base) t-butyl carbamate (9.6g).
Step 4:(4- chloro- 6- (chloromethyl) pyridine -2- base) t-butyl carbamate synthesis
Pyridine (3.8g) and thionyl chloride (5.4g) are added into methylene chloride (200mL) solution of (4- chloro- 6- (methylol) pyridine -2- base) t-butyl carbamate (9.6g), reaction mixture is stirred overnight at room temperature.Reaction mixture is poured into water, then saturated sodium bicarbonate aqueous solution is added and adjusts pH to 8, (250mL × 2) are extracted with dichloromethane, organic phase is dry with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=20:1) obtain (4- chloro- 6- (chloromethyl) pyridine -2- base) t-butyl carbamate (4.8g).
The chloro- 6- of step 5:(4- ((1,3- dioxoisoindolin -2- base) methyl) pyridine -2- base) t-butyl carbamate synthesis
To the N of (4- chloro- 6- (chloromethyl) pyridine -2- base) t-butyl carbamate (2.8g), potassium phthalimide (2.0g) is added in dinethylformamide (100mL) solution, reaction mixture is stirred overnight at room temperature.Reaction mixture is poured into water, (150mL × 2) are extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=20:1) obtain (the chloro- 6- of 4- ((1,3- dioxoisoindolin -2- base) methyl) pyridine -2- base) t-butyl carbamate (2.3g).
Step 6:(6- (amino methyl) -4- chloropyridine -2- base) t-butyl carbamate synthesis
To (the chloro- 6- ((1 of 4-, 3- dioxoisoindolin -2- base) methyl) pyridine -2- base) and t-butyl carbamate (2.3g) ethyl alcohol (100mL) solution in be added hydrazine hydrate (0.3g), by reaction mixture be heated to 80 DEG C stir 2 hours.Reaction mixture is cooled to room temperature, filtering, filtrate decompression concentration, residue obtain (6- (amino methyl) -4- chloropyridine -2- base) t-butyl carbamate (1.0g) with silica gel chromatograph column purification (methylene chloride: methanol=20:1).
Step 7,8 respectively with reference to intermediate 1 synthesis in step 5,6.
The synthesis of step 9:7- chlorine imidazo [1,5-a] -5- amine
With reference to the step 5 in the synthesis of intermediate 12. 1H-NMR(400MHz,DMSO-d 6): δ 8.46 (s, 1H), 7.64 (d, J=2.0Hz 1H), 7.39 (s, 1H), 6.55 (d, J=2.0Hz, 1H), 6.44 (brs, 2H).
The synthesis of intermediate 14:6- chlorine imidazo [1,5-a] -8- amine
The synthesis of step 1:5- chloro-2-methyl -3- nitropyridine
1,3- dichloro isoquinolin is substituted for 2,5- dichloro-3-nitropyridine, obtains 5- chloro-2-methyl -3- nitropyridine with reference to the step 1 in the synthesis of intermediate 1.
Step 2:5- chloro-2-methyl pyridine -3- amine
With reference to the step 2 in the synthesis of intermediate 5, title compound is obtained.
Step 3:(5- chloro-2-methyl pyridin-3-yl)-tertiary fourth oxanamide
With reference to the step 3 in the synthesis of intermediate 15, title compound is obtained.
Step 4:(2- bromomethyl -5- chloropyridine -3- base)-tertiary fourth oxanamide
With reference to the step 2 in the synthesis of intermediate 1, title compound is obtained.
The chloro- 2- of step 5:(5- ((1,3- dioxoisoindolin -2- base) methyl) pyridin-3-yl)-tertiary fourth oxanamide
With reference to the step 5 in the synthesis of intermediate 13, title compound is obtained.
Step 6:(2- amino methyl -5- chloropyridine -3- base)-tertiary fourth oxanamide
With reference to the step 6 in the synthesis of intermediate 13, title compound is obtained.
Step 7,8 respectively with reference to intermediate 1 synthesis in step 5,6.
The synthesis of step 9:6- chlorine imidazo [1,5-a] -8- amine
With reference to the step 5 in the synthesis of intermediate 12. 1H-NMR (400MHz, DMSO-d6): δ 9.09 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.00 (s, 1H), 6.87 (brs, 2H).
The synthesis of intermediate 15:6- trifluoromethyl imidazoles simultaneously [1,5-a] -8- amine
The synthesis of step 1:2- chloro- 5- (trifluoromethyl) pyridine -3- amine
Stannous chloride dihydrate (43.9g) is added into ethyl acetate (250mL) solution of 5- trifluoromethyl -3- nitro -2- chloropyridine (10.0g), reaction mixture is heated to 80 DEG C and is stirred 2 hours.Reaction mixture is cooled to during room temperature falls back, adjusts pH to 8, filtering with saturated sodium bicarbonate aqueous solution, by filtrate liquid separation, organic phase is dried, filtered with anhydrous sodium sulfate, and 2- chloro- 5- (trifluoromethyl) pyridine -3- amine (8.3g) is obtained after reduced pressure.
The synthesis of step 2:3- amino -5- (trifluoromethyl) pyridine carbonitrile
To 2- chloro- 5- (trifluoromethyl) pyridine -3- amine (5.1g), zinc cyanide (3.9g), tris(dibenzylideneacetone) dipalladium (1.2g) and 1 under nitrogen, 1'- dinaphthalene -2, N is added in the mixture of the bis- diphenyl phosphines of 2'- (1.42g), dinethylformamide (50mL), by mixture heated overnight at reflux.After reaction mixture is cooled to room temperature, it is poured into water, it is extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, filtering, filtrate decompression is concentrated, residue obtains 3- amino -5- (trifluoromethyl) pyridine carbonitrile (2.5g) with silica gel chromatograph column purification (methylene chloride: methanol=20:1).
Step 3:(2- cyano -5- (trifluoromethyl) pyridin-3-yl) t-butyl carbamate synthesis
Di-tert-butyl dicarbonate (3.5g), triethylamine (2.16g) and 4-dimethylaminopyridine (0.13g), reaction mixture are added into tetrahydrofuran (100mL) solution of 3- amino -5- (trifluoromethyl) pyridine carbonitrile (2.0g) to be stirred at room temperature 4 hours.Water quenching reaction is added, (150mL × 2) are extracted with ethyl acetate, organic phase is dry with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue with silica gel column chromatography purify (methylene chloride: methanol=50:1) obtain (2- cyano -5- (trifluoromethyl) pyridin-3-yl) t-butyl carbamate (2.3g).
Step 4:(2- (amino methyl) -5- (trifluoromethyl) pyridin-3-yl) t-butyl carbamate synthesis
Raney's nickel (1.0g) is added into ethyl acetate (50mL) solution of (2- cyano -5- (trifluoromethyl) pyridin-3-yl) t-butyl carbamate (1.3g), mixture is stirred overnight at room temperature under an atmospheric pressure hydrogen.Filtering, filtrate decompression concentration, residue obtain (2- (amino methyl) -5- (trifluoromethyl) pyridin-3-yl) t-butyl carbamate (0.3g) with silica gel chromatograph column purification (methylene chloride: methanol=20:1).
Step 5, the step 5 in the 6 reference synthesis of intermediate 1,6.
The synthesis of step 7:6- trifluoromethyl imidazoles simultaneously [1,5-a] -8- amine
With reference to the step 5 in the synthesis of intermediate 12. 1H-NMR (400MHz, DMSO-d6): δ 8.43 (1H, s), 8.30 (1H, s), 7.65 (1H, s), 6.35 (2H, brs), 5.87 (1H, s).
The synthesis of intermediate 16:8- chlorine imidazo [5,1-a] isoquinolin -5- amine
Steps 1 and 2,3,4,5,6,7,8,9,10 obtain title compound with reference to the synthesis step 1,2,3,4,5,6,7,8,9,10 of centre 3 respectively.
LC-MS[M+1] +=218.
The synthesized reference synthesis general formula A of embodiment 1-49 compound obtains each title compound, and the synthesized reference synthesis Formula B of embodiment 50-63 obtains each title compound, as shown in table 1:
Table 1: embodiment 1-49
Test example 1: biological activity determination
The protein induced expression of 1.IDO and TDO and purification process
First, according to kit specification, PCR amplification IDO (derived from the RNA of HeLa cell) and TDO (derived from the RNA of U87MG cell) gene, the PCR product of amplification recycles, then pET28a plasmid and IDO (TDO) glue recovery product (are carried out (37 DEG C of digestion with two kinds of restriction enzymes of BamH1 and Xhol) for TDO plasmid construction with NotI and EcoRI, digestion 2h) run glue and glue recycling, T4 quick ligase connection product is added in bacillus coli DH 5 alpha (E.coli DH5 α) competent cell, 30min is placed on ice, the heat shock 90s at 42 DEG C, bacterium and coated plate are shaken in LB culture medium, picking monoclonal shakes bacterium overnight, extract plasmid enzyme restriction identification, sequencing is sent to reflect again It is fixed, take positive colony, i.e. His-IDO/pET28a and His-TDO/pET28a plasmid construction success.
The e. coli bl21 bacterium of the 300ml of the plasmid containing His-IDO/pET28a His-TDO/pET28a built is shaken into bacterium to OD in LB culture medium at 37 DEG C 600The IPTG of final concentration of 0.5mM is added in=0.6-0.8, and 3.5h is induced at 30 DEG C, is centrifuged 45min after induction at 6000rpm and collects thallus.
By the thallus of the collection lysate (Tris-HCl of 40mM, pH 8.0；The NaCl of 110mM；The KCl of 2.2mM；10% glycerol；0.5% Tween-20；The imidazoles of 20mM；The DTT of 1mM) it hangs again, ultrasound cracking (power 30%, crack 15min on ice), the bacterium solution after cracking is centrifuged 60min at 12000rpm, 4 DEG C, and 0.22 μM of filter of gained supernatant is filtered, it is stand-by to get out sample.Nickel column lysate is balanced into 5 column volumes, then by ready supernatant samples in nickel column, after loading, with the eluent (Tris-HCl of 40mM, pH 8.0；The NaCl of 110mM；The KCl of 2.2mM；10% glycerol；The imidazoles of 20-250mM) gradient elution albumen, the protein solution of elution is dialyzed overnight at 4 DEG C, concentration packing, saves backup in -80 DEG C after dialysis.
The test of 2.IDO and TDO the enzyme activity
The enzyme activity detection platform of IDO and TDO is established using the method for light absorption, compound is carried out since 10mM with 100%DMSO to 10 times of gradient dilution (totally 5 concentration), each concentration takes 4 μ L to be added to (50mM K in the reaction buffer of 96 μ L 2HPO 4-KH 2PO 4Phosphate buffer, pH 6.5) it mixes, it is stand-by as 4* compound.2*IDO enzyme is prepared using reaction buffer, final concentration of 75nM (the final concentration of 300nM of TDO enzyme), (final concentration is respectively 20 μM L- (+)-Absorbate to 4* substrate, is purchased from Alfa Aesar, article No. A15613；10 μM of Methylene blue is purchased from Sigma, article No. M9140-25G；The Catalase of 0.2mg/ml is purchased from Sigma, article No. C1345-1G and 20 μM of L-Trp, is purchased from Sigma, article No. T0254-25G (TDO is 300 μM of L-Trp)) it is stand-by.The 4* compound of 10 μ L is taken to be added to 384 orifice plates (Assay plate, it buys in Corning, article No. 3701), then the 2*IDO enzyme (or TDO enzyme) of 20 μ L is added, centrifugation mixes, and adds the 4* substrate mixture starting reaction of 10 μ L (total reaction volume is 40 μ L).384 orifice plates are put in incubator and are reacted 180 minutes (TDO reacts 120 minutes) for 23 DEG C, then the 6M TCA that 4 μ L are added in every hole is incubated for 30min at 55 DEG C, 10min is centrifuged under 2500rpm, every hole takes 40 μ L supernatants, and 2%4- dimethylaminobenzaldehyde is added (purchased from TCI, article No. D495, is dissolved with glacial acetic acid), absorbance value (480nM light absorption) is read on FlexStation 3 after 5min.Each compound measures the activity of enzyme under 5 concentration respectively, and the IC of the compound is calculated using GraphtPad Prism5.0 software for data 50Value.
Table 2: measurement result of the embodiment to IDO and TDO enzyme inhibition activity
Test example 2: pharmacokinetic data
Male SD rat derives from Beijing Vital River Experimental Animals Technology Co., Ltd., rat is grouped, every group 3, takes orally single oral gavage respectively and gives sample to be tested suspension (5mg/kg).Animal overnight fasting before experiment, fasting time is from administration first 10 hours to 4 hours after administration.0.25 after administration, take a blood sample within 0.5,1,2,4,6,8 and 24 hours.0.3mL whole blood is taken by eyeground vein clump after isoflurane is anaesthetized using toy Anesthesia machine, is put in anticoagulant heparin pipe, sample is centrifuged 5min in 4 DEG C, 4000rpm, and blood plasma is transferred in centrifuge tube, and is put in -80 DEG C and saves until analysis.Sample is extracted using precipitation of protein in blood plasma, and extract liquor is analyzed by LC/MS/MS.
Table 3: the pharmacokinetic data of embodiment compound
Embodiment 51 40 52
Dosage (mg/kg) 5 5 5
T 1/2(hr) 3.28 4.31 3.56
T max(hr) 0.25 0.58 0.33
C max(ng/mL) 721 243 507
AUC 0-inf(hr*ng/mL) 1520 1018 2180

Claims (44)

  1. The compound of Formulas I or its pharmaceutically acceptable salt,
    Wherein,
    Ring A is not present or ring A is phenyl ring or the 5-6 member hetero-aromatic ring containing 1,2 or 3 selected from N, O or S atom；
    Ring B is 5-membered aromatic ring, wherein 1,2,3 or 4 in W, V, X, Y and Z is selected from N or NH, other to be selected from C or CH, specifically,
    I) it is CH that Y and V, which is N, Z and W, and X is C；
    Ii) Y, Z, V and W are N, and X is C；
    Iii it is CH that) X and V, which is N, Z and W, and Y is C；
    Iv) Y, Z and V are N, and W is CH, and X is C；
    V) X, Z and V are N, and W is CH, and Y is C；
    Vi) X is N, and Z, V and W are CH, and Y is C；
    Vii) Y is N, and Z, V and W are CH, and X is C；
    Viii it be CH, X and Y is C that) Z, which is NH, V and W,；
    Ix it be CH, X and Y is C that) V, which is NH, Z and W,；
    X) it be CH, X and Y is C that W, which is NH, V and Z,；
    Xi) V and W is N or NH, and Z is that CH, X and Y are C；
    Xii) V and Z is N or NH, and W is that CH, X and Y are C；
    Xiii) Z and W is N or NH, and V is that CH, X and Y are C；
    Xiv it is CH that) Y and W, which is N, V and Z, and X is C；
    Xv it is CH that) X and W, which is N, V and Z, and Y is C；
    Xvi) X and Z is N or NH, and V and W are CH, and Y is C；
    Xvii it is CH that) Y and Z, which is N, V and W, and X is C；
    Xviii) Y, V and W are N, and Z is CH, and X is C；
    Xix) Z, V and W are N or NH, and X and Y are C；
    Xx) X, W and V are N, and Z is CH, and Y is C；
    Xxi) Y, Z and W are N, and V is CH, and X is C；Or
    Xxii) X, Z, V and W are N, and Y is C；
    P is C (R 6) or N；
    Q is O or S；
    D is selected from NH, O, S or CH 2；
    E is selected from NH, O or CH 2；
    L is selected from singly-bound, S, SO, SO 2, CO, C (O) O, S (O) O or S (O) 2O；
    Each R 1Independently selected from halogen, amino, hydroxyl, cyano, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
    R 2Selected from C 3-12Naphthenic base, C 3-12Heterocyclylalkyl, 6-12 member aryl or the 5-12 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；
    R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2-、-OR 4、-SR 4、-N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-C(O)R 4、-S(O)R 4、-S(O)OR 4、-S(O)N(R 4) 2、-S(O) 2R 4、-S(O) 2OR 4、-S(O) 2N(R 4) 2、-OC(O)R 4、-OC(O)OR 4、-OC(O)N(R 4) 2、-N(R 4)C(O)R 4、-N(R 4)C(O)OR 4、-N(R 4)C(O)N(R 4) 2、-N(R 4)S(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2Optionally it is independently selected by one or more from R 5Group replace；
    Each R 4Independently selected from H, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom；
    R 5Selected from halogen, amino, cyano, hydroxyl ,-COOH, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
    R 6Selected from H, halogen, amino, cyano, hydroxyl ,-COOH or halogenated C 1-3Alkyl；
    M is 0,1 or 2.
  2. Compound described in claim 1 or its pharmaceutically acceptable salt, ring A is not present or ring A is phenyl ring, furan nucleus, thiphene ring, pyrrole ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, thiazole ring, isothiazole ring, oxazole ring, isozole ring, tetrazole ring or triazine ring；It is preferred that ring A is not present or ring A is phenyl ring or pyridine ring；Further preferably, ring A is not present or ring A is
  3. Compound of any of claims 1 or 2 or its pharmaceutically acceptable salt, each R 1Independently selected from halogen, halogenated C 1-3Alkyl or C 1-6Alkyl；It is preferred that each R 1Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl；Further preferably, each R 1Independently selected from fluorine, chlorine or trifluoromethyl.
  4. Compound of any of claims 1-3 or its pharmaceutically acceptable salt, m are 0 or 1.
  5. Compound of any of claims 1-4 or its pharmaceutically acceptable salt, ring B are aromatic rings, wherein it is CH that i) Y and V, which is N, Z and W, and X is C；Ii) Y, Z, V and W are N, and X is C；Iii it is CH that) X and V, which is N, Z and W, and Y is C；Iv) Y, Z and V are N, and W is CH, and X is C；V) X, Z and V are N, and W is CH, and Y is C.
  6. Compound of any of claims 1-5 or its pharmaceutically acceptable salt, structural unit It is selected from
  7. Compound of any of claims 1-6 or its pharmaceutically acceptable salt, structural unit It is selected from
  8. Compound of any of claims 1-7 or its pharmaceutically acceptable salt, D are selected from NH, O or CH 2；E is selected from NH, O or CH 2。
  9. Compound of any of claims 1-8 or its pharmaceutically acceptable salt ,-D-C (Q)-E- are selected from-NHC (O) NH- ,-NHC (S) NH- ,-OC (O) NH- ,-NHC (O) CH 2Or-CH 2C(O)NH-。
  10. Compound of any of claims 1-9 or its pharmaceutically acceptable salt, L are selected from singly-bound or SO 2。
  11. Compound of any of claims 1-10 or its pharmaceutically acceptable salt, R 2Selected from C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；It is preferred that R 2Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, any position loses a hydrogen atom Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, are optionally independently selected by one or more from R 3Group replace；Further preferably, R 2A hydrogen atom is lost selected from cyclohexyl, any position Phenyl, pyridyl group or pyrimidine radicals, are optionally independently selected by one or more from R 3Group replace；Still more preferably, R 2A hydrogen atom is lost selected from cyclohexyl, any position Phenyl, pyridyl group or pyrimidine radicals, are optionally independently selected by one or more from R 3Group replace；Still more preferably, R 2It is selected from
  12. Compound of any of claims 1-11 or its pharmaceutically acceptable salt, R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Heterocyclylalkyl CH 2-、-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Heterocyclylalkyl contains 1,2 or 3 5-6 unit's heteroaryl or C selected from N, O or S atom 3-6Heterocyclylalkyl CH 2Optionally it is independently selected by one or more from R 5Group replace；It is preferred that R 3Selected from fluorine, chlorine, bromine, cyano, nitro, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position loses a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Wherein methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position lose a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Optionally it is independently selected by one or more from R 5Group replace；Further preferably, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, any position lose a hydrogen atom Tetrazole radical or Wherein methyl, any position lose a hydrogen atom Tetrazole radical or Optionally it is independently selected by one or more from R 5Group replace；Still more preferably, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OCF 3、-SCH 3、-S(O) 2CH 3、-S(O) 2NH 2、-C(O)OCH 3、-COOH、-C(O)NHCH 3、-C(O)NH 2、-NHS(O) 2NH 2、-P(O)(CH 3) 2、-P(O)(OCH 2CH 3) 2、-C(OH)(CF 3) 2、
  13. Compound of any of claims 1-12 or its pharmaceutically acceptable salt, each R 4Independently selected from H, halogenated C 1-3Alkyl or C 1-6Alkyl；It is preferred that each R 4Independently selected from H, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；Further preferably, each R 4Independently selected from H, trifluoromethyl, methyl or ethyl.
  14. Compound of any of claims 1-13 or its pharmaceutically acceptable salt, R 5Selected from hydroxyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl；It is preferred that R 5Selected from hydroxyl or trifluoromethyl.
  15. Compound described in any one of claim 1-14 or its pharmaceutically acceptable salt, R 6Selected from H or halogen, preferably R 6Selected from H or chlorine.
  16. The compound of Formula II or its pharmaceutically acceptable salt,
    Wherein,
    Ring A is phenyl ring or the 5-6 member hetero-aromatic ring containing 1,2 or 3 selected from N, O or S atom；
    Ring B is aromatic rings, wherein 1,2,3 or 4 in W, V, X, Y and Z is selected from N or NH, other to be selected from C or CH, specifically,
    I) it is CH that Y and V, which is N, Z and W, and X is C；
    Ii) Y, Z, V and W are N, and X is C；
    Iii it is CH that) X and V, which is N, Z and W, and Y is C；
    Iv) Y, Z and V are N, and W is CH, and X is C；
    V) X, Z and V are N, and W is CH, and Y is C；
    Vi) X is N, and Z, V and W are CH, and Y is C；
    Vii) Y is N, and Z, V and W are CH, and X is C；
    Viii it be CH, X and Y is C that) Z, which is NH, V and W,；
    Ix it be CH, X and Y is C that) V, which is NH, Z and W,；
    X) it be CH, X and Y is C that W, which is NH, V and Z,；
    Xi) V and W is N or NH, and Z is that CH, X and Y are C；
    Xii) V and Z is N or NH, and W is that CH, X and Y are C；
    Xiii) Z and W is N or NH, and V is that CH, X and Y are C；
    Xiv it is CH that) Y and W, which is N, V and Z, and X is C；
    Xv it is CH that) X and W, which is N, V and Z, and Y is C；
    Xvi) X and Z is N or NH, and V and W are CH, and Y is C；
    Xvii it is CH that) Y and Z, which is N, V and W, and X is C；
    Xviii) Y, V and W are N, and Z is CH, and X is C；
    Xix) Z, V and W are N or NH, and X and Y are C；
    Xx) X, W and V are N, and Z is CH, and Y is C；
    Xxi) Y, Z and W are N, and V is CH, and X is C；Or
    Xxii) X, Z, V and W are N, and Y is C；
    P is C (R 6) or N；
    Q is O or S；
    L is selected from singly-bound, S, SO, SO 2, CO, C (O) O, S (O) O or S (O) 2O；
    Each R 1Independently selected from halogen, amino, hydroxyl, cyano, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
    R 2Selected from C 3-12Naphthenic base, C 3-12Heterocyclylalkyl, 6-12 member aryl or the 5-12 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；
    R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2-、-OR 4、-SR 4、-N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-C(O)R 4、-S(O)R 4、-S(O)OR 4、-S(O)N(R 4) 2、-S(O) 2R 4、-S(O) 2OR 4、-S(O) 2N(R 4) 2、-OC(O)R 4、-OC(O)OR 4、-OC(O)N(R 4) 2、-N(R 4)C(O)R 4、-N(R 4)C(O)OR 4、-N(R 4)C(O)N(R 4) 2、-N(R 4)S(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2Optionally it is independently selected by one or more from R 5Group replace；
    Each R 4Independently selected from H, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom；
    R 5Selected from halogen, amino, cyano, hydroxyl ,-COOH, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
    R 6Selected from H, halogen, amino, cyano, hydroxyl ,-COOH or halogenated C 1-3Alkyl；
    M is 0,1 or 2.
  17. Compound described in claim 16 or its pharmaceutically acceptable salt, ring A are phenyl ring, furan nucleus, thiphene ring, pyrrole ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, thiazole ring, isothiazole ring, oxazole ring, isozole ring, tetrazole ring or triazine ring；It is preferred that ring A is phenyl ring or pyridine ring；Further preferably, ring A is not present or ring A is
  18. Compound described in claim 16 or 17 or its pharmaceutically acceptable salt, each R 1Independently selected from halogen, halogenated C 1-3Alkyl or C 1-6Alkyl；It is preferred that each R 1Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl；Further preferably, each R 1Independently selected from fluorine, chlorine or trifluoromethyl.
  19. Compound described in any one of claim 16-18 or its pharmaceutically acceptable salt, m are 0 or 1.
  20. Compound described in any one of claim 16-19 or its pharmaceutically acceptable salt, ring B are aromatic rings, wherein it is CH that i) Y and V, which is N, Z and W, and X is C；Ii) Y, Z, V and W are N, and X is C；Iii it is CH that) X and V, which is N, Z and W, and Y is C；Iv) Y, Z and V are N, and W is CH, and X is C；V) X, Z and V are N, and W is CH, and Y is C.
  21. Compound described in any one of claim 16-20 or its pharmaceutically acceptable salt, structural unit It is selected from
  22. Compound described in any one of claim 16-21 or its pharmaceutically acceptable salt, structural unit It is selected from
  23. Compound described in any one of claim 16-22 or its pharmaceutically acceptable salt, L are selected from singly-bound or SO 2。
  24. Compound described in any one of claim 16-23 or its pharmaceutically acceptable salt, R 2Selected from C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；It is preferred that R 2Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, any position loses a hydrogen atom Phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, are optionally independently selected by one or more from R 3Group replace；Further preferably, R 2A hydrogen atom is lost selected from cyclohexyl, any position Phenyl, pyridyl group or pyrimidine radicals, are optionally independently selected by one or more from R 3Group replace；Still more preferably, R 2It is selected from It is optionally independently selected by one or more from R 3Group replace；Still more preferably, R 2It is selected from
  25. Compound described in any one of claim 16-24 or its pharmaceutically acceptable salt, R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Heterocyclylalkyl CH 2-、-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Heterocyclylalkyl contains 1,2 or 3 5-6 unit's heteroaryl or C selected from N, O or S atom 3-6Heterocyclylalkyl CH 2Optionally it is independently selected by one or more from R 5Group replace；It is preferred that R 3Selected from fluorine, chlorine, bromine, cyano, nitro, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position loses a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Wherein methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, any position lose a H atom Furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, Optionally it is independently selected by one or more from R 5Group replace；Further preferably, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OR 4、-SR 4、-S(O) 2R 4、-S(O) 2N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2、-P(O)(OR 4) 2, methyl, any position lose a hydrogen atom Tetrazole radical or Wherein methyl, any position lose a hydrogen atom Tetrazole radical or Optionally it is independently selected by one or more from R 5Group replace；Still more preferably, R 3Selected from fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl ,-OCF 3、-SCH 3、-S(O) 2CH 3、-S(O) 2NH 2、-C(O)OCH 3、-COOH、-C(O)NHCH 3、-C(O)NH 2、-NHS(O) 2NH 2、-P(O)(CH 3) 2、-P(O)(OCH 2CH 3) 2、-C(OH)(CF 3) 2、
  26. Compound described in any one of claim 16-25 or its pharmaceutically acceptable salt, each R 4Independently selected from H, halogenated C 1-3Alkyl or C 1-6Alkyl；It is preferred that each R 4Independently selected from H, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；Further preferably, each R 4Independently selected from H, trifluoromethyl, methyl or ethyl.
  27. Compound described in any one of claim 16-26 or its pharmaceutically acceptable salt, R 5Selected from hydroxyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl；It is preferred that R 5Selected from hydroxyl or trifluoromethyl.
  28. Compound described in any one of claim 16-27 or its pharmaceutically acceptable salt, R 6Selected from H or halogen；It is preferred that R 6Selected from H or chlorine.
  29. The compound of formula III or its pharmaceutically acceptable salt,
    Wherein,
    Ring B is aromatic rings, wherein 1,2,3 or 4 in W, V, X, Y and Z is selected from N or NH, other to be selected from C or CH, specifically,
    I) it is CH that Y and V, which is N, Z and W, and X is C；
    Ii) Y, Z, V and W are N, and X is C；
    Iii it is CH that) X and V, which is N, Z and W, and Y is C；
    Iv) Y, Z and V are N, and W is CH, and X is C；
    V) X, Z and V are N, and W is CH, and Y is C；
    Vi) X is N, and Z, V and W are CH, and Y is C；
    Vii) Y is N, and Z, V and W are CH, and X is C；
    Viii it be CH, X and Y is C that) Z, which is NH, V and W,；
    Ix it be CH, X and Y is C that) V, which is NH, Z and W,；
    X) it be CH, X and Y is C that W, which is NH, V and Z,；
    Xi) V and W is N or NH, and Z is that CH, X and Y are C；
    Xii) V and Z is N or NH, and W is that CH, X and Y are C；
    Xiii) Z and W is N or NH, and V is that CH, X and Y are C；
    Xiv it is CH that) Y and W, which is N, V and Z, and X is C；
    Xv it is CH that) X and W, which is N, V and Z, and Y is C；
    Xvi) X and Z is N or NH, and V and W are CH, and Y is C；
    Xvii it is CH that) Y and Z, which is N, V and W, and X is C；
    Xviii) Y, V and W are N, and Z is CH, and X is C；
    Xix) Z, V and W are N or NH, and X and Y are C；
    Xx) X, W and V are N, and Z is CH, and Y is C；
    Xxi) Y, Z and W are N, and V is CH, and X is C；Or
    Xxii) X, Z, V and W are N, and Y is C；
    Q is O or S；
    D is selected from NH, O, S or CH 2；
    E is selected from NH, O or CH 2；
    L is selected from singly-bound, S, SO, SO 2, CO, C (O) O, S (O) O or S (O) 2O；
    Each R 1Independently selected from halogen, amino, hydroxyl, cyano, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
    R 2Selected from C 3-12Naphthenic base, C 3-12Heterocyclylalkyl, 6-12 member aryl or the 5-12 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom, are optionally independently selected by one or more from R 3Group replace；
    R 3Selected from halogen, cyano, nitro, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2-、-OR 4、-SR 4、-N(R 4) 2、-C(O)OR 4、-C(O)N(R 4) 2、-C(O)R 4、-S(O)R 4、-S(O)OR 4、-S(O)N(R 4) 2、-S(O) 2R 4、-S(O) 2OR 4、-S(O) 2N(R 4) 2、-OC(O)R 4、-OC(O)OR 4、-OC(O)N(R 4) 2、-N(R 4)C(O)R 4、 -N(R 4)C(O)OR 4、-N(R 4)C(O)N(R 4) 2、-N(R 4)S(O)N(R 4) 2、-N(R 4)S(O) 2N(R 4) 2、-P(O)(R 4) 2Or-P (O) (OR 4) 2, wherein C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl is selected from N, O or the 5-6 unit's heteroaryl of S atom, C containing 1,2 or 3 3-6Naphthenic base CH 2-、C 3-6Heterocyclylalkyl CH 2, contain 1,2 or 3 5-6 unit's heteroaryl CH selected from N, O or S atom 2Optionally it is independently selected by one or more from R 5Group replace；
    Each R 4Independently selected from H, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base, C 3-6Heterocyclylalkyl, phenyl or the 5-6 unit's heteroaryl containing 1,2 or 3 selected from N, O or S atom；
    R 5Selected from halogen, amino, cyano, hydroxyl ,-COOH, halogenated C 1-3Alkyl, C 1-6Alkyl, C 3-6Naphthenic base or C 3-6Heterocyclylalkyl；
    M is 0,1 or 2.
  30. Compound described in claim 29 or its pharmaceutically acceptable salt, each R 1Independently selected from halogen, halogenated C 1-3Alkyl or C 1-6Alkyl；It is preferred that each R 1Independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group, chloromethyl, dichloromethyl or trichloromethyl；Further preferably, each R 1Independently selected from chlorine or trifluoromethyl.
  31. Compound described in claim 29 or 30 or its pharmaceutically acceptable salt, m are 0 or 1.
  32. Compound described in any one of claim 29-31 or its pharmaceutically acceptable salt, ring B are aromatic rings, wherein it is CH that i) Y and V, which is N, Z and W, and X is C；Ii it is CH that) X and V, which is N, Z and W, and Y is C.
  33. Compound described in any one of claim 29-32 or its pharmaceutically acceptable salt, structural unit It is selected from
  34. Compound described in any one of claim 29-33 or its pharmaceutically acceptable salt, structural unit It is selected from
  35. Compound described in any one of claim 29-34 or its pharmaceutically acceptable salt, D are selected from NH, O or CH 2；E is selected from NH, O or CH 2。
  36. Compound described in any one of claim 29-35 or its pharmaceutically acceptable salt ,-D-C (Q)-E- are selected from-NHC (O) NH- ,-NHC (S) NH- ,-OC (O) NH- ,-NHC (O) CH 2Or-CH 2C(O)NH-。
  37. Compound described in any one of claim 29-36 or its pharmaceutically acceptable salt, L are selected from singly-bound.
  38. Compound described in any one of claim 29-37 or its pharmaceutically acceptable salt, R 25-6 unit's heteroaryl selected from phenyl or containing 1,2 or 3 selected from N, O or S atom, is optionally independently selected by one or more from R 3Group replace；It is preferred that R 2Selected from phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazole radical, triazine radical, it is optionally independently selected by one or more from R 3Group replace；Further preferably, R 2Selected from phenyl, pyridyl group or pyrimidine radicals, it is optionally independently selected by one or more from R 3Group replace；Still more preferably, R 2It is selected from It is optionally independently selected by one or more from R 3Group replace；Still more preferably, R 2It is selected from
  39. Compound described in any one of claim 29-38 or its pharmaceutically acceptable salt, R 3Selected from halogen or halogenated C 1-3Alkyl；It is preferred that R 3Selected from fluorine, chlorine, bromine or trifluoromethyl.
  40. Compound described in any one of claim 1-39 or its pharmaceutically acceptable salt, wherein the compound is preferred are as follows:
  41. Pharmaceutical composition, it includes the Formulas I of therapeutically effective amount, Formula II or formula III compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
  42. Compound described in any one of claim 1-40 or the treatment of its pharmaceutically acceptable salt are by indoleamine 2,3- dioxygenase (IDO) and tryptophan 2,3- oxygenase (TDO) mediate immunosuppressant disease method, including to need the treatment mammal, preferably the mankind give therapeutically effective amount Formulas I, Formula II or formula III compound or its pharmaceutically acceptable salt or claim 41 described in pharmaceutical composition.
  43. Pharmaceutical composition described in compound described in any one of claim 1-40 or its pharmaceutically acceptable salt or claim 41 is in preparation prevention or treats by indoleamine 2, purposes in the drug for the immunosuppressant disease that 3- dioxygenase (IDO) and tryptophan 2,3- oxygenase (TDO) mediate.
  44. Purposes described in claim 43, the immunosuppressant disease is related to communicable disease or cancer, and the communicable disease is selected from following virus infection: influenza, Hepatitis C Virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), poliovirus, herpes zoster virus, human immunodeficiency virus (HIV), epstein-Barr virus (EBV) or Coxsackie virus；The cancer is selected from colon cancer, cancer of pancreas, breast cancer, prostate cancer, lung cancer, the cancer of the brain, oophoroma, cervix cancer, carcinoma of testis, kidney, head or neck cancer, lymthoma, leukaemia or melanoma.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115572262A (en) * 2022-10-27 2023-01-06 厦门沃克沃德医药科技有限公司 Isoquinoline derivative and preparation method thereof

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3505517A4 (en) * 2016-08-23 2020-01-15 Beijing InnoCare Pharma Tech Co., Ltd. Fused heterocyclic derivative, preparation method therefor and medical use thereof
CN111601810A (en) 2018-01-15 2020-08-28 爱杜西亚药品有限公司 Inhibitors of indoleamine 2, 3-dioxygenase and/or tryptophan 2, 3-dioxygenase
JP2022540146A (en) 2019-07-11 2022-09-14 イドーシア ファーマシューティカルズ リミテッド Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase
AU2022222781A1 (en) * 2021-02-22 2023-08-24 Regents Of The University Of Minnesota Immunomodulators and immunomodulator conjugates
WO2023102800A1 (en) * 2021-12-09 2023-06-15 Theravance Biopharma R&D Ip, Llc Synthesis of 5, 7-dichloro-1, 6-naphthyridine
WO2024193464A1 (en) * 2023-03-17 2024-09-26 西藏海思科制药有限公司 Nitrogen-containing tricyclic derivative and use thereof in medicine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1856304A (en) * 2003-09-19 2006-11-01 默沙东有限公司 Derivatives of N-(1H-indazolyl)- and N-(1H-indolyl)-urea as well as related compounds as modulators of the vanilloid-1 receptor (VR1) for the treatment of pain
CN105884780A (en) * 2015-02-16 2016-08-24 上海迪诺医药科技有限公司 Polycyclic compound and pharmaceutical composition and application thereof
CN106478634A (en) * 2015-09-01 2017-03-08 上海璎黎药业有限公司 Condensed imidazole compound, its preparation method, pharmaceutical composition and purposes
CN107033087A (en) * 2016-02-04 2017-08-11 西华大学 1H- indazole -4- aminated compounds and its purposes as IDO inhibitor
CN109689652A (en) * 2016-08-23 2019-04-26 北京诺诚健华医药科技有限公司 Fused heterocycle derivative, preparation method and its application medically

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1856304A (en) * 2003-09-19 2006-11-01 默沙东有限公司 Derivatives of N-(1H-indazolyl)- and N-(1H-indolyl)-urea as well as related compounds as modulators of the vanilloid-1 receptor (VR1) for the treatment of pain
CN105884780A (en) * 2015-02-16 2016-08-24 上海迪诺医药科技有限公司 Polycyclic compound and pharmaceutical composition and application thereof
CN106478634A (en) * 2015-09-01 2017-03-08 上海璎黎药业有限公司 Condensed imidazole compound, its preparation method, pharmaceutical composition and purposes
CN107033087A (en) * 2016-02-04 2017-08-11 西华大学 1H- indazole -4- aminated compounds and its purposes as IDO inhibitor
CN109689652A (en) * 2016-08-23 2019-04-26 北京诺诚健华医药科技有限公司 Fused heterocycle derivative, preparation method and its application medically

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PAWAR CD ET AL.: "Synthesis and Antimicrobial Evaluation of Novel Substituted Acetamido-4-subtituted-thiazole-5-indazole Derivatives", 《RESEARCH & REVIEWS: JOURNAL OF CHEMISTRY》 *
张胜男等: "吲哚胺2，3-双加氧化酶1及其抑制剂的研究", 《复旦学报（医学版）》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115572262A (en) * 2022-10-27 2023-01-06 厦门沃克沃德医药科技有限公司 Isoquinoline derivative and preparation method thereof

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